"Hands off hand hygiene training": Implementation of a COVID safe auditor training program.

Optimal hand hygiene practices reduce the risk of healthcare-associated infections, especially in high-risk settings of immunocompromised patients. In 2020, face-to-face learning was disallowed in the environment of coronavirus disease 2019 transmission. We developed a revised learning program for hand hygiene auditors for our cancer care facility. The learning package resulted in a 2-fold increase in the number of participants, with effective promotion by managers, due in part to reduced time and resources for training, and flexibility for staff.

Adenosine triphosphate bioluminescence to validate decontamination of endoscopes.

The reports of outbreaks involving carbapenemase-resistant Enterobacteriaceae (CRE) associated with gastrointestinal endoscopy prompted a review and study of a novel method of assessing cleaning. This study assessed adenosine triphosphate (ATP) bioluminescence to demonstrate cleanliness prior to endoscopy. ATP testing was compared with microbiological monitoring for 127 endoscopes. Samples were taken after cleaning, reprocessing and storage, but immediately before the endoscopy procedure. We recommend implementing ATP testing prior to endoscopy procedures as an alternative to microbiological testing at periodic intervals. ATP testing provides a convenient assessment of endoscopy hygiene to demonstrate safety and quality assurance.

Antibiotic use and misuse in residential aged care facilities.

BACKGROUND: The prevention and control of transmission of antimicrobial-resistant pathogens in residential aged care facilities (RACF) is an area that has been neglected yet has significant implications for health services. AIMS: The aims of this study were to describe the prevalence and appropriateness of antibiotic use within five RACF associated with our health service. METHODS: Demographic data on each RACF and all residents were obtained, and antibiotics prescribed (the type, indication and duration) at the time of the survey were recorded. The appropriateness of antibiotic prescribing was assessed using well-established criteria. RESULTS: Of the 257 residents, 28% were greater than 85 years of age, almost 50% were male and 71% had been in their RACF for more than a year. Sixty-seven per cent were incontinent of urine or faeces, and 80% had some degree of cognitive impairment. Among the residents, 23 (9%) were receiving antibiotics at the time of the survey. Seventeen (74%) were for treatment, while six (26%) were given for prophylactic reasons. Data on the appropriateness of antibiotic use were available for the preceding 26-month period. During this time, there were 988 antibiotic courses administered; of these, 392 (39.7%) did not fulfil the criteria for bacterial infection. CONCLUSION: This Australian study is one of the first to report on the use of antibiotics within RACF, shows a high rate of antimicrobial prescribing and inappropriate antibiotic use. Antibiotic stewardship is of paramount importance in RACF. Programmes to promote the rational use of antibiotics and minimise the emergence of resistant pathogens are urgently required in Australian RACF.

A bundle of care to reduce colorectal surgical infections: an Australian experience.

Use of 'bundles of care' to improve patient outcomes is becoming more widespread; however, their use is more common internationally than in Australia. The objective of this study was to assess the feasibility of implementing a bundle of care for patients undergoing colorectal surgery with the aim of reducing surgical site infections. Each component of the bundle was evidence based, focusing on normothermia, normoglycaemia, oxygen delivery and use of appropriate antibiotics. Implementation required extensive consultation and education, together with a checklist to accompany patients and record whether processes were followed and outcomes achieved. Difficulties were experienced with achieving compliance with processes, although some improvements were seen. There was a link between the use of warming devices and improved maintenance of normothermia. The infection rate fell from 15% [95% confidence interval (CI) 10.4-20.2] before the project to 7% (95% CI 3.4-12.6) 12 months after the project. While the small sample size does not allow definitive conclusions to be drawn, the results are promising. Potential reasons for low compliance with individual components of the bundle of care are discussed. In conclusion, introduction of a bundle of care for patients undergoing colorectal surgery into an Australian hospital was only modestly successful. Despite this, infection rates decreased over the 12 months following introduction of the bundle.

Adverse events related to medications identified by a Canadian poison centre.

