Radiation dose rate effects: what is new and what is needed?

Despite decades of research to understand the biological effects of ionising radiation, there is still much uncertainty over the role of dose rate. Motivated by a virtual workshop on the "Effects of spatial and temporal variation in dose delivery" organised in November 2020 by the Multidisciplinary Low Dose Initiative (MELODI), here, we review studies to date exploring dose rate effects, highlighting significant findings, recent advances and to provide perspective and recommendations for requirements and direction of future work. A comprehensive range of studies is considered, including molecular, cellular, animal, and human studies, with a focus on low linear-energy-transfer radiation exposure. Limits and advantages of each type of study are discussed, and a focus is made on future research needs.

Isolation of five different primary cell types from a single sample of human skin.

We have developed a technique to isolate primary keratinocytes, melanocytes, fibroblasts, preadipocytes, and microvascular endothelial cells from an individual sample of human skin. The protocol describes step-by-step instructions for processing, cells isolation, and culture of neonatal foreskin, with adaptation for more demanding adult tissues. The availability of multiple isogenic cell types derived from individual skin samples offers the ability to investigate various areas of biology, in the context of cell-type specificity without potential confounding influence of inter-individual or genetic differences. For complete details on the use and execution of this protocol, please refer to Holliman et al. (2017), Horvath et al. (2019), Horvath et al. (2018), Kabacik et al. (2018), Lowe et al. (2020), Lu et al. (2019), and Lu et al. (2018).

The relationship between epigenetic age and the hallmarks of aging in human cells.

Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells1,2. The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors2, indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified3. We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.

Chronic irradiation of human cells reduces histone levels and deregulates gene expression.

Over the past decades, there have been huge advances in understanding cellular responses to ionising radiation (IR) and DNA damage. These studies, however, were mostly executed with cell lines and mice using single or multiple acute doses of radiation. Hence, relatively little is known about how continuous exposure to low dose ionising radiation affects normal cells and organisms, even though our cells are constantly exposed to low levels of radiation. We addressed this issue by examining the consequences of exposing human primary cells to continuous ionising γ-radiation delivered at 6-20 mGy/h. Although these dose rates are estimated to inflict fewer than a single DNA double-strand break (DSB) per hour per cell, they still caused dose-dependent reductions in cell proliferation and increased cellular senescence. We concomitantly observed histone protein levels to reduce by up to 40%, which in contrast to previous observations, was not mainly due to protein degradation but instead correlated with reduced histone gene expression. Histone reductions were accompanied by enlarged nuclear size paralleled by an increase in global transcription, including that of pro-inflammatory genes. Thus, chronic irradiation, even at low dose-rates, can induce cell senescence and alter gene expression via a hitherto uncharacterised epigenetic route. These features of chronic radiation represent a new aspect of radiation biology.

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies.

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

Audit on the Use of Dangerous Abbreviations, Symbols, and Dose Designations in Paper Compared to Electronic Medication Orders: A Multicenter Study.

BACKGROUND: Dangerous abbreviations on the Institute for Safe Medication Practices Canada's "Do Not Use" list have resulted in medication errors leading to harm. Data comparing rates of use of dangerous abbreviations in paper and electronic medication orders are limited. OBJECTIVE: To compare rates of use of dangerous abbreviations from the "Do Not Use" list, in paper and electronic medication orders. Secondary objectives include determining the proportion of patients at risk for medication errors due to dangerous abbreviations and the most commonly used dangerous abbreviations. METHODS: One-day cross-sectional audits of medication orders were conducted at a 6-site hospital network in Toronto, Canada, between December 2013 and January 2014. Proportions of paper and electronic medication orders containing dangerous abbreviation(s) were compared using a χ2 test. The proportion of patients with at least 1 medication order containing dangerous abbreviation(s) and the top 5 dangerous abbreviations used were described. RESULTS: Overall, 255 patient charts were reviewed. The proportions of paper and electronic medication orders containing dangerous abbreviation(s) were 172/714 (24.1%) and 9/2207 (0.4%), respectively ( P < 0.001). Almost one-third of patients had medication order(s) containing dangerous abbreviation(s). The proportions of patients with at least 1 medication order during the audit period containing dangerous abbreviation(s) for patients with paper only, electronic only, or a hybrid of paper and electronic medication orders were 50.5%, 5%, and 47.2%, respectively. Those most commonly used were "D/C", drug name abbreviations, "OD," "cc," and "U." CONCLUSIONS: Electronic medication orders have significantly lower rates of dangerous abbreviation use compared to paper medication orders.

Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses.

Background and Purpose: Radiotherapy is an essential tool for cancer treatment. In order to spare normal tissues and to reduce the risk of normal tissue complications, particle therapy is a method of choice. Although a large part of healthy tissues can be spared due to improved depth dose characteristics, little is known about the biological and molecular mechanisms altered after particle irradiation in healthy tissues. Elucidation of these effects is also required in the context of long term space flights, as particle radiation is the main contributor to the radiation effects observed in space. Endothelial cells (EC), forming the inner layer of all vascular structures, are especially sensitive to irradiation and, if damaged, contribute to radiation-induced cardiovascular disease. Materials and Methods: Transcriptomics, proteomics and cytokine analyses were used to compare the response of ECs irradiated or not with a single 2 Gy dose of X-rays or Fe ions measured one and 7 days post-irradiation. To support the observed inflammatory effects, monocyte adhesion on ECs was also assessed. Results: Experimental data indicate time- and radiation quality-dependent changes of the EC response to irradiation. The irradiation impact was more pronounced and longer lasting for Fe ions than for X-rays. Both radiation qualities decreased the expression of genes involved in cell-cell adhesion and enhanced the expression of proteins involved in caveolar mediated endocytosis signaling. Endothelial inflammation and adhesiveness were increased with X-rays, but decreased after Fe ion exposure. Conclusions: Fe ions induce pro-atherosclerotic processes in ECs that are different in nature and kinetics than those induced by X-rays, highlighting radiation quality-dependent differences which can be linked to the induction and progression of cardiovascular diseases (CVD). Our findings give a better understanding of the underlying processes triggered by particle irradiation in ECs, a crucial aspect for the development of protective measures for cancer patients undergoing particle therapy and for astronauts in space.

Ultraviolet Radiation-Induced Production of Nitric Oxide:A multi-cell and multi-donor analysis.

Increasing evidence regarding positive effects of exposure to sunlight has led to suggestions that current advice may be overly weighted in favour of avoidance. UV-A has been reported to lower blood pressure, possibly through nitric oxide (NO) production in skin. Here, we set out to investigate effects of UV-A and solar-simulated radiation on the potential source of dermal NO, the effective doses and wavelengths, the responsiveness of different human skin cells, the magnitude of inter-individual differences and the potential influence of age. We utilised isogenic keratinocytes, microvascular endothelial cells, melanocytes and fibroblasts isolated from 36 human skins ranging from neonates to 86 years old. We show that keratinocytes and microvascular endothelial cells show greatest NO release following biologically relevant doses of UV-A. This was consistent across multiple neonatal donors and the effect is maintained in adult keratinocytes. Our observations are consistent with a bi-phasic mechanism by which UV-A can trigger vasodilatory effects. Analyses of NO-production spectra adds further evidence that nitrites in skin cells are the source of UV-mediated NO release. These potentially positive effects of ultraviolet radiation lend support for objective assessment of environmental influence on human health and the idea of "healthy sun exposure".

Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process.

Radiation is the most common treatment of cancer. Minimizing the normal tissue injury, especially the damage to vascular endothelium, remains a challenge. This study aimed to analyze direct and indirect radiation effects on the endothelium by investigating mechanisms of signal transfer from irradiated to nonirradiated endothelial cells by means of secreted proteins. Human coronary artery endothelial cells (HCECest2) undergo radiation-induced senescence in vitro 14 days after exposure to 10 Gy X-rays. Proteomics analysis was performed on HCECest2 14 days after irradiation with X-ray doses of 0 Gy (control) or 10 Gy using label-free technology. Additionally, the proteomes of control and radiation-induced secretomes, and those of nonirradiated HCECest2 exposed for 24 h to secreted proteins of either condition were measured. Key changes identified by proteomics and bioinformatics were validated by immunoblotting, ELISA, bead-based multiplex assays, and targeted transcriptomics. The irradiated cells, their secretome, and the nonirradiated recipient cells showed similar inflammatory response, characterized by induction of interferon type I-related proteins and activation of the STAT3 pathway. These data indicate that irradiated endothelial cells may adversely affect nonirradiated surrounding cells via senescence-associated secretory phenotype. This study adds to our knowledge of the pathological background of radiation-induced cardiovascular disease.

Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways.

PURPOSE: Epidemiological studies indicate that radiation doses as low as 0.5 Gy increase the risk of cardiovascular disease decades after the exposure. The aim of the present study was to investigate whether this radiation dose causes late molecular alterations in endothelial cells that could support the population-based data. MATERIALS AND METHODS: Human coronary artery endothelial cells were irradiated at 0.5 Gy (X-ray) and radiation-induced changes in the proteome were investigated after different time intervals (1, 7 and 14 d) using ICPL technology. Key changes identified by proteomics and bioinformatics were validated by immunoblotting and ELISA. RESULTS: The radiation-induced alteration of the endothelial proteome was characterized by sustained perturbation of Rho GDP-dissociation inhibitor (RhoGDI) and nitric oxide (NO) signalling pathways. At later time-points, this was accompanied by reduced proteasome activity, enhanced protein carbonylation indicating augmented oxidative stress, and senescence. CONCLUSIONS: These molecular changes are indicative of long-term premature endothelial dysfunction and provide a mechanistic framework to the epidemiological data showing increased risk of cardiovascular disease at 0.5 Gy.

Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose.

Background and Purpose: Epidemiological data suggests an excess risk of cardiovascular disease (CVD) at low doses (0.05 and 0.1 Gy) of ionizing radiation (IR). Furthermore, the underlying biological and molecular mechanisms of radiation-induced CVD are still unclear. Because damage to the endothelium could be critical in IR-related CVD, this study aimed to identify the effects of radiation on immortalized endothelial cells in the context of atherosclerosis. Material and Methods: Microarrays and RT-qPCR were used to compare the response of endothelial cells irradiated with a single X-ray dose (0.05, 0.1, 0.5, 2 Gy) measured after various post-irradiation (repair) times (1 day, 7 days, 14 days). To consolidate and mechanistically support the endothelial cell response to X-ray exposure identified via microarray analysis, DNA repair signaling (γH2AX/TP53BP1-foci quantification), cell cycle progression (BrdU/7AAD flow cytometric analysis), cellular senescence (ß-galactosidase assay with CPRG and IGFBP7 quantification) and pro-inflammatory status (IL6 and CCL2) was assessed. Results: Microarray results indicated persistent changes in cell cycle progression and inflammation. Cells underwent G1 arrest in a dose-dependent manner after high doses (0.5 and 2 Gy), which was compensated by increased proliferation after 1 week and almost normalized after 2 weeks. However, at this point irradiated cells showed an increased ß-Gal activity and IGFBP7 secretion, indicative of premature senescence. The production of pro-inflammatory cytokines IL6 and CCL2 was increased at early time points. Conclusions: IR induces pro-atherosclerotic processes in endothelial cells in a dose-dependent manner. These findings give an incentive for further research on the shape of the dose-response curve, as we show that even low doses of IR can induce premature endothelial senescence at later time points. Furthermore, our findings on the time- and dose-dependent response regarding differentially expressed genes, cell cycle progression, inflammation and senescence bring novel insights into the underlying molecular mechanisms of the endothelial response to X-ray radiation. This may in turn lead to the development of risk-reducing strategies to prevent IR-induced CVD, such as the use of cell cycle modulators and anti-inflammatory drugs as radioprotectors and/or radiation mitigators.

Epigenetic clock analyses of cellular senescence and ageing.

A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific DNA methylation changes that occur in function of age. Using primary cells, telomerase-expressing cells and oncogene-expressing cells of the same genetic background, we show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing. Consistent with this, we observed that telomerase-immortalised cells aged in culture without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of ageing from telomeres and senescence. Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.

Utilization of Dabigatran for Atrial Fibrillation at 3 Tertiary Care Centres.

