Pentastatin, a matrikine of the collagen IVα5, is a novel endogenous mediator of pulmonary endothelial dysfunction.

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to ß1-integrin subunit clustering and Rho/ROCK activation. Blockage of the ß1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.NEW & NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the ß1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.

Diastolic exercise stress testing in heart failure with preserved ejection fraction: The DEST-HF study.

AIMS: Pulmonary capillary wedge pressure (PAWP) ≥25 mmHg during bicycle ergometry is recommended to uncover occult heart failure with preserved ejection fraction. We hypothesized that PAWP increase would differ in available diastolic stress tests and that the margin of PAWP ≥25 mmHg would only be reliably achieved through ergometry. METHODS AND RESULTS: We conducted a prospective, single-arm study in patients with an intermediate risk for heart failure with preserved ejection fraction according to the ESC HFA-PEFF score. A total of 19 patients underwent four stress test modalities in randomized order: leg raise, fluid challenge, handgrip, and bicycle ergometry. The primary outcome was the difference (Δ) between resting and exercise PAWP in each modality. Secondary outcomes were differences (Δ) in mean pulmonary artery pressure (mPAP), cardiac output (CO), as well as the ratios between mPAP and PAWP to CO. Compared to resting values, passive leg raise (Δ7.7 ± 8.0 mmHg, p = 0.030), fluid challenge (Δ9.2 ± 6.4 mmHg, p = 0.003), dynamic handgrip (Δ9.6 ± 7.5 mmHg, p = 0.002), and bicycle ergometry (Δ22.3 ± 5.0 mmHg, p < 0.001) uncovered increased PAWP during exercise. Amongst these, bicycle ergometry also demonstrated the highest ΔmPAP (27.2 ± 7.1 mmHg, p < 0.001), ΔCO (3.3 ± 2.6 L/min, p < 0.001), ΔmPAP/CO ratio (2.3 ± 2.0 mmHg/L/min, p < 0.001), and ΔPAWP/CO ratio (2.2 ± 1.4 mmHg/L/min, p < 0.001) compared to other modalities. PAWP ≥25 mmHg was only reliably achieved in bicycle ergometry (31.1 ± 3.9 mmHg). In all other modalities only 10.5% of patients achieved PAWP ≥25 mmHg (handgrip 18.4 ± 6.6 mmHg, fluid 18.1 ± 5.6 mmHg, leg raise 16.5 ± 7.0 mmHg). CONCLUSIONS: We demonstrate that bicycle ergometry exhibits a distinct haemodynamic response with higher increase of PAWP compared to other modalities. This finding needs to be considered for valid detection of exercise PAWP ≥25 mmHg when non-bicycle tests remain inconclusive.

[Measures and Recommendations for Ensuring Adequate Inpatient Care Capacities for Pandemic Management within a Region: Results of a Hybrid Delphi Method]. / Maßnahmen und Empfehlungen für die Sicherstellung adäquater stationärer Versorgungskapazitäten für das Pandemiemanagement innerhalb einer Region ­ Ergebnisse eines hybriden Delphi-Verfahrens.

INTRODUCTION: Since the beginning of the pandemic in spring 2020, inpatient healthcare has been under enormous burden, which is reflected especially in overworked staff, imprecise bed planning and/or data transfer. According to the recommendation of the Science Council, university clinics should play a controlling role in regional healthcare and act in conjunction with surrounding hospitals and practices. METHODS: In September 2021, 31 representatives from 18 university hospitals were invited to a hybrid Delphi study with a total of 4 survey rounds to discuss criteria for effective inpatient care in a pandemic situation, which were extracted from previous expert interviews. Criteria that were classified as very important/relevant by≥75% of the participants in the first round of the survey (consensus definition) were then further summarized in 4 different small groups. In a third Delphi round, all participants came together again to discuss the results of the small group discussions. Subsequently, these were prioritized as Optional ("can"), Desirable ("should") or Necessary ("must") recommendations. RESULTS: Of the invited clinical experts, 21 (67.7%) participated in at least one Delphi round. In an online survey (1st Delphi round), 233 criteria were agreed upon and reduced to 84 criteria for future pandemic management in four thematic small group discussions (2nd Delphi round) and divided into the small groups as follows: "Crisis Management and Crisis Plans" (n=20), "Human Resources Management and Internal Communication" (n=16), "Regional Integration and External Communication" (n=24) and "Capacity Management and Case & Care" (n=24). In the following group discussion (3rd Delphi round), the criteria were further modified and agreed upon by the experts, so that in the end result, there were 23 essential requirements and recommendations for effective inpatient care in a pandemic situation. CONCLUSION: The results draw attention to key demands of clinical representatives, for example, comprehensive digitization, standardization of processes and better (supra) regional networking in order to be able to guarantee needs-based care even under pandemic conditions. The present consensus recommendations can serve as guidelines for future pandemic management in the inpatient care sector.

