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Corticosteroids are often administered prophylactically to attenuate the inflammatory response associated with cardiac surgery using cardiopulmonary bypass (CPB). However, the efficacy and safety profile of corticosteroids remain uncertain. The primary aim of this systematic review and meta-analysis was to investigate the effect of corticosteroids on mortality in adult cardiac surgery using CPB. Secondary aims were to examine the effect of corticosteroids on myocardial adverse events, pulmonary adverse events, atrial fibrillation, surgical site infection, gastrointestinal bleeding and duration of stay in the intensive care unit and hospital. Randomized controlled trials (RCTs) were systematically searched in electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL and Web of Science) from their inception until March 2019. Observational studies, case reports, case series and literature reviews were excluded. Sixty-two studies (n = 16 457 patients) were included in this meta-analysis. There was no significant difference in mortality between the corticosteroid and placebo groups [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81–1.14; P = 0.65, participants = 14 693, studies = 24, evidence of certainty: moderate]. Compared to those receiving a placebo, patients who were given corticosteroids had a significantly higher incidence of myocardial adverse events (OR 1.17, 95% CI 1.03–1.33; P = 0.01, participants = 14 512, studies = 23) and a lower incidence of pulmonary adverse events (OR 0.86, 95% CI 0.75–0.98; P = 0.02, participants = 13 426, studies = 17). The incidences of atrial fibrillation (OR 0.87, 95% CI 0.81–0.94; P

When statistically comparing outcomes between two groups, researchers have to decide whether to use parametric methods, such as the t-test, or non-parametric methods, like the Mann–Whitney test. In endocrinology, for example, many studies compare hormone levels between groups, or at different points in time. Many papers apply non-parametric tests to compare groups. We will explain that non-parametric tests have clear drawbacks in medical research, and, that’s the good news, they are often not necessary.

Context Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P Conclusions These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Objective The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up for the Obesity Guideline of the European Society of Endocrinology. Design Systematic review and meta-analysis of the literature. Methods A search was performed in MEDLINE, EMBASE, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% confidence intervals (95% CI). Results Sixty-eight studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI: 9.7–18.9) and 14.6% (95% CI: 9.2–20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI: 0.3–1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI: 37.6–48.0) and 32.7% (95% CI: 23.1–43.0), respectively. Heterogeneity was high for all analyses. Conclusions The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.

Contains fulltext : 224863.pdf (Publisher’s version ) (Open Access) [(18)F]-FDG-PET/CT ([(18)F]-fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT)) is increasingly used as a diagnostic tool in suspected infectious or inflammatory conditions. Studies on the value of FDG-PET/CT in children are scarce. This study assesses the role of FDG-PET/CT in suspected infection or inflammation in children. In this multicenter cohort study, 64 scans in 59 children with suspected infection or inflammation were selected from 452 pediatric FDG-PET/CT scans, performed in five hospitals between January 2016 and August 2017. Main outcomes were diagnostic information provided by FDG-PET/CT for diagnostic scans and impact on clinical management for follow-up scans. Of these 64 scans, 50 were performed for primary diagnosis and 14 to monitor disease activity. Of the positive diagnostic scans, 23/27 (85%) contributed to establishing a diagnosis. Of the negative diagnostic scans, 8/21 (38%) contributed to the final diagnosis by narrowing the differential or by providing information on the disease manifestation. In all follow-up scans, FDG-PET/CT results guided management decisions. CRP was significantly higher in positive scans than in negative scans (p = 0.004). In 6% of diagnostic scans, relevant incidental findings were identified. In conclusion, FDG-PET/CT performed in children with suspected infection or inflammation resulted in information that contributed to the final diagnosis or helped to guide management decisions in the majority of cases. Prospective studies assessing the impact of FDG-PET/CT results on diagnosis and patient management using a structured diagnostic protocol are feasible and necessary.

Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI -0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD -0.80 (95% CI -1.09; -0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD -0.33 (95% CI -0.54; -0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats.

Purpose In the Netherlands, radiotherapy after breast-conserving surgery (BCS) is omitted in up to 30% of patients aged ≥ 75 years. Although omission of radiotherapy is considered an option for older women treated with endocrine treatment, the majority of these patients do not receive systemic treatment following Dutch treatment guidelines. Therefore, the aim of this study was to evaluate the effect of omission of radiotherapy on locoregional recurrence risk in this patient population. Methods Patients aged ≥ 75 years undergone BCS for T1-2N0 breast cancer diagnosed between 2003 and 2009 were selected from the Netherlands Cancer Registry. To minimize confounding by indication, hospital variation was used to assess the impact of radiotherapy-use on locoregional recurrence risk using cox proportional hazards regression. Hazards ratios with 95% confidence interval (CI) were estimated. Results Overall, 2390 patients were included. Of the patients with hormone receptor-positive breast cancer, 39.3% received endocrine treatment. Five-year incidences of locoregional recurrence were 1.9%, 2.8%, and 3.0% in patients treated at hospitals with higher (average radiotherapy-use 96.0%), moderate (88.0%), and lower radiotherapy-use (72.2%) respectively, and nine-year incidences were 2.2%, 3.1%, and 3.2% respectively. Adjusted hazard ratios were 1.46 (95% CI 0.77–2.78) and 1.50 (95% CI 0.79–2.85) for patients treated at hospitals with moderate and lower radiotherapy-use, compared to patient treated at hospitals with higher radiotherapy-use. Conclusions Despite endocrine treatment in only 39.3%, locoregional recurrence risk was low, even in patients treated at hospitals with lower radiotherapy-use. This provides reasonable grounds to consider omission of radiotherapy in patients aged ≥ 75 years with T1-2N0 breast cancer. Electronic supplementary material The online version of this article (10.1007/s10549-019-05412-8) contains supplementary material, which is available to authorized users.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by a high risk of developing primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors (PITs). It is unclear if having MEN1 leads to psychological distress because of fear of disease occurrence (FDO), thereby potentially affecting quality of life.Design: A cross-sectional study was performed using the Dutch MEN1 cohort. All patients received the Cancer Worry Scale (a score >= 14 reflects high FDO), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), and questions on sociodemographic and medical history.Results: A total of 227 of 285 (80%) eligible patients with MEN1 completed the questionnaire. The mean (+/- standard deviation) age was 47 6 15 years. Overall, patients experienced an FDO of 15.1 +/- 4.7, with 58% of patients having a score >= 14. This is higher than reported in previous studies assessing fear of cancer recurrence in different cancer populations (31% to 52%). Adjusted for age and sex, the FDO score was negatively associated with almost all SF-36 subscales. In multivariable analysis, the diagnosis of a PIT, a pancreatic neuroendocrine tumor, and not being employed were associated with FDO (P Conclusion: The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life.