BACKGROUND: The outpatient management of stroke prevention for patients with atrial fibrillation has recently been published and provides insight into the benefits and risks of the new direct-acting oral anti-coagulants. However, real-world use of these agents for hospital inpatients requires additional study. OBJECTIVE: To determine prescribing patterns for dabigatran at 3 Canadian hospitals, specifically adherence with the hospitals' prescribing restriction limiting dabigatran to patients with nonvalvular atrial fibrillation and creatinine clearance above 30 mL/min (primary outcome) and assessment of age-related prescribing, prescribing of medications with defined contraindications or potential for interaction when given concurrently with dabigatran, and use of risk stratification tools (secondary outcomes). METHODS: A retrospective chart review of patients for whom dabigatran was prescribed from August to October 2011 was performed at 3 hospitals in Toronto, Ontario. Descriptive statistics were used for all outcomes assessed. RESULTS: Overall, dabigatran was prescribed for 69 inpatients, of whom 16 (23%) were new users (dabigatran initiated during hospital admission) and 53 (77%) were prior users (dabigatran prescribed before admission to hospital). Fifty-eight patients (84%; 14 new users and 44 prior users) received dabigatran according to the hospitals' prescribing restriction. For the remaining 11 patients, dabigatran therapy did not meet prescribing restrictions for use because of valvular disease or presence of prosthetic valve (10 patients [14% of the total sample]) and impaired renal function (1 patient [1%]). Among those whose dabigatran therapy met the prescribing restrictions for use, amiodarone and acetylsalicylic acid were the most common concurrently prescribed medications (17 patients [29%] and 14 patients [24%], respectively). Stroke and bleeding risk were documented for only 27 patients (47%) and 10 patients (17%), respectively. CONCLUSION: At the study hospitals, dabigatran was appropriately prescribed for the indication of nonvalvular atrial fibrillation in patients without renal impairment in most cases. However, greater consideration of cardiac history (including valvular disease and presence of prosthetic valves), drug interactions, and documentation of risks and benefits is warranted. These research findings highlight the importance of and opportunity for pharmacist review and involvement in assessment and selection of patients with indications for anticoagulant therapy, particularly when agents are new to the market.

CONTEXTE: La publication récente sur la prévention des accidents vasculaires cérébraux (AVC) chez les patients externes atteints de fibrillation auriculaire permet de mieux comprendre les avantages et les risques des nouveaux anticoagulants oraux directs. Cependant, il est nécessaire de faire de plus amples études sur l'utilisation de ces agents en situation réelle chez les patients hospitalisés. OBJECTIFS: Déterminer les habitudes de prescription de dabigatran dans trois hôpitaux canadiens, particulièrement en ce qui a trait au respect des restrictions de prescription en vigueur dans les hôpitaux qui limitent le dabigatran aux patients souffrants de fibrillation auriculaire non valvulaire et présentant une clairance de la créatinine supérieure à 30 mL/min (principal paramètre d'évaluation) et à l'évaluation de la prescription en fonction de l'âge du patient, de la prescription de médicaments avec des contre-indications précises ou un potentiel d'interactions médicamenteuses lorsqu'ils sont administrés en concomitance avec du dabigatran et de l'emploi d'outils de stratification du risque (paramètres d'évaluation secondaires). MÉTHODES: Une analyse rétrospective des dossiers médicaux des patients à qui on avait prescrit du dabigatran entre août et octobre 2011 a été menée dans trois centres hospitaliers de Toronto en Ontario. Des statistiques descriptives ont été employées pour tous les paramètres analysés. RÉSULTATS: Dans l'ensemble, on a prescrit du dabigatran à 69 patients hospitalisés. Parmi eux, 16 (23 %) n'en avaient jamais reçu (traitement amorcé pendant l'hospitalisation) et 53 (77 %) en avaient déjà reçu (dabigatran prescrit avant l'hospitalisation). Cinquante-huit patients (84 %; 14 n'en ayant jamais reçu et 44 en ayant déjà reçu) ont reçu du dabigatran selon les restrictions de prescription en vigueur dans les hôpitaux. Pour les 11 patients restants, le traitement par dabigatran ne répondait pas aux restrictions d'utilisation pour cause de valvulopathie ou de présence d'une prothèse valvulaire (10 patients [14 % de l'échantillon total]) ou d'insuffisance rénale (1 patient [1 %]). Au sein du groupe de patients pour lesquels les restrictions d'utilisation ont été respectées, l'amiodarone et l'acide acétylsalicylique étaient les médicaments les plus souvent coprescrits (respectivement, 17 patients [29 %] et 14 patients [24 %]). Le risque d'AVC et d'hémorragie n'était consigné respectivement que pour 27 patients (47 %) et 10 patients (17 %). CONCLUSION: Dans les hôpitaux de l'étude, le dabigatran était habituellement prescrit de façon appropriée pour l'indication de fibrillation auriculaire non valvulaire chez des patients ne présentant pas d'insuffisance rénale. Cependant, il est justifié de tenir davantage compte des antécédents cardiaques (notamment les valvulopathies et la présence de prothèses valvulaire), des interactions médicamenteuses ainsi que de la consignation des risques et des avantages. Ces données mettent en relief l'importance et la possibilité de la participation du pharmacien à l'évaluation et à la sélection des patients ayant des indications pour un traitement par anticoagulant ainsi que de son analyse de ces cas, particulièrement lorsque les médicaments sont nouveaux sur le marché.