Development and validation of a screening questionnaire for early identification of pregnant women at risk for excessive gestational weight gain.

BACKGROUND: Excessive weight gain during pregnancy is associated with adverse health outcomes for mother and child. Intervention strategies to prevent excessive gestational weight gain (GWG) should consider women's individual risk profile, however, no tool exists for identifying women at risk at an early stage. The aim of the present study was to develop and validate a screening questionnaire based on early risk factors for excessive GWG. METHODS: The cohort from the German "Gesund leben in der Schwangerschaft"/ "healthy living in pregnancy" (GeliS) trial was used to derive a risk score predicting excessive GWG. Sociodemographics, anthropometrics, smoking behaviour and mental health status were collected before week 12th of gestation. GWG was calculated using the last and the first weight measured during routine antenatal care. The data were randomly split into development and validation datasets with an 80:20 ratio. Using the development dataset, a multivariate logistic regression model with stepwise backward elimination was performed to identify salient risk factors associated with excessive GWG. The ß coefficients of the variables were translated into a score. The risk score was validated by an internal cross-validation and externally with data from the FeLIPO study (GeliS pilot study). The area under the receiver operating characteristic curve (AUC ROC) was used to estimate the predictive power of the score. RESULTS: 1790 women were included in the analysis, of whom 45.6% showed excessive GWG. High pre-pregnancy body mass index, intermediate educational level, being born in a foreign country, primiparity, smoking, and signs of depressive disorder were associated with the risk of excessive GWG and included in the screening questionnaire. The developed score varied from 0-15 and divided the women´s risk for excessive GWG into low (0-5), moderate (6-10) and high (11-15). The cross-validation and the external validation yielded a moderate predictive power with an AUC of 0.709 and 0.738, respectively. CONCLUSIONS: Our screening questionnaire is a simple and valid tool to identify pregnant women at risk for excessive GWG at an early stage. It could be used in routine care to provide targeted primary prevention measures to women at particular risk to gain excessive gestational weight. TRIAL REGISTRATION: NCT01958307, ClinicalTrials.gov, retrospectively registered 9 October 2013.

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

One Website to Gather them All: Usability Testing of the New German SKin Cancer INFOrmation (SKINFO) Website-A Mixed-methods Approach.

Skin cancer patients increasingly search the internet to acquire disease-related information. However, information on the internet may be misleading. Recently, SKINFO has been launched, a website exclusively created for German-speaking skin cancer patients providing information as well as additional resources of verified quality. Here, we describe the results of the first usability test of SKINFO using a mixed-methods approach. Ten adult patients with skin cancer were recruited for usability testing in the skin cancer units of the University Hospitals of Erlangen and Dresden, Germany. Testing consisted of three different scenarios where patients were asked to find specific information on the SKINFO website guided by the think-aloud method. Descriptive analysis and content analyses were performed. All patients would recommend SKINFO and appreciated its content, design, and structure. Think-aloud analysis identified the topics layout, navigation, and content and structure which would benefit from refinement. Major criticism included the navigation through the website, and the desire for more specific information addressing patients' relatives and the latest, up-to-date information. Overall, usability testing showed that the unique web-based information platform has the potential to support patients coping with skin cancer and thus strengthen informed decision-making.

Exercise oscillatory ventilation in patients with advanced heart failure with and without left ventricular assist device.

