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Introduction: Micro ribonucleic acids (miRNA) respond to acute bouts of vigorous exercise, such as maximal cardiopulmonary exercise tests (CPET), by expressing an anti-atherogenic, anti-inflammatory and hence probably ergogenic profile. However, the impact of long-term engagement in physical exercise on CPET-induced miRNA response in sedentary individuals, with subsequent increased risk for cardiovascular diseases, remains unclear. Methods: Thirty-four sedentary participants underwent CPET before and after a four-month app-assisted exercise intervention, during which the moderate to vigorous physical activity (MVPA) was increased to over 150 min/week. Capillary blood samples were collected before and after CPET at baseline and after the exercise intervention. Twenty target miRNAs previously reported to be responsive to exercise and exercise adaptive pathways, or linked to atherogenic properties as inflammation, or previously identified upregulated following exercise in subjects with coronary artery disease versus healthy subjects were analyzed via real-time polymerase chain reaction. Results: Physical activity increased from 64 ± 48 to 354 ± 332 min/week of MVPA (p<0.001, +553%), accompanied by an improvement in maximal power output during CPET (ΔWattmax: 19 ± 13, p<0.001, +9%). Eleven of the selected twenty miRNAs showed significant responses to CPETs at either the beginning or end of the study. We found a significant increase both times for miR-103a (glycolysis, %change base: +12%, post +17%), miR-146a (inflammation, %change base: +20%, post +21%), and miR-222 (cardiac remodeling, %change base: +10%, post +21%), while miR-30a (inflammation, %change base: -27%, post: -38%) decreased significantly (all p≤0.043). Conclusion: Increased physical activity led to a significant CPET-induced change in three miRNAs from an atherogenic profile to a healthier one, indicating improved metabolic health and reduced inflammation. [ABSTRACT FROM AUTHOR]

Background: Shared decision making (SDM) between healthcare professionals and persons with CVD can have a positive impact on motivation, adherence, or sustainability regarding long-term goals and integration of cardiovascular disease (CVD) rehabilitation in the everyday lives of persons with CVD. SDM can foster the transition between regular heart-healthy activity at rehabilitation facilities and more independent activity at home, but it is often challenging to implement SDM given limited time and resources, e.g., in the daily practice of rehabilitation. Digital tools can help but must be appropriately tailored for situated use and user needs. Objective: We aimed to (1) describe in how far SDM is manifested in the situated context when using a digital tool developed by our group, and, based on that, (2) reflect on how digital health tools can be designed to facilitate and improve the SDM process. Methods: In the context of a field study, we investigated how SDM is already naturally applied and manifested when using a digital tool for joint physical activity planning in cardiac rehabilitation in clinical practice. In a two-week qualitative study, we collected data on expectations, experiences and interactions during the use of a digital health tool by seven persons with CVD and five healthcare professionals. Data was collected by means of observations, interviews, questionnaires and a self-reported diary, and analysed with a particular focus on episodes related to SDM. Results: We found that SDM was manifested in the situated context to limited extent. For example, we identified high improvement potential for more structured goalsetting and more explicit consideration of preferences and routines. Based on mapping our findings to temporal phases where SDM can be adopted, we highlight implications for design to further support SDM in clinical practice. We consider this as “SDM supportive design in digital health apps,” suggesting for example step-by-step guidance to be used during the actual consultation. Conclusion: This study contributes to further understanding and integration of SDM in digital health tools with a focus on rehabilitation, to empower and support both persons with CVD and healthcare professionals. [ABSTRACT FROM AUTHOR]

