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Objective Type D personality, a joint tendency toward negative affectivity and social inhibition, has been linked to adverse events in patients with heart disease, although with inconsistent findings. Here, we apply an individual patient-data meta-analysis to data from 19 prospective cohort studies (N = 11,151) to investigate the prediction of adverse outcomes by type D personality in patients with acquired cardiovascular disease. Method For each outcome (all-cause mortality, cardiac mortality, myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiac event, any adverse event), we estimated type D's prognostic influence and the moderation by age, sex, and disease type. Results In patients with cardiovascular disease, evidence for a type D effect in terms of the Bayes factor (BF) was strong for major adverse cardiac event (BF = 42.5; odds ratio [OR] = 1.14) and any adverse event (BF = 129.4; OR = 1.15). Evidence for the null hypothesis was found for all-cause mortality (BF = 45.9; OR = 1.03), cardiac mortality (BF = 23.7; OR = 0.99), and myocardial infarction (BF = 16.9; OR = 1.12), suggesting that type D had no effect on these outcomes. This evidence was similar in the subset of patients with coronary artery disease (CAD), but inconclusive for patients with heart failure (HF). Positive effects were found for negative affectivity on cardiac and all-cause mortality, with the latter being more pronounced in male than female patients. Conclusion Across 19 prospective cohort studies, type D predicts adverse events in patients with CAD, whereas evidence in patients with HF was inconclusive. In both patients with CAD and HF, we found evidence for a null effect of type D on cardiac and all-cause mortality.

IntroductionCardiovascular disease is a significant cause of morbidity and mortality in COPD. Endothelial dysfunction is suggested to be involved in cardiovascular disease pathogenesis, and multiple studies report endothelial dysfunction in COPD. This article summarized the current knowledge on endothelial function in COPD patients.Areas coveredDatabases were screened until November 2022 for studies using ultrasound-based flow-mediated dilation in patients with stable COPD. Pooled effect sizes were calculated using random effects model. Meta-regression analyses assessed the effects of demographic and clinical variables.Expert opinion34 studies were identified (1365 COPD patients; 617 controls). Pooled analysis demonstrated an impaired endothelial-dependent (-2.33%; 95%CI -3.30/-1.35; p < 0.001) and endothelial-independent dilation (-3.11%; 95%CI -5.14/-1.08; p = 0.003) in COPD patients when compared to non-COPD controls. Meta-regression identified that higher age, worse severity of airflow obstruction, and current smoking were significantly associated with impaired endothelial function. Studies evaluating the effects of pharmacological and non-pharmacological interventions on endothelial function in COPD patients demonstrated conflicting results.

Objective Negative emotional states, such as anger and anxiety, are associated with the onset of myocardial infarction and other acute clinical manifestations of ischemic heart disease. The likelihood of experiencing these short-term negative emotions has been associated with long-term psychological background factors such as depression, generalized anxiety, and personality factors. We examined the association of acute emotional states preceding cardiac stress testing (CST) with inducibility of myocardial ischemia and to what extent psychological background factors account for this association. Methods Emotional states were assessed in patients undergoing CST (n = 210; mean [standard deviation] age = 66.9 [8.2] years); 91 (43%) women) using self-report measures and video recordings of facial emotion expression. Video recordings were analyzed for expressed anxiety, anger, sadness, and happiness before CST. Psychological background factors were assessed with validated questionnaires. Single-photon emission computed tomography was used to evaluate inducibility of ischemia. Results Ischemia occurred in 72 patients (34%). Emotional states were not associated with subsequent inducibility of ischemia during CST (odds ratio between 0.93 and 1.04; p values > .50). Psychological background factors were also not associated with ischemia (odds ratio between 0.96 and 1.06 per scale unit; p values > .20) and did not account for the associations of emotional states with ischemia. Conclusions Emotional states immediately before CST and psychological background factors were not associated with the inducibility of ischemia. These findings indicate that the well-documented association between negative emotions with acute clinical manifestations of ischemic heart disease requires a different explanation than a reduced threshold for inducible ischemia.

Autoantibodies, in particular anti-dsDNA antibodies, are increasingly used for diagnosis, classification and follow-up of patients with SLE. Since standardization of autoantibody assays is a major challenge, more attention should be paid to harmonization initiatives and better definition of required test characteristics in classification criteria. For diagnosis and follow-up separate multi-center studies are required to establish test characteristics of distinct immuno-assays for both purposes. Finally, such studies should consider not to evaluate SLE as a single disease, but as a disease with distinct subtypes.

IntroductionCardiovascular disease is a significant cause of morbidity and mortality in COPD. Endothelial dysfunction is suggested to be involved in cardiovascular disease pathogenesis, and multiple studies report endothelial dysfunction in COPD. This article summarized the current knowledge on endothelial function in COPD patients.Areas coveredDatabases were screened until November 2022 for studies using ultrasound-based flow-mediated dilation in patients with stable COPD. Pooled effect sizes were calculated using random effects model. Meta-regression analyses assessed the effects of demographic and clinical variables.Expert opinion34 studies were identified (1365 COPD patients; 617 controls). Pooled analysis demonstrated an impaired endothelial-dependent (-2.33%; 95%CI -3.30/-1.35; p < 0.001) and endothelial-independent dilation (-3.11%; 95%CI -5.14/-1.08; p = 0.003) in COPD patients when compared to non-COPD controls. Meta-regression identified that higher age, worse severity of airflow obstruction, and current smoking were significantly associated with impaired endothelial function. Studies evaluating the effects of pharmacological and non-pharmacological interventions on endothelial function in COPD patients demonstrated conflicting results.

