OBJECTIVE: To describe the incidence, indications, risk factors, outcomes, and management of emergency peripartum hysterectomy globally and to compare outcomes among different income settings. DATA... Show moreOBJECTIVE: To describe the incidence, indications, risk factors, outcomes, and management of emergency peripartum hysterectomy globally and to compare outcomes among different income settings. DATA SOURCES: PubMed, MEDLINE, EMBASE, , Cochrane Library, Web of Science, and Emcare databases up to December 10, 2021. METHODS OF STUDY SELECTION: Update of a systematic review and meta-analysis (2016). Studies were eligible if they reported the incidence of emergency peripartum hysterectomy, defined as surgical removal of the uterus for severe obstetric complications up to 6 weeks postpartum. Title and abstract screening and full-text review were performed using Endnote data-management software. Of 8,775 articles screened, 26 were included that were published after 2015, making the total number of included studies 154. A subanalysis was performed for the outcomes of interest per income setting. TABULATION, INTEGRATION, AND RESULTS: The meta-analysis included 154 studies: 14,409 emergency peripartum hysterectomies were performed in 17,127,499 births in 42 countries. Overall pooled incidence of hysterectomy was 1.1 per 1,000 births (95% CI 1.0-1.3). The highest incidence was observed in lower middle-income settings (3/1,000 births, 95% CI 2.5-3.5), and the lowest incidence was observed in high-income settings (0.7/1,000 births, 95% CI 0.5-0.8). The most common indications were placental pathology (38.0%, 95% CI 33.9-42.4), uterine atony (27.0%, 95% CI 24.6-29.5), and uterine rupture (21.2%, 95% CI 17.8-25.0). In lower middle-income countries, uterine rupture (44.5%, 95% CI 36.6-52.7) was the most common indication; placental pathology (48.4%, 95% CI 43.5-53.4) was most frequent in high-income settings. To prevent hysterectomy, uterotonic medication was used in 2,706 women (17%): 53.2% received oxytocin, 44.6% prostaglandins, and 17.3% ergometrine. Surgical measures to prevent hysterectomy were taken in 80.5% of women, the most common being compressive techniques performed in 62.6% (95% CI 38.3-81.9). The most common complications were febrile (29.7%, 95% CI 25.4-34.3) and hematologic (27.5%, 95% CI 20.4-35.9). The overall maternal case fatality rate was 3.2 per 100 emergency peripartum hysterectomies (95% CI 2.5-4.2) and was higher in lower middle-income settings (11.2/100 emergency peripartum hysterectomies 95% CI 8.9-14.1) and lower in high-income settings (1.0/100 emergency peripartum hysterectomies 95% CI 0.6-1.6). CONCLUSION: Substantial differences across income settings exist in the incidence of emergency peripartum hysterectomy. Women in lower-income settings have a higher risk of undergoing emergency peripartum hysterectomy and suffer more procedure-related morbidity and mortality. The frequency of emergency peripartum hysterectomy is likely to increase in light of increasing cesarean delivery rates. Show less
Kooij, M.K. van der; Joosse, A.; Suijkerbuijk, K.P.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Blank, C.U.; ... ; Kapiteijn, E. 2022
Treatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either... Show moreTreatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either primary non-responders or will eventually develop secondary resistance. In 2017, Nosrati and colleagues published a prediction scale in the British Journal of Cancer, which included five clinical parameters that were associated with lower response to anti-PD-1 treatment; female sex (1 point), age <65 years (1 point), history of ipilimumab (anti-CTLA-4) treatment (2 points), elevated lactate dehydrogenase (LDH) (1 point), and the presence of liver metastasis (2 points) [1]. This study used a derivation cohort of 228 patients treated in California, and a validation cohort of 87 patients treated in Switzerland. The primary outcome measure was best tumour response to treatment evaluated using computed tomography at 12 and 16 weeks after the first administration of anti-PD-1 monotherapy, and every 12 weeks thereafter. The aim of this correspondence is to validate the prediction scale, published by Nosrati and colleagues. Show less
Purpose Recent data have shown a decreasing overall mortality in acromegaly over the last decades. However, cancer incidence and cancer-related mortality still appear to be increased. Our aim was... Show morePurpose Recent data have shown a decreasing overall mortality in acromegaly over the last decades. However, cancer incidence and cancer-related mortality still appear to be increased. Our aim was to obtain updated epidemiological data from Norway in a clinically well-defined cohort with complete register-based follow-up.Methods Patients diagnosed with acromegaly from South-Eastern Norway between 1999-2019 (n = 262) and age and sex matched population controls (1:100) were included (n = 26,200). Mortality and cancer data were obtained from the Norwegian Cause of Death and Cancer Registry. Mortality and cancer incidence were compared by Kaplan-Meier analyses and Cox