Quantitation of Endothelial Cell Adhesiveness In Vitro.

One of the cardinal processes of inflammation is the infiltration of immune cells from the lumen of the blood vessel to the surrounding tissue. This occurs when endothelial cells, which line blood vessels, become adhesive to circulating immune cells such as monocytes. In vitro measurement of this adhesiveness has until now been done by quantifying the total number of monocytes that adhere to an endothelial layer either as a direct count or by indirect measurement of the fluorescence of adherent monocytes. While such measurements do indicate the average adhesiveness of the endothelial cell population, they are confounded by a number of factors, such as cell number, and do not reveal the proportion of endothelial cells that are actually adhesive. Here we describe and demonstrate a method which allows the enumeration of adhesive cells within a tested population of endothelial monolayer. Endothelial cells are grown on glass coverslips and following desired treatment are challenged with monocytes (that may be fluorescently labeled). After incubation, a rinsing procedure, involving multiple rounds of immersion and draining, the cells are fixed. Adhesive endothelial cells, which are surrounded by monocytes are readily identified and enumerated, giving an adhesion index that reveals the actual proportion of endothelial cells within the population that are adhesive.

Thiamine prescribing practices within university-affiliated hospitals: a multicenter retrospective review.

BACKGROUND: Patients with suspected thiamine deficiency should receive treatment with parenteral thiamine to achieve the high serum thiamine levels necessary to reverse the effects of deficiency and to circumvent problems with absorption common in the medically ill. OBJECTIVE: To quantify rates of parenteral administration of thiamine across university-affiliated hospitals and to identify factors associated with higher rates of parenteral prescribing. DESIGN: Multicenter, retrospective observational study of thiamine prescriptions. METHODS: Prescriptions for thiamine were captured from computerized pharmacy information systems across participating centers, providing information concerning dose, route, frequency, and duration of thiamine prescribed from January 2010 to December 2011. SETTING: Fourteen university-affiliated tertiary care hospitals geographically distributed across Canada, including 48,806 prescriptions for thiamine provided to 32,213 hospitalized patients. RESULTS: Parenteral thiamine accounted for a statistically significant majority of thiamine prescriptions (57.6%, P < 0.001); however, oral thiamine constituted a significant majority of the total doses prescribed (68.4%, z = 168.9; P < 0.001). Protocols prioritizing parenteral administration were associated with higher rates of parenteral prescribing (61.3% with protocol, 45.8% without protocol; P < 0.001). Patients admitted under psychiatry services were significantly more likely to be prescribed oral thiamine (P < 0.001). CONCLUSIONS: Although parenteral thiamine accounted for a statistically significant majority of prescriptions, oral thiamine was commonly prescribed within academic hospitals. Additional strategies are needed to promote parenteral thiamine prescribing to patients with suspected thiamine deficiency.

Premature aging induced by radiation exhibits pro-atherosclerotic effects mediated by epigenetic activation of CD44 expression.

Age is undoubtedly a major risk factor for heart disease. However, the reason for this is not entirely clear. In the course of our investigation into the mechanism of radiation-induced cardiovascular disease, we made several unexpected findings that inform us on this question. We observed that human coronary endothelial cells, while being able to initiate repair of radiation-induced DNA damage, often fail to complete the repair and become senescent. Such radiation-induced cellular aging occurs through a mutation-independent route. Endothelial cells that aged naturally through replication or as a result of radiation exhibited indistinguishable characteristics. The promoter regions of the CD44 gene in aging endothelial cells become demethylated, and the proteins are highly expressed on the cell surface, making the cells adhesive for monocytes. Adhesion is a cardinal feature that recruits monocytes to the endothelium, allowing them to infiltrate the vessel wall and initiate atherosclerosis. The epigenetic activation of CD44 expression is particularly significant as it causes persistent elevated CD44 protein expression, making senescent endothelial cells chronically adhesive. In addition to understanding why cardiovascular disease increases with age, these observations provide insights into the puzzling association between radiation and cardiovascular disease and highlight the need to consider premature aging as an additional risk of radiation to human health.