Objective: To determine if supervised training, after the completion of cardiac rehabilitation program, performed for a further two years would help maintain beneficial effects achieved during prolonged outpatient cardiac rehabilitation. Design: Longitudinal parallel-grouped intervention study. Subjects: Patients with coronary artery disease (n = 41, age 59.5 ± 9.3 years), who finished cardiac rehabilitation phase III in our outpatient cardiac rehabilitation facility. Intervention: Two years of supervised exercise training consisting of endurance (either high intensity interval training or pyramid training) and resistance training sessions once a week. Main measurement: Peak physical work capacity was assessed via an ergometry testing at the beginning and at the end of the study. Results: Comparisons between end-of-cardiac rehabilitation and two years post cardiac rehabilitation revealed maintenance of peak physical work capacity after two years (begin vs end: 170 ± 59 W vs 167 ± 60 W; −0.5 ± 12.8%; p = 0.521). This was independent of exercise training protocols (percent change begin vs end: pyramid: 1.5 ± 11.8%; interval: −1.6 ± 13.4%; p = 0.459). Conclusion: Improvement of physical exercise capacity gained during outpatient cardiac rehabilitation can be maintained for up to two years by once-weekly supervised exercise training. Long-term, group-based exercise programs offered at the end of cardiac rehabilitation might be an effective tool to help patients maintain their physical work capacity. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the leading non-cardiovascular cause of death in women. In endocrine receptor positive women, aromatase inhibitors (AI) are the therapy of choice despite the fact that a decrease in systemic estrogen levels may result in endothelial dysfunction and eventually in cardiovascular disease. In this study, we assessed whether exercise training (ET), which has repeatedly shown to lead to an improvement of endothelial dysfunction, will also exert this effect in postmenopausal women with AI treated breast cancer. Methods: Thirty two postmenopausal women with AI treated breast cancer were randomized to an intervention group (ET; 6 months, supervised training plus 6 months without intervention) or control group of usual care (UC; 12 months without intervention plus initial exercise counseling). Endothelial function was assessed via Reactive Hyperemia Index (RHI) measured non-invasively with the EndoPAT-System at baseline, 6 and 12 months. Results: After 6 months of supervised ET, changes in maximal exercise capacity were significantly greater in ET than in UC (ΔW: 24.1 ± 11.5 vs. 1.1 ± 8.2 watts; p < 0.001). Even though 43.8% of all participants had endothelial dysfunction at baseline, there were no significant group differences in the changes of RHI between ET (ΔRHI: -0.1 ± 1.04) and UC (0.02 ± 0.75; p = 0.323) after 6 months. Conclusion: Even though ET led to significantly greater improvement in exercise capacity in postmenopausal women with AI treated breast cancer than exercise counseling only, it did not exert any measurable effects on endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Hiking is one of the most popular forms of exercise in the alpine region. However, besides its health benefits, hiking is the alpine activity with the highest incidence of cardiac events. Most incidents occur due to overexertion or underestimation of the physiological strain of hiking. Objective: This project will establish a standardized cardio trekking test trail to evaluate the exercise capacity of tourists within hiking areas and deliver a tool for the prevention of hiking-associated cardiac incidents. Further, individual exercise intensity for a hiking tour will be predicted and visualized in digital maps. Methods: This cooperation study between Austria and Germany will first validate a 1-km outdoor cardio trekking test trail at 2 different study sites. Then, exercise intensity measures on 8-km hiking trails will be evaluated during hiking to estimate overall hiking intensity. A total of 144 healthy adults (aged >45 years) will perform a treadmill test in the laboratory and a 1-km hiking test outdoors. They will wear a portable spirometry device that measures gas exchange, as well as heart rate, walking speed, ventilation, GPS location, and altitude throughout the tests. Estimation models for exercise capacity based on measured parameters will be calculated. Results: The project "Connect2Move" was funded in December 2019 by the European Regional Development Fund (INTERREG V-A Programme Austria-Bavaria - 2014-2020; Project Number AB296). "Connect2Move" started in January 2020 and runs until the end of June 2022. By the end of April 2022, 162 participants were tested in the laboratory, and of these, 144 were tested outdoors. The data analysis will be completed by the end of June 2022, and results are expected to be published by the end of 2022. Conclusions: Individual prediction of exercise capacity in healthy individuals with interest in hiking aims at the prevention of hiking-associated cardiovascular events caused by overexertion. Integration of a mathematical equation into existing hiking apps will allow individual hiking route recommendations derived from individual performance on a standardized cardio trekking test trail. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of the closure of group-based cardiac rehabilitation (CR) training during the first COVID-19 lockdown in spring 2020 on patients' physical activity, cardiorespiratory fitness, and cardiovascular risk, and to describe the patient experience of lockdown and home-based exercise training during lockdown. Design: Mixed methods study. Prospectively collected post-lockdown measurements were compared to pre-lockdown medical record data. Quantitative measurements were supplemented with qualitative interviews about the patient experience during lockdown. Setting: Outpatient CR centre in Salzburg, Austria. Participants: Twenty-seven patients [six female, mean (SD) age 69 (7.4) years] who attended weekly CR training sessions until the first COVID-19 lockdown in March 2020. Outcome Measure(s): Quantitative: exercise capacity (maximal ergometer test, submaximal ergometer training), cardiovascular risk (Framingham risk score, blood pressure, body mass index, lipids). Qualitative: individual semi-structured interviews. Results: Exercise capacity had significantly reduced from pre- to post-lockdown: mean (SD) power (W) in maximal ergometry 165 (70) vs. 151 (70), p < 0.001; submaximal ergometer training 99 (40) vs. 97 (40), p = 0.038. There was no significant difference in Framingham risk score and other cardiovascular risk factors. Qualitative data showed that almost all patients had kept physically active during lockdown, but 17 (63%) said they had been unable to maintain their exercise levels, and 15 (56%) felt their cardiorespiratory fitness had deteriorated. Many patients missed the weekly CR training and the motivation and sense of community from training together with others. Several patients stated that without professional supervision they had felt less confident to carry out home-based exercise training at high intensity. Conclusion: This study highlights the importance of group-based supervised exercise training for patients who engage well in such a setting, and the detrimental impact of disruption to this type of CR service on physical activity levels and exercise capacity. Additionally, learning from the COVID-19 pandemic may inform the development and implementation of remote CR modalities going forward. [ABSTRACT FROM AUTHOR]