regression; we report hazard ratios (HRs) with 95% confidence intervals (95% CI).Results Median age at diagnosis was 48.0 years (interquartile range (IQR): 37.6-58.0). Mean annual acromegaly incidence rate was 4.7 (95% CI 4.2-5.3) cases/10(6) person-years, and the point prevalence (2019) was 83 (95% CI 72.6-93.5) cases/10(6) persons. Overall mortality was not increased in acromegaly, HR 0.8 (95% CI 0.5-1.4), cancer-specific and cardiovascular-specific mortality was also not increased (HR: 0.7 (95% CI 0.3-1.8) and 0.8 (95% CI: 0.3-2.5) respectively). The HR for all cancers was 1.45 (1.0-2.1; p = 0.052).Conclusion In this large cohort study, covering the period 1999-2019, patients were treated with individualized multimodal management. Mortality was not increased compared to the general population and comparable with recent registry studies from the Nordic countries and Europe. Overall cancer risk was slightly, but not significantly increased in the patients. Show less
BackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the... Show moreBackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs). MethodsPatients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up. ResultsA total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0-95.6) and 92.8% (89.4-95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3-96.0) and 85.3% (80.5-89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1-100) and 87.1% (76.3-93.6) and for CT, 60.0% (22.9-88.4) and 70.4% (51.3-84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0-98.8) and 87.0% (75.3-93.9), respectively, for MRI and 100% (74.9-100) and 77.8% (54.3-91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma. ConclusionAs the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA. Show less
Burman, P.; Trouillas, J.; Losa, M.; McCormack, A.; Petersenn, S.; Popovic, V.; ... ; ESE survey collaborators 2022
ObjectiveTo describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). DesignElectronic survey... Show moreObjectiveTo describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). DesignElectronic survey August 2020-May 2021. Results96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was >= 3% in 74/93 (80%) and >= 10% in 38/93 (41%) tumours. An absolute increase of Ki67 >= 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 >= 10% and ACTH-secretion were associated with worse prognosis. ConclusionAPT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers. Show less
Jansen, M.S.; Dekkers, O.M.; Groenwold, R.H.H.; Siegerink, B. 2022
Objective: To investigate publication rates in small trials and to explore which factors are associated with publication rates in small trials, including sample size, the type and number of primary... Show moreObjective: To investigate publication rates in small trials and to explore which factors are associated with publication rates in small trials, including sample size, the type and number of primary and secondary outcomes. Study design and setting: We studied a subgroup of 'small' trials from a pre-existing dataset (IntoValue), containing German trials completed between 2009 and 2017. Small trials were defined as phase II-III, III and IV trials with 150 or fewer participants. We performed an updated publication search and collected additional data from online trial records. Results: Out of 499 trials, 325 (65%) trials published their results in a journal article or dissertation. Median time-to-publication was 3.41 years (95% CI: 3.04-4.10). Planned sample size was not associated with publication rates, but the difference between planned and achieved sample size was (per 10% unsuccessfully recruited participants, HR = 0.95, 95% CI: 0.91-1.00). Phase III vs. II-III trials, studied intervention (device vs. other) and clearly vs. unclearly defined primary outcomes predicted a higher likelihood of earlier publication. Conclusion: About 35% of small trials in Germany remain unpublished, even after an extensive follow-up period of over 9 years. Publication rates are low and were associated with sample size, trial phase and type of intervention. Show less
Objectives: Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named sternocostoclavicular... Show moreObjectives: Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named sternocostoclavicular hyperostosis (SCCH) and mainly occurs in adults. Literature on CNO/SCCH is scattered and lacks diagnostic and therapeutic consensus. Methods: Systematic review and meta-analysis aiming to characterize clinical presentation and therapeutic modalities applied in adult CNO/SCCH patients. Untransformed numerical data and double-arcsine transformed proportional data were pooled in a random effects model in R-4.0.5; proportions were reported with 95% CI. Results: Forty studies were included, containing data on 2030 and 642 patients for aim 1 and 2, respectively. A female predisposition (67%, 95% CI 60, 73) and major diagnostic delay (5 years 95% CI 3, 7) were noted. Clinical presentation included chest pain (89%, 95% CI 79, 96) and swelling (79%, 95% CI 62, 91). Patients suffered from pustulosis palmoplantaris (53%, 95% CI 37, 68), arthritis (24%, 95% CI 11, 39) and