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Seltene Erkrankungen (SE) werden durch die im deutschen Gesundheitssystem verwendete Diagnosenklassifikation ICD-10-GM (International Statistical Classification of Diseases and Related Health problems, 10th Revision, German Modification) nur zu einem kleinen Teil eindeutig erfasst. Daher sind Aussagen zur Häufigkeit von SE sowie zum speziellen Versorgungs- und Finanzierungsbedarf nicht möglich, was zu einer lückenhaften Datenlage als Entscheidungsgrundlage für Krankenkassen, Leistungserbringer und Gesundheitspolitik führt. Das Fehlen exakter Informationen behindert auch die wissenschaftliche Arbeit. Daher wird deutschlandweit ab 2023 die Verwendung der Alpha-ID-SE-Datei und der ORPHAcodes für die spezifische Erfassung von SE bei stationären Fällen verpflichtend.
Die Alpha-ID-SE-Datei verknüpft die ICD-10-GM-Kodes mit den international anerkannten ORPHAcodes für die Diagnose von SE. Kommerzielle Anbieter stellen zunehmend die benötigten IT-Tools zur Kodierung von SE zur Verfügung. An mehreren Universitätskliniken mit Zentren für SE wurden Lösungen etabliert, die eine vollständige Kodierung gewährleisten sollen. Hierzu gehören finanzielle Anreize für die kodierenden Bereiche, konkrete Nachfragen nach dem Vorliegen einer SE beim Kodiervorgang und eine semiautomatische Kodierung bei Patient*innen, die schon einmal mit einer SE an der Einrichtung betreut worden waren. Eine Kombination der verschiedenen Ansätze verspricht die höchste Wahrscheinlichkeit einer vollständigen Kodierung.
Für ein umfängliches Bild der SE im Gesundheitssystem und um dem speziellen Versorgungs- und Finanzierungsbedarf besser Rechnung tragen zu können, wäre auch im ambulanten Bereich eine möglichst spezifische und eindeutige Kodierung wünschenswert. Für komplexe SE und bisher undiagnostizierte Patient*innen wird zusätzlich eine strukturierte Erfassung des Phänotyps benötigt.
Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.
Understanding the causal relationship between genotype and phenotype is a major objective in biology. Genome-wide association studies (GWAS) correlate genetic polymorphisms with trait variation and have already identified causative variants for various traits in many different organisms, from humans to plants. Importantly, many adaptive traits, like the regulation of flowering time in plants, are not regulated by distinct genetic effects, but by more sophisticated gene regulatory networks.
FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.
Composite optimization problems, where the sum of a smooth and a merely lower semicontinuous function has to be minimized, are often tackled numerically by means of proximal gradient methods as soon as the lower semicontinuous part of the objective function is of simple enough structure. The available convergence theory associated with these methods (mostly) requires the derivative of the smooth part of the objective function to be (globally) Lipschitz continuous, and this might be a restrictive assumption in some practically relevant scenarios. In this paper, we readdress this classical topic and provide convergence results for the classical (monotone) proximal gradient method and one of its nonmonotone extensions which are applicable in the absence of (strong) Lipschitz assumptions. This is possible since, for the price of forgoing convergence rates, we omit the use of descent-type lemmas in our analysis.