BACKGROUND: Exercise oscillatory ventilation (EOV), indicating pathological fluctuations on pulmonary arterial pressure, is associated with mortality in patients with heart failure (HF). Whether left ventricular assist device (LVAD)-induced ventricular unloading can reverse EOV and may prevent short-term rehospitalization has not been investigated. METHODS: We performed a retrospective single-center in- and outpatient analysis of patients with (n = 20, LVAD) and without (n = 27, HF) circulatory support and reduced ejection fraction (EF, 22.8 ± 7.9%). The association of cardiopulmonary exercise testing (CPET) variables and 3 months-rehospitalization (3MR) as a primary outcome was analyzed. Furthermore, CPET variables were compared regarding the presence of EOV (+/-). RESULTS: Lower VO2peak (11.6 ± 4.9 ml/kg/min vs. 14.4 ± 4.3 ml/kg/min, p = 0.039), lower increase of PETCO2 (CI = 0.049-1.127; p = 0.068), and higher VE/VCO2 (43.8 ± 9.5 vs. 38.3 ± 10.6; p = 0.069) were associated with 3MR. Flattening of O2 pulse (CI = 0.139-2.379; p = 0.487) had no impact on 3MR. EOV was present in 59.5% (n = 28/47) of patients, without a significant difference between LVAD and HF patients (p = 0.959). Patients with HF/EOV+ demonstrated significantly lower VO2peak compared with HF/EOV- (p = 0.039). LVAD/EOV+ displayed significantly lower EF (p = 0.004) and fewer aortic valve opening than LVAD/EOV- (p = 0.027). CONCLUSIONS: Lower VO2peak , but not EOV, was associated with 3MR. EOV occurred at a similar rate in LVAD and HF patients, which may illustrate insufficient unloading during exercise in chronic LVAD therapy and may contribute to the limited exercise capacity following LVAD implantation. Simultaneous CPET and right heart catheterization studies are needed to elucidate whether EOV may serve as a non-invasive predictor of insufficient LV unloading necessitating LVAD reprograming.

A novel TTR mutation (p.Ala65Val) underlying late-onset hereditary transthyretin (ATTRv) amyloidosis with mixed cardiac and neuropathic phenotype: a case report.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous and phenotypically variable systemic disease characterized by deposition of misfolded transthyretin fibrils in various tissues. ATTRv cardiomyopathy and progressive axonal polyneuropathy are the most common manifestations, leading to severe disability and ultimately death within approximately ten years. As disease-modifying treatment options evolve, timely diagnosis and treatment initiation are crucial to prevent rapid disease progression. CASE PRESENTATION: Here, we report on a 73-year old patient initially diagnosed with cardiac wild-type ATTR (ATTRwt) amyloidosis by endomyocardial biopsy. Molecular genetic analysis revealed a novel TTR sequence variant (p.Ala65Val) that is highly likely to be amyloidogenic in light of previously reported TTR mutations and the patient's clinical presentation and family history. CONCLUSIONS: Our findings expand the spectrum of known pathogenic TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers.

Cochlear Implantation in Obliterated Cochlea: A Retrospective Analysis and Comparison between the IES Stiff Custom-Made Device and the Split-Array and Regular Electrodes.

Anatomical malformations, obliterations of the cochlea, or re-implantations pose particular challenges in cochlear implantation. Treatment methods rely on radiological and intraoperative findings and include incomplete insertion, the implantation of a double array, and radical cochleostomy. In addition, a stiff electrode array, e.g., the IE stiff (IES) custom-made device (CMD, MED-EL), was prescribed individually for those special cases and pre-inserted prior to facilitate cochlear implantation in challenging cases. Data on outcomes after implantation in obliterated cochleae are usually based on individual case reports since standardised procedures are lacking. A retrospective analysis was conducted to analyse our cases on obliterated cochleae treated with MED-EL devices in order to allow the different cases to be compared. Impedances and speech perception data of patients treated with the IES CMD and the double array were retrospectively compared to patients treated with a STANDARD or FLEX electrode array (the REGULAR group). Patients with a Split-Array CMD had a poor speech perception when compared to patients treated with the IES CMD device. Thus, the IES CMD can successfully be used in patients with obliterated cochleae who would otherwise be non-users, candidates for a Split-Array CMD, or candidates for partial insertion with insufficient cochlear coverage.