CspA and four other small proteins with DNA- and RNA-binding sites constitute the family of dimeric major cold shock protein homologs in the psychrotrophic Bacillus cereus WSBC 10201. The amino acid sequences of the proteins are similar to each other, other prokaryotic cold shock proteins and the cold shock region of Y-box proteins. The CspA and CspE proteins are recovered as dimers with a molecular mass of 15 kDa by gel filtration. The proteins dissociate into their monomers at high salt levels. CspA shows strong expression during growth at low temperature and after cold shock.

Micro ribonucleic acids (miRNAs) are small non-coding RNA molecules that control gene expression by translational inhibition. Exercise has been shown to affect several miRNAs' expression in healthy subjects, but this has not yet been studied in patients with coronary artery disease (CAD). Since exercise training confers beneficial long-term effects and may also trigger acute coronary events, it is of utmost interest to be able to identify those who are risk for untoward effects. Therefore, we set out to assess miRNA expression in response to maximal ergospirometry in patients with CAD. Total RNA was extracted from blood drawn immediately before and 5 min after maximal cycle-ergospirometry (10 male and 10 female CAD patients). A qRT-PCR was performed for 187 target miRNAs associated with endothelial function/dysfunction, cardiovascular disease, myocardial infarction, and sudden cardiac death. In response to a maximal ergospirometry, 33 miRNAs significantly changed their expression levels. Of these miRNAs 16 were significantly differently expressed between gender. Using multi-variance analysis, nine miRNAs (let-7e-5p; miR-1; miR-19b-1-5p; miR-103a-3p; miR-148b-3p; miR-181b-5p; miR-188-5p; miR-423-5p; miR-874-3p) showed significantly different responses to maximal ergospirometry between genders. We report for the first time that in patients with CAD, miRNA expression is amenable to maximal ergospirometry and that the extent of changes differs between genders. Affected by exercise and gender were miRNAs that are associated, among others, with pathways for glucose metabolism, oxidative stress, and angiogenesis. Future studies should assess whether disease-specific miRNA expression in response to maximal exercise might serve as a marker for patient outcome. [ABSTRACT FROM AUTHOR]