BACKGROUND: Poison centres are an underutilized source of information on adverse events related to medications, including therapeutic errors and adverse drug reactions. OBJECTIVE: To demonstrate the feasibility of using a poison centres' electronic data to identify and describe adverse events related to medications. METHODS: This one-year, retrospective cross-sectional pilot study was conducted at one Canadian Poison Centre. All records from the IWK Regional Poison Centre database in Nova Scotia between November 1, 2007 and October 31, 2008 for unintentional exposures were abstracted for a descriptive data analysis. RESULTS: An issue related to use of a medication was the main reason for 1,525 (32.5%) of 4,697 eligible calls. Of the 1,525 calls, 970 (63.6%) were coded as 'unintentional-general.' There were 470 (30.8%) calls for unintentional therapeutic errors and 61 (4.0%) for adverse drug reactions. The majority of calls involving medications were judged to have resulted in minimal or no toxic effect (78.4%). However, 3.3% of calls involving adverse drug reactions resulted in admission to a critical care unit (n=2). Approximately 1% of calls involving unintentional therapeutic errors resulted in admission to hospital (n=6). CONCLUSIONS: Calls to poison centres provide a potentially valuable source of information on adverse events related to medications that are likely not reported elsewhere. Establishment of a mechanism to routinely share information from all Canadian poison centres with relevant national drug safety programs (e.g., MedEffect™ Canada) will provide a supplementary source of information and contribute to building capacity for detection of sentinel events and pharmacosurveillance.

The feasibility of automating audit and feedback for ART guideline adherence in Malawi.

OBJECTIVE: To determine the feasibility of using electronic medical record (EMR) data to provide audit and feedback of antiretroviral therapy (ART) clinical guideline adherence to healthcare workers (HCWs) in Malawi. MATERIALS AND METHODS: We evaluated recommendations from Malawi's ART guidelines using GuideLine Implementability Appraisal criteria. Recommendations that passed selected criteria were converted into ratio-based performance measures. We queried representative EMR data to determine the feasibility of generating feedback for each performance measure, summed clinical encounters representing each performance measure's denominator, and then measured the distribution of encounter frequency for individual HCWs across nurse and clinical officer groups. RESULTS: We analyzed 423,831 encounters in the EMR data and generated automated feedback for 21 recommendations (12%) from Malawi's ART guidelines. We identified 11 nurse recommendations and eight clinical officer recommendations. Individual nurses and clinical officers had an average of 45 and 59 encounters per month, per recommendation, respectively. Another 37 recommendations (21%) would support audit and feedback if additional routine EMR data are captured and temporal constraints are modeled. DISCUSSION: It appears feasible to implement automated guideline adherence feedback that could potentially improve HCW performance and supervision. Feedback reports may support workplace learning by increasing HCWs' opportunities to reflect on their performance. CONCLUSION: A moderate number of recommendations from Malawi's ART guidelines can be used to generate automated guideline adherence feedback using existing EMR data. Further study is needed to determine the receptivity of HCWs to peer comparison feedback and barriers to implementation of automated audit and feedback in low-resource settings.

The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells.

MicroRNAs (miRNAs) are important regulators of cell fate determination and homeostasis. Expression of these small RNA genes is tightly regulated during development and in normal tissues, but they are often misregulated in cancer. MiRNA expression is also affected by DNA damaging agents, such as radiation. In particular, mammalian miR-34 is upregulated by p53 in response to radiation, but little is known about the role of this miRNA in vivo. Here we show that Caenorhabditis elegans with loss-of-function mutations in the mir-34 gene have an abnormal cellular survival response to radiation; these animals are highly radiosensitive in the soma and radioresistant in the germline. These findings show a role for mir-34 in both apoptotic and non-apoptotic cell death in vivo, much like that of cep-1, the C. elegans p53 homolog. These results have been additionally validated in vitro in breast cancer cells, wherein exogenous addition of miR-34 alters cell survival post-radiation. These observations confirm that mir-34 is required for a normal cellular response to DNA damage in vivo resulting in altered cellular survival post-irradiation, and point to a potential therapeutic use for anti-miR-34 as a radiosensitizing agent in p53-mutant breast cancer.

The impact of gender on survival amongst patients with implantable cardioverter defibrillators for primary prevention against sudden cardiac death.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are a life-saving therapy for many patients with cardiovascular disease at increased risk of fatal dysrhythmias. As men comprise the majority of the study population (67-92%) in clinical trials, the benefit to women is unknown. We performed a meta-analysis of primary prevention trials to evaluate the impact of ICDs in men and women on death from any cause. METHODS: Included trials met the following criteria: (i) randomized controlled trials versus standard of care, (ii) ICD used as primary prevention in a well-described protocol and (iii) data provided on risk of death from any cause for both male and female patients. RESULTS: Five clinical trials were included in this meta-analysis. The risk of death from any cause was significantly reduced by 26% in male patients who received ICD therapy compared to control, hazard ratio (HR) 0.74 (95% CI 0.60-0.91) but not amongst female patients, HR 0.81 (95% CI 0.60-1.09). As the COMPANION trial evaluated the combination of biventricular pacemaker with ICD therapy we conducted a separate analysis without the inclusion of this study. Male patients receiving ICD therapy demonstrated a similar 24% reduction in risk of death from any cause, HR 0.76 (95% CI 0.58-0.99) whilst female patients demonstrated a reduction of only 12%, HR 0.88 (95% CI 0.63-1.22). CONCLUSIONS: Unlike their male counterparts, females did not significantly benefit from ICD therapy and without concurrent biventricular pacing, appear only to achieve a nonsignificant 12% reduction in risk of death.