Dietary Supplementation Before, During and After Pregnancy: Results of the Cluster-Randomized GeliS Study.

Introduction The nutritional status of women before, during, and after pregnancy plays an important role in the health of mother and child. In addition to a balanced mixed diet, the increased need for folic acid and iodine should be met and ensured with supplements. The aim of this study was to assess dietary supplementation in the context of pregnancy and to investigate the effect of targeted counselling on supplementation behavior during and after pregnancy. Methods In the context of the "Gesund leben in der Schwangerschaft" (GeliS; "Healthy living in pregnancy") trial, women in the intervention group (IG) received four structured lifestyle counselling sessions during pregnancy as well as postpartum, during which they were informed about appropriate dietary supplementation. The women in the control group (CG) received routine prenatal care. The intake of dietary supplements was recorded at different points using a questionnaire. Results In total, 2099 women were included in the analysis. Prior to conception, 31.3% of the women in the IG and 31.4% of the women in the CG took folic acid supplements. Prenatally, about half of the women took folic acid (IG: 54.1%; CG: 52.0%) and iodine (IG: 50.2%; CG: 48.2%). Statistically significant differences between the groups with regard to supplementation behavior could not be observed, neither prior to inclusion in the study nor during the intervention. During pregnancy, 23.0% of all women took docosahexaenoic acid (DHA) supplements and 21.8% iron supplements. 49.4% of the women additionally took vitamin D supplements. A higher educational level (p < 0.001), advanced age (p < 0.001), primiparity (p < 0.001), and a vegetarian diet (p = 0.037) were all associated with a higher level of dietary supplementation. Conclusion The GeliS lifestyle counselling did not significantly improve the supplementation behavior of women during and after pregnancy. Women should be informed about adequate dietary supplementation early on within the scope of gynecological prenatal care.

Impairment of the NKT-STAT1-CXCL9 Axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Caused by Lung Fibrosis.

Rationale: Pulmonary hypertension (PH) is a common, severe comorbidity in interstitial lung diseases such as pulmonary fibrosis (PF), and it has limited treatment options. Excessive vascular fibrosis and inflammation are often present in PH, but the underlying mechanisms are still not well understood. Objectives: To identify a novel functional link between natural killer T (NKT) cell activation and vascular fibrosis in PF-PH. Methods: Multicolor flow cytometry, secretome, and immunohistological analyses were complemented by pharmacological NKT cell activation in vivo, in vitro, and ex vivo. Measurements and Main Results: In pulmonary vessels of patients with PF-PH, increased collagen deposition was linked to a local NKT cell deficiency and decreased IL-15 concentrations. In a mouse model of PH caused by lung fibrosis, pharmacological NKT cell activation using a synthetic α-galactosylceramide analog (KRN7000) restored local NKT cell numbers and ameliorated vascular remodeling and right ventricular systolic pressure. Supplementation with activated NKT cells reduced collagen deposition in isolated human pulmonary arterial smooth muscle cells (hPASMCs) and in ex vivo precision-cut lung slices of patients with end-stage PF-PH. Coculture with activated NKT cells induced STAT1 signaling in hPASMCs. Secretome analysis of peripheral blood mononuclear cells identified CXCL9 and CXCL10 as indicators of NKT cell activation. Pharmacologically, CXCL9, but not CXCL10, potently inhibited collagen deposition in hPASMCs via the chemokine receptor CXCR3. Conclusions: Our results indicate that the absence of NKT cells impairs the STAT1-CXCL9-CXCR3 axis in PF-PH and that restoration of this axis by NKT cell activation may unravel a novel therapeutic strategy to target vascular fibrosis in interstitial lung disease.

Parents' experiences regarding neonatal care during the COVID-19 pandemic: country-specific findings of a multinational survey.