OBJECTIVE: To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis.BACKGROUND: MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager.METHODS: MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment.RESULTS: Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs 3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery.CONCLUSIONS: MEN1 patients with NF-pNETs 3 cm, watchful waiting seems not advisable.

Purpose: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. Methods: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. Results: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. Conclusions: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Purpose To systematically review the effectiveness of medical treatment for Cushing’s syndrome in clinical practice, regarding cortisol secretion, clinical symptom improvement, and quality of life. To assess the occurrence of side effects of these medical therapies. Methods Eight electronic databases were searched in March 2017 to identify potentially relevant articles. Randomized controlled trials and cohort studies assessing the effectiveness of medical treatment in patients with Cushing’s syndrome, were eligible. Pooled proportions were reported including 95% confidence intervals. Results We included 35 articles with in total 1520 patients in this meta-analysis. Most included patients had Cushing’s disease. Pooled reported percentage of patients with normalization of cortisol ranged from 35.7% for cabergoline to 81.8% for mitotane in Cushing’s disease. Patients using medication monotherapy showed a lower percentage of cortisol normalization compared to use of multiple medical agents (49.4 vs. 65.7%); this was even higher for patients with concurrent or previous radiotherapy (83.6%). Mild side effects were reported in 39.9%, and severe side effects were seen in 15.2% of patients after medical treatment. No meta-analyses were performed for clinical symptom improvement or quality of life due to lack of sufficient data. Conclusions This meta-analysis shows that medication induces cortisol normalization effectively in a large percentage of patients. Medical treatment for Cushing’s disease patients is thus a reasonable option in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery. When experiencing side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered. Electronic supplementary material The online version of this article (10.1007/s11102-018-0897-z) contains supplementary material, which is available to authorized users.

Systematic review and meta-analysis comparing endoscopic and microscopic transsphenoidal surgery for Cushing’s disease regarding surgical outcomes (remission, recurrence, and mortality) and complication rates. To stratify the results by tumor size. Nine electronic databases were searched in February 2017 to identify potentially relevant articles. Cohort studies assessing surgical outcomes or complication rates after endoscopic or microscopic transsphenoidal surgery for Cushing’s disease were eligible. Pooled proportions were reported including 95% confidence intervals. We included 97 articles with 6695 patients in total (5711 microscopically and 984 endoscopically operated). Overall, remission was achieved in 5177 patients (80%), with no clear difference between both techniques. Recurrence was around 10% and short term mortality

Background Systematic reviews and meta-analyses of observational studies are frequently performed, but no widely accepted guidance is available at present. We performed a systematic scoping review of published methodological recommendations on how to systematically review and meta-analyse observational studies. Methods We searched online databases and websites and contacted experts in the field to locate potentially eligible articles. We included articles that provided any type of recommendation on how to conduct systematic reviews and meta-analyses of observational studies. We extracted and summarised recommendations on pre-defined key items: protocol development, research question, search strategy, study eligibility, data extraction, dealing with different study designs, risk of bias assessment, publication bias, heterogeneity, statistical analysis. We summarised recommendations by key item, identifying areas of agreement and disagreement as well as areas where recommendations were missing or scarce. Results The searches identified 2461 articles of which 93 were eligible. Many recommendations for reviews and meta-analyses of observational studies were transferred from guidance developed for reviews and meta-analyses of RCTs. Although there was substantial agreement in some methodological areas there was also considerable disagreement on how evidence synthesis of observational studies should be conducted. Conflicting recommendations were seen on topics such as the inclusion of different study designs in systematic reviews and meta-analyses, the use of quality scales to assess the risk of bias, and the choice of model (e.g. fixed vs. random effects) for meta-analysis. Conclusion There is a need for sound methodological guidance on how to conduct systematic reviews and meta-analyses of observational studies, which critically considers areas in which there are conflicting recommendations. Electronic supplementary material The online version of this article (10.1186/s12874-018-0495-9) contains supplementary material, which is available to authorized users.

Objectives To study predictors of emergency department (ED) revisits and the association between ED revisits and 90‐day functional decline or mortality. Design Multicenter cohort study. Setting One academic and two regional Dutch hospitals. Participants Older adults discharged from the ED (N=1,093). Measurements At baseline, data on demographic characteristics, illness severity, and geriatric parameters (cognition, functional capacity) were collected. All participants were prospectively followed for an unplanned revisit within 30 days and for functional decline and mortality 90 days after the initial visit. Results The median age was 79 (interquartile range 74–84), and 114 participants (10.4%) had an ED revisit within 30 days of discharge. Age (hazard ratio (HR)=0.96, 95% confidence interval (CI)=0.92–0.99), male sex (HR=1.61, 95% CI=1.05–2.45), polypharmacy (HR=2.06, 95% CI=1.34–3.16), and cognitive impairment (HR=1.71, 95% CI=1.02–2.88) were independent predictors of a 30‐day ED revisit. The area under the receiver operating characteristic curve to predict an ED revisit was 0.65 (95% CI=0.60–0.70). In a propensity score–matched analysis, individuals with an ED revisit were at higher risk (odds ratio=1.99 95% CI=1.06–3.71) of functional decline or mortality. Conclusion Age, male sex, polypharmacy, and cognitive impairment were independent predictors of a 30‐day ED revisit, but no useful clinical prediction model could be developed. However, an early ED revisit is a strong new predictor of adverse outcomes in older adults.

ObjectiveEpigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.Design and methodsMethylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.ResultsWe found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages ofCASP8in MEN1-related PanNETs (median: 59% vs 16.5%,P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5;P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869;P = 0.013). Hypermethylation ofMGMT2was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%;P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.ConclusionPromoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Fibrous dysplasia (FD) is a rare bone disorder caused by mutations of the GNAS gene, which are also identified in malignancies. We explored the potential relationship between breast cancer and fibrous dysplasia in two fibrous dysplasia cohorts from the Netherlands and the United States. Data on fibrous dysplasia and breast cancer diagnosis were retrieved from hospital records of 134 (Netherlands) and 121 (US) female patients. Results were validated with breast cancer data of 645 female fibrous dysplasia patients from the Dutch Pathology Registry (PALGA). Standardized morbidity ratios for breast cancer were estimated with data from Dutch and US general population registries. GNAS mutation was analyzed in 9 available breast cancer specimens. A combined total of 15 patients (6 polyostotic, 9 McCune-Albright Syndrome) had breast cancer (87% thoracic localizations). In the Netherlands, a breast cancer incidence rate of 7.5% at median age of 46 years was validated in PALGA (6.5% at age 51 years). Breast cancer risk was 3.4-fold increased (95% confidence interval [CI] 1.6-5.9) compared with the Dutch general population; OR 13.2-fold (95% CI 6.2-22.8) in thoracic disease. In the US cohort, breast cancer incidence rate was 4.5% at a median age of 36 years. Breast cancer risk was 3.9-fold increased (95% CI 1.2-8.2) compared with the general population; 5.7-fold (95% CI 1.4-13.0) in thoracic disease. GNAS mutation was positive in 4 breast cancer specimens (44%). Risk of breast cancer is increased at a younger age, particularly in polyostotic FD, suggesting that screening for breast cancer should be considered in this particular group at a younger age than currently advocated by national guidelines. © 2017 American Society for Bone and Mineral Research.

Objective: Multiple Endocrine Neoplasia type 1 (MEN1) is associated with an early onset elevated breast cancer risk. This finding potentially has implications for breast cancer screening for females with MEN1. Considering the impact for females with MEN1, regarding distress and anxiety, it is necessary to assess if other risk factors are involved to identify those at greatest risk. Design: A cross-sectional case control study was performed using the Dutch MEN1 cohort, including >90% of the Dutch MEN1 population of 18 years and older. All females with a confirmed MEN1 mutation received a questionnaire regarding breast cancer related endocrine risk factors, cancer family history and other known risk factors for breast cancer. Results: A total of 138 of 165 (84%) eligible females with MEN1 completed the questionnaire. Eleven of the 138 females had breast cancer. Another 34 relatives with breast cancer were identified in the families of the included females, of whom 11 were obligate MEN1 carriers, 14 had no MEN1 mutation and nine had an unknown MEN1 status. The median age at breast cancer diagnosis of females with MEN1 (n=22) was 45 (range 30-80) years in comparison with 57.5 (range 40-85) years in female relatives without MEN1 (n= 14) (p=0.03) and 61.2 years in the Dutch reference population. Known endocrine risk factors as age at menarche, oral contraception use, pregnancy, age at first birth, parity and breast-feeding were not different for females with and without breast cancer. In addition, smoking and alcohol consumption did not differ between respondents with and without breast cancer. Conclusion: The increased breast cancer risk in MEN1 carriers was not related to other known breast cancer risk factors or familial cancer history and therefore breast cancer surveillance from the age of 40 years for all females with the MEN1 is justifiable.

Purpose To explore the experiences and preferences of population-based research participants to whom an incidental finding was communicated. Materials and Methods Of the 2580 participants of the Netherlands Epidemiology of Obesity (NEO) study who underwent magnetic resonance imaging (MRI) scanning of the abdomen, heart, and/or brain, an incidental finding with presumed health importance was disclosed to 56 (2%) participants. These participants were invited to discuss their experiences regarding the communication of the finding by the NEO research team in a focus group discussion. Transcripts of the discussions were analyzed using thematic content analysis with an open coding system. Results Twenty-three persons participated in four discussions: 57% male; mean age 58 years; 74% findings were suspect for a malignancy. Overall, the participants were grateful for the disclosure of the incidental finding. They had assumed that any finding would be disclosed, and this was an important reason to participate in research. None regretted their informed consent to be notified about incidental findings. Disclosure of the finding had great impact on the lives of most participants. Difficulties with the transition from research participant to patient were frequently mentioned. Conclusion This study provides information to improve the communication of incidental findings by 1) giving clear information about which findings will be disclosed, and 2) demarcating the transition from research participant to patient, by making clear arrangements with medical specialists to guarantee careful follow-up of the finding. Level of Evidence: 3 J. Magn. Reson. Imaging 2017.

Objective Cushing’s syndrome (CS) affects all age groups, but epidemiologic data in young patients are very limited. We therefore examined the incidence, prevalence and hospital morbidity of CS in children and adolescents. Design In a nationwide cohort study, we included all Danish citizens aged 0–20 years from 1977 to 2012. Data were obtained from the Danish National Patient Registry using the International Classification of Diseases (ICD) codes and the Danish Civil Registration System. The diagnosis and treatment were validated by means of individual patient charts. Incidence rate of CS patients aged 0–20 years at diagnosis were computed (standardized to the age and sex distribution of the Danish population). The patients were followed for a maximum of 36 years. Standardized incidence ratios (SIRs) of different hospital-recorded outcomes based on the ICD codes in patients with CS compared to the general population were assessed. Results We identified a total of 40 pediatric patients with CS, yielding an annual incidence of 0.89 cases/106 population (95% confidence interval (CI) = 0.63–1.16). The median age at the time of diagnosis was 13.8 years (interquartile range: 10.5–18.2 years), 58% were female and 70% had adrenocorticotropic hormone-producing pituitary adenomas. During follow-up, CS patients (excluding three malignant cases) were at increased risk of being diagnosed with infections (SIR: 3.24, 95% CI: 1.05–7.54) and infertility (SIR: 4.56, 95% CI: 1.48–10.63). The three patients with an adrenocortical carcinoma died shortly after diagnosis, but mortality was not increased in the remaining patients. Conclusions CS is rare in the pediatric population. The risk of morbidity related to infections and infertility is elevated and merits further attention.

