Biochemical Control in Cushing's syndrome: Outcomes of the treatment in a large single center cohort.

BACKGROUND: Normalization of hypercortisolism is essential to reduce morbidity and mortality in patients with Cushing's syndrome (CS). The aim of this analysis was to assess biochemical control rates in patients with Cushing's disease (CD), ectopic Cushing's syndrome (ECS) and adrenal Cushing's syndrome (ACS). METHODS: Patients with confirmed CS (n= 296) treated in a single tertiary care center were retrospectively analysed (185 CD, 27 ECS, 84 uni- and bilateral ACS). RESULTS: Firstline treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, IQR) was longer in CD (11.0 weeks, 5.6-29.8; p< 0.05) than in ACS (7.7 weeks, 4.1-17.1) and ECS (5.6 weeks, 4.1-23.3). Disease persistence or recurrence after first-line therapy was observed more often in CD (24% and 18%; p< 0.05) than in ECS (15% and 15%) and ACS (6% and 4%). Total time in hypercortisolism since diagnosis was significantly shorter in patients with CD diagnosed since 2013, after specialized patient care was implemented, compared to patients diagnosed before 2013 (13.5 weeks, vs. 26.1 weeks; p< 0.0070). Control of hypercortisolism at last follow up (76 months, 38-163) was achieved in 94% of patients with ACS, 100% of patients with ECS and 92% of patients with CD. CONCLUSIONS: Biochemical control can be achieved in most patients with different subtypes of CS within a reasonable time frame. Control of hypercortisolism has improved over time.

Sleep disturbances in primary aldosteronism are associated to depressive symptoms - Could specific mineralocorticoidreceptors be a common pathway?

Symptoms of depression and anxiety are frequent in patients with primary aldosteronism (PA) and are supposed to be independent risk factors for cardiovascular diseases (CVD). As patients with PA have an increased cardiovascular risk compared to patients with essential hypertension, sleep disturbances, which often accompany depressive and anxiety symptoms, may be an additional contributor to the cardiometabolic consequences of PA. To clarify this possible link we investigated 132 patients with PA at baseline and after one year after initiation of treatment either by adrenalectomy (ADX) or mineralocorticoid-receptor-antagonist (MRA). Sleep disturbances and daytime sleepiness were assessed with Pittsburg sleep Inventory (PSQI) and Epworth sleepiness scale (ESS). Patients with PA showed pathological scores for sleep disturbances at baseline according to PSQI, with females being more affected (8.1 vs. 5.7 p < 0.001), which was significantly improved after initiation of specific treatment (p = 0.002). For ESS we found scores within the normal range, but higher than the general population, which significantly improved at follow-up (p < 0.001). The intensity of sleep disturbances was highly correlated with scores of anxiety and depression at baseline and follow-up. However, clinical and biochemical markers of PA (e.g. aldosterone, blood pressure) and metabolic markers did not show a consistent association with sleep changes. The degree of improvement in PSQI was significantly associated with the improvement of brief patients health questionnaire (PHQD) (p = 0.0151). Sleep disturbances seem not to be an independent risk factor for cardiovascular and metabolic problems in PA. They are strongly associated to depressive symptoms and maybe mediated by the same mineralocorticoid receptor circuits.

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping.

BACKGROUND: Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS: We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS: Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11ß-OH-An + 11ß-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION: GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING: The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.

Introduction: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. Methods: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. Results: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. Discussion: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Insights into diagnostic errors in endocrinology: a prospective, case-based, international study.

BACKGROUND: Diagnostic errors in internal medicine are common. While cognitive errors have previously been identified to be the most common contributor to errors, very little is known about errors in specific fields of internal medicine such as endocrinology. This prospective, multicenter study focused on better understanding the causes of diagnostic errors made by general practitioners and internal specialists in the area of endocrinology. METHODS: From August 2019 until January 2020, 24 physicians completed five endocrine cases on an online platform that simulated the diagnostic process. After each case, the participants had to state and explain why they chose their assumed diagnosis. The data gathering process as well as the participants' explanations were quantitatively and qualitatively analyzed to determine the causes of the errors. The diagnostic processes in correctly and incorrectly solved cases were compared. RESULTS: Seven different causes of diagnostic error were identified, the most frequent being misidentification (mistaking one diagnosis with a related one or with more frequent and similar diseases) in 23% of the cases. Other causes were faulty context generation (21%) and premature closure (17%). The diagnostic confidence did not differ between correctly and incorrectly solved cases (median 8 out of 10, p = 0.24). However, in incorrectly solved cases, physicians spent less time on the technical findings (such as lab results, imaging) (median 250 s versus 199 s, p < 0.049). CONCLUSIONS: The causes for errors in endocrine case scenarios are similar to the causes in other fields of internal medicine. Spending more time on technical findings might prevent misdiagnoses in everyday clinical practice.