Effect of educational and policy interventions on institutional utilization of wet nebulization respiratory drugs and portable inhalers.

BACKGROUND: Asthma and chronic obstructive pulmonary disease treatment guidelines support the preferential use of portable inhalers (PIs) over wet nebulization (WN) respiratory therapy. Hospital- and community-based educational initiatives and a community-based provincial drug program policy change were previously implemented to promote the conversion of WN therapy to PI and spacer device use in Nova Scotia. OBJECTIVE: To examine the effect of these interventions on salbutamol, ipratropium bromide, and spacer device (Aerochamber) use at the Queen Elizabeth II Health Sciences Centre (QEII HSC). METHODS: We conducted a time-series analysis of drug utilization data from August 1998 to July 2005. We used two intervention phases compared to the pre-intervention phase to determine whether the educational and policy interventions were associated with significant changes in monthly drug and spacer device utilization rates at the QEII HSC (1000-bed teaching hospital; Halifax, Nova Scotia). RESULTS: Salbutamol and ipratropium bromide PI use significantly increased in both intervention phases, compared to the pre-intervention phase. Mean (SD) defined daily doses/100 bed-days for salbutamol PI increased from 30.4 (0.4) in the pre-intervention phase to 34.6 (0.9) and 37.0 (0.4) in intervention phases I and II respectively (p<0.001 for both), and ipratropium bromide PI increased from 27.3 (3.5) to 32.8 (2.5) in intervention phase I (p=0.004) and 35.6 (3.5) in intervention phase II (p<0.001). However, a significant corresponding decrease was observed with salbutamol WN only. Mean (SD) Aerochamber units/100 bed-days significantly increased. CONCLUSIONS: Educational and policy interventions had limited effects on converting WN to PI use at the QEII HSC.

Povidone-iodine-induced burn: case report and review of the literature.

Burns are a rare but potentially serious complication of povidone-iodine use. This rare adverse drug reaction developed in a 38-year-old woman who underwent laparoscopic right ovarian cystectomy and endometrial ablation as a day procedure involving application of the topical antiseptic 10% povidone-iodine solution. Two days later, the patient was admitted to the hospital with burning, pain, itching, marked redness, and blistering extending from her midback to buttocks. A stain on her back also was evident. Partial-thickness chemical burn was diagnosed. Review of the literature yielded 13 other cases of povidone-iodine-induced burn. This underrecognized adverse effect of povidone-iodine application typically occurs when the povidone-iodine has not been allowed to dry or has been trapped under the body of a patient in a pooled dependent position. The burn is usually seen immediately after the procedure or on the next day, and typically heals with minimum scarring within 3-4 weeks with conservative treatment. The commonly postulated mechanism is a chemical burn due to irritation coupled with maceration, friction, and pressure. Given the widespread use of povidone-iodine and the potential for development of infection after a burn, clinicians need to be aware of this possible povidone-iodine-associated adverse drug reaction, and of preventive measures.

Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study.

BACKGROUND: Previous studies have examined the association between proton pump inhibitor (PPI) use and the risk of Clostridium difficile-associated disease (CDAD), with conflicting results. Whether outpatient PPI use influences the risk of hospital admission for CDAD among older patients who have recently been treated with antibiotics is unknown. METHODS: We conducted a population-based, nested case-control study of linked health care databases in Ontario, Canada, from 1 April 2002 through 31 March 2005. We identified patients aged > or = 66 years who were hospitalized for CDAD within 60 days of receiving outpatient antibiotic therapy. Each case patient with CDAD was matched with 10 control subjects on the basis of age, sex, and details of antibiotic use (antibiotic class, timing, and number of antibiotics used). PPI use by case patients and control subjects was categorized as current (within 90 days), recent (91-180 days), or remote (181-365 days). We used conditional logistic regression to estimate the odds ratio for the association between outpatient PPI use and risk of hospitalization for CDAD. RESULTS: We identified 1389 case patients and 12,303 matched control subjects. Case patients were no more likely than control subjects to have received a PPI in the preceding 90 days (adjusted odds ratio, 0.9; 95% confidence interval, 0.8-1.1). Similarly, we found no association between hospitalization for CDAD and more remote use of PPIs. CONCLUSIONS: Among community-dwelling older patients, PPI use is not a risk factor for hospitalization with CDAD.