Functional impairment caused by chronic obstructive pulmonary disease (COPD) impacts on activities of daily living and quality of life. Indeed, patients' submaximal exercise capacity is of crucial importance. It was the aim of this study to investigate the effects of an exercise training intervention with and without supplemental oxygen on submaximal exercise performance. This is a secondary analysis of a randomized, controlled, double‐blind, crossover trial. 29 COPD patients (63.5 ± 5.9 years; FEV1 46.4 ± 8.6%) completed two consecutive 6‐week periods of high‐intensity interval cycling and strength training, which was performed three times/week with either supplemental oxygen or medical air (10 L/min). Submaximal exercise capacity as well as the cardiocirculatory, ventilatory, and metabolic response were evaluated at isotime (point of termination in the shortest cardiopulmonary exercise test), at physical work capacity at 110 bpm of heart rate (PWC 110), at the anaerobic threshold (AT), and at the lactate‐2 mmol/L threshold. After 12 weeks of exercise training, patients improved in exercise tolerance, shown by decreased cardiocirculatory (heart rate, blood pressure) and metabolic (respiratory exchange ratio, lactate) effort at isotime; ventilatory response was not affected. Submaximal exercise capacity was improved at PWC 110, AT and the lactate‐2 mmol/L threshold, respectively. Although supplemental oxygen seems to affect patients' work rate at AT and the lactate‐2 mmol/L threshold, no other significant effects were found. The improved submaximal exercise capacity and tolerance might counteract patients' functional impairment. Although cardiovascular and metabolic training adaptations were shown, ventilatory efficiency remained essentially unchanged. The impact of supplemental oxygen seems less important on submaximal training effects. [ABSTRACT FROM AUTHOR]

Sedentary lifestyle is a major modifiable risk factor for many chronic diseases. Global guidelines recommend for maintaining health in adults, at least 150 minutes of moderate intensity of physical activity throughout the week, but compliance is insufficient and health problems arise. One obvious way to overcome this is to integrate physical activity into the daily routine for example by active commuting to work. Scientific evidence, however, is scarce and therefore we set out to perform this systematic review of the available literature to improve understanding of the efficiency of active commuting initiatives on health. Literature searches were performed in PubMed and Cochrane database. Altogether, 37 studies were screened. Thereof, eight publications were reviewed, which included 555 participants. The mean study duration of the reviewed research was 36 ± 26 (8‐72) weeks. Overall, active commuting in previously untrained subjects of both sexes significantly improved exercise capacity, maximal power, blood pressure, lipid parameters including cholesterol, high‐density lipoprotein, and waist circumference. Improvement was independent of the type of active commuting. Despite relatively few studies that were previously performed, this review revealed that active commuting has health beneficial effects comparable to those of moderate exercise training. [ABSTRACT FROM AUTHOR]

Wildflower strips (WFS) are increasingly used to counteract the negative consequences of agricultural intensification. To date, it is poorly understood how WFS promote flower visitation and pollination services in nearby insect‐pollinated crops. We therefore ask whether WFS enhance pollination service in adjacent strawberry crops, and how such an effect depends on the distance from WFS. Over 2 years, we examined the effects of experimentally sown WFS compared to grassy strips on pollination services in adjacent strawberry (Fragaria ananassa) crops across a total of 19 study sites. Moreover, we examined flower visitation, species richness and community composition of the most important insect pollinator taxa at different within‐field locations varying in distance to WFS. We found increased pollination services at the edge of WFS compared to locally reduced pollination services at the center, which resulted in no significant difference in seed set between WFS and control fields. Total flower visits and species richness of pollinators were higher in WFS than in adjacent strawberry fields. Moreover, wild bee visitation was enhanced in adjacent strawberry crops near WFS compared to field centers, and intermediate at field edges near grassy strips. Our study demonstrates that diverse WFS can increase wild bee visitation and pollination services in the field edges of adjacent strawberry crops, but that overall visitation and pollination services do not increase. Moreover, our findings show that major pollinator taxa exhibit distinct responses, resulting in a shift of pollinator community composition as a function of distance to WFS with direct effects on crop pollination. Our results that WFS enhance rather than reduce crop pollination services near WFS should distract possible concerns by farmers that WFS may locally absorb rather than export crop pollinators. Considering the spatial restricted enhancement of wild bees and associated pollination services we suggest to establish WFS in the center of crop fields. Wildflower strips (WFS) are increasingly used to counteract the negative consequences of agricultural intensification on pollinators. We therefore show whether WFS enhance pollination service in adjacent strawberry crops, and how such an effect depends on the distance from WFS. Moreover, we show which of the major pollinator groups might cause such an effect. [ABSTRACT FROM AUTHOR]