In what seems like the blink of an eye, many of the routines and certainties of our personal and professional worlds have been systematically dismantled. The global march of the novel coronavirus SARS-CoV-2 and the disease it causes, Covid-19, has played out at exponential pace, and almost no facet of our lives has been left untouched. Many are wrestling with worries for their own health and that of their families, often also riven with concern for their livelihoods. We are denied many of life’s pleasures and leisure activities, prevented from travelling, and starved of gatherings with friends. Endocrinologists share this personal reality, but have a critical professional role to play as well. Many combine endocrine practice with contribution to acute internal medicine and so can frequently be found on the ‘front line’, directly caring for the most unwell. They must also look to the patients with endocrine or metabolic disease under their speciality care, while dealing with access restrictions to the diagnostic and therapeutic tools we are used to. Endocrinologists must continue to deliver urgent care for their patients while minimising risks of viral transmission, and they must prepare the vulnerable for the worst-case scenario of severe Covid-19. This must be achieved while mitigating collateral harm arising from enforced pausing of less urgent clinical services. Fortunately, children appear to be more mildly affected than adults; however, clinical care delivery for children with endocrine disorders is adjusted in similar ways as in adults due to the overall healthcare crisis. The clinical practice of endocrinology as we know it depends on quantitative biochemical assessments of hormonal status, often coupled to imaging, generally reliant on sophisticated laboratory and radiological support. Treatments are often delivered by multidisciplinary teams, encompassing nurse specialists, radiologists, surgeons, oncologists, nuclear medicine physicians, ophthalmologists, clinical biochemists, and pathologists among others. We aim for evidence-based practice, with service innovation informed by randomised trials, replicated, corroborated, and meta-analysed. The process is cautious and deliberative, informed by the injunction first to do no harm. Now the rulebook has been ripped up. The exponentially accelerating speed of the pandemic spread in many countries, and the upheaval of clinical care it has engendered, demands an immediate and rational response. There is no time to ensure that care in times of Covid-19 crisis is strictly evidence-based, and service remodelling must be implemented while facing evolving staff shortages as the pandemic illness also strikes healthcare workers. We must, in short, be adept and nimble at delivering clinical care outside our comfort zone, without resources that we normally take for granted. Consequently, sharing of expert opinion and leadership has rarely been of more importance. The European Journal of Endocrinology is responding to this challenge by providing a platform to share and disseminate such expert advice. We have already started to commission international key opinion leaders involved in front-line endocrine care to deliver clinical management guidance documents in an accessible, bullet point format to facilitate rapid information and adjustment of endocrine service delivery in this time of crisis. In a departure from normal practice, peer review will be highly expedited and open, with reviewers named in the final articles, recognising their critical role in refining recommendations and making them rapidly available. Articles will appear over the next few weeks, with all publication fees waived, and online Open Access publication on the EJE website as soon as the final revised version has been accepted. We start the first wave of these publication with clinical management guidance on the endocrine and metabolic conditions identified by the EJE Lead Editors as requiring most urgent advice: Adrenal Insufficiency; Cushing’s Syndrome; Pituitary Tumours; Hyponatraemia and Diabetes Insipidus; Hyper- and Hypo-thyroidism; Diabetes in Pregnancy; Restructuring of Diabetes Services in the Time of Crisis; Primary Hyperparathyroidism and Hypercalcaemia; Thyroid Cancer; Adrenal Tumours; and Neuroendocrine Tumours. These guidance statements are not based on systematic review or meta-analysis (there is no evidence on how to adopt endocrine care in times of a pandemic), but rather on rapid expert consensus; neither are these guidance statements intended to determine absolute standards of medical care. This should, as ever, be carefully tailored to individual circumstances of specific patients, specific hospitals, and specific countries. Nevertheless, in commissioning this series, we have been mindful of the perils of excessive deliberation or over-thinking. As war-based imagery splashes across media coverage of the pandemic, it is perhaps apt to remember the words of the British physicist Robert Watson-Watt, charged with rapidly assembling radar defences at the onset of a world war. In his ‘cult of the imperfect’, channelling an idea articulated by thinkers from Aristotle to Voltaire, he said ‘give them the third best; the second best is too slow and the best never arrives’. This spirit of pragmatic expediency must now animate the endocrine community’s immediate response to help adapt endocrine care to the unforeseen demands of the pandemic crisis. Focus on short term crisis management does not mean abandoning an evidence-based ideal, however. Hand in hand with forced service re-organisation, many are creatively incorporating research into clinical practice, optimising data and sample acquisition, or even undertaking intervention studies. In due course, these efforts may allow practice to be more solidified around an evidence base, and we shall revisit each of the areas covered now in the time of crisis with more reflective, data-informed analysis once the first peak has passed. Finally, we have also asked authors to consider where opportunity may arise in disruption. Multidisciplinary, patient-focused care of long-term endocrine conditions lends itself to creative use of remote review and conferencing; both rapid triage of new referrals and regular follow-up of patients with established diagnosis could be undertaken effectively via teleconferencing, preferably by video link, linked to diagnostic assessment in to-be-established peripheral blood letting satellite centres. For many endocrine conditions, self-management by patients is of paramount importance, and a staggered approach, choosing or alternating between face-to-face contact and teleconferencing, would also permit systematic enhancement of patients’ involvement in their own care, following the principles of the 3E framework (Educate, Equip, Empower) and reinforcing their motivation and resilience. In the response to Covid-19 lies a major opportunity to breach barriers to implementation of more streamlined care pathways exploiting transformative online technologies. Importantly, this challenge forces us to concentrate on the essentials, the ‘clinical bioassay’, that is, the patient himself/herself. This may also facilitate the development of care pathways highly suited to endocrine care delivery in countries with chronically restricted access to the latest and most sophisticated diagnostic and therapeutic modalities. The Chinese word for crisis can be translated either as ‘danger’ or ‘opportunity’. If the endocrine community can grasp this opportunity with determination and ingenuity, then a lasting legacy of good may yet emerge from the dark times in which we currently live. The gauntlet has been thrown down, and the European Journal of Endocrinology looks forward to playing its part in the response. Declaration of interest Wiebke Arlt is Editor-in-Chief of European Journal of Endocrinology. Olaf Dekkers, Juliane Leger, and Rob Semple are Lead Editors of European Journal of Endocrinology. They were not involved in the editorial or review process of this paper, on which they are listed as authors. Funding This editorial did not receive any funding from any funding agency in the public, commercial, or not-for-profit sector.