Diagnostic challenges in cyclic Cushing's syndrome: a systematic review.

Cyclic Cushing's syndrome is a subentity of Cushing's syndrome in which phases of biochemical hypercortisolism (peaks) are followed by spontaneous periods of physiological or even hypocortisolaemic cortisol secretion (troughs). To identify common features of cyclic Cushing's syndrome, we systematically reviewed single case reports and case series in MEDLINE from database inception to Oct 10, 2022, and identified 707 articles, of which 149 articles were assessed for eligibility and 118 articles (covering 212 cases) were included in the analysis. Pituitary tumours accounted for 67% of cases of cyclic Cushing's syndrome (n=143), ectopic tumours for 17% (n=36), and adrenal tumours for 11% (n=23). Occult tumours accounted for 2% of cases (n=4), and 3% of cases were unclassified (n=6). We compared the clinical symptoms and comorbidities of patients with cyclic Cushing's syndrome with those of patients with non-cyclic Cushing's syndrome and observed no major difference. In adrenocorticotropic hormone (ACTH)-dependent cyclic Cushing's syndrome, bilateral inferior petrosal sinus sampling had a positive (ie, true pituitary) and negative (ie, true ectopic) predictive value of 100% when performed during periods of hypercortisolism, versus a positive predictive value of 73% and a negative predictive value of 86% when performed, irrespective of cortisolaemic status. Overall, 6% of patients (n=12) with cyclic Cushing's syndrome had unnecessary surgery due to misclassification. Remission rates were significantly lower and the time to remission significantly longer in patients with cyclic Cushing's syndrome compared with patients with non-cyclic Cushing's syndrome (p<0·001). Variations in biochemical test results due to unpredictable cycle duration and frequency might cause diagnostic challenges resulting in misdiagnoses and missed diagnoses.

Bayesian versus diagnostic information in physician-patient communication: Effects of direction of statistical information and presentation of visualization.

BACKGROUND: Communicating well with patients is a competence central to everyday clinical practice, and communicating statistical information, especially in Bayesian reasoning tasks, can be challenging. In Bayesian reasoning tasks, information can be communicated in two different ways (which we call directions of information): The direction of Bayesian information (e.g., proportion of people tested positive among those with the disease) and the direction of diagnostic information (e.g., the proportion of people having the disease among those tested positive). The purpose of this study was to analyze the impact of both the direction of the information presented and whether a visualization (frequency net) is presented with it on patient's ability to quantify a positive predictive value. MATERIAL AND METHODS: 109 participants completed four different medical cases (2⨯2⨯4 design) that were presented in a video; a physician communicated frequencies using different directions of information (Bayesian information vs. diagnostic information). In half of the cases for each direction, participants were given a frequency net. After watching the video, participants stated a positive predictive value. Accuracy and speed of response were analyzed. RESULTS: Communicating with Bayesian information led to participant performance of only 10% (without frequency net) and 37% (with frequency net) accuracy. The tasks communicated with diagnostic information but without a frequency net were correctly solved by 72% of participants, but accuracy rate decreased to 61% when participants were given a frequency net. Participants with correct responses in the Bayesian information version without visualization took longest to complete the tasks (median of 106 seconds; median of 13.5, 14.0, and 14.5 seconds in other versions). DISCUSSION: Communicating with diagnostic information rather than Bayesian information helps patients to understand specific information better and more quickly. Patients' understanding of the relevance of test results is strongly dependent on the way the information is presented.

Low-grade inflammation during the glucocorticoid withdrawal phase in patients with Cushing's syndrome.

IMPORTANCE: Endogenous Cushing's syndrome (CS) leads to profound immunosuppression. Successful surgery induces biochemical remission and reversal of immunosuppression, which is characterized by clinical signs of glucocorticoid withdrawal and associated with increased susceptibility to infections and thromboembolic complications. OBJECTIVE: We hypothesized that the glucocorticoid withdrawal phase is characterized by low-grade inflammation that may be related to patient-relevant outcomes. SETTING: In this retrospective observational study, we analyzed longitudinal data from 80 patients with CS prospectively enrolled in the German Cushing's registry between 2012 and 2021. All enrolled patients underwent successful surgery. In a second step, a case-control study was performed in 25 of the patients with age-, gender-, and body mass index-matched control patients in whom hypercortisolism was excluded. Analyses included the inflammatory markers C-reactive protein and interleukin-6, as well as body composition, muscle function testing, and quality-of-life questionnaires. The patients were studied during active CS and in the postoperative remission phase 1, 3, 6, 12, and 24 months after surgery. RESULTS: Compared with the preoperative phase and matched controls, patients with CS had increased systemic inflammatory markers in the early remission phase. One month following surgery, median (interquartile range) C-reactive protein was 0.48 mg dL-1 (0.14-0.90) vs 0.10 mg dL-1 (0.06-0.39) during active CS (P ≤ .001). Similarly, interleukin-6 1 month after surgery was 7.2 pg mL-1 (3.3-11.7) vs 1.7 pg mL-1 (1.5-2.5) during active CS (P ≤ .001). Obesity and hemoglobin A1c (HbA1c) were associated with increased inflammation levels. This proinflammatory state lasted until 1 year following surgery. Moreover, inflammatory markers during early remission showed an inverse correlation with long-term muscle function. CONCLUSIONS: The glucocorticoid withdrawal phase is associated with a low-grade inflammatory state, which is particularly pronounced in obese and hyperglycemic patients and related to lower muscle function.

Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.

CONTEXT: Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). OBJECTIVE: Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. HYPOTHESIS: GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. METHODS: 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. RESULTS: Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. CONCLUSION: BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.

Lack of sensitivity of diagnostic Cushing-scores in Germany: a multicenter validation.

OBJECTIVE: Endogenous Cushing's syndrome (CS) is a severe condition, often diagnosed at a late stage. To reduce mortality, early diagnosis plays an important role. Two screening tools for early identification of patients with CS have been developed in multicentric cohorts, but have not yet been validated in cohorts with different geographic backgrounds. DESIGN: We validated the Spanish score published by Leon-Justel et al. in 2016 and the Italian score by Parasiliti-Caprino et al. published in 2021 in our cohort. METHODS: In the multicentric German Cushing registry, patients with confirmed and expected but ruled out Cushing's syndrome are prospectively diagnosed and followed up. We validated both scores in a cohort of 458 subjects: 176 patients with confirmed CS and 282 patients with suspected, but finally excluded CS. RESULTS: Using the Spanish score, 17.5% of our patients with proven CS biochemical screening would not have been recommended. This concerned patients with pituitary CS (22%) and with adrenal CS (10%). On the contrary, only 14% of patients without CS would have received a recommendation for biochemical screening. Using the Italian score, 29% of patients with proven CS were classified into the low-risk classes not recommended for biochemical screening. This mostly affected patients with adrenal (31%) and pituitary CS (30%). About 12% of subjects without CS would have received a biochemical screening recommendation. CONCLUSIONS: Both scores had limited sensitivity and high specificity in a German validation cohort. Further research is necessary to develop a screening score, which is effective in different healthcare systems and ethnicities.

Whole blood methylome-derived features to discriminate endocrine hypertension.

BACKGROUND: Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. RESULTS: Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. CONCLUSIONS: The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.

11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease.

Background: Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD. Methods: We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated. Results: Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. Conclusion: Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

Whom Should We Screen for Cushing Syndrome? The Endocrine Society Practice Guideline Recommendations 2008 Revisited.

CONTEXT: Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. OBJECTIVE: This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. METHODS: As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. RESULTS: Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. CONCLUSION: The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022.

Preanalytical Considerations and Outpatient Versus Inpatient Tests of Plasma Metanephrines to Diagnose Pheochromocytoma.

CONTEXT: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. OBJECTIVE: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. METHODS: Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. RESULTS: Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. CONCLUSION: Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.

Types of therapeutic errors in the management of osteoporosis made by physicians and medical students.

BACKGROUND: Clinical reasoning is of high importance in clinical practice and thus in medical education research. Regarding the clinical reasoning process, the focus has primarily been on diagnostic reasoning and diagnostic errors, but little research has been done on the subsequent management reasoning process, although the therapeutic decision-making process is at least equally important. The aim of this study was to investigate the frequency of therapeutic decision errors and the cognitive factors leading to these errors in the context of osteoporosis, as it is known to be frequently associated with inadequate treatment decisions in clinical practice worldwide. METHODS: In 2019, 19 medical students and-for comparison-23 physicians worked on ten patient cases with the medical encounter of osteoporosis. A total of 254 cases were processed. The therapeutic decision errors were quantitatively measured, and the participants' cognitive contributions to therapeutic errors and their clinical consequences were qualitatively analysed. RESULTS: In 26% of the cases, all treatment decisions were correct. In the remaining 74% cases, multiple errors occurred; on average, 3 errors occurred per case. These 644 errors were further classified regarding the cognitive contributions to the error. The most common cognitive contributions that led to errors were faulty context generation and interpretation (57% of students, 57% of physicians) and faulty knowledge (38% of students, 35% of physicians). Errors made due to faulty metacognition (5% of students, 8% of physicians) were less common. Consequences of these errors were false therapy (37% of cases), undertreatment (30% of cases) or overtreatment (2.5% of cases). CONCLUSION: The study is the first to show that errors in therapy decisions can be distinguished and classified, similar to the already known classification for errors in diagnostic reasoning. Not only the correct diagnosis, but particularly the correct therapy, is critical for the outcome of a patient.

Long-term morbidity and mortality in patients with Cushing's syndrome.