Objective The aim of the study was to obtain an updated overview of regression, persistence, and progression rates of conservatively managed cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3. Methods Data sources were MEDLINE, Embase, and Cochrane (January 1, 1973-April 14, 2020). Two reviewers extracted data and assessed risk of bias. To estimate outcome rates, we pooled proportions of the individual study results using random-effects meta-analysis, resulting in point estimates and corresponding 95% CIs. Heterogeneity was quantified by the I-2 and tau(2) measures. Results Eighty-nine studies were included, 63 studies on CIN 1 (n = 6,080-8,767), 42 on CIN 2 (n = 2,909-3,830), and 7 on CIN 3 (n = 245-351). The overall regression, persistence, and progression to CIN 2 or worse and CIN 3 or worse rates for women with conservatively managed CIN 1 were 60% (95% CI = 55-65, I-2 = 92%), 25% (95% CI = 20-30, I-2 = 94%), 11% (95% CI = 8-13, I-2 = 89%), and 2% (95% CI = 1-3, I-2 = 82%), respectively. The overall regression, persistence, and progression rates for CIN 2 were 55% (95% CI = 50-60, I-2 = 85%), 23% (95% CI = 19-28, I-2 = 83%), and 19% (95% CI = 15-23, I-2 = 88%), respectively. Finally, for CIN 3, these were 28% (95% CI = 17-41, I-2 = 68%), 67% (95% CI = 36-91, I-2 = 84%), and 2% (95% CI = 0-25, I-2 = 95%), respectively. Cervical intraepithelial neoplasia grade 2 regression was significantly higher in women 30 years or younger and high-risk human papillomavirus-negative women (66%, 95% CI = 62-70, I-2 = 76%; 94%, 95% CI = 84-99, I-2 = 60%). Only 2/7,180 (0.03%) and 10/3,037 (0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer. Conclusions Most CIN 1/CIN 2 will regress spontaneously in less than 24 months, with the highest rates in high-risk human papillomavirus-negative and young women, whereas progression to cancer is less than 0.5%. Conservative management should be considered, especially in fertile women and with expected high compliance. Given the heterogeneity in regression rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to guide management.

Item does not contain fulltext OBJECTIVE: The aim of the study was to obtain an updated overview of regression, persistence, and progression rates of conservatively managed cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3. METHODS: Data sources were MEDLINE, Embase, and Cochrane (January 1, 1973-April 14, 2020). Two reviewers extracted data and assessed risk of bias. To estimate outcome rates, we pooled proportions of the individual study results using random-effects meta-analysis, resulting in point estimates and corresponding 95% CIs. Heterogeneity was quantified by the I2 and τ2 measures. RESULTS: Eighty-nine studies were included, 63 studies on CIN 1 (n = 6,080-8,767), 42 on CIN 2 (n = 2,909-3,830), and 7 on CIN 3 (n = 245-351). The overall regression, persistence, and progression to CIN 2 or worse and CIN 3 or worse rates for women with conservatively managed CIN 1 were 60% (95% CI = 55-65, I2 = 92%), 25% (95% CI = 20-30, I2 = 94%), 11% (95% CI = 8-13, I2 = 89%), and 2% (95% CI = 1-3, I2 = 82%), respectively. The overall regression, persistence, and progression rates for CIN 2 were 55% (95% CI = 50-60, I2 = 85%), 23% (95% CI = 19-28, I2 = 83%), and 19% (95% CI = 15-23, I2 = 88%), respectively. Finally, for CIN 3, these were 28% (95% CI = 17-41, I2 = 68%), 67% (95% CI = 36-91, I2 = 84%), and 2% (95% CI = 0-25, I2 = 95%), respectively. Cervical intraepithelial neoplasia grade 2 regression was significantly higher in women 30 years or younger and high-risk human papillomavirus-negative women (66%, 95% CI = 62-70, I2 = 76%; 94%, 95% CI = 84-99, I2 = 60%). Only 2/7,180 (0.03%) and 10/3,037 (0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer. CONCLUSIONS: Most CIN 1/CIN 2 will regress spontaneously in less than 24 months, with the highest rates in high-risk human papillomavirus-negative and young women, whereas progression to cancer is less than 0.5%. Conservative management should be considered, especially in fertile women and with expected high compliance. Given the heterogeneity in regression rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to guide management.

Trophoblast-specific expression of human leukocyte antigen G (HLA-G) induces immune tolerance for the developing fetus. Pathological HLA-G expression later in life might contribute to immune escape of various cancers. We studied the still controversial role of HLA-G in colorectal carcinoma (CRC) using the MEM-G/1 antibody and a tissue microarray series of CRC tumors (n=317). HLA-G expression appeared in 20% of the tumors and showed high intratumoral heterogeneity. HLA-G positivity was associated with better differentiation (p=0.002) and non-mucinous histology (p=0.008). However, HLA-G expression alone showed no prognostic value: 5-years disease-specific survival among patients with HLA-G expression was 68.9% (95% CI: 62.7-75.0%) compared to 74.8% (95% CI: 63.2-86.3%) among those without expression. These results support a modulatory role of HLA-G in CRC. This article is protected by copyright. All rights reserved.