Immunization of preterm infants: current evidence and future strategies to individualized approaches
(2022)
Preterm infants are at particularly high risk for infectious diseases. As this vulnerability extends beyond the neonatal period into childhood and adolescence, preterm infants benefit greatly from infection-preventive measures such as immunizations. However, there is an ongoing discussion about vaccine safety and efficacy due to preterm infants’ distinct immunological features. A significant proportion of infants remains un- or under-immunized when discharged from primary hospital stay. Educating health care professionals and parents, promoting maternal immunization and evaluating the potential of new vaccination tools are important means to reduce the overall burden from infectious diseases in preterm infants. In this narrative review, we summarize the current knowledge about vaccinations in premature infants. We discuss the specificities of early life immunity and memory function, including the role of polyreactive B cells, restricted B cell receptor diversity and heterologous immunity mediated by a cross-reactive T cell repertoire. Recently, mechanistic studies indicated that tissue-resident memory (Trm) cell populations including T cells, B cells and macrophages are already established in the fetus. Their role in human early life immunity, however, is not yet understood. Tissue-resident memory T cells, for example, are diminished in airway tissues in neonates as compared to older children or adults. Hence, the ability to make specific recall responses after secondary infectious stimulus is hampered, a phenomenon that is transcriptionally regulated by enhanced expression of T-bet. Furthermore, the microbiome establishment is a dominant factor to shape resident immunity at mucosal surfaces, but it is often disturbed in the context of preterm birth. The proposed function of Trm T cells to remember benign interactions with the microbiome might therefore be reduced which would contribute to an increased risk for sustained inflammation. An improved understanding of Trm interactions may determine novel targets of vaccination, e.g., modulation of T-bet responses and facilitate more individualized approaches to protect preterm babies in the future.
Task-based measures that capture neurocognitive processes can help bridge the gap between brain and behavior. To transfer tasks to clinical application, reliability is a crucial benchmark because it imposes an upper bound to potential correlations with other variables (e.g., symptom or brain data). However, the reliability of many task readouts is low. In this study, we scrutinized the retest reliability of a probabilistic reversal learning task (PRLT) that is frequently used to characterize cognitive flexibility in psychiatric populations. We analyzed data from N = 40 healthy subjects, who completed the PRLT twice. We focused on how individual metrics are derived, i.e., whether data were partially pooled across participants and whether priors were used to inform estimates. We compared the reliability of the resulting indices across sessions, as well as the internal consistency of a selection of indices. We found good to excellent reliability for behavioral indices as derived from mixed-effects models that included data from both sessions. The internal consistency was good to excellent. For indices derived from computational modeling, we found excellent reliability when using hierarchical estimation with empirical priors and including data from both sessions. Our results indicate that the PRLT is well equipped to measure individual differences in cognitive flexibility in reinforcement learning. However, this depends heavily on hierarchical modeling of the longitudinal data (whether sessions are modeled separately or jointly), on estimation methods, and on the combination of parameters included in computational models. We discuss implications for the applicability of PRLT indices in psychiatric research and as diagnostic tools.
Due to computational advances in the past decades, so-called intelligent systems can learn from increasingly complex data, analyze situations, and support users in their decision-making to address them. However, in practice, the complexity of these intelligent systems renders the user hardly able to comprehend the inherent decision logic of the underlying machine learning model. As a result, the adoption of this technology, especially for high-stake scenarios, is hampered. In this context, explainable artificial intelligence offers numerous starting points for making the inherent logic explainable to people. While research manifests the necessity for incorporating explainable artificial intelligence into intelligent systems, there is still a lack of knowledge about how to socio-technically design these systems to address acceptance barriers among different user groups. In response, we have derived and evaluated a nascent design theory for explainable intelligent systems based on a structured literature review, two qualitative expert studies, a real-world use case application, and quantitative research. Our design theory includes design requirements, design principles, and design features covering the topics of global explainability, local explainability, personalized interface design, as well as psychological/emotional factors.
Contemporary decision support systems are increasingly relying on artificial intelligence technology such as machine learning algorithms to form intelligent systems. These systems have human-like decision capacity for selected applications based on a decision rationale which cannot be looked-up conveniently and constitutes a black box. As a consequence, acceptance by end-users remains somewhat hesitant. While lacking transparency has been said to hinder trust and enforce aversion towards these systems, studies that connect user trust to transparency and subsequently acceptance are scarce. In response, our research is concerned with the development of a theoretical model that explains end-user acceptance of intelligent systems. We utilize the unified theory of acceptance and use in information technology as well as explanation theory and related theories on initial trust and user trust in information systems. The proposed model is tested in an industrial maintenance workplace scenario using maintenance experts as participants to represent the user group. Results show that acceptance is performance-driven at first sight. However, transparency plays an important indirect role in regulating trust and the perception of performance.
Purpose
To determine whether 24-h IOP monitoring can be a predictor for glaucoma progression and to analyze the inter-eye relationship of IOP, perfusion, and progression parameters.
Methods
We extracted data from manually drawn IOP curves with HIOP-Reader, a software suite we developed. The relationship between measured IOPs and mean ocular perfusion pressures (MOPP) to retinal nerve fiber layer (RNFL) thickness was analyzed. We determined the ROC curves for peak IOP (T\(_{max}\)), average IOP(T\(_{avg}\)), IOP variation (IOP\(_{var}\)), and historical IOP cut-off levels to detect glaucoma progression (rate of RNFL loss). Bivariate analysis was also conducted to check for various inter-eye relationships.
Results
Two hundred seventeen eyes were included. The average IOP was 14.8 ± 3.5 mmHg, with a 24-h variation of 5.2 ± 2.9 mmHg. A total of 52% of eyes with RNFL progression data showed disease progression. There was no significant difference in T\(_{max}\), T\(_{avg}\), and IOP\(_{var}\) between progressors and non-progressors (all p > 0.05). Except for T\(_{avg}\) and the temporal RNFL, there was no correlation between disease progression in any quadrant and T\(_{max}\), T\(_{avg}\), and IOP\(_{var}\). Twenty-four-hour and outpatient IOP variables had poor sensitivities and specificities in detecting disease progression. The correlation of inter-eye parameters was moderate; correlation with disease progression was weak.
Conclusion
In line with our previous study, IOP data obtained during a single visit (outpatient or inpatient monitoring) make for a poor diagnostic tool, no matter the method deployed. Glaucoma progression and perfusion pressure in left and right eyes correlated weakly to moderately with each other.
Key messages
What is known:
● Our prior study showed that manually obtained 24-hour inpatient IOP measurements in right eyes are poor predictors for glaucoma progression. The inter-eye relationship of 24-hour IOP parameters and disease progression on optical coherence tomography (OCT) has not been examined.
What we found:
● 24-hour IOP profiles of left eyes from the same study were a poor diagnostic tool to detect worsening glaucoma.
● Significant inter-eye correlations of various strengths were found for all tested parameters
The surgical treatment of parastomal hernias is considered complex and is known to be prone to complications. Traditionally, this condition was treated using relocation techniques or local suture repairs. Since then, several mesh-based techniques have been proposed and are nowadays used in minimally invasive surgery. Since the introduction of robot-assisted surgery to the field of abdominal wall surgery, several adaptations to these techniques have been made, which may significantly improve patient outcomes. In this contribution, we provide an overview of available techniques in robot-assisted parastomal hernia repair. Technical considerations and preliminary results of robot-assisted modified Sugarbaker repair, robot-assisted Pauli technique, and minimally invasive use of a funnel-shaped mesh in the treatment of parastomal hernias are presented. Furthermore, challenges in robot-assisted ileal conduit parastomal hernia repair are discussed. These techniques are illustrated by photographic and video material. Besides providing a comprehensive overview of robot-assisted parastomal hernia repair, this article focuses on the specific advantages of robot-assisted techniques in the treatment of this condition.
Purpose of Review
We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production.
Recent Findings
Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes.
Summary
The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.
Severe and prolonged liver damage in pityriasis rubra pilaris treated with acitretin: a case report
(2022)
Acitretin is a systemic retinoid that is used in dermatology for treatment of various inflammatory and especially hyperkeratotic diseases. Elevation of liver enzymes may occur occasionally but normally resolves spontaneously, at the latest after termination of acitretin. However, it can very rarely develop into a life-threatening adverse event including drug-induced liver injury (DILI). A 45-year-old man with classical pityriasis rubra pilaris, a frequently severe, inflammatory skin disease, was started on acitretin. After a seemingly harmless elevation of transaminases, a few weeks after initiation of acitretin, the patient experienced a dramatic course of liver injury with hepatic jaundice though acitretin was stopped immediately. Eventually, laboratory values recovered upon high-dose oral prednisolone therapy. Prescribing physicians should keep in mind that acitretin might induce severe liver injury. Even after termination of acitretin laboratory values should be monitored for a while in order to recognize symptomless but harmful drug-induced liver injury in time.