acne (8%, 95% CI 4, 13). Inflammatory markers were inconsistently elevated. Autoantibody and HLA-B27 prevalence was normal, and histopathology unspecific. Increased isotope uptake (99%, 95% CI 96, 100) was a consistent imaging finding. Among manifold treatments, pamidronate and biologicals yielded good response in 83%, 95% CI 60, 98 and 56%, 95% CI 26, 85, respectively. Conclusion: CNO/SCCH literature proves heterogeneous regarding diagnostics and treatment. Timely diagnosis is challenging and mainly follows from increased isotope uptake on nuclear examination. Biopsies, autoantibodies and HLA status are non-contributory, and biochemical inflammation only variably detected. Based on reported data, bisphosphonates and biologicals seem reasonably effective, but due to limitations in design and heterogeneity between studies the precise magnitude of their effect is uncertain. Fundamentally, international consensus seems imperative to advance clinical care for CNO/SCCH. Show less
Papadimitropoulou, K.; Riley, R.D.; Dekkers, O.M.; Stijnen, T.; Cessie, S. le 2022
Meta-analysis is a widely used methodology to combine evidence from different sources examining a common research phenomenon, to obtain a quantitative summary of the studied phenomenon. In the... Show moreMeta-analysis is a widely used methodology to combine evidence from different sources examining a common research phenomenon, to obtain a quantitative summary of the studied phenomenon. In the medical field, multiple studies investigate the effectiveness of new treatments and meta-analysis is largely performed to generate the summary (average) treatment effect. In the meta-analysis of aggregate continuous outcomes measured in a pretest-posttest design using differences in means as the effect measure, a plethora of methods exist: analysis of final (follow-up) scores, analysis of change scores and analysis of covariance. Specialised and general-purpose statistical software is used to apply the various methods, yet, often the choice among them depends on data availability and statistical affinity. We present a new web-based tool, MA-cont:pre/post effect size, to conduct meta-analysis of continuous data assessed pre- and post-treatment using the aforementioned approaches on aggregate data and a more flexible approach of generating and analysing pseudo individual participant data. The interactive web environment, available by R Shiny, is used to create this free-to-use statistical tool, requiring no programming skills by the users. A basic statistical understanding of the methods running in the background is a prerequisite and we encourage the users to seek advice from technical experts when necessary. Show less
Meulen, M. van der; Amaya, J.M.; Dekkers, O.M.; Meijer, O.C. 2022
Objective: To test the hypothesis that systemic and inhaled glucocorticoid use is associated with changes in grey matter volume (GMV) and white matter microstructure. Design: Cross-sectional study.... Show moreObjective: To test the hypothesis that systemic and inhaled glucocorticoid use is associated with changes in grey matter volume (GMV) and white matter microstructure. Design: Cross-sectional study. Setting: UK Biobank, a prospective population-based cohort study of adults recruited in the UK between 2006 and 2010. Participants: After exclusion based on neurological, psychiatric or endocrinological history, and use of psychotropic medication, 222 systemic glucocorticoid users, 557 inhaled glucocorticoid users and 24 106 controls with available T1 and diffusion MRI data were included. Main outcome measures: Primary outcomes were differences in 22 volumetric and 14 diffusion imaging parameters between glucocorticoid users and controls, determined using linear regression analyses adjusted for potential confounders. Secondary outcomes included cognitive functioning (six tests) and emotional symptoms (four questions). Results: Both systemic and inhaled glucocorticoid use were associated with reduced white matter integrity (lower fractional anisotropy (FA) and higher mean diffusivity (MD)) compared with controls, with larger effect sizes in systemic users (FA: adjusted mean difference (AMD)=-3.7e-3, 95% CI=-6.4e-3 to 1.0e-3; MD: AMD=7.2e-6, 95% CI=3.2e-6 to 1.1e-5) than inhaled users (FA: AMD=-2.3e-3, 95% CI=-4.0e-3 to -5.7e-4; MD: AMD=2.7e-6, 95% CI=1.7e-7 to 5.2e-6). Systemic use was also associated with larger caudate GMV (AMD=178.7 mm(3), 95% CI=82.2 to 275.0), while inhaled users had smaller amygdala GMV (AMD=-23.9 mm(3), 95% CI=-41.5 to -6.2) than controls. As for secondary outcomes, systemic users performed worse on the symbol digit substitution task (AMD=-0.17 SD, 95% CI=-0.34 to -0.01), and reported more depressive symptoms (OR=1.76, 95% CI=1.25 to 2.43), disinterest (OR=1.84, 95% CI=1.29 to 2.56), tenseness/restlessness (OR=1.78, 95% CI=1.29 to 2.41), and tiredness/lethargy (OR=1.90, 95% CI=1.45 to 2.50) compared with controls. Inhaled users only reported more tiredness/lethargy (OR=1.35, 95% CI=1.14 to 1.60). Conclusions: Both systemic and inhaled glucocorticoid use are associated with decreased white matter integrity and limited changes in GMV. This association may contribute to the neuropsychiatric side effects of glucocorticoid medication, especially with chronic use. Show less