Objective Type 2 diabetes (T2D) and Cushing’s syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients. Design Systematic review and meta-analysis of the literature. Methods A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals (95% CI). Results Fourteen articles were included, with a total of 2827 T2D patients. The pooled prevalence of hypercortisolism and CS was 3.4% (95% CI: 1.5–5.9) and 1.4% (95 CI: 0.4–2.9) respectively. The prevalence did not differ between studies of unselected patients and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression). Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors and pituitary tumors in 52 and 14% respectively. Conclusions Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications.

Supplemental Digital Content is available in the text., It has been argued that survival bias may distort results in Mendelian randomization studies in older populations. Through simulations of a simple causal structure we investigate the degree to which instrumental variable (IV)-estimators may become biased in the context of exposures that affect survival. We observed that selecting on survival decreased instrument strength and, for exposures with directionally concordant effects on survival (and outcome), introduced downward bias of the IV-estimator when the exposures reduced the probability of survival till study inclusion. Higher ages at study inclusion generally increased this bias, particularly when the true causal effect was not equal to null. Moreover, the bias in the estimated exposure-outcome relation depended on whether the estimation was conducted in the one- or two-sample setting. Finally, we briefly discuss which statistical approaches might help to alleviate this and other types of selection bias. See video abstract at, http://links.lww.com/EDE/B589.

Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m2 and proteinuria with a standardized mean difference of −0.58 (95%-CI:−0.88; −0.29). The network meta-analysis for the separate endpoints showed broad confidence intervals due to the small number available RCTs for each individual comparison. In conclusion, 1-year statin use versus control attenuated the progression of kidney function decline and proteinuria. Due to the imprecision of individual comparisons, results were inconclusive as to which statin performs best with regard to renal outcome.

Contains fulltext : 215696.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels >/=20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET >/=2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs >/=2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

Background Cushing’s syndrome is characterized by glucocorticoid excess, which induces physical and mental symptoms, impairments in functional status and perceived health, resulting in impaired quality of life. Biochemical remission is urgently required; however, quality of life and cognitive function may remain impaired. Objective To perform a systematic review and meta-analysis evaluating changes in health-related quality of life and cognitive functioning in patients with Cushing’s syndrome after treatment. Methods Eight electronic databases were searched in March 2017, and PubMed again in May 2018, to identify potentially relevant articles. Eligible studies were (randomized controlled) trials, cohort studies, and cross-sectional studies assessing quality of life or cognitive functioning in patients treated for Cushing’s syndrome. Differences were expressed as standardized mean difference, and reported with 95% confidence intervals. We compared patients before and after treatment (improvement), and patients after treatment and healthy controls (normalization). Results We included 47 articles with 2,643 patients. Most patients had Cushing’s disease and were in remission after treatment. Quality of life and cognitive functioning improved after treatment in all studied domains. Compared to a healthy control population, quality of life did not normalize. Cognitive functioning normalized in part, but not all, of the studied domains. Conclusions Treatment of Cushing’s syndrome improves quality of life and cognitive functioning. As normalization was not achieved in quality of life and in some aspects of cognitive functioning, special and continuous attention should be given to these aspects for patients after treatment. Effective interventions for further improvement and possibly normalization are urgently needed.

Importance It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism. Objective To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older. Design, Setting, and Participants Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018. Exposures Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial). Main Outcomes and Measures Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9). Results Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants). Conclusions and Relevance In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older. Trial Registration ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

Sciatica is a condition that is characterised by radicular pain in the leg and primarily caused by a herniated lumbar intervertebral disk. In addition to leg pain, patients can experience back pain, leg numbness and leg weakness resulting in decreased productivity and social activity. The majority of sciatica cases recovers spontaneously and therefore patients are initially treated conservatively with oral pain medication. However, some patients experience intractable pain that severely impedes them and no consensus exists on the optimal conservative treatment to reduce this discomfort in the acute phase of sciatica. The aim of the TEIAS trial is to assess the effectiveness, cost-effectiveness and predictive capability on patient outcome of transforaminal epidural injection (TEI) compared to treatment with standard pain medication. This study is designed as a prospective, open-label, mono-centered, randomized controlled trial. Patients that visit their general practitioner with complaints of radicular leg pain and meet the selection criteria are asked to participate in this study. Eligible patients will be randomized to treatment with TEI or to treatment with standard oral pain medication. Treatment of TEI will comprise lidocaine with methylprednisolone acetate for L3 and below and lidocaine with dexamethasone above L3. A total of 142 patients will be recruited and follow-up will occur after 1, 2, 4, 10 and 21 weeks for assessment of pain, functionality, patient received recovery and cost-effectiveness. The primary outcome will be the average score for leg pain at 2 weeks. For this outcome we defined a clinically relevant difference as 1.5 on the 11-point NRS scale. Adequate conservative treatment in the acute phase of sciatica is lacking, particularly for patients with severe symptoms. Focusing on effectiveness, cost-effectiveness and predictive capability on patient outcome of TEI will produce useful information allowing for more lucid decision making in the conservative treatment of sciatica in the acute phase. This trial is registered in the ClinicalTrials.gov database under registry number NCT03924791 on April 23, 2019.

P values should not merely be used to categorize results into significant and non-significant. This practice disregards clinical relevance, confounds non-significance with no effect and underestimates the likelihood of false-positive results. Better than to use the P value as a dichotomizing instrument, the P values and the confidence intervals around effect estimates can be used to put research findings in a context, thereby taking clinical relevance but also uncertainty genuinely into account.