Purpose
A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures.
Methods
A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels.
Results
From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13–93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24–33.56).
Conclusion
[\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.
Background
An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied.
Methods
In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls.
Results
Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0% vs. 32.2%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53% vs 23.78 ± 9.89% after 1 year, p < 0.05 and 32.13 ± 10.5% vs 22.21 ± 10.9% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up.
Conclusion
A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients’ expectations.
The July 2021 heavy rainfall episode in parts of Western Europe caused devastating floods, specifically in Germany. This study examines circulation types (CTs) linked to extreme precipitation in Germany. It was investigated if the classified CTs can highlight the anomaly in synoptic patterns that contributed to the unusual July 2021 heavy rainfall in Germany. The North Atlantic Oscillation was found to be the major climatic mode related to the seasonal and inter-annual variations of most of the classified CTs. On average, wet (dry) conditions in large parts of Germany can be linked to westerly (northerly) moisture fluxes. During spring and summer seasons, the mid-latitude cyclone when located over the North Sea disrupts onshore moisture transport from the North Atlantic Ocean by westerlies driven by the North Atlantic subtropical anticyclone. The CT found to have the highest probability of being associated with above-average rainfall in large part of Germany features (i) enhancement and northward track of the cyclonic system over the Mediterranean; (ii) northward track of the North Atlantic anticyclone, further displacing poleward, the mid-latitude cyclone over the North Sea, enabling band of westerly moisture fluxes to penetrate Germany; (iii) cyclonic system over the Baltic Sea coupled with northeast fluxes of moisture to Germany; (iv) and unstable atmospheric conditions over Germany. In 2021, a spike was detected in the amplitude and frequency of occurrence of the aforementioned wet CT suggesting that in addition to the nearly stationary cut-off low over central Europe, during the July flood episode, anomalies in the CT contributed to the heavy rainfall event.
New U–Pb age and Hf isotope data obtained on detrital zircon grains from Au- and U-bearing Archaean quartz-pebble conglomerates in the Singhbhum Craton, eastern India, specifically the Upper Iron Ore Group in the Badampahar Greenstone Belt and the Phuljhari Formation below the Dhanjori Group provide insights into the zircon provenance and maximum age of sediment deposition. The most concordant, least disturbed \(^{207}\)Pb/\(^{206}\)Pb ages cover the entire range of known magmatic and higher grade metamorphic events in the craton from 3.48 to 3.06 Ga and show a broad maximum between 3.38 and 3.18 Ga. This overlap is also mimicked by Lu–Hf isotope analyses, which returned a wide range in \(_{εHf}\)(t) values from + 6 to − 5, in agreement with the range known from zircon grains in igneous and metamorphic rocks in the Singhbhum Craton. A smaller but distinct age peak centred at 3.06 Ga corresponds to the age of the last major magmatic intrusive event, the emplacement of the Mayurbhanj Granite and associated gabbro, picrite and anorthosite. Thus, these intrusive rocks must form a basement rather than being intrusive into the studied conglomerates as previously interpreted. The corresponding detrital zircon grains all have a subchondritic Hf isotopic composition. The youngest reliable zircon ages of 3.03 Ga in the case of the basal Upper Iron Ore Group in the east of the craton and 3.00 Ga for the Phuljhari Formation set an upper limit on the age of conglomerate sedimentation. Previously published detrital zircon age data from similarly Au-bearing conglomerates in the Mahagiri Quartzite in the Upper Iron Ore Group in the south of the craton gave a somewhat younger maximum age of sedimentation of 2.91 Ga. There, the lower limit on sedimentation is given by an intrusive relationship with a c. 2.8 Ga granite. The time window thus defined for conglomerate deposition on the Singhbhum Craton is almost identical to the age span established for the, in places, Au- and U-rich conglomerates in the Kaapvaal Craton of South Africa: the 2.98–2.78 Ga Dominion Group and Witwatersrand Supergroup in South Africa. Since the recognition of first major concentration of gold on Earth’s surface by microbial activity having taken place at around 2.9 Ga, independent of the nature of the hinterland, the above similarity in age substantially increases the potential for discovering Witwatersrand-type gold and/or uranium deposits on the Singhbhum Craton. Further age constraints are needed there, however, to distinguish between supposedly less fertile (with respect to Au) > 2.9 Ga and more fertile < 2.9 Ga successions.