OBJECTIVES: The COVID-19 pandemic has disrupted healthcare systems, challenging neonatal care provision globally. Curtailed visitation policies are known to negatively affect the medical and emotional care of sick, preterm and low birth weight infants, compromising the achievement of the 2030 Development Agenda. Focusing on infant and family-centred developmental care (IFCDC), we explored parents' experiences of the disruptions affecting newborns in need of special or intensive care during the first year of the pandemic. DESIGN: Cross-sectional study using an electronic, web-based questionnaire. SETTING: Multicountry online-survey. METHODS: Data were collected between August and November 2020 using a pretested online, multilingual questionnaire. The target group consisted of parents of preterm, sick or low birth weight infants born during the first year of the COVID-19 pandemic and who received special/intensive care. The analysis followed a descriptive quantitative approach. RESULTS: In total, 1148 participants from 12 countries (Australia, Brazil, Canada, China, France, Italy, Mexico, New Zealand, Poland, Sweden, Turkey and Ukraine) were eligible for analysis. We identified significant country-specific differences, showing that the application of IFCDC is less prone to disruptions in some countries than in others. For example, parental presence was affected: 27% of the total respondents indicated that no one was allowed to be present with the infant receiving special/intensive care. In Australia, Canada, France, New Zealand and Sweden, both the mother and the father (in more than 90% of cases) were allowed access to the newborn, whereas participants indicated that no one was allowed to be present in China (52%), Poland (39%), Turkey (49%) and Ukraine (32%). CONCLUSIONS: The application of IFCDC during the COVID-19 pandemic differs between countries. There is an urgent need to reconsider separation policies and to strengthen the IFCDC approach worldwide to ensure that the 2030 Development Agenda is achieved.

Child Anthropometrics and Neurodevelopment at 2 and 3 Years of Age Following an Antenatal Lifestyle Intervention in Routine Care-A Secondary Analysis from the Cluster-Randomised GeliS Trial.

Maternal characteristics around pregnancy may influence obesity risk and neurodevelopment in children. To date, the effect of antenatal lifestyle interventions on long-term child development is unclear. The objective was to investigate the potential long-term effects of an antenatal lifestyle intervention programme conducted alongside routine care on child anthropometrics and neurodevelopment up to 3 years of age. Mother-child pairs from the cluster-randomised GeliS trial were followed up to 3 years of age. Data on child anthropometrics in both groups were collected from routine health examinations. Neurodevelopment was assessed via questionnaire. Of the 2286 study participants, 1644 mother-child pairs were included in the analysis. Children from the intervention group were less likely to score below the cut-off in Fine motor (p = 0.002), and more likely to have a score below the cut-off in Problem-solving (p < 0.001) compared to the control group at 3 years of age. Mean weight, height, head circumference, body mass index, and the respective z-scores and percentiles were comparable between the groups at 2 and 3 years of age. We found no evidence that the lifestyle intervention affected offspring development up to 3 years of age. Further innovative intervention approaches are required to improve child health in the long-term.

Are pre- and early pregnancy lifestyle factors associated with the risk of preterm birth? A secondary cohort analysis of the cluster-randomised GeliS trial.

BACKGROUND: Maternal lifestyle is discussed as a modifiable determinant in the prevention of preterm birth. However, previous research on associations between individual lifestyle factors and preterm birth risk is inconclusive. In this secondary analysis, we investigated the associations between several modifiable antenatal lifestyle factors and the odds of preterm birth. METHODS: This secondary cohort analysis used data from the cluster-randomised controlled "healthy living in pregnancy" (GeliS) trial. Data were collected from early pregnancy to birth with maternity records, validated questionnaires and birth protocols. Women with complete datasets for all covariates were eligible for analysis. Multivariate logistic regression models, adjusted for recognised risk factors, were fitted to determine whether dietary quality, assessed with a healthy eating index (HEI), physical activity (PA) levels and antenatal anxiety/distress influenced the odds of preterm birth. Moreover, the combined association between pre-pregnancy body mass index (BMI) and HEI on the odds of preterm birth was explored. The independent associations of individual dietary components and types of PA on prematurity were assessed by adjusted logistic regression models. RESULTS: Overall, 1738 women were included in the analysis. A low HEI significantly increased the odds of preterm birth (OR 1.54 (CI 1.04 - 2.30), p = 0.033), while no associations with either low PA levels or antenatal anxiety/distress were observed. BMI significantly interacted with HEI on the association with prematurity (p = 0.036). Energy % from protein and the intake of average portions of vegetables and cereals were significantly negatively associated with the odds of preterm birth. There was no significant evidence of an association between different types of PA and prematurity. CONCLUSIONS: This cohort analysis revealed that low dietary quality in early pregnancy may increase the chance of giving birth prematurely, while healthier dietary choices may help to prevent preterm birth. More research on pre- and early pregnancy modifiable lifestyle factors is warranted. TRIAL REGISTRATION: This trial is registered with the Clinical Trial Registry ClinicalTrials.gov ( NCT01958307 ). Registration date 09 October 2013, retrospectively registered.