Background Research suggests increased risk of hypothyroidism among breast cancer survivors, but whether this risk is modified by treatment modalities is unclear. We estimated the incidence of hypothyroidism in breast cancer survivors, and in strata of treatment modalities. Methods Using nationwide registries, we identified all Danish women aged ≥35 years with non-metastatic breast cancer diagnosed from 1996 through 2009. Each breast cancer survivor was matched with up to five cancer-free women (hereafter ‘controls’) on birth year and area of residence. We excluded all women with prevalent hypothyroidism or hyperthyroidism. We considered cancer-directed treatment as the receipt of chemotherapy (yes/no), with or without radiotherapy—either to the chest wall only or with addition of the lymph nodes. Hypothyroidism was defined using diagnostic codes, and/or levothyroxine prescriptions. We calculated incidence rates (IR) of hypothyroidism per 1000 person-years and associated 95% confidence intervals (CI), and estimated hazard ratios (HR) and 95%CI of hypothyroidism using Cox regression, adjusting for comorbidities. Results We included 45,514 breast cancer survivors and 209,195 matched controls with 2,631,488 person-years of follow-up. Median follow-up was 8.4 years in the breast cancer cohort, and 10.6 years in the control cohort. Median age in both cohorts was 61 years. Breast cancer survivors had more comorbidities than the matched controls. Breast cancer survivors had higher incidence of hypothyroidism than matched controls [IR=4.3 (95%CI=4.2, 4.5), and 3.8 (95%CI=3.7, 3.9), respectively], corresponding to an adjusted HR of 1.15 (95%CI=1.09, 1.21). Breast cancer survivors who received radiotherapy to the lymph nodes with or without chemotherapy had highest risk of hypothyroidism when compared with matched controls [HR=1.66 (95%CI=1.43, 1.93) and HR=1.27 (95%CI=1.10, 1.46), respectively]. This pattern was also evident when comparing breast cancer survivors who received radiotherapy to the lymph nodes with or without chemotherapy with breast cancer survivors who did not undergo radiotherapy or chemotherapy (HR=1.65 (95%CI=1.41, 1.94) and HR=1.37, 95%CI=1.18, 1.58), respectively]. Conclusion Breast cancer survivors treated with radiotherapy to the lymph nodes had excess risk of hypothyroidism compared with age-matched women from the general population, and when compared with breast cancer survivors who do not undergo nodal radiotherapy. The risk of hypothyroidism was particularly high among patients treated with both nodal radiotherapy and chemotherapy. Our findings support systematic screening for hypothyroidism during follow-up among breast cancer survivors who receive nodal radiotherapy, and especially those who receive nodal radiotherapy and chemotherapy.

Measurement errors commonly occur in 24-h hormonal data and may affect the outcomes of such studies. Measurement errors often appear as outliers in such data sets; however, no well-established method is available for their automatic detection. In this study, we aimed to compare performances of different methods for outlier detection in hormonal serial data. Hormones (glucose, insulin, thyroid-stimulating hormone, cortisol, and growth hormone) were measured in blood sampled every 10 min for 24 h in 38 participants of the Leiden Longevity Study. Four methods for detecting outliers were compared: (1) eyeballing, (2) Tukey’s fences, (3) stepwise approach, and (4) the expectation-maximization (EM) algorithm. Eyeballing detects outliers based on experts’ knowledge, and the stepwise approach incorporates physiological knowledge with a statistical algorithm. Tukey’s fences and the EM algorithm are data-driven methods, using interquartile range and a mathematical algorithm to identify the underlying distribution, respectively. The performance of the methods was evaluated based on the number of outliers detected and the change in statistical outcomes after removing detected outliers. Eyeballing resulted in the lowest number of outliers detected (1.0% of all data points), followed by Tukey’s fences (2.3%), the stepwise approach (2.7%), and the EM algorithm (11.0%). In all methods, the mean hormone levels did not change materially after removing outliers. However, their minima were affected by outlier removal. Although removing outliers affected the correlation between glucose and insulin on the individual level, when averaged over all participants, none of the 4 methods influenced the correlation. Based on our results, the EM algorithm is not recommended given the high number of outliers detected, even where data points are physiologically plausible. Since Tukey’s fences is not suitable for all types of data and eyeballing is time-consuming, we recommend the stepwise approach for outlier detection, which combines physiological knowledge and an automated process.

Surgery is the treatment of choice for non-functioning pituitary macroadenomas (NFPAs). In cases of postoperative remnant growth or tumor recurrence, radiotherapy (RT) can be considered. The role of RT in the postoperative management of NFPAs is still debated. The main arguments against routine use of RT are the lack of randomized controlled trials, the use of clinically irrelevant endpoints in most studies on RT, the benign character of the condition, the potential for side effects of RT, and the option to apply RT at a later stage. However, because of its excellent efficacy in inhibiting tumor growth, reducing tumor volume and improving any existing visual defects, and as its side effects seem to be limited compared to the benefits provided, RT keeps a place in the management of NFPAs when a tumor remnant persists, particularly if it is invasive and displays high proliferation markers, if surveillance shows a relevant increase in tumor volume or if the tumor is close to the optic chiasm. The size of the remnant, its vicinity with the optic pathways, and the potential risk to healthy surrounding tissues need to be considered when deciding on an RT procedure.

Background: Heart failure with reduced ejection fraction due to a post-infarction anteroseptal aneurysm carries a poor prognosis. Patients with refractory heart failure may be considered for advanced surgery, including left ventricular assist device implantation, heart transplantation and left ventricular reconstruction. The aim of this study was to evaluate outcomes after an integrated approach of left ventricular reconstruction with concomitant procedures (mitral/tricuspid valve repair, coronary revascularization), and assess risk factors for event-free survival, focusing on left ventricular geometry/function and presence of functional mitral regurgitation (MR). Methods: A total of 159 consecutive heart failure patients who underwent left ventricular reconstruction between 2002 and 2011 were included. Mid-term echocardiographic and long-term clinical outcomes were evaluated. Preoperative risk factors were correlated to event-free survival (freedom from mortality, left ventricular assist device implantation, and heart transplantation). Results: Mid-term echocardiography demonstrated decreased indexed left ventricular end-systolic volumes (89 ± 42 mL/m2 preoperatively; 51 ± 18 at mid-term, p < 0.001), and absence of MR ≥ grade 2. Event-free survival was 83% ± 3% at 1-year, 68% ± 4% at 5-year, and 46% ± 4% at 10-year follow-up. Preoperative wall motion score index (WMSI; hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.7–5.8, p < 0.001) and presence of MR ≥ grade 2 (HR 1.9, 95% CI 1.1–3.1, p = 0.014) were independently associated with adverse event-free survival. Conclusions: Event-free survival is favorable in patients with WMSI < 2.5 and significantly worse when WMSI is ≥ 2.5. In both groups, the presence of preoperative MR ≥ grade 2 negatively affects event-free survival, despite successful correction of MR. Risk stratification by preoperative WMSI and MR grade supports the Heart team in choosing the optimal surgical strategy for patients with refractory heart failure.

