Genetic Aspects of the Estrogen Signaling Pathway

__Abstract__ Estradiol, one of the sex hormones responsible for gender dimorphism and reproduction, is a pleitropic hormone with widespread biological actions far beyond human reproduction alone. For example, withdrawal of the effects of estradiol at menopause from non-reproductive tissues like the skeleton, the cardiovascular system, and the brain, is a major risk factor for the development of osteoporosis, coronary artery disease, stroke, and perhaps neurodegenerative diseases like Alzheimer’s disease. On the other hand, continuous exposure of reproductive tissues to estrogen during the post reproductive part of life is a risk factor for the development of breast, and uterine cancer

Screening for hazardous alcohol use in the Emergency Department:Comparison of phosphatidylethanol with the Alcohol Use Disorders Identification Test and the Timeline Follow-back

Background: Up to 15% of all visits to the Emergency Department (ED) are alcohol related. Identification of problematic alcohol use is important in this setting because it allows for intervention and prevention efforts. This study investigated the correlation between the objective phosphatidylethanol (PEth) marker and the subjective Alcohol Use Disorders Identification Test (AUDIT) and Timeline Followback Questionnaire (TLFB) as screening methods for hazardous alcohol use in the general ED population. Methods: This prospective cohort study included 301 ED patients (57% male) who were seen in the ED and required to give a blood sample. The correlation between the values of PEth (PEth 16:0/18:1 and PEth 16:0/18:2) and the scores on the AUDIT and TLFB were analyzed using Spearman's rank correlation coefficient. Differences between risk categories of PEth and AUDIT were also examined. Results: The Spearman correlation coefficients between PEth 16:0/18:1|PEth 16:0/18:2 values and the AUDIT scores were moderate (PEth 16:0/18:1: 0.67, p < 0.001; PEth 16:0/18:2: 0.67, p < 0.001). Of the patients who scored ‘low risk drinking/abstinence’ according to the AUDIT questionnaire, respectively 1% and 4% had PEth 16:0/18:1|PEth 16:0/18:2 values indicating excessive alcohol use, and another 10% and 12% had PEth 16:0/18:1|PEth 16:0/18:2 values indicating moderate alcohol consumption. Of the 12 (PEth 16:0/18:1) and 25 (PEth 16:0/18:2) patients with high-risk values, respectively 25% and 40% scored in the lowest risk category on the AUDIT questionnaire. Spearman correlation coefficients between PEth 16:0/18:1|PEth 16:0/18:2 values and TLFB two-week scores were high (PEth 16:0/18:1: 0.74, p < 0.001; PEth 16:0/18:2: 0.82, p < 0.001). Conclusions: AUDIT scores were moderately correlated with PEth values in the general ED population. In almost all cases where there was not a good correlation, patients had high PEth values with low AUDIT scores. We conclude that PEth identifies patients with problematic alcohol use who are missed by the AUDIT questionnaire and therefore PEth could be used as an additional screening method for hazardous alcohol use in this population

The association of body temperature with antibiotic therapy and mortality in patients attending the emergency department with suspected infection

BACKGROUND AND IMPORTANCE: Previous studies found that septic patients with normothermia have higher mortality than patients with fever. We hypothesize that antibiotic therapy is less frequently initiated if infectious patients present with normothermia to the emergency department (ED). OBJECTIVES: To examine the association of body temperature with the initiation of antibiotic therapy in patients attending the ED with suspected and proven infection. Additionally, the association of temperature with 30-day mortality was assessed. DESIGN, SETTINGS AND PARTICIPANTS: We conducted a retrospective cohort study between 2012 and 2016 at a tertiary university hospital. Adult patients attending the ED with a blood culture taken (i.e. suspected infection) and a positive blood culture (i.e. proven bacteremia) were included. EXPOSURE: Tympanic temperature at arrival was categorized as hypothermia (38.0°C). OUTCOME MEASURES AND ANALYSIS: Primary outcome was the initiation of antibiotic therapy. A secondary outcome was 30-day mortality. Multivariable logistic regression was used to control for covariates. MAIN RESULTS: Of 5997 patients with a suspected infection, 45.8% had normothermia, 44.6% hyperthermia and 5.6% hypothermia. Patients with hyperthermia received more often antibiotic therapy (53.5%) compared to normothermic patients (27.6%, adjusted odds ratio [95% confidence interval], 2.59 [2.27–2.95]). Patients with hyperthermia had lower mortality (4.7%) than those with normothermia (7.4%, adjusted odds ratio [95% confidence interval], 0.50 [0.39–0.64]). Sensitivity analyses in patients with proven bacteremia (n = 934) showed similar results. CONCLUSION: Normothermia in patients presenting with infection was associated with receiving less antibiotic therapy in the ED compared to presentations with hyperthermia. Moreover, normothermia was associated with a higher mortality risk than hyperthermia

Oromandibular dystonia: a serious side effect of capecitabine

textabstractBackground: Capecitabine has activity against several types of cancer. In 10-15% of patients treated with capecitabine, treatment is discontinued because of serious adverse reactions, mostly within the first weeks of treatment. Case presentation: A 56 year-old female patient presented at the emergency department after ten days of chemotherapy with progressive airway obstruction and complaints of numbness of the tongue. She also had difficulty swallowing and was unable to speak. Laboratory findings were completely normal and no co-medication was used, in particular no dopamine antagonists. A diagnosis of oromandibular dystonia due to capecitabine use was made. After the anticholinergic drug biperiden (Akineton) was given intravenously, complaints disappeared within twenty minutes. Due to an early discontinuation of biperiden, however, the symptoms of oromandibular dystonia recurred. Again, she was successfully treated with an anticholinergic drug. Capecitabine was permanently discontinued. Three days after the initial presentation the anticholinergic drug was stopped after which symptoms did not reappear. Conclusion: The case highlights the need for awareness that capecitabine may potentially lead to severe life-threatening complaints of oromandibular dystonia. We hypothesize that capecitabine passed the blood brain barrier which led to a disruption within the basal ganglia in this case. Prompt treatment with an anticholinergic drug and cessation of capecitabine in the patient case led to disappearance of complaints