OBJECTIVES: Monotherapy with pembrolizumab is the preferred first-line treatment for metastatic non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression ≥50 %, without targetable oncogenic drivers. Although targeted therapies are in development for patients with specific Kirsten rat sarcoma (KRAS) mutations, these are not available in daily care yet. It is not clear whether there is a difference in survival on first-line pembrolizumab for patients with a high PD-L1 status with or without a KRAS mutation. We aim to compare this survival based on real-world data.MATERIALS AND METHODS: This is a real-world retrospective population-based study using data from the Netherlands Cancer Registry. We selected patients with stage IV lung adenocarcinoma with PD-L1 expression ≥50 % diagnosed between January 2017 and December 2018, treated with first-line pembrolizumab. Patients with EGFR mutations, ALK translocations or ROS1 rearrangements were excluded. The primary outcome parameter was overall survival.RESULTS: 388 (57 %) of 595 patients had a KRAS mutation. KRAS was seen more frequently in women than in men (65 % versus 49 % respectively, p CONCLUSION: The survival of KRAS mutated versus KRAS wild-type lung adenocarcinoma patients, treated with first-line pembrolizumab monotherapy, is similar, suggesting that KRAS has no prognostic value with respect to treatment with pembrolizumab.

Objective Medullary thyroid cancer (MTC) originates from parafollicular cells (C cell) and produces calcitonin (CT). Basal serum CT was used in the diagnosis and treatment of MTC. If basal CT level is 100 pg/ml or higher, it is likely to have MTC, but if basal CT level is below 10 pg/ml, the probability of developing thyroid disease is low. In cases with basal CT level between 10-100 pg/ml, pentagastrin-stimulated (PS) CT level is studied to evaluate MTC and C cell hyperplasia (CHH). This study aimed to determine cut-off value for basal and PS peak CT level for diagnosis of MTC. Patients-methods We retrospectively reviewed files of patients presented to endocrine outpatient clinic of Ege University, Medicine School, between 2010 and 2019, 176 patients with basal CT level of 10-100 pg/ml and patients with PS test were included to the study. Findings The ROC analysis was used to determine cut-off value for basal CT that can discriminate cases with MTC and those with nodular goiter. Cut-off value for basal CT was calculated as 46.5 pg/ml (specificity; 100 %, sensitivity; 74 %). In the ROC analysis for peak PS CT, cut-off value was calculated as 285 pg/ml (specificity:100 %; sensitivity:82 %). When peak CT level was > 290 pg/ml in PS test, both specificity and sensitivity for MTC were determined as 100 %. The PS peak CT level > 285 pg/ml was significant for MTC diagnosis while level of 117-274 pg/ml was significant for CHH. Conclusion In this study, cut-off value was calculated as 46.5 pg/ml for basal CT whereas 285 pg/ml for PS peak CT in the diagnosis of preoperative MTC. Key words: Medullary thyroid cancer, C cell hyperplasia, Calcitonin, Pentagastrin, Cut-off.

Background Infants with mild HIE are at risk of significant disability at follow-up. In the pre-therapeutic hypothermia (TH) era, electroencephalography (EEG) within 6 hours of birth was most predictive of outcome. This study aims to identify and describe features of early EEG and heart rate variability (HRV) ( Methods Infants >36 weeks with mild HIE, not undergoing TH, with EEG before 6 hours of age were identified from 4 prospective cohort studies conducted in the Cork University Maternity Services, Ireland (2003–2019). Control infants were taken from a contemporaneous study examining brain activity in healthy term infants. EEGs were qualitatively analysed by two neonatal neurophysiologists and quantitatively assessed using multiple features of amplitude, spectral shape and inter-hemispheric connectivity. Quantitative features of HRV were assessed in both the groups. Results Fifty-eight infants with mild HIE and sixteen healthy term infants were included. Seventy-two percent of infants with mild HIE had at least one abnormal EEG feature on qualitative analysis and quantitative EEG analysis revealed significant differences in spectral features between the two groups. HRV analysis did not differentiate between the groups. Conclusions Qualitative and quantitative analysis of the EEG before 6 hours of age identified abnormal EEG features in mild HIE, which could aid in the objective identification of cases for future TH trials in mild HIE. Impact Infants with mild HIE currently do not meet selection criteria for TH yet may be at risk of significant disability at follow-up. In the pre-TH era, EEG within 6 hours of birth was most predictive of outcome; however, TH has delayed this predictive value. 72% of infants with mild HIE had at least one abnormal EEG feature in the first 6 hours on qualitative assessment. Quantitative EEG analysis revealed significant differences in spectral features between infants with mild HIE and healthy term infants. Quantitative EEG features may aid in the objective identification of cases for future TH trials in mild HIE.