The effects of drought on tree mortality at forest stands are not completely understood. For assessing their water supply, knowledge of the small-scale distribution of soil moisture as well as its temporal changes is a key issue in an era of climate change. However, traditional methods like taking soil samples or installing data loggers solely collect parameters of a single point or of a small soil volume. Electrical resistivity tomography (ERT) is a suitable method for monitoring soil moisture changes and has rarely been used in forests. This method was applied at two forest sites in Bavaria, Germany to obtain high-resolution data of temporal soil moisture variations. Geoelectrical measurements (2D and 3D) were conducted at both sites over several years (2015–2018/2020) and compared with soil moisture data (matric potential or volumetric water content) for the monitoring plots. The greatest variations in resistivity values that highly correlate with soil moisture data were found in the main rooting zone. Using the ERT data, temporal trends could be tracked in several dimensions, such as the interannual increase in the depth of influence from drought events and their duration, as well as rising resistivity values going along with decreasing soil moisture. The results reveal that resistivity changes are a good proxy for seasonal and interannual soil moisture variations. Therefore, 2D- and 3D-ERT are recommended as comparatively non-laborious methods for small-spatial scale monitoring of soil moisture changes in the main rooting zone and the underlying subsurface of forested sites. Higher spatial and temporal resolution allows a better understanding of the water supply for trees, especially in times of drought.
Background
Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients.
Objectives
PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points.
Methods and results
The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression.
Conclusions
PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care.
Trial registration
ClinicalTrials.gov; NCT04398654, 13-MAY-2020.
A fuzzy classification scheme that results in physically interpretable meteorological patterns associated with rainfall generation is applied to classify homogeneous regions of boreal summer rainfall anomalies in Germany. Four leading homogeneous regions are classified, representing the western, southeastern, eastern, and northern/northwestern parts of Germany with some overlap in the central parts of Germany. Variations of the sea level pressure gradient across Europe, e.g., between the continental and maritime regions, is the major phenomenon that triggers the time development of the rainfall regions by modulating wind patterns and moisture advection. Two regional climate models (REMO and CCLM4) were used to investigate the capability of climate models to reproduce the observed summer rainfall regions. Both regional climate models (RCMs) were once driven by the ERA-Interim reanalysis and once by the MPI-ESM general circulation model (GCM). Overall, the RCMs exhibit good performance in terms of the regionalization of summer rainfall in Germany; though the goodness-of-match with the rainfall regions/patterns from observational data is low in some cases and the REMO model driven by MPI-ESM fails to reproduce the western homogeneous rainfall region. Under future climate change, virtually the same leading modes of summer rainfall occur, suggesting that the basic synoptic processes associated with the regional patterns remain the same over Germany. We have also assessed the added value of bias-correcting the MPI-ESM driven RCMs using a simple linear scaling approach. The bias correction does not significantly alter the identification of homogeneous rainfall regions and, hence, does not improve their goodness-of-match compared to the observed patterns, except for the one case where the original RCM output completely fails to reproduce the observed pattern. While the linear scaling method improves the basic statistics of precipitation, it does not improve the simulated meteorological patterns represented by the precipitation regimes.