[Process for the Implementation of Evidence-Based Parenteral Nutrition in German Perinatal Centres - Outcomes of a Multidisciplinary Network]. / Prozess zur Implementierung Evidenzbasierter Parenteraler Ernährung in Deutschen Perinatalzentren ­ Ergebnisse eines Multidisziplinären Netzwerks.

INTRODUCTION: Parenteral nutrition, usually indicated for preterm infants with a birthweight<1500 g and sick newborns, enables the supply with critical nutrients. As a high degree of therapy safety is required, a European guideline provides recommendations for safe therapy procedures. The present project aimed to evaluate the implementation of the European guideline in German perinatal centers and to identify possible barriers that impede its implementation. A further goal was to develop solution approaches to overcome possible barriers. METHODS AND RESULTS: A multidisciplinary cooperation conducted an online survey questioning the current implementation procedures of the European guideline among pediatricians and hospital pharmacists. Results show barriers in the provisioning process of parenteral nutrition that hinder a guideline-compliant implementation in practice. Based on results of this survey, an expert network developed an interactive toolkit with simplified guideline recommendations, guideline-compliant advice for practice, best-practice examples, forms, and handouts. It seeks to encourage critical reflection of routine processes and provides concrete solutions to overcome barriers in practice. CONCLUSION: The current procedures related to parenteral nutrition deviate from guideline recommendations. The developed toolkit provides practice-oriented support aiming to enhance the guideline-compliant implementation of parenteral nutrition in perinatal centers.

Clinical features and predictors of atrial fibrillation in patients with light-chain or transthyretin cardiac amyloidosis.

AIMS: The study aimed to investigate the prevalence, phenotypic characteristics, and predictors of atrial fibrillation (AF) in patients presenting with cardiac amyloidosis (CA) of light-chain (AL) or transthyretin (ATTR) type. METHODS AND RESULTS: Clinical, biochemical, and echocardiographic data of patients presenting with CA between 2005 and 2020 were retrospectively collected. CA staging was based on established biomarker systems. Binomial logistic regression was run to analyse the effects of clinical variables on the likelihood of AF. The study included 133 patients [53% AL, 41% wild-type (wt) ATTR-CA, & 6% hereditary ATTR-CA]. Mean age was 71 years, and 80% were male patients. AF was diagnosed in 64 (48%) patients (28% in AL-CA, 80% in wtATTR, 13% in hATTR, P < 0.001). Patients with AF were older (74 vs. 69 years, P < 0.001), more likely to have wtATTR-CA (67 vs. 16%, P < 0.001), exhibited more often New York Heart Association ≥ III symptoms (66 vs. 45%, P = 0.02) and carried a higher burden of comorbidities. AF patients had lower left ventricular ejection fraction (47 vs. 53%, P < 0.005), higher left atrial volume index (54 vs. 46 mL/m2 , P = 0.007), higher pulmonary artery pressure (42 vs. 31 mmHg, P = 0.008), and worse tricuspid annular plane systolic excursion values (17 vs. 20 mm, P = 0.01). Mitral regurgitation ≥ Grade 2 was more frequent in AF (56 vs. 25%, P < 0.001). Higher ATTR-CA stage was associated with higher AF prevalence (47% vs. 74% vs. 94%, P < 0.001, for Stages I, II, & III, respectively). Higher AL-CA stage was associated with lower AF prevalence (0% vs. 40% vs. 31% vs. 18%, P < 0.001, for Stages I, II, IIIa, & IIIb, respectively). Three independent predictors for AF were identified in a multivariate logistic regression model with 81.5% classification accuracy: AL type [odds ratio (OR) 0.1, confidence interval (CI) 0.01-0.29, P = 0.001], estimated glomerular filtration rate (OR 0.9, CI 0.93-0.99, P = 0.03), and body mass index (OR 1.3, CI 1.07-1.66, P = 0.01). ATTR amyloidosis was associated with a 10-fold higher risk of AF. During 1 year follow-up, only one episode of ischaemic stroke was reported. CONCLUSIONS: Atrial fibrillation affects nearly half of all patients with CA. Patients presenting with AF have more severe symptoms and higher burden of comorbidities. ATTR type of amyloidosis is the strongest predictor of AF. Prospective screening for occult AF may be considered in ATTR-CA.