Introduction: Type D personality, operationalized as high scores on negative affectivity (NA) and social inhibition (SI), has been associated with various medical and psychosocial outcomes. The recent failure to replicate several earlier findings could result from the various methods used to assess the Type D effect. Despite recommendations to analyze the continuous NA and SI scores, a popular approach groups people as having Type D personality or not. This method does not adequately detect a Type D effect as it is also sensitive to main effects of NA or SI only, suggesting the literature contains false positive Type D effects. Here, we systematically assess the extent of this problem.Method: We conducted a systematic review including 44 published studies assessing a Type D effect with both a continuous and dichotomous operationalization.Results: The dichotomous method showed poor agreement with the continuous Type D effect. Of the 89 significant dichotomous method effects, 37 (41.6%) were Type D effects according to the continuous method. The remaining 52 (58.4%) are therefore likely not Type D effects based on the continuous method, as 42 (47.2%) were main effects of NA or SI only.Conclusion: Half of the published Type D effect according to the dichotomous method may be false positives, with only NA or SI driving the outcome.

Introduction Type D personality, operationalized as high scores on negative affectivity (NA) and social inhibition (SI), has been associated with various medical and psychosocial outcomes. The recent failure to replicate several earlier findings could result from the various methods used to assess the Type D effect. Despite recommendations to analyze the continuous NA and SI scores, a popular approach groups people as having Type D personality or not. This method does not adequately detect a Type D effect as it is also sensitive to main effects of NA or SI only, suggesting the literature contains false positive Type D effects. Here, we systematically assess the extent of this problem. Method We conducted a systematic review including 44 published studies assessing a Type D effect with both a continuous and dichotomous operationalization. Results The dichotomous method showed poor agreement with the continuous Type D effect. Of the 89 significant dichotomous method effects, 37 (41.6%) were Type D effects according to the continuous method. The remaining 52 (58.4%) are therefore likely not Type D effects based on the continuous method, as 42 (47.2%) were main effects of NA or SI only. Conclusion Half of the published Type D effect according to the dichotomous method may be false positives, with only NA or SI driving the outcome.

Contains fulltext : 251419.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1alpha] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON). MATERIALS AND METHODS: Immunohistochemical staining was performed for HIF-1alpha and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1alpha expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker. RESULTS: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1alpha and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1alpha expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR. CONCLUSION: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1alpha and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor.

Aim Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). Methods and results A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. Conclusion The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.

Aim Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). Methods and results A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. Conclusion The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.

Objective Social behavior (e.g., loneliness, isolation) has been indicated as an important risk factor for cardiovascular disease. Recent studies show that Type D personality might be an important predictor of social behavior. Hence, the current exploratory study aims to examine, using ecological assessment, whether Type D personality is associated with a lower likelihood to engage in social encounters in patients with cardiovascular disease. Method Cardiac patients who participated in the Do CHANGE (Phase 2) trial were included in current analysis. As part of the Do CHANGE intervention, real-life data were collected in the intervention group using the MOVES app, which was installed on patients' mobile phones. For a period of 6 months, Global Positioning System (GPS) data from the participating patients were collected. From the GPS data, 3 target variables were computed: (a) general activity level, (b) social variety, and (c) social opportunity. Results A total of 70 patients were included in the analysis. Patients with a Type D personality had lower scores on the "social opportunity" variable compared to non-Type D patients (F = 6.72; p = .01). Type D personality was associated with lower social participation after adjusting for depression and anxiety. No association between Type D personality and general activity or behavioral variety was observed. Conclusions This is the first study to use an ecological measure to assess social behavior of cardiac patients with a Type D personality. Results show that Type D personality might be associated with lower social engagement, which could, in turn, partly explain its association with adverse health outcomes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background Fetal growth restriction, i.e. the restriction of genetically predetermined growth potential due to placental dysfunction, is a major cause of neonatal morbidity and mortality. The consequences of inadequate fetal growth can be life-long, but the risks can be reduced substantially if the condition is identified prenatally. Currently, screening strategies are based on ultrasound detection of a small-for-gestational age fetus and do not take into account the underlying vascular pathology in the placenta. Measurement of maternal circulating angiogenic biomarkers placental growth factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) are increasingly used in studies on fetal growth restriction as they reflect the pathophysiological process in the placenta. However, interpretation of the role of angiogenic biomarkers in prediction of fetal growth restriction is hampered by the varying design, population, timing, assay technique and cut-off values used in these studies. Methods We conducted a systematic-review in PubMed (MEDLINE), EMBASE (Ovid) and Cochrane to explore the predictive performance of maternal concentrations of placental growth factor, sFlt-1 and their ratio for fetal growth restriction and small-for-gestational age, at different gestational ages, and describe the longitudinal changes in biomarker concentrations and optimal discriminatory cut-off values. Results We included 26 studies with 2514 cases with small-for-gestational age, 27 cases of fetal growth restriction, 582 cases mixed small-for-gestational age/fetal growth restriction and 29,374 reference. The largest mean differences for the two biomarkers and their ratio were found after 26 weeks of gestational age and not in the first trimester. The ROC-AUC varied between 0.60 and 0.89 with sensitivity and specificity matching the different cut-off values or a preset false-positive rate of 10%. Conclusions Most of the studies did not make a distinction between small-for-gestational age and fetal growth restriction, and therefore the small-for-gestational age group consists of fetuses with growth restriction and fetuses that are constitutionally normal. The biomarkers can be a valuable screening tool for small-for-gestational age pregnancies, but unfortunately, there is not yet a clear cut-off value to use for screening. More research is needed to see if these biomarkers are sufficiently able to differentiate growth restriction on their own and how these biomarkers in combination with other relevant clinical and ultrasound parameters can be used in clinical routine diagnostics.