Lyko, C.; Blum, M.R.; Abolhassani, N.; Stuber, M.J.; Giovane, C. del; Feller, M.; ... ; Rodondi, N. 2022
Background Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed... Show moreBackground Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results Among 660 participants (54% women) >= 65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4. Show less
Endt, V.H.W. van der; Milders, J.; Vries, B.B.L.P. de; Trines, S.A.; Groenwold, R.H.H.; Dekkers, O.M.; ... ; Jong, Y. de 2022
Aims Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations... Show moreAims Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations and updates, assess their methodological quality, and calculate pooled estimates of the predictive performance.Methods and results We searched PubMed and Web of Science for studies developing, validating, or updating risk scores for IS in AF patients. Methodological quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). To assess discrimination, pooled c-statistics were calculated using random-effects meta-analysis. We identified 19 scores, which were validated and updated once or more in 70 and 40 studies, respectively, including 329 validations and 76 updates-nearly all on the CHA(2)DS(2)-VASc and CHADS(2). Pooled c-statistics were calculated among 6 267 728 patients and 359 373 events of IS. For the CHA(2)DS(2)-VASc and CHADS(2), pooled c-statistics were 0.644 [95% confidence interval (CI) 0.635-0.653] and 0.658 (0.644-0.672), respectively. Better discriminatory abilities were found in the newer risk scores, with the modified-CHADS(2) demonstrating the best discrimination [c-statistic 0.715 (0.674-0.754)]. Updates were found for the CHA(2)DS(2)-VASc and CHADS(2) only, showing improved discrimination. Calibration was reasonable but available for only 17 studies. The PROBAST indicated a risk of methodological bias in all studies.Conclusion Nineteen risk scores and 76 updates are available to predict IS in patients with AF. The guideline-endorsed CHA(2)DS(2)-VASc shows inferior discriminative abilities compared with newer scores. Additional external validations and data on calibration are required before considering the newer scores in clinical practice. Show less
Nordenstrom, A.; Ahmed, S.F.; Akker, E. van den; Blair, J.; Bonomi, M.; Brachet, C.; ... ; Dekkers, O.M. 2022
An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was... Show moreAn Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions. Show less
Purpose In epidemiological research, measurements affected by medication, for example, blood pressure lowered by antihypertensives, are common. Different ways of handling medication are required... Show morePurpose In epidemiological research, measurements affected by medication, for example, blood pressure lowered by antihypertensives, are common. Different ways of handling medication are required depending on the research questions and whether the affected measurement is the exposure, the outcome, or a confounder. This study aimed to review handling of medication use in observational research. Methods PubMed was searched for etiological studies published between 2015 and 2019 in 15 high-ranked journals from cardiology, diabetes, and epidemiology. We selected studies that analyzed blood pressure, glucose, or lipid measurements (whether exposure, outcome or confounder) by linear or logistic regression. Two reviewers independently recorded how medication use was handled and assessed whether the methods used were in accordance with the research aim. We reported the methods used per variable category (exposure, outcome, confounder). Results A total of 127 articles were included. Most studies did not perform any method to account for medication use (exposure 58%, outcome 53%, and confounder 45%). Restriction (exposure 22%, outcome 23%, and confounders 10%), or adjusting for medication use using a binary indicator were also used frequently (exposure: 18%, outcome: 19%, confounder: 45%). No advanced methods were applied. In 60% of studies, the methods' validity could not be judged due to ambiguous reporting of the research aim. Invalid approaches were used in 28% of the studies, mostly when the affected variable was the outcome (36%). Conclusion Many studies ambiguously stated the research aim and used invalid methods to handle medication use. Researchers should consider a valid methodological approach based on their research question. Show less
Haalen, F.M. van; Kaya, M.; Pelsma, I.C.M.; Dekkers, O.M.; Biermasz, N.R.; Cannegieter, S.C.; ... ; Endo-ERN Cushing Thrombosis study 2022