Background: There is a well‐known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment. Methods: Postmenopausal, estrogen receptor‐positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week). Results: Twenty‐three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early‐stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 ±  standard deviation [SD] 34; 95% confidence interval [CI] 117‐147) compared to baseline (107 ± 25; 95%CI 97‐117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 ± 25; 95%CI 105‐125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1‐24 unsupervised: 18.3 (7.6‐58.3); supervised: 28.5 (6.7‐40.1); P = 0.043; week 25‐48; P = 0.041)). Conclusion: This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training. Our findings on breast cancer patients under aromatase inhibitor treatment indicate that patients achieve higher fitness levels during supervised training compared to unsupervised training. [ABSTRACT FROM AUTHOR]

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33 cats, suffering from chronic stomatitis, were treated with orally given paramunity inducer PIND-ORF (local paramunization). As a control 39 cats in the same practice were treated with other conventional methods. The reconvalescence rate (healing without rezidives) of experimental animals was 42%. From control animals only 13% reached this status. Oral paramunization with PIND-ORF is recommended as an alternative treatment for hitherto existing therapeutic measures against chronic stomatitis. [ABSTRACT FROM AUTHOR]

International and national laws promote stakeholder collaboration and the inclusion of the community in flood risk management (FRM). Currently, relocation as a mitigation strategy against river floods in Central Europe is rarely applied. FRM needs sufficient preparation and engagement for successful implementation of household relocation. This case study deals with the extreme flood event in June 2016 at the Simbach torrent in Bavaria (Germany). The focus lies on the planning process of structural flood defense measures and the small-scale relocation of 11 households. The adaptive planning process started right after the damaging event and was executed in collaboration with authorities and stakeholders of various levels and disciplines while at the same time including the local citizens. Residents were informed early, and personal communication, as well as trust in actors, enhanced the acceptance of decisions. Although technical knowledge was shared and concerns discussed, resident participation in the planning process was restricted. However, the given pre-conditions were found beneficial. In addition, a compensation payment contributed to a successful process. Thus, the study illustrates a positive image of the implementation of the alleviation scheme. Furthermore, preliminary planning activities and precautionary behavior (e.g., natural hazard insurance) were noted as significant factors to enable effective integrated flood risk management (IFRM). [ABSTRACT FROM AUTHOR]

Sedentary lifestyle predisposes to endothelial dysfunction, increased arterial stiffness and cardiovascular diseases, all of which can be positively modified by regular physical exercise training. A decrease in physical activity during winter months coincides with higher rates of cardiovascular events. In order to identify winter sports suitable to overcome this seasonal exercise deficit and thus contribute to cardiovascular health, it was the aim of this study to compare immediate effects of cross-country skiing (XCS) and alpine skiing (AS) on arterial stiffness as an alternative to indoor cycling (IC). After baseline assessment, eighteen healthy subjects performed one session of XCS, AS, and IC in randomized order. Pulse wave analysis was conducted (Mobil-o-Graph®) before and 10-min after exercise. Parameters of arterial stiffness and wave reflection were reduced after XCS and IC, but not after AS: central systolic blood pressure (IC: -8.0 ± 5.4 mmHg; p < 0.001), amplitude of the backward pressure wave (IC: -1.4 ± 2.7 mmHg; p < 0.05), reflection coefficient (XCS: -6.0 ± 7.8%; IC: -5.7 ± 8.1%; both p < 0.1), and pulse wave velocity (IC by -0.19 ± 0.27 m/s; p < 0.01). Higher exercise intensities correlated with greater reductions of arterial stiffness (all p < 0.05). Single sessions of XCS, IC but not AS led to comparable improvement in arterial stiffness, which was even more pronounced during higher exercise intensities. With regard to arterial stiffness, IC and XCS emerge as more effective to counteract the winter exercise deficit and thus the deleterious cardiovascular effects of a sedentary lifestyle. [ABSTRACT FROM AUTHOR]