Effect of dietary intake and lifestyle factors on in vivo mutant frequency at the HPRT gene locus in healthy human subjects.

This paper describes the results of a study designed to assess the effects of a variety of dietary and lifestyle factors on background levels of mutant frequency (MF) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene locus in humans. Eighty-three healthy and free-living subjects (aged 20-80 yr; 61 males and 22 females; mean age of 63.07 +/- 14.71 yr) were recruited. Background levels of MF were determined for each subject using a cloning assay. The mean MF/10(6) clonable cells (MF) for the study subjects was 4.63 +/- 2.20. An interview-administered questionnaire was completed by each study subject in order to assess details of dietary history, physical activity, health and potential genotoxin exposure history. A 7-day estimated dietary record method with a food frequency questionnaire was used to determine average intakes of energy and macronutrients (including alcohol), and a range of micronutrients (including vitamin and mineral supplement usage). The relationships between individual dietary and lifestyle factors and HPRT MF were investigated by univariate and multivariate analysis (data was adjusted for age, lymphocyte plating efficiency [PE] and energy intake [EI]). Univariate analysis revealed a significant positive correlation between EI and MF and multivariate analysis revealed significant positive correlations between, body mass index (BMI), % energy intake from total carbohydrate, starch, fat and MF. These findings suggest that a reduction in EI may be a useful preventative measure against the onset of carcinogenesis in humans. No correlations were found between alcohol intake and MF or between estimated antioxidant intake and MF. Thus, estimated intakes of antioxidants may not reflect their bioavailability and functional capacity in vivo and it may be more useful to examine actual plasma/cell levels vs. MF to establish if any significant relationship exists.

In vivo antioxidant status, DNA damage, mutation and DNA repair capacity in cultured lymphocytes from healthy 75- to 80-year-old humans.

The accumulation of damage to cellular biomolecules, including DNA, over time may play a significant role in the aetiology of the ageing process. We have previously quantified DNA damage and mutation within cultured lymphocytes from healthy human male subjects in three different age groups (35-39, 50-54 and 65-69 years). The results of that study showed an age-related increase in DNA damage and mutations in lymphocytes. In addition, an age-related decrease in the capacity of the lymphocytes to repair H2O2-induced DNA damage was found. In this article, we report the findings of an extension to the earlier study. Thirty-one generally healthy male and female subjects between the ages of 75 and 80 years were recruited. Using a number of bioassays, we were able to determine; basal levels of DNA damage (for 18 subjects) and mutant frequency at the hypoxanthine phosphoribosyltransferase (hprt) gene locus (for 16 subjects) within cultured lymphocytes. In addition, in vivo antioxidant status (for all study subjects) and the capacity of lymphocytes to repair H2O2-induced DNA damage (for 18 subjects) were also assessed. The results obtained showed: that the mean basal level of DNA damage in lymphocytes from subjects in the 75- to 80-year age group (12.6 +/- 4.7%) was similar to that of the 35- to 39-year age group (13.3 +/- 3.3%), p = 0.42 (Mann-Whitney); there was no significant difference between log mean mutant frequency at the hprt gene locus in lymphocytes from the 75- to 80-year age group (0.31 +/- 0.33) compared to that observed in the 35- to 39-year age group (0.24 +/- 0.21; Student's t-test, t = 0.68, p > 0.05). Levels of the antioxidants glutathione peroxidase (GPx EC 1.11.1.9), catalase (CAT; EC 1.11.1.6) and caeruloplasmin (CPL; EC 1.16.3.1) were significantly elevated in the 75- to 80-year age group, compared to the 35- to 39-, 50- to 54- and 65- to 69-year age groups. Levels of bilirubin (BR) were reduced in the 75- to 80-year age group, the decrease being contributed by the female subjects. No differences in levels of superoxide dismutase (SOD; EC 1.15.1.1) or uric acid (UA) were found between the 4 age groups. Following treatment of lymphocytes with H2O2, we did not find any difference in the susceptibility of lymphocytes to DNA damage in the 75- to 80-year age group, compared to the other age groups. The DNA repair capacity in lymphocytes from individuals in the 75- to 80-year age group was similar to that of the 35- to 39-year age group, for all time points assessed. These results highlight the importance of DNA repair processes and antioxidant defence systems for maintaining genomic stability in vivo.

An investigation of mutation as a function of age in humans.