Background Cushing's syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in... Show moreBackground Cushing's syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in patients with CS are currently lacking. We aimed to map the current clinical practice for thromboprophylaxis management in patients with CS across reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), which are endorsed specifically for the diagnosis and treatment of CS. Using the EU survey tool, a primary screening survey, and subsequently a secondary, more in-depth survey were developed. Results The majority of the RCs provided thromboprophylaxis to patients with CS (n = 23/25), although only one center had a standardized thromboprophylaxis protocol (n = 1/23). RCs most frequently started thromboprophylaxis from CS diagnosis onwards (n = 11/23), and the majority stopped thromboprophylaxis based on individual patient characteristics, rather than standardized treatment duration (n = 15/23). Factors influencing the initiation of thromboprophylaxis were 'medical history of VTE' (n = 15/23) and 'severity of hypercortisolism' (n = 15/23). Low-Molecular-Weight-Heparin was selected as the first-choice anticoagulant drug for thromboprophylaxis by all RCs (n = 23/23). Postoperatively, the majority of RCs reported 'severe immobilization' as an indication to start thromboprophylaxis in patients with CS (n = 15/25). Most RCs (n = 19/25) did not provide standardized testing for variables of hemostasis in the postoperative care of CS. Furthermore, the majority of the RCs provided preoperative medical treatment to patients with CS (n = 23/25). About half of these RCs (n = 12/23) took a previous VTE into account when starting preoperative medical treatment, and about two-thirds (n = 15/23) included 'reduction of VTE risk' as a goal of treatment. Conclusions There is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with CS, even in Endo-ERN RCs. Randomized controlled trials are needed to establish the optimal prophylactic anticoagulant regimen, carefully balancing the increased risk of (perioperative) bleeding, and the presence of additional risk factors for thrombosis. Show less
OBJECTIVETo provide considerations for reporting and interpretation that can improve assessment of the credibility of exploratory analyses in aetiologic research.DESIGNMini-review of the literature... Show moreOBJECTIVETo provide considerations for reporting and interpretation that can improve assessment of the credibility of exploratory analyses in aetiologic research.DESIGNMini-review of the literature and account of exploratory research principles.SETTINGThis study focuses on a particular type of causal research, namely aetiologic studies, which investigate the causal effect of one or multiple risk factors on a particular health outcome or disease. The mini review included aetiologic research articles published in four epidemiology journals in the first issue of 2021: American Journal of Epidemiology, Epidemiology, European Journal of Epidemiology, and International Journal of Epidemiology, specifically focusing on observational studies of causal risk factors of diseases.MAIN OUTCOME MEASURESNumber of exposure-outcome associations reported, grouped by type of analysis (main, sensitivity, and additional).RESULTSThe journal articles reported many exposure-outcome associations: a mean number of 33 (range 1-120) exposure-outcome associations for the primary analysis, 30 (0-336) for sensitivity analyses, and 163 (0-1467) for additional analyses. Six considerations were discussed that are important in assessing the credibility of exploratory analyses: research problem, protocol, statistical criteria, interpretation of findings, completeness of reporting, and effect of exploratory findings on future causal research.CONCLUSIONSBased on this mini-review, exploratory analyses in aetiologic research were not always reported properly. Six considerations for reporting of exploratory analyses in aetiologic research were provided to stimulate a discussion about their preferred handling and reporting. Researchers should take responsibility for the results of exploratory analyses by clearly reporting their exploratory nature and specifying which findings should be investigated in future research and how. Show less
Electronic health record (EHR) data not only offer many exciting research opportunities but also come with their own inherent limitations. Researchers may not always realise the challenges... Show moreElectronic health record (EHR) data not only offer many exciting research opportunities but also come with their own inherent limitations. Researchers may not always realise the challenges associated with the use of EHR data for research, or the fact that using large datasets of 'real-world data' does not necessarily provide valuable real-world evidence. This article discusses some of the main differences between EHR data and data collected primarily for research purposes, and the challenges encountered when using EHR data for research. It also offers suggestions on how to deal with these challenges based on worked-out examples. It therefore serves as a quick guide for researchers interested in either reading or performing EHR-based research. Show less
Rossen, T.M. van; Ooijevaar, R.E.; Vandenbroucke-Grauls, C.M.J.E.; Dekkers, O.M.; Kuijper, E.J.; Keller, J.J.; Prehn, J. van 2022