Objectives: To provide an overview of published mathematical estimation approaches to quantify the duration of the preclinical detectable phase using data from cancer screening programs.Methods: A systematic search in PubMed and Embase for original studies presenting mathematical approaches using screening data. The studies were categorized by mathematical approach, data source and assumptions made. Furthermore, estimates of the duration of the preclinical detectable phase of breast and colorectal cancer were reported per study population.Results: From 689 publications, 34 estimation methods were included. Five distinct types of mathematical estimation approaches were identified: prevalence to incidence ratio (n=8), maximum likelihood estimation (n=16), expectation-maximization algorithm (n=1), regression of observed on expected (n=6) and Bayesian Markov Chain Monte Carlo estimation (n=5). Fourteen studies used data of a screened and an unscreened population whereas nineteen studies included only information from a screened population. Estimates of the duration of the preclinical detectable phase varied between two and seven years for breast cancer within the HIP study (annual mammography and clinical breast examination in women aged 40-64 years) and two and five years for colorectal cancer within the Calvados study (one guaiac fecal occult blood test in men and women aged 45-74 years).Conclusion: Different types of mathematical approaches lead to different estimates of the duration of preclinical detectable phase. We advise researchers to use the method that matches the data available, and use multiple methods for estimation when possible as no method is perfect.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. ispartof: NPJ BREAST CANCER vol:7 issue:1 ispartof: location:United States status: published

STUDY QUESTION Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? SUMMARY ANSWER Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. WHAT IS KNOWN ALREADY In the field of endometriosis, several classification, staging and reporting systems have been developed. PARTICIPANTS/MATERIALS, SETTING, METHODS A systematic PUBMED literature search was performed. Data were extracted and summarized. MAIN RESULTS AND THE ROLE OF CHANCE Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. LARGE SCALE DATA NA. LIMITATIONS, REASONS FOR CAUTION The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. WIDER IMPLICATIONS OF THE FINDINGS It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working toward a universally accepted endometriosis classification. STUDY FUNDING/COMPETING INTEREST(S) The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, European Society of Human Reproduction and Embryology and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics, outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. C.T. reports grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER NA.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539–0.735, p &lt, 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727–0.864, p &lt, 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561–0.756, p &lt, 0.001) and 40% (ICC 0.644, 95% CI 0.546–0.745, p &lt, 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.

Whether the vascular effects of inorganic nitrate, observed in clinical trials, translate to a reduction in cardiovascular disease (CVD) with habitual dietary nitrate intake in prospective studies warrants investigation. We aimed to determine if vegetable nitrate, the major dietary nitrate source, is associated with lower blood pressure (BP) and lower risk of incident CVD. Among 53,150 participants of the Danish Diet, Cancer, and Health Study, without CVD at baseline, vegetable nitrate intake was assessed using a comprehensive vegetable nitrate database. Hazard ratios (HRs) were calculated using restricted cubic splines based on multivariable-adjusted Cox proportional hazards models. During 23 years of follow-up, 14,088 cases of incident CVD were recorded. Participants in the highest vegetable nitrate intake quintile (median, 141 mg/day) had 2.58 mmHg lower baseline systolic BP (95%CI − 3.12, − 2.05) and 1.38 mmHg lower diastolic BP (95%CI − 1.66, − 1.10), compared with participants in the lowest quintile. Vegetable nitrate intake was inversely associated with CVD plateauing at moderate intakes (~ 60 mg/day); this appeared to be mediated by systolic BP (21.9%). Compared to participants in the lowest intake quintile (median, 23 mg/day), a moderate vegetable nitrate intake (median, 59 mg/day) was associated with 15% lower risk of CVD [HR (95% CI) 0.85 (0.82, 0.89)]. Moderate vegetable nitrate intake was associated with 12%, 15%, 17% and 26% lower risk of ischemic heart disease, heart failure, ischemic stroke and peripheral artery disease hospitalizations respectively. Consumption of at least ~ 60 mg/day of vegetable nitrate (~ 1 cup of green leafy vegetables) may mitigate risk of CVD. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00747-3.

Aim: To study whether auditory function measured with brainstem auditory evoked potential and brainstem audiometry recordings in the neonatal period associates with language development 1 year later in preterm infants.Methods: This retrospective study included 155 preterm infants (birthweight ≤1500 g and/or birth ≤32 gestational weeks) born between 2007 and 2012 at the Turku University Hospital. Auditory function was recorded in neonatal period. Information of language development was gathered at the mean corrected age of 1 year by using the Finnish version of the MacArthur Communicative Development Inventory.Results: Slower auditory processing (longer interpeak interval, IPI I-V) in the right ear in the neonatal brainstem auditory evoked potential recording associated with smaller receptive lexicon size at 1 year (P = .043). Infants with longer IPI I-V were more likely to have a deviant (≤17 words) receptive lexicon size (P = .033). The ab-sence of a contralateral response with right ear stimulation increased the risk for deviant lexicon size (P = .049).Conclusion: The results suggest that impaired auditory function in the neonatal pe-riod in preterm infants may lead to a poorer receptive language outcome 1 year later. Auditory pathway function assessment provides information for the identification of preterm children at risk for weak language development.