An accumulation of mutations on their own or together with other age-related changes may contribute to aging and the development of age-related pathologies. The aim of this investigation was to assess the extent of DNA mutations as a function of age in humans. The mutant frequency (MF) at the hypoxanthine-guanine phosphoribosyl-transferase (hgprt) locus was assessed in lymphocytes isolated from male volunteers in each of three age groups (35-39, 50-54 and 65-69 years). Results show that the mean MF in the 65-69 years group was approximately twice that in the 35-39 and 50-54 years groups (4.1/10(6) cells, 1.9/10(6) cells and 1.79/10(6) cells, respectively) increasing by about 1.33% per year, after 54 years. In addition, there was an increased frequency of chromosomal aberrations in the 65-69 years group compared to the other two age groups. The results of this investigation show an increase in DNA mutations in cultured human lymphocytes with age. Factors which may influence the extent of DNA damage in human lymphocytes are discussed.

Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.

Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

Why do most primary bladder neoplasms first appear around the ureteric orifices?

The majority of primary bladder neoplasms are known to arise within the mucosa around the ureteric orifices and bladder base. This may be due to the mucosa in this area being more susceptible to carcinogens than other areas of the bladder. Deficiency in the nucleotide salvage pathway enzyme thymidine kinase (TK), and especially its TK1 isozyme, has been shown to predispose cell lines to increased mutagenesis. Total TK and TK1 activities were measured in mucosal samples taken adjacent to the ureteric orifices and dome in 32 normal bladders and both total TK and TK1 were shown to be significantly decreased in the mucosa adjacent to the ureteric orifices. This may explain why primary bladder neoplasms occur more commonly in this site.

Inhibitors of blood platelet cAMP phosphodiesterase. 2. Structure-activity relationships associated with 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones substituted with functionalized side chains.

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives, substituted at the 7-position with functionalized side chains, was synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) as well as ADP- and collagen-induced platelet aggregation, in vitro. Structural modifications focused on variation of the side-chain terminus, side-chain length, and side-chain connecting atom. Functionality incorporated at the side-chain terminus included carboxylic acid, ester and amide, alcohol, acetate, nitrile, tetrazole, and phenyl sulfone moieties. cAMP PDE inhibitory potency varied and was dependent upon the side-chain terminus and its relationship with the heterocyclic nucleus. Methylation at N-1 or N-3 of the heterocycle diminished cAMP PDE inhibitory potency. Several representatives of this structural class demonstrated potent inhibition of ADP- and collagen-induced blood platelet aggregation and were half-maximally effective at low nanomolar concentrations. Amides 13d, 13f, 13h, 13k, 13m, and 13w are substantially more potent than relatively simply substituted compounds. However, platelet inhibitory properties did not always correlate with cAMP PDE inhibition across the series, probably due to variations in membrane permeability. Several compounds inhibited platelet aggregation measured ex vivo following oral administration to rats. Ester 11b, acid 12b, amide 13d, and sulfone 29c protected against thrombus formation in two different animal models following oral dosing and were found to be superior to anagrelide (2) and BMY 20844 (5). However, ester 11b and acid 12b demonstrated a unique pharmacological profile since they did not significantly affect hemodynamic parameters in dogs at doses 100-fold higher than that required for complete prevention of experimentally induced vessel occlusion in a dog model of thrombosis.

Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility.

Two series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation. The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility. From a series of 7-aminoimidazo[4,5-b]quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c. However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis. A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accommodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity. Structural modifications of this series focused on variation of the piperazine substituent and side-chain length. The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties. The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM, and ADP-induced platelet aggregation, IC50 = 0.51 microM after a 3-min exposure and 0.1 microM after a 15-min exposure of platelet-rich plasma to the drug. Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.

1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation.

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives was synthesized and evaluated as inhibitors of cAMP hydrolysis by a crude human platelet phosphodiesterase preparation and as inhibitors of ADP- and collagen-induced aggregation of rabbit blood platelets. The parent structure 7a, demonstrated potent inhibitory activity that was enhanced by the introduction of alkyl, alkoxy, or halogen substituents at the 5-, 6-, 7-, and 8-positions. Methylation at N-1 or N-3 produced weaker inhibitors of cAMP PDE and platelet aggregation. 1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-ones (6) were found to be equipotent with their fully oxidized congeners (7). On the basis of platelet inhibitory properties in vitro, efficacy at preventing thrombus formation in animal models of thrombosis, and a favorable hemodynamic profile, 1,3-dihydro-7,8-dimethyl-2H- imidazo[4,5-b]quinolin-2-one (7o, BMY 20844) was selected for advancement into toxicological evaluation and clinical trial. An efficient synthesis of 7o is described.