Long Term Effects on Risk Factors for Cardiovascular Disease after 12-Months of Aerobic Exercise Intervention:A Worksite RCT among Cleaners

<div><p>Objectives</p><p>Occupational groups exposed to high occupational physical activity have an increased risk for cardiovascular disease (CVD). This may be explained by the high relative aerobic workload. Enhanced cardiorespiratory fitness reduces the relative aerobic workload. Thus, the aim was to evaluate the 12-months effects of worksite aerobic exercise on risk factors for CVD among cleaners.</p><p>Methods</p><p>One hundred and sixteen cleaners aged 18–65 years were randomized to a group performing aerobic exercise and a reference group receiving lectures. Outcomes were collected at baseline and after 12-months. A repeated measures 2×2 multi-adjusted mixed-model design was applied to compare the between-group differences using intention-to-treat analysis.</p><p>Results</p><p>Between-group differences (<i>p</i><0.05) were found favouring the aerobic exercise group: cardiorespiratory fitness 2.15 (SE 1.03) mlO₂/min/kg, aerobic workload -2.15 (SE 1.06) %HRR, resting HR -5.31 (SE 1.61) beats/min, high sensitive C-reactive protein -0.65 (SE 0.24) μg/ml. The blood pressure was unaltered. Stratified analyses on relative aerobic workload at baseline revealed that those with relative aerobic workloads ≥30% of HRR seems to impose a notable adverse effect on resting and ambulatory blood pressure.</p><p>Conclusion</p><p>This long-term worksite aerobic exercise intervention among cleaners led to several beneficial effects, but also potential adverse effects among those with high relative aerobic workloads.</p><p>Trial Registration</p><p>Controlled-Trials.com <a href="http://www.controlled-trials.com/ISRCTN86682076" target="_blank">ISRCTN86682076</a></p></div

Implementation of Isavuconazole in a Fluorescence-Based High-Performance Liquid Chromatography Kit Allowing Simultaneous Detection of All Four Currently Licensed Mold-Active Triazoles

ABSTRACT Isavuconazole (ISZ) is a newly available broad-spectrum triazole agent recently approved for the treatment of both invasive aspergillosis and mucormycosis. The aim of this study was to develop a simple and reliable method for therapeutic drug monitoring (TDM) of ISZ in human plasma samples. The method involves using a kit from ChromSystems intended for TDM of itraconazole (ITZ), posaconazole (PSZ), and voriconazole (VRZ) in serum/plasma for sample preparation and high-performance liquid chromatography, using fluorescence detection with emission and excitation wavelengths set to 261 and 366 nm, respectively. The assay was linear over the ISZ concentration range of 0.2 to 20.0 mg/liter, using a 0.1-ml sample volume. The inter- and intraday coefficients of variation were all below 3.7%, whereas the accuracies ranged from 95.0 to 106.2% and the mean extraction recovery was 91.9%. In addition, the method worked well using four different Vacutainer types, with six different healthy volunteers and under a number of relevant storage conditions. Finally, the ISZ detection could be seamlessly implemented in the TDM kit for VRZ, PSZ, and ITZ, enabling simultaneous detection of all four triazoles. This method proved to be simple, accurate, precise, and well suited for routine analysis work. It has been implemented in our laboratory for the simultaneous quantitative analysis of ISZ, VRZ, PSZ, and ITZ for TDM and pharmacokinetic research. IMPORTANCE Isavuconazole is a new broad-spectrum triazole agent recently approved for the treatment of both invasive aspergillosis and mucormycosis. Currently, there is no consensus regarding the potential need for TDM of isavuconazole, and no therapeutic window has been defined. However, at the ECIL-6 meeting in 2015, it was advised that TDM is indicated in a number of different settings. In this study, we describe a rapid and validated isocratic HPLC method for fluorescence-based detection and quantification of isavuconazole in human plasma/serum samples. The method is simple and efficient with good accuracy and precision and importantly only requires a small volume of patient plasma/serum. Furthermore, this method is highly sensitive and selective and can be detected simultaneously with the three other triazoles, itraconazole, voriconazole, and posaconazole, without the need for expensive mass spectrometry equipment

Increasing Terbinafine Resistance in Danish Trichophyton Isolates 2019–2020

Terbinafine resistance in Trichophyton species has emerged and appears to be increasing. A new EUCAST susceptibility testing method and tentative ECOFFs were recently proposed for Trichophyton. Terbinafine resistance and target gene mutations were detected in 16 Danish isolates in 2013–2018. In this study, samples/isolates submitted for dermatophyte susceptibility testing 2019–2020 were examined. Species identification (ITS sequencing for T. mentagrophytes/T. interdigitale species complex (SC) isolates), EUCAST MICs and squalene epoxidase (SQLE) profiles were obtained. Sixty-three isolates from 59 patients were included. T. rubrum accounted for 81% and T. mentagrophytes/T. interdigitale SC for 19%. Approximately 60% of T. rubrum and T. mentagrophytes/interdigitale SC isolates were terbinafine non-wildtype and/or had known/novel SQLE mutations with possible implications for terbinafine MICs. All infections with terbinafine-resistant T. mentagrophytes/interdigitale SC isolates were caused by Trichophyton indotineae. Compared to 2013–2018, the number of patients with terbinafine-resistant Trichophyton isolates increased. For T. rubrum, this is partly explained by an increase in number of requests for susceptibility testing. Terbinafine-resistant T. indotineae was first detected in 2018, but accounted for 19% of resistance (4 of 21 patients) in 2020. In conclusion, terbinafine resistance is an emerging problem in Denmark. Population based studies are warranted and susceptibility testing is highly relevant in non-responding cases