ObjectivesWe investigated whether changes in mammographic technique and screening policy have improved mammographic sensitivity, and elongated the mean sojourn time, since the introduction of biennial breast cancer screening in Nijmegen, the Netherlands, in 1975.MethodsMaximum likelihood estimation, non-linear regression, and Markov Chain Monte Carlo simulation were used to estimate test sensitivity, mean sojourn time, and underlying breast cancer incidence in four time periods, covering 40 years of breast cancer screening in Nijmegen (1975–2012).ResultsMaximum likelihood estimation generated an estimated test sensitivity of approximately 90% and a mean sojourn time around three years, while the estimates based on non-linear regression and Markov Chain Monte Carlo simulation were 80% and four years, respectively. All three methods estimated a rise in the underlying breast cancer incidence over time, with approximately one case more per 1000 women per year in the final period compared with the first period.ConclusionsThe three methods showed a slightly higher mammographic sensitivity and a longer mean sojourn time in the last period, after the introduction of digital mammography. Estimates were more realistic for the more sophisticated methods, non-linear regression and Markov Chain Monte Carlo simulation, while the simple closed form approximation of maximum likelihood estimation led to rather high estimates for sensitivity in the early periods.

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Background Sarcopenia is defined as low skeletal muscle mass with poor physical performance, representing a strong prognostic factor for mortality in older people. Although highly prevalent in hospitalized geriatric patients, it is unknown whether sarcopenia can also predict mortality in these patients. Objective To determine the association between sarcopenia according the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP), International Working Group on Sarcopenia (IWGS), Special Interest Group of Sarcopenia, Cachexia and Wasting Disorders (SIG) and Foundation for the National Institutes of Health (FNIH) and 2-year mortality in acutely hospitalized geriatric patients. Design 81 patients (84±5 y) admitted to the acute geriatric ward participated in this study. Body composition assessment (bio-impedance, Maltron Bioscan 920-II) and physical performance tests were performed, and mortality information was retrieved through patient files. Results Prevalence rates of sarcopenia were 51% (EWGSOP), 75% (IWGS), 69% (SIG), and 27% (FNIH). Based on Cox proportional hazard ratio (HR) analysis, 2-year mortality was significantly higher in sarcopenic patients versus non-sarcopenic patients when using the EWGSOP (2-y: HR 4.310; CI-95%:2.092- 8.850; P

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity.Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is - considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult.Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation.This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society.

Preterm children (born &lt, 37 gestational weeks) who are born at very early gestational age (&lt, 32 weeks, very preterm, VP) and/or with very low birth weight (≤1500 g, VLBW) are at increased risk for language and literacy deficits. The continuum between very early language development and literacy skills among these children is not clear. Our objective was to investigate the associations between language development at 2 years (corrected age) and literacy skills at 7 years in VP/VLBW children. Participants were 136 VP/VLBW children and 137 term controls (a 6-year regional population cohort, children living in Finnish-speaking families). At 2 years of corrected age, language (lexical development, utterance length) was assessed using the Finnish version of the MacArthur–Bates Communicative Development Inventory and the Expressive Language Scale from Bayley scales of Infant Development, second edition. At 7 years, children’s literacy skills (pre-reading skills, reading, and writing) were evaluated. Statistically significant correlations were found in both groups between language development at 2 years and literacy skills at 7 years (r-values varied between 0.29 and 0.43, p &lt, 0.01). In the VP/VLBW group, 33% to 74% of the children with early weak language development had weak literacy skills at 7 years relative to those with more advanced early language skills (11% to 44%, p &lt, 0.001 to 0.047). Language development at 2 years explained 14% to 28% of the variance in literacy skills 5 years later. Language development at 2 years had fair predictive value for literacy skills at 7 years in the VP/VLBW group (area under the receiver operating characteristic (ROC) curve (AUC) values varied between 0.70 and 0.77, p &lt, 0.001). Findings provide support for the continuum between very early language development and later language ability, in the domain of literacy skills in preterm children.

Supplemental Digital Content is available in the text., Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02–1.08) and 1.06 (95% CI, 1.02–1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01–1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00–1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01–1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06–1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227

Background Short ECG P‐wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single‐pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P‐wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms–138 ms; range, 71 ms–180 ms). At Cox regression, PWD was significantly associated with AF recurrence ( P =0.012). Patients with a PWD P =0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06–3.30; P =0.031) had a nearly 2‐fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.

INTRODUCTION: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849). METHODS: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored. RESULTS: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p= 0.031) and HRG12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p= 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HRG12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p= 0.030). In addition, among all patients, for relapse-free survival, HRG12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p= 0.017). CONCLUSIONS: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.