Analysis of the Excess of Papanicolaou Tests in Brazil from 2006 to 2015.

OBJECTIVE: To analyze the quantity of cervical smears, also designated Papanicolaou tests, between 2006 and 2015 in all the Federal units of Brazil, as well as to verify the quantity of exams collected outside the recommended age range and the economic impact of such excess. METHODS: The data was collected from the Ministry of Health's database called Sistema de Informação do Câncer do Colo de Útero (SISCOLO), which contains all the test results collected nationwide by the Unified Health System (SUS, in the Portuguese acronym). From that, the number of exams and the age range of the women who underwent them were analyzed; besides, these numbers were stratified according to the state of where the exam was performed. The quantity of exams collected outside the recommended age range was verified, and, so, the economic impact generated was noted. RESULTS: Between 2006 and 2015, 87,425,549 Papanicolaou tests were collected in Brazil. Of these, 20,215,052 tests were collected outside the age range recommended by the Brazilian Ministry of Health; this number corresponded to 23.12% of all exams. From such data, considering that each Pap smear collected by SUS generates a cost of BRL 7.30 to the government, according to the information in the Tabela SUS dated September 2018, there was a total charge of BRL 147,569,880 for tests collected outside the protocol. CONCLUSION: In Brazil, according to the Ministry of Health's protocol about the recommended practices on collecting Pap smears, whose newest edition dates of 2016, it is recommended that Pap smears are collected in women from a specific age range, in whom the potential diagnosing advantages overcome the onus of overdiagnosis or of a lesion with great regression potential. However, such protocols have not been correctly followed, promoting more than 20 million tests in excess, and an exorbitant cost for the Brazilian public health system. It is relevant to take measures to correctly use the official protocol, reducing the patients risks, as well as the economic impact for SUS.

OBJETIVO: Analisar a quantidade de exames cérvico-vaginais, também chamados de Teste de Papanicolau, entre os anos de 2006 e 2015 em todos os estados brasileiros, bem como verificar o número de exames realizados fora da faixa etária indicada, e o impacto econômico desse excesso. MéTODOS: Os dados foram coletados a partir da base de dados do Ministério da Saúde chamada Sistema de Informação do Câncer do Colo de Útero (SISCOLO), que reúne os resultados de exames realizados em todo o Brasil pelo sistema único de saúde (SUS). A partir disso, foi analisado o número de exames e a faixa-etária de realização dos mesmos; além disso, esses números foram estratificados de acordo com o estado brasileiro de origem do exame. Foi verificada a quantidade de exames fora da idade recomendada, e, assim, foi observado o impacto econômico gerado. RESULTADO: Entre 2006 e 2015, 87.425.549 exames de Papanicolau foram realizados no Brasil. Deste montante, 20.215.052 testes foram realizados fora da faixa-etária preconizada pelo Ministério da Saúde do Brasil, o que equivale a 23,12% do total. A partir desse número, considerando que cada exame cérvico -vaginal realizado pelo SUS gera um custo de R$ 7,30 para o governo, de acordo com informações na Tabela SUS datada de setembro de 2018, foram gastos R$ 147.569.880 em exames realizados sem indicação. CONCLUSãO: No Brasil, no protocolo do Ministério da Saúde sobre as práticas adequadas em coleta de exames cérvico-vaginais, sendo sua edição mais recente de 2016, a recomendação é realizar o teste de Papanicolau em mulheres dentro de uma faixa-etária específica, na qual a chance de se diagnosticar uma lesão supera o ônus de um sobrediagnóstico ou uma lesão com grande potencial de regressão. Entretanto, essa recomendação não tem sido seguida corretamente, gerando mais de 20 milhões de exames excedentes e um custo monetário exorbitante para o sistema público de saúde. É importante que medidas sejam tomadas para que o protocolo seja empregado corretamente a fim de reduzir riscos para a paciente, bem como a redução de gastos desnecessários para o SUS.