Cardiorespiratory fitness, cardiovascular workload and risk factors among cleaners; a cluster randomized worksite intervention

BACKGROUND: Prevalence of cardiovascular risk factors is unevenly distributed among occupational groups. The working environment, as well as lifestyle and socioeconomic status contribute to the disparity and variation in prevalence of these risk factors. High physical work demands have been shown to increase the risk for cardiovascular disease and mortality, contrary to leisure time physical activity. High physical work demands in combination with a low cardiorespiratory fitness infer a high relative workload and an excessive risk for cardiovascular mortality. Therefore, the aim of this study is to examine whether a worksite aerobic exercise intervention will reduce the relative workload and cardiovascular risk factors by an increased cardiorespiratory fitness. METHODS/DESIGN: A cluster-randomized controlled trial is performed to evaluate the effect of the worksite aerobic exercise intervention on cardiorespiratory fitness and cardiovascular risk factors among cleaners. Cleaners are eligible if they are employed ≥ 20 hours/week, at one of the enrolled companies. In the randomization, strata are formed according to the manager the participant reports to. The clusters will be balanced on the following criteria: Geographical work location, gender, age and seniority. Cleaners are randomized to either I) a reference group, receiving lectures concerning healthy living, or II) an intervention group, performing worksite aerobic exercise “60 min per week”. Data collection will be conducted at baseline, four months and 12 months after baseline, at the worksite during working hours. The data collection will consist of a questionnaire-based interview, physiological testing of health and capacity-related measures, and objective diurnal measures of heart rate, physical activity and blood pressure. Primary outcome is cardiorespiratory fitness. DISCUSSION: Information is lacking about whether an improved cardiorespiratory fitness will affect the cardiovascular health, and additionally decrease the objectively measured relative workload, in a population with high physical work demands. Previous intervention studies have lacked robust objective measurements of the relative workload and physical work demands. This study will monitor the relative workload and general physical activity before, during after the intervention, and contribute to the understanding of the previously observed opposing effects on cardiovascular health and mortality from occupational and leisure time physical activity. TRIAL REGISTRATION: The study is registered as ISRCTN86682076

Worksite interventions for preventing physical deterioration among employees in job-groups with high physical work demands: Background, design and conceptual model of FINALE

<p>Abstract</p> <p>Background</p> <p>A mismatch between individual physical capacities and physical work demands enhance the risk for musculoskeletal disorders, poor work ability and sickness absence, termed physical deterioration. However, effective intervention strategies for preventing physical deterioration in job groups with high physical demands remains to be established. This paper describes the background, design and conceptual model of the FINALE programme, a framework for health promoting interventions at 4 Danish job groups (i.e. cleaners, health-care workers, construction workers and industrial workers) characterized by high physical work demands, musculoskeletal disorders, poor work ability and sickness absence.</p> <p>Methods/Design</p> <p>A novel approach of the FINALE programme is that the interventions, i.e. 3 randomized controlled trials (RCT) and 1 exploratory case-control study are tailored to the physical work demands, physical capacities and health profile of workers in each job-group. The RCT among cleaners, characterized by repetitive work tasks and musculoskeletal disorders, aims at making the cleaners less susceptible to musculoskeletal disorders by physical coordination training or cognitive behavioral theory based training (CBTr). Because health-care workers are reported to have high prevalence of overweight and heavy lifts, the aim of the RCT is long-term weight-loss by combined physical exercise training, CBTr and diet. Construction work, characterized by heavy lifting, pushing and pulling, the RCT aims at improving physical capacity and promoting musculoskeletal and cardiovascular health. At the industrial work-place characterized by repetitive work tasks, the intervention aims at reducing physical exertion and musculoskeletal disorders by combined physical exercise training, CBTr and participatory ergonomics. The overall aim of the FINALE programme is to improve the safety margin between individual resources (i.e. physical capacities, and cognitive and behavioral skills) and physical work demands, and thereby reduce the physical deterioration in a long term perspective by interventions tailored for each respective job-group.</p> <p>Discussion</p> <p>The FINALE programme has the potential to provide evidence-based knowledge of significant importance for public health policy and health promotion strategies for employees at high risk for physical deterioration.</p> <p>Trial registrations</p> <p>ISRCTN96241850, NCT01015716 and NCT01007669</p

Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations

Objectives The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. Methods Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel-Cox tests. Results P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. Conclusions C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validatio