Type D (Distressed) personality combines negative affectivity (NA) and social inhibition (SI) and is associated with an increased risk of cardiovascular disease. We aimed to (1) validate a new proxy based on the Achenbach System of Empirically Based Assessment (ASEBA) for Type D personality and its NA and SI subcomponents and (2) estimate the heritability of the Type D proxy in an extended twin-pedigree design in the Netherlands Twin Register (NTR). Proxies for the dichotomous Type D classification, and continuous NA, SI, and NAxSI (the continuous measure of Type D) scales were created based on 12 ASEBA items for 30,433 NTR participants (16,449 twins and 13,984 relatives from 11,106 pedigrees) and sources of variation were analyzed in the ‘Mendel’ software package. We estimated additive and non-additive genetic variance components, shared household and unique environmental variance components and ran bivariate models to estimate the genetic and non-genetic covariance between NA and SI. The Type D proxy showed good reliability and construct validity. The best fitting genetic model included additive and non-additive genetic effects with broad-sense heritabilities for NA, SI and NAxSI estimated at 49%, 50% and 49%, respectively. Household effects showed small contributions (4–9%) to the total phenotypic variation. The genetic correlation between NA and SI was .66 (reflecting both additive and non-additive genetic components). Thus, Type D personality and its NA and SI subcomponents are heritable, with a shared genetic basis for the two subcomponents. Electronic supplementary material The online version of this article (10.1007/s10519-020-10023-x) contains supplementary material, which is available to authorized users.

International audience; Semen analysis is the first, and frequently, the only step in the evaluation of male fertility. Although the laboratory procedures are conducted according to the World Health Organization (WHO) guidelines, semen analysis and especially sperm morphology assessment is very difficult to standardize and obtain reproducible results. This is mainly due to the highly subjective nature of their evaluation. ICSI is the choice of treatment when sperm morphology is severely abnormal (teratozoospermic). Hence, the standardization of laboratory protocols for sperm morphology evaluation represents a fundamental step to ensure reliable, accurate and consistent laboratory results that avoid misdiagnoses and inadequate treatment of the infertile patient. This article aims to promote standardized laboratory procedures for an accurate evaluation of sperm morphology, including the establishment of quality control and quality assurance policies. Additionally, the clinical importance of sperm morphology results in assisted reproductive outcomes is discussed, along with the clinical management of teratozoospermic patients.

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:22 issue:9 pages:1586-1597 ispartof: location:England status: published

Background Several methods for tumor delineation are used in literature on breast diffusion weighted imaging (DWI) to measure the apparent diffusion coefficient (ADC). However, in the process of reaching consensus on breast DWI scanning protocol, image analysis and interpretation, still no standardized optimal breast tumor tissue selection (BTTS) method exists. Therefore, the purpose of this study is to assess the impact of BTTS methods on ADC in the discrimination of benign from malignant breast lesions in DWI in terms of sensitivity, specificity and area under the curve (AUC). Methods and findings In this systematic review and meta-analysis, adhering to the PRISMA statement, 61 studies, with 65 study subsets, in females with benign or malignant primary breast lesions (6291 lesions) were assessed. Studies on DWI, quantified by ADC, scanned on 1.5 and 3.0 Tesla and using b-values 0/50 and >= 800 s/mm(2) were included. PubMed and EMBASE were searched for studies up to 23-10-2019 (n = 2897). Data were pooled based on four BTTS methods (by definition of measured region of interest, ROI): BTTS1: whole breast tumor tissue selection, BTTS2: subtracted whole breast tumor tissue selection, BTTS3: circular breast tumor tissue selection and BTTS4: lowest diffusion breast tumor tissue selection. BTTS methods 2 and 3 excluded necrotic, cystic and hemorrhagic areas. Pooled sensitivity, specificity and AUC of the BTTS methods were calculated. Heterogeneity was explored using the inconsistency index (I-2) and considering covariables: field strength, lowest b-value, image of BTTS selection, pre-or post-contrast DWI, slice thickness and ADC threshold. Pooled sensitivity, specificity and AUC were: 0.82 (0.72-0.89), 0.79 (0.65-0.89), 0.88 (0.85-0.90) for BTTS1; 0.91 (0.89-0.93), 0.84 (0.80-0.87), 0.94 (0.91-0.96) for BTTS2; 0.89 (0.86-0.92), 0.90 (0.85-0.93), 0.95 (0.93-0.96) for BTTS3 and 0.90 (0.86-0.93), 0.84 (0.81-0.87), 0.86 (0.82-0.88) for BTTS4, respectively. Significant heterogeneity was found between studies (I-2 = 95). Conclusions None of the breast tissue selection (BTTS) methodologies outperformed in differentiating benign from malignant breast lesions. The high heterogeneity of ADC data acquisition demands further standardization, such as DWI acquisition parameters and tumor tissue selection to substantially increase the reliability of DWI of the breast.