Objectives Clostridium difficile infections (CDI) account for 1.5% of diarrhoeic episodes in patients attending a general practitioner in the Netherlands, but its sources are unknown. We searched for community clusters to recognize localized point sources of CDI. Methods Between October 2010 and February 2012, a community-based prospective nested case–control study was performed in three laboratories in the Netherlands with a study population of 2 810 830 people. Bernoulli spatial scan and space–time permutation models were used to detect spatial and/or temporal clusters of CDI. In addition, a multivariate conditional logistic regression model was constructed to test livestock exposure as a supposed risk factor in CDI patients without hospital admission within the previous 12 weeks (community-acquired (CA) CDI). Results In laboratories A, B and C, 1.3%, 1.8% and 2.1% of patients with diarrhoea tested positive for CDI, respectively. The mean age of CA-CDI patients (n = 124) was 49 years (standard deviation, 22.6); 64.5% were female. No spatial or temporal clusters of CDI cases were detected compared to C. difficile–negative diarrhoeic controls. Except for one false-positive signal, no spatiotemporal interaction amongst CDI cases was found. Livestock exposure was not related to CA-CDI (odds ratio, 0.99; 95% confidence interval, 0.44–2.24). Ten percent of CA-CDIs was caused by PCR ribotype 078, spatially dispersed throughout the study area. Conclusions The absence of clusters of CDI cases in a community cohort of diarrhoeic patients suggests a lack of localized point sources of CDI in the living environment of these patients.

Background Organ transplant recipients (OTR) have a higher risk of developing cutaneous squamous cell carcinoma (cSCC) compared to the immunocompetent population. Immunosuppression is often stated as a risk factor for metastasis. However, evidence for this is scarce. Objectives To investigate the cSCC metastasis risk in OTR and the immunocompetent population by systematically reviewing the literature. Methods A systematic review of the literature was performed up to January 2018 using: Medline; Embase; Web of Science and ISI Science Citation Index. Studies assessing cSCC metastasis risk in ORT or immunocompetent cohorts were considered. A pooled risk estimate for metastasis was calculated for the immunocompetent population and OTR separately. Results The pooled metastasis risk estimate for OTR was, respectively, 7.3% (95% CI 6.2–8.4) for cSCC on total body, and 11.0% (95% CI 7.7–14.8) for cSCC of the head neck area. For the immunocompetent population reported risk estimate analysis showed a pooled metastatic risk of 3.1% (95% CI 2.8–3.4) in total body cSCC and of 8.5% (95% CI 7.3– 9.8) in cSCC of the head and neck area. Pooled risk estimate per single cSCC in OTR was 1.3% (95% CI 1.0–1.7) in total body cSCC and 4.0% (95% CI 2.7–5.5) in cSCC of the head and neck area. In the immunocompetent population, these pooled risk estimates were, respectively, 2.4% (95% CI 2.1–2.6) and 6.7% (95% CI 5.7–7.8). Conclusions Organ transplant recipients show a higher overall risk of cSCC metastasis compared to the immunocompetent population. Metastasis risks per single cSCC were substantially lower in both groups. However, due to heterogeneity and differences between studies, comparisons are difficult. Comprehensive follow-up studies with defined cohorts are necessary to adequately asses the risk for cSCC metastasis.

OBJECTIVE The increased use of opioids has resulted in an unprecedented opioid epidemic, with non-negligible numbers of opioid-induced deaths. It is well-known that chronic opioid use affects the activity of the gonadal axis, but the frequency of this and other potential pituitary hormone deficiencies remains unclear. The aim of this systematic review and meta-analysis was to systematically review the effect of exogenous opioids on endocrine function METHODS Following the PRISMA statement, eight electronic databases were searched in May 2018 for randomized, and observational studies assessing endocrine function in patients using exogenous opioids. A random effects model meta-analysis was performed to obtain weighted proportions of hypogonadism and hypocortisolism with a 95% confidence interval. Due to the heterogeneity in studies, meta-analysis for the effects on other axes, and for subgroups could not be performed, and is systematically reviewed. RESULTS 52 articles were included with 18.428 patients in total. The patient population consisted mainly of pain patients (n=21 studies), patients on maintenance treatment for opioid addiction (n=9) and healthy volunteers (n=4) with similar opioid effects between these groups. Morphine (n=17) was mostly used, followed by methadone (n=15) and opioid dose defined as morphine equivalent daily dose (MEDD) (n=14) with no difference in effects between groups. Based on 15 studies containing 3.250 patients (% male: 99.5) on chronic opioids, the prevalence of hypogonadism was 65% (95% CI: 57% to 73%, I2=91.16%). Based on 5 studies with a total of 207 patients (% male: 57.5), the prevalence of hypocortisolism, based on non-dynamic testing, was 19% (95% CI: 10%, 29%, I2=74.21). Results of the systematic review showed an increasing trend for serum prolactin concentrations, and no clear effects on the somatotropic (n=5) and thyrotropic axes (n=7). Six studies reported that testosterone replacement in opioid induced hypogonadism increased testosterone levels, but clinical effects were not reported. CONCLUSION While the evidence on other endocrine axes remains insufficient, hypogonadism occurs in more than half of the male chronic opioid users, and hypocortisolism in approximately a fifth of all patients. Periodical evaluation of endocrine function, especially of the activity of the gonadal and adrenal axes, is mandatory in these patients. More studies are needed on the effects of chronic opioid use on the female gonadal axis and the other endocrine axes, also focusing on experienced symptoms and symptom management.