Specific Disease Knowledge as Predictor of Susceptibility to Availability Bias in Diagnostic Reasoning:a Randomized Controlled Experiment

BACKGROUND: Bias in reasoning rather than knowledge gaps has been identified as the origin of most diagnostic errors. However, the role of knowledge in counteracting bias is unclear. OBJECTIVE: To examine whether knowledge of discriminating features (findings that discriminate between look-alike diseases) predicts susceptibility to bias. DESIGN: Three-phase randomized experiment. Phase 1 (bias-inducing): Participants were exposed to a set of clinical cases (either hepatitis-IBD or AMI-encephalopathy). Phase 2 (diagnosis): All participants diagnosed the same cases; 4 resembled hepatitis-IBD, 4 AMI-encephalopathy (but all with different diagnoses). Availability bias was expected in the 4 cases similar to those encountered in phase 1. Phase 3 (knowledge evaluation): For each disease, participants decided (max. 2 s) which of 24 findings was associated with the disease. Accuracy of decisions on discriminating features, taken as a measure of knowledge, was expected to predict susceptibility to bias. PARTICIPANTS: Internal medicine residents at Erasmus MC, Netherlands. MAIN MEASURES: The frequency with which higher-knowledge and lower-knowledge physicians gave biased diagnoses based on phase 1 exposure (range 0-4). Time to diagnose was also measured. KEY RESULTS: Sixty-two physicians participated. Higher-knowledge physicians yielded to availability bias less often than lower-knowledge physicians (0.35 vs 0.97; p = 0.001; difference, 0.62 [95% CI, 0.28-0.95]). Whereas lower-knowledge physicians tended to make more of these errors on subjected-to-bias than on not-subjected-to-bias cases (p = 0.06; difference, 0.35 [CI, - 0.02-0.73]), higher-knowledge physicians resisted the bias (p = 0.28). Both groups spent more time to diagnose subjected-to-bias than not-subjected-to-bias cases (p = 0.04), without differences between groups. CONCLUSIONS: Knowledge of features that discriminate between look-alike diseases reduced susceptibility to bias in a simulated setting. Reflecting further may be required to overcome bias, but succeeding depends on having the appropriate knowledge. Future research should examine whether the findings apply to real practice and to more experienced physicians

An experimental study on the effects of a simulation game on students’ clinical cognitive skills and motivation

Simulation games are becoming increasingly popular in education, but more insight in their critical design features is needed. This study investigated the effects of fidelity of open patient cases in adjunct to an instructional e-module on students’ cognitive skills and motivation. We set up a three-group randomized post-test-only design: a control group working on an e-module; a cases group, combining the e-module with low-fidelity text-based patient cases, and a game group, combining the e-module with a high-fidelity simulation game with the same cases. Participants completed questionnaires on cognitive load and motivation. After a 4-week study period, blinded assessors rated students’ cognitive emergency care skills in two mannequin-based scenarios. In total 61 students participated and were assessed; 16 control group students, 20 cases students and 25 game students. Learning time was 2 h longer for the cases and game groups than for the control group. Acquired cognitive skills did not differ between groups. The game group experienced higher intrinsic and germane cognitive load than the cases group (p = 0.03 and 0.01) and felt more engaged (p < 0.001). Students did not profit from working on open cases (in adjunct to an e-module), which nonetheless challenged them to study longer. The e-module appeared to be very effective, while the high-fidelity game, although engaging, probably distracted students and impeded learning. Medical educators designing motivating and effective skills training for novices should align case complexity and fidelity with students’ proficiency level. The relation between case-fidelity, motivation and skills development is an important field for further study

An experimental study on the effects of a simulation game on students’ clinical cognitive skills and motivation

textabstractSimulation games are becoming increasingly popular in education, but more insight in their critical design features is needed. This study investigated the effects of fidelity of open patient cases in adjunct to an instructional e-module on students’ cognitive skills and motivation. We set up a three-group randomized post-test-only design: a control group working on an e-module; a cases group, combining the e-module with low-fidelity text-based patient cases, and a game group, combining the e-module with a high-fidelity simulation game with the same cases. Participants completed questionnaires on cognitive load and motivation. After a 4-week study period, blinded assessors rated students’ cognitive emergency care skills in two mannequin-based scenarios. In total 61 students participated and were assessed; 16 control group students, 20 cases students and 25 game students. Learning time was 2 h longer for the cases and game groups than for the control group. Acquired cognitive skills did not differ between groups. The game group experienced higher intrinsic and germane cognitive load than the cases group (p = 0.03 and 0.01) and felt more engaged (p < 0.001). Students did not profit from working on open cases (in adjunct to an e-module), which nonetheless challenged them to study longer. The e-module appeared to be very effective, while the high-fidelity game, although engaging, probably distracted students and impeded learning. Medical educators designing motivating and effective skills training for novices should align case complexity and fidelity with students’ proficiency level. The relation between case-fidelity, motivation and skills development is an important field for further study