Increased multisystem morbidity and mortality in patients with Cushing's syndrome comprise clinical problems and challenges, both at the time of diagnosis and in remission. Relevant comorbidities and clinical problems include hypertension, diabetes, overweight, myopathy and a high risk for acute complications such as infections and venous thrombembolism. Although there are therapy recommendations for most of these comorbidities, there is a lack of large, prospective studies to confirm and optimise them. Mortality is especially high during active disease and within the first year after diagnosis, as a result of cardiovascular events, infections and suicide. All in all, interdisciplinary therapy management is important for reducing morbidity and mortality over the long-term.

The role of adrenal venous sampling (AVS) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH): a study of 16 patients.

OBJECTIVE: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing's syndrome. Current guidelines recommend bilateral adrenalectomy for PBMAH, but several studies showed clinical effectiveness of unilateral adrenalectomy despite bilateral disease in selected patients. Our aim was to evaluate the gain of information which can be obtained through adrenal venous sampling (AVS) based cortisol lateralization ratios for guidance of unilateral adrenalectomy. DESIGN: We performed a retrospective analysis of 16 patients with PBMAH and clinical overt cortisol secretion in three centers METHODS: Selectivity of adrenal vein sampling during AVS was defined as a gradient of cortisol or a reference adrenal hormone ≥2.0 between adrenal and peripheral vein. Lateralization was assumed if the dominant to non-dominant ratio of cortisol to reference hormone was ≥4.0. RESULTS: AVS was technically successful in all patients based on absolute cortisol levels and in 13 of 16 patients (81%) based on reference hormone levels. Lateralization was documented in 8 of 16 patients. In patients with lateralization, in 5 of 8 cases this occurred toward morphologically larger adrenals, while in 3 patients lateralization was present in bilaterally identical adrenals. The combined volume of adrenals correlated positively with urinary free cortisol, suggesting that adrenal size is the dominant determinant of cortisol secretion. CONCLUSIONS: In this study the gain of information through AVS for unilateral adrenalectomy was limited in patients with PBMAH and marked adrenal asymmetry.

Improving Diagnostic Efficiency with Frequency Double-Trees and Frequency Nets in Bayesian Reasoning.

Background. Medical students often have problems with Bayesian reasoning situations. Representing statistical information as natural frequencies (instead of probabilities) and visualizing them (e.g., with double-trees or net diagrams) leads to higher accuracy in solving these tasks. However, double-trees and net diagrams (which already contain the correct solution of the task, so that the solution could be read of the diagrams) have not yet been studied in medical education. This study examined the influence of information format (probabilities v. frequencies) and visualization (double-tree v. net diagram) on the accuracy and speed of Bayesian judgments. Methods. A total of 142 medical students at different university medical schools (Munich, Kiel, Goettingen, Erlangen, Nuremberg, Berlin, Regensburg) in Germany predicted posterior probabilities in 4 different medical Bayesian reasoning tasks, resulting in a 3-factorial 2 × 2 × 4 design. The diagnostic efficiency for the different versions was represented as the median time divided by the percentage of correct inferences. Results. Frequency visualizations led to a significantly higher accuracy and faster judgments than did probability visualizations. Participants solved 80% of the tasks correctly in the frequency double-tree and the frequency net diagram. Visualizations with probabilities also led to relatively high performance rates: 73% in the probability double-tree and 70% in the probability net diagram. The median time for a correct inference was fastest with the frequency double tree (2:08 min) followed by the frequency net diagram and the probability double-tree (both 2:26 min) and probability net diagram (2:33 min). The type of visualization did not result in a significant difference. Discussion. Frequency double-trees and frequency net diagrams help answer Bayesian tasks more accurately and also more quickly than the respective probability visualizations. Surprisingly, the effect of information format (probabilities v. frequencies) on performance was higher in previous studies: medical students seem also quite capable of identifying the correct solution to the Bayesian task, among other probabilities in the probability visualizations. Highlights: Frequency double-trees and frequency nets help answer Bayesian tasks not only more accurately but also more quickly than the respective probability visualizations.In double-trees and net diagrams, the effect of the information format (probabilities v. natural frequencies) on performance is remarkably lower in this high-performing sample than that shown in previous studies.

Diurnal Salivary Cortisol Profiles in Patients with Cushing's Syndrome.

BACKGROUND: Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing's syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping. MATERIAL AND METHODS: Among 428 patients including those with confirmed Cushing's syndrome (N=111, of those 75 with Cushing's disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day. RESULTS: At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing's disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low. DISCUSSION: The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS.

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis.

OBJECTIVE: Cushing's syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing's syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing's syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers. DESIGN: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing's syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation. METHODS: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features. RESULTS: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing's syndrome correction. In Cushing's syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts. CONCLUSIONS: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.