Background Hypothyroidism may occur as a late effect of breast cancer-directed treatment, particularly after radiotherapy, but little is known whether hypothyroidism affects the prognosis after breast cancer. We investigated the association between hypothyroidism and breast cancer recurrence, and all-cause mortality. Methods In this population-based cohort study, we used national medical registries to identify all Danish women 35 years or older diagnosed with stage I–III, operable breast cancer between 1996 and 2009. Hypothyroidism was defined as hospital diagnoses ascertained via diagnostic codes, or as prescriptions for levothyroxine. Two analytic models were used: (i) hypothyroidism present at the time of the breast cancer diagnosis (prevalent) and (ii) hypothyroidism diagnosed during follow-up as a time-varying exposure lagged by 1 year (incident). Breast cancer recurrence was defined as any local, regional, or distant recurrence or contralateral breast cancer. All-cause mortality included death from any cause in any setting. We used Cox regression models accounting for competing risks to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer recurrence and all-cause mortality. Results The study cohort included 35,463 women with breast cancer with 212,641 person-years of follow-up. At diagnosis, 1272 women had hypothyroidism and 859 women developed hypothyroidism during follow-up. In total, 5810 patients developed recurrent breast cancer. Neither prevalent nor incident hypothyroidism was associated with breast cancer recurrence (adjusted HRprevalent 1.01, 95% CI 0.87–1.19; adjusted HRincident 0.93, 95% CI 0.75–1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HRprevalent 1.02, 95% CI 0.92–1.14, and HRincident 1.08, 95% CI 0.95–1.23, respectively). Stratification by menopausal status, oestrogen receptor status, chemotherapy, or radiotherapy did not alter the estimates. Conclusions Hypothyroidism present at diagnosis or during follow-up was not associated with breast cancer recurrence or all-cause mortality in women with breast cancer. Our findings provide reassurance to patients and their physicians that hypothyroidism is unlikely to impact on the clinical course of breast cancer or survival. Electronic supplementary material The online version of this article (10.1186/s13058-019-1122-3) contains supplementary material, which is available to authorized users.

Background Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing’s syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. Methods Cohort study included consecutive patients with Cushing’s syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. Results We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7–12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2–4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. Conclusions The incidence of adrenal crises after treatment for Cushing’s syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing’s syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.

Objective The aim of this study was to improve clinical identification of patients with a prolonged treatment course for depressive and anxiety disorders early in treatment. Method We conducted a cohort study in 1.225 adult patients with a depressive or anxiety disorders in psychiatric specialty care setting between 2007 and 2011, with at least two Brief Symptom Inventory (BSI) assessments within 6 months. With logistic regression, we modelled baseline age, gender, ethnicity, education, marital status, housing situation, employment status, psychiatric comorbidity and both baseline and 1st follow-up BSI scores to predict prolonged treatment course (>2 years). Based on the regression coefficients, we present an easy to use risk prediction score. Results BSI at 1st follow-up proved to be a strong predictor for both depressive and anxiety disorders (OR = 2.17 (CI95% 1.73–2.74); OR = 2.52 (CI95% 1.86–3.23)). The final risk prediction score included BSI 1st follow-up and comorbid axis II disorder for depressive disorder, for anxiety disorders BSI 1st follow-up and age were included. For depressive disorders, for 28% of the patients with the highest scores, the positive predictive value for a prolonged treatment course was60% (sensitivity 0.38, specificity 0.81). For anxiety disorders, for 35% of the patients with the highest scores, the positive predictive value for a prolonged treatment course was 52% (sensitivity 0.55, specificity 0.75). Conclusions A high level of symptoms at 2–6 months of follow-up is a strong predictor for prolonged treatment course. This facilitates early identification of patients at risk of a prolonged course of treatment; in a relatively easy way by a self-assessed symptom severity.

Background: First-choice treatment for Cushing's disease is transsphenoidal adenomectomy. Since its introduction in the 1970s, many centers have now switched from microscopic to endoscopic surgery. We compared both techniques for the treatment of Cushing's disease at the Leiden University Medical Center, a European reference center for pituitary diseases.Methods: Cohort study with inclusion and follow-up of consecutive Cushing's disease patients primarily treated by transsphenoidal surgery at the Leiden University Medical Center between 1978 and 2016. We compared remission rates (primary endpoint), mortality, and complications between microscopic (performed up to 2005) and endoscopic (performed from 2003 onwards) surgery. Subgroup analyses were performed by tumor size, surgical experience, and preoperative imaging techniques. Additionally, surgeons' intraoperative findings regarding presence and removal of the adenoma were related to surgical outcome.Results: Of 137 included patients, 87 were treated microscopically and 50 endoscopically. Three months after microscopic surgery, 74 patients (86%) were in remission. Five-year recurrence-free survival was 89% (95% confidence interval [CI]: 82-96%), and ten-year recurrence free survival was 84% (95% CI: 75-93%). After endoscopic surgery, 39 patients (83%) were in remission. Both five-year and ten-year recurrence-free survival were 71% (95% CI: 55-87%). Hazard ratio for recurrence was 0.47 (95% CI: 0.19-1.14), and for mortality 2.79 (95% CI: 0.35-22.51), for microscopic versus endoscopic surgery. No learning curve was found for endoscopy, nor an influence of preoperative imaging technique for microscopy. In addition, we did not find a clear relation between the surgeons' intraoperative findings and surgical outcomes.Conclusions: This study did not identify a clear advantage of microscopic or endoscopic transsphenoidal surgery for the treatment of Cushing's disease based on clinical outcome. The transition to endoscopic surgery at our center was not accompanied by transient worsening of outcomes, which may be reassuring for those considering transitioning.

Introduction The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking. Methods We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration. Results One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5–12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6–6.6, P Conclusions The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Propensity score analysis is a popular method to control for confounding in observational studies. A challenge in propensity methods is missing values in confounders. Several strategies for handling missing values exist, but guidance in choosing the best method is needed. In this simulation study, we compared four strategies of handling missing covariate values in propensity matching and propensity weighting. These methods include: complete case analysis, missing indicator method, multiple imputation and combining multiple imputation and missing indicator method. Concurrently, we aimed to provide guidance in choosing the optimal strategy. Simulated scenarios varied regarding missing mechanism, presence of effect modification or unmeasured confounding. Additionally, we demonstrated how missingness graphs help clarifying the missing structure. When no effect modification existed, complete case analysis yielded valid causal treatment effects even when data were missing not at random. In some situations, complete case analysis was also able to partially correct for unmeasured confounding. Multiple imputation worked well if the data were missing (completely) at random, and if the imputation model was correctly specified. In the presence of effect modification, more complex imputation models than default options of commonly used statistical software were required. Multiple imputation may fail when data are missing not at random. Here, combining multiple imputation and the missing indicator method reduced the bias as the missing indicator variable can be a proxy for unobserved confounding. The optimal way to handle missing values in covariates of propensity score models depends on the missing data structure and the presence of effect modification. When effect modification is present, default settings of imputation methods may yield biased results even if data are missing at random.