BackgroundThe exact onset of brain injury in infants with congenital heart disease (CHD) is unknown. Our aim was, therefore, to assess the association between prenatal Doppler flow patterns, postnatal cerebral oxygenation and short-term neurological outcome.MethodsPrenatally, we measured pulsatility indices of the middle cerebral (MCA-PI) and umbilical artery (UA-PI) and calculated cerebroplacental ratio (CPR). After birth, cerebral oxygen saturation (r(c)SO(2)) and fractional tissue oxygen extraction (FTOE) were assessed during the first 3 days after birth, and during and for 24 hours after every surgical procedure within the first 3 months after birth. Neurological outcome was determined preoperatively and at 3 months of age by assessing general movements and calculating the Motor Optimality Score (MOS).ResultsThirty-six infants were included. MOS at 3 months was associated with MCA-PI (rho 0.41, P = 0.04), UA-PI (rho -0.39, P = 0.047, and CPR (rho 0.50, P = 0.01). Infants with abnormal MOS had lower MCA-PI (P = 0.02) and CPR (P = 0.01) and higher UA-PI at the last measurement (P = 0.03) before birth. In infants with abnormal MOS, r(c)SO(2) tended to be lower during the first 3 days after birth, and FTOE was significantly higher on the second day after birth (P = 0.04). Intraoperative and postoperative r(c)SO(2) and FTOE were not associated with short-term neurological outcome.ConclusionIn infants with prenatally diagnosed CHD, the prenatal period may play an important role in developmental outcome. Additional research is needed to clarify the relationship between preoperative, intra-operative and postoperative cerebral oxygenation and developmental outcome in infants with prenatally diagnosed CHD.

Background T-wave area dispersion (TW-Ad) is a novel electrocardiographic (ECG) repolarization marker associated with sudden cardiac death. However, limited data is available on the clinical correlates of TW-Ad. In addition, there are no previous studies on cardiovascular drug effects on TW-Ad. In this study, we examined the relation between TW-Ad and left ventricular mass. We also studied the effects of four commonly used antihypertensive drugs on TW-Ad. Methods A total of 242 moderately hypertensive males (age, 51±6 years; office systolic/diastolic blood pressure during placebo, 153±14/100±8 mmHg), participating in the GENRES study, were included. Left ventricular mass index was determined by transthoracic echocardiography. Antihypertensive four-week monotherapies (a diuretic, a beta-blocker, a calcium channel blocker, and an angiotensin receptor antagonist) were administered in a randomized rotational fashion. Four-week placebo periods preceded all monotherapies. The average value of measurements (over 1700 ECGs in total) from all available placebo periods served as a reference to which measurements during each drug period were compared. Results Lower, i.e. risk-associated TW-Ad values correlated with a higher left ventricular mass index (r = −0.14, p = 0.03). Bisoprolol, a beta-blocker, elicited a positive change in TW-Ad (p = 1.9×10−5), but the three other drugs had no significant effect on TW-Ad. Conclusions Our results show that TW-Ad is correlated with left ventricular mass and can be modified favorably by the use of bisoprolol, although demonstration of any effects on clinical endpoints requires long-term prospective studies. Altogether, our results suggest that TW-Ad is an ECG repolarization measure of left ventricular arrhythmogenic substrate.

BackgroundThyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable.ObjectivesThe objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules.Search methodsWe searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018.Selection criteriaWe included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed).Data collection and analysisTwo review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible.Main resultsIn 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%.An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment.At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%).Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100).Authors' conclusionsBoth basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Background Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable. Objectives The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules. Search methods We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018. Selection criteria We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed). Data collection and analysis Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible. Main results In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . Authors' conclusions Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Background Fetal growth restriction, i.e. the restriction of genetically predetermined growth potential due to placental dysfunction, is a major cause of neonatal morbidity and mortality. The consequences of inadequate fetal growth can be life-long, but the risks can be reduced substantially if the condition is identified prenatally. Currently, screening strategies are based on ultrasound detection of a small-for-gestational age fetus and do not take into account the underlying vascular pathology in the placenta. Measurement of maternal circulating angiogenic biomarkers placental growth factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) are increasingly used in studies on fetal growth restriction as they reflect the pathophysiological process in the placenta. However, interpretation of the role of angiogenic biomarkers in prediction of fetal growth restriction is hampered by the varying design, population, timing, assay technique and cut-off values used in these studies. Methods We conducted a systematic-review in PubMed (MEDLINE), EMBASE (Ovid) and Cochrane to explore the predictive performance of maternal concentrations of placental growth factor, sFlt-1 and their ratio for fetal growth restriction and small-for-gestational age, at different gestational ages, and describe the longitudinal changes in biomarker concentrations and optimal discriminatory cut-off values. Results We included 26 studies with 2514 cases with small-for-gestational age, 27 cases of fetal growth restriction, 582 cases mixed small-for-gestational age/fetal growth restriction and 29,374 reference. The largest mean differences for the two biomarkers and their ratio were found after 26 weeks of gestational age and not in the first trimester. The ROC-AUC varied between 0.60 and 0.89 with sensitivity and specificity matching the different cut-off values or a preset false-positive rate of 10%. Conclusions Most of the studies did not make a distinction between small-for-gestational age and fetal growth restriction, and therefore the small-for-gestational age group consists of fetuses with growth restriction and fetuses that are constitutionally normal. The biomarkers can be a valuable screening tool for small-for-gestational age pregnancies, but unfortunately, there is not yet a clear cut-off value to use for screening. More research is needed to see if these biomarkers are sufficiently able to differentiate growth restriction on their own and how these biomarkers in combination with other relevant clinical and ultrasound parameters can be used in clinical routine diagnostics.