Objectives: Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Identifying... Show moreObjectives: Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Identifying patients diagnosed with initial CDI who are at increased risk of developing sCDI/rCDI could lead to more cost-effective therapeutic choices. In this systematic review we aimed to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI.Methods: PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched from database inception through March, 2021. The study eligibility criteria were cohort and caseecontrol studies. Participants were patients >= 18 years old diagnosed with CDI, in which clinical or laboratory factors were analysed to predict sCDI/rCDI. Risk of bias was assessed by using the Quality in Prognostic Research (QUIPS) tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool modified for prognostic studies. Study selection was performed by two independent reviewers. Overview tables of prognostic factors were constructed to assess the number of studies and the respective effect direction and statistical significance of an association.Results: 136 studies were included for final analysis. Greater age and the presence of multiple comorbidities were prognostic factors for sCDI. Identified risk factors for rCDI were greater age, healthcareassociated CDI, prior hospitalization, proton pump inhibitors (PPIs) started during or after CDI diagnosis, and previous rCDI.Conclusions: Prognostic factors for sCDI and rCDI could aid clinicians to make treatment decisions based on risk stratification. We suggest that future studies use standardized definitions for sCDI/rCDI and systematically collect and report the risk factors assessed in this review, to allow for meaningful metaanalysis of risk factors using data of high-quality trials. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. Show less
Puy, R.S. du; Poortvliet, R.K.E.; Mooijaart, S.P.; Stott, D.J.; Quinn, T.; Sattar, N.; ... ; Elzen, W.P.J. den 2022
Context Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine... Show moreContext Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism. Methods This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months. Results Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65-97) and mean baseline hemoglobin of 13.8 +/- 1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (-0.03 g/dL [95% CI, -0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (-0.33 g/dL [95% CI, -0.87 to 0.21]). Conclusion In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia. Show less
Voorend, C.G.N.; Oevelen, M. van; Verberne, W.R.; Wittenboer, I.D. van den; Dekkers, O.M.; Dekker, F.; ... ; Bos, W.J.W. 2022
Background Non-dialytic conservative care (CC) has been proposed as a treatment option for patients with kidney failure. This systematic review and meta-analysis aims at comparing survival outcomes... Show moreBackground Non-dialytic conservative care (CC) has been proposed as a treatment option for patients with kidney failure. This systematic review and meta-analysis aims at comparing survival outcomes between dialysis and CC in studies where patients made an explicit treatment choice. Methods Five databases were systematically searched from origin through 25 February 2021 for studies comparing survival outcomes among patients choosing dialysis versus CC. Adjusted and unadjusted survival rates were extracted and meta-analysis performed where applicable. Risk of bias analysis was performed according to the Cochrane Risk Of Bias In Non-randomized Studies of Interventions. Results A total of 22 cohort studies were included covering 21 344 patients. Most studies were prone to selection bias and confounding. Patients opting for dialysis were generally younger and had fewer comorbid conditions, fewer functional impairments and less frailty than patients who chose CC. The unadjusted median survival from treatment decision or an estimated glomerular filtration rate <15 mL/min/1.73 m(2) ranged from 20 and 67 months for dialysis and 6 and 31 months for CC. Meta-analysis of 12 studies that provided adjusted hazard ratios (HRs) for mortality showed a pooled adjusted HR of 0.47 (95% confidence interval 0.39-0.57) for patients choosing dialysis compared with CC. In subgroups of patients with older age or severe comorbidities, the reduction of mortality risk remained statistically significant, although analyses were unadjusted. Conclusions Patients opting for dialysis have an overall lower mortality risk compared with patients opting for CC. However, a high risk of bias and heterogeneous reporting preclude definitive conclusions and results cannot be translated to an individual level. Show less
Haneveld, M.J.K.; Treijen, M.J.C. van; Pieterman, C.R.C.; Dekkers, O.M.; Ven, A. van de; Herder, W.W. de; ... ; Leeuwaarde, R.S. van 2021
Context: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1).... Show moreContext: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate.Objective: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients.Methods: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size >= 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease.Results: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively.Conclusion: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified.The psychological and medical burden of screening at a young age should be considered. Show less