Background: Shared decision making (SDM) between healthcare professionals and persons with CVD can have a positive impact on motivation, adherence, or sustainability regarding long-term goals and integration of cardiovascular disease (CVD) rehabilitation in the everyday lives of persons with CVD. SDM can foster the transition between regular heart-healthy activity at rehabilitation facilities and more independent activity at home, but it is often challenging to implement SDM given limited time and resources, e.g., in the daily practice of rehabilitation. Digital tools can help but must be appropriately tailored for situated use and user needs., Objective: We aimed to (1) describe in how far SDM is manifested in the situated context when using a digital tool developed by our group, and, based on that, (2) reflect on how digital health tools can be designed to facilitate and improve the SDM process., Methods: In the context of a field study, we investigated how SDM is already naturally applied and manifested when using a digital tool for joint physical activity planning in cardiac rehabilitation in clinical practice. In a two-week qualitative study, we collected data on expectations, experiences and interactions during the use of a digital health tool by seven persons with CVD and five healthcare professionals. Data was collected by means of observations, interviews, questionnaires and a self-reported diary, and analysed with a particular focus on episodes related to SDM., Results: We found that SDM was manifested in the situated context to limited extent. For example, we identified high improvement potential for more structured goal-setting and more explicit consideration of preferences and routines. Based on mapping our findings to temporal phases where SDM can be adopted, we highlight implications for design to further support SDM in clinical practice. We consider this as "SDM supportive design in digital health apps," suggesting for example step-by-step guidance to be used during the actual consultation., Conclusion: This study contributes to further understanding and integration of SDM in digital health tools with a focus on rehabilitation, to empower and support both persons with CVD and healthcare professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wurhofer, Neunteufel, Strumegger, Höppchen, Mayr, Egger, Sareban, Reich, Neudorfer, Niebauer, Smeddinck and Kulnik.)

Unlabelled: The aim of this study was to determine the frequencies and specificities of "enzyme-only" detected red blood cell (RBC) alloantibodies in the routine antibody screening and antibody identification in patients hospitalized in Austria. Routine blood samples of 2420 patients were investigated. The antibody screening was performed with a 3-cell panel in the low-ionic strength saline- (LISS-) indirect antiglobulin test (IAT) and with an enzyme-pretreated (papain) 3-cell panel fully automated on the ORTHO AutoVue Innova System. The antibody identification was carried out manually with an 11-cell panel in the LISS-IAT and with an enzyme-pretreated (papain) 11-cell panel. In total 4.05% (n = 98) of all patients (n = 2420) had a positive RBC antibody screening result. Of them 25.51% (25/98) showed "enzyme-only" detected specific or nonspecific RBC alloantibodies. Rhesus and Lewis system antibodies were found the only specificities of "enzyme-only" RBC alloantibodies: all in all 4.8% (4/98) were detected with anti-E, 3.06% (3/98) with anti-Le(a), 3.06% (3/98) with anti-D after anti-D prophylaxis and 1.02% (1/98) with anti-e. In total, 14.29% (14/98) showed a nonspecific RBC alloantibody result with the enzyme test. The results of the present study demonstrate that a high number of unwanted positive reactions with the enzyme technique overshadows the detection of "enzyme-only" RBC alloantibodies. (, Trial Registration: K-37-13).

Methotrexate (MTX) is an effective disease modifying antirheumatic drug (DMARD) with a relatively safe profile, and it is widely used to treat neoplastic diseases and dermatologic and rheumatologic disorders. As indications for use of MTX increase, more accidental overdoses are noted to occur. Typical problems include deficiencies in labeling, instructions, or packaging, as well as erroneous use. We describe 5 fatal cases of repeated oral overdose of MTX prescribed by physicians in the treatment of rheumatoid arthritis to focus attention on the design of the underlying system and the organizational practices as sources of problems.