Analysis of the Excess of Papanicolaou Tests in Brazil from 2006 to 2015 / Análise do excesso de testes de Papanicolaou no Brasil entre 2006 e 2015

Abstract Objective To analyze the quantity of cervical smears, also designated Papanicolaou tests, between 2006 and 2015 in all the Federal units of Brazil, as well as to verify the quantity of exams collected outside the recommended age range and the economic impact of such excess. Methods The data was collected from the Ministry of Health's database called Sistema de Informação do Câncer do Colo de Útero (SISCOLO), which contains all the test results collected nationwide by the Unified Health System (SUS, in the Portuguese acronym). From that, the number of exams and the age range of thewomen who underwent them were analyzed; besides, these numbers were stratified according to the state of where the exam was performed. The quantity of exams collected outside the recommended age range was verified, and, so, the economic impact generated was noted. Results Between 2006and2015, 87,425,549Papanicolaoutestswere collected in Brazil. Of these, 20,215,052 testswere collected outside the age range recommended by the Brazilian Ministry of Health; this number corresponded to 23.12% of all exams. From such data, considering that each Pap smear collected by SUS generates a cost of BRL 7.30 to the government, according to the information in the Tabela SUS dated September 2018, there was a total charge of BRL 147,569,880 for tests collected outside the protocol. Conclusion In Brazil, according to the Ministry of Health's protocol about the recommended practices on collecting Pap smears, whose newest edition dates of 2016, it is recommended that Pap smears are collected inwomen from a specific age range, inwhom the potential diagnosing advantages overcome the onus of overdiagnosis or of a lesion with great regression potential. However, such protocols have not been correctly followed, promoting more than 20 million tests in excess, and an exorbitant cost for the Brazilian public health system. It is relevant to take measures to correctly use the official protocol, reducing the patients risks, as well as the economic impact for SUS.

Resumo Objetivo Analisar a quantidade de exames cérvico-vaginais, também chamados de Teste de Papanicolau, entre os anos de 2006 e 2015 em todos os estados brasileiros, bem como verificar o número de exames realizados fora da faixa etária indicada, e o impacto econômico desse excesso. Métodos Os dados foram coletados a partir da base de dados do Ministério da Saúde chamada Sistema de Informação do Câncer do Colo de Útero (SISCOLO), que reúne os resultados de exames realizados em todo o Brasil pelo sistema único de saúde (SUS). A partir disso, foi analisado o número de exames e a faixa-etária de realização dos mesmos; além disso, esses números foram estratificados de acordo com o estado brasileiro de origem do exame. Foi verificada a quantidade de exames fora da idade recomendada, e, assim, foi observado o impacto econômico gerado. Resultado Entre 2006 e 2015, 87.425.549 exames de Papanicolau foram realizados no Brasil. Deste montante, 20.215.052 testes foram realizados fora da faixa-etária preconizada pelo Ministério da Saúde do Brasil, o que equivale a 23,12% do total. A partir desse número, considerando que cada exame cérvico -vaginal realizado pelo SUS gera um custo de R$ 7,30 para o governo, de acordo com informações na Tabela SUS datada de setembro de 2018, foram gastos R$ 147.569.880 em exames realizados sem indicação. Conclusão No Brasil, no protocolo do Ministério da Saúde sobre as práticas adequadas em coleta de exames cérvico-vaginais, sendo sua edição mais recente de 2016, a recomendação é realizar o teste de Papanicolau em mulheres dentro de uma faixaetária específica, na qual a chance de se diagnosticar uma lesão supera o ônus de um sobrediagnóstico ou uma lesão com grande potencial de regressão. Entretanto, essa recomendação não tem sido seguida corretamente, gerando mais de 20 milhões de exames excedentes e umcusto monetário exorbitante para o sistema público de saúde. É importante que medidas sejam tomadas para que o protocolo seja empregado corretamente a fim de reduzir riscos para a paciente, bem como a redução de gastos desnecessários para o SUS.