In European Union countries, any disease affecting less than 5 people in 10,000 is considered rare. As expertise is scarce and rare diseases (RD) are complex, RD patients can remain undiagnosed for ...many years. The period of searching for a diagnosis, called diagnostic delay, sometimes leads to a diagnostic dead end when the patient's disease is impossible to diagnose after undergoing all available investigations. In recent years, extensive efforts have been made to support the implementation of ORPHA nomenclature in health information systems (HIS) so as to allow RD coding. Until recently, the nomenclature only encompassed codes for specific RD. Persons suffering from a suspected RD who could not be diagnosed even after full investigation, could not be coded with ORPHAcodes. The recognition of the RD status is necessary for patients, even if they do not have a precise diagnosis. It can facilitate reimbursement of care, be socially and psychologically empowering, and grant them access to scientific advances.
The RD-CODE project aimed at making those patients identifiable in HIS in order to produce crucial epidemiological data. Undiagnosed patients were defined as patients for whom no clinically-known disorder could be confirmed by an expert center after all reasonable efforts to obtain a diagnosis according to the state-of-the-art and diagnostic capabilities available. Three recommendations for the coding of undiagnosed RD patients were produced by a multi-stakeholder panel of experts: 1/ Capture the diagnostic ascertainment for all rare disease cases; 2/ Use the newly created ORPHAcode (ORPHA:616874 "Rare disorder without a determined diagnosis after full investigation"), available in the Orphanet nomenclature: as the code is new, guidelines are essential to ensure its correct and homogeneous use for undiagnosed patients' identification in Europe and beyond; 3/ Use additional descriptors in registries.
The recommendations can now be implemented in HIS (electronic health records and/or registries) and could be a game-changer for patients, clinicians and researchers in the field, enabling assessment of the RD population, including undiagnosed patients, adaptation of policy measures including financing for care and research programs, and to improved access of undiagnosed patients to research programs.
Direct visualisation of ciliary beat pattern (CBP) and ciliary beat frequency (CBF) has been recommended as the first-line diagnostic test in patients suspected of having primary ciliary dyskinesia ...(PCD). However, the test procedure is not yet completely standardised, and centres measure the CBF at different temperatures.
It was the aim of the study to compare CBF at different temperatures, to establish normative values, to check for age dependency and to measure the temperature on the nasal mucosa of the participants.
High-speed video-microscopy analysis with a Sisson-Ammons Video Analysis (SAVA) system was used to determine CBP and CBF in the participants.
Nasal brushings were taken and CBF was measured in randomised order at three temperatures: 25°C, 32°C and 37°C.
In total, 100 healthy young adults (74 female, 26 male), aged 20.2-31.9 years, were included in the study. We found a highly significant difference among the groups: the median CBF was 7.0 Hz at 25°C, 7.6 Hz at 32°C and 8.0 Hz at 37°C. The maximum time period
was 65 min and did not differ significantly. However, CBF was significantly higher when the cilia were kept at a higher temperature before the measurements were made. We found no correlation between CBF and the age of the participants. The median nasal mucosal temperature in our study participants was 30.2°C (range 24.7-35.8°C) comparable to the 30.2-34.4°C described in the literature.
The most appropriate temperature at which to measure CBF is 32°C. In our study, with 95% confidence for this temperature the CBF was between 6.3 and 9.0 Hz.
Drinking water production in the vicinity of rivers not only requires the consideration of different spatiotemporal scales and settings of river-groundwater interaction processes, but also of local ...and regional scale groundwater regimes.
Selected case studies in combination with field-experiments and the setup of high-resolution groundwater flow models enabled the investigation of the spatiotemporal development of microbial (classical fecal indicator bacteria and total cell counts) and selected organic micropollutants in riverine and regional groundwater for different hydrological settings, including low and high flow conditions. Proxy indicators suitable as surrogates for the diverse contaminations in alluvial aquifers with different settings could be identified.
Based on the study results, the basic elements for both groundwater management and river restoration concepts are derived, which include the: (1) compilation and evaluation of the “current state” concerning hydrogeology, microbiology and contamination by organic micropollutants, (2) definition of field-experiments to qualitatively assess variability related to the “current state”, and (3) quantitative assessment of groundwater regimes, including variability of groundwater components and inflow areas, by application of high-resolution groundwater flow models.
The validity and transferability of the concept and inferred controls (specifically drivers and controls of river-groundwater interaction) are tested by evaluations derived from hydraulic relationships to river sections with comparable settings and regional groundwater flow regimes in general.
The results of our investigations illustrate the influence of dynamic hydrologic boundary conditions on river-groundwater interaction and of regional scale groundwater flow regimes on the water composition of riverine groundwater systems. It is demonstrated how to identify river sections and their variations with intensified river-groundwater exchange processes and how to quantify the transient character of the different groundwater components that constitute the raw water quality of drinking water wells near rivers.
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•Extending local views to the regional scale of groundwater flow regimes•Proxy indicators for microbial and organic micropollutant contaminations•Quantification of groundwater components to assess raw water quality•Identification of river sections within the inflow area of drinking water wells•Filter-efficiencies as a function of aquifer characteristics, distance and hydraulics
Although there is convincing evidence for socio-cognitive impairments in schizophrenia spectrum disorder (SSD), little evidence is found for deficient moral cognition. We investigated whether ...patients with SSD showed altered moral judgments in a story task where the protagonist either had a neutral or malicious intention towards another person. This paradigm examined whether SSD relates to altered moral cognition in general or specifically to impaired integration of prior information (such as beliefs) in moral judgments.
23 patients and 32 healthy controls read vignettes created in a 2 x 2 design. The protagonist in each story either had a neutral or negative intention towards another person which, as a result, either died (negative outcome) or did not die (neutral outcome). Participants rated the moral permissibility of the protagonist's action. Standard null hypothesis significance testing and equivalent Bayes analyses are reported.
Schizophrenia patients did not differ significantly in permissibility ratings from healthy controls. This finding was supported by the Bayes analyses which favoured the null hypothesis. Task performance was not related to symptom severity or medication.
The current findings do not support the notion that moral judgments are deficient in schizophrenia. Furthermore, the current study shows that patients do not have observable difficulties in integrating the protagonist's belief in the rating of the moral permissibility of the action-outcome.
Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from ...intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function.
Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA.
Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%).
The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.
Estimates of rare disease (RD) population impact in terms of number of affected patients and accurate disease definition is hampered by their under-representation in current coding systems. This ...study tested the use of a specific RD codification system (ORPHAcodes) in five European countries/regions (Czech Republic, Malta, Romania, Spain, Veneto region-Italy) across different data sources over the period January 2019-September 2021. Overall, 3133 ORPHAcodes were used to describe RD diagnoses, mainly corresponding to the disease/subtype of disease aggregation level of the Orphanet classification (82.2%). More than half of the ORPHAcodes (53.6%) described diseases having a very low prevalence (< 1 case per million), and most commonly captured rare developmental defects during embryogenesis (31.3%) and rare neurological diseases (17.6%). ORPHAcodes described disease entities more precisely than corresponding ICD-10 codes in 83.4% of cases. ORPHAcodes were found to be a versatile resource for the coding of RD, able to assure easiness of use and inter-country comparability across population and hospital databases. Future research on the impact of ORPHAcoding as to the impact of numbers of RD patients with improved coding in health information systems is needed to inform on the real magnitude of this public health issue.
Podocytes are highly differentiated kidney cells playing an important role in maintaining the glomerular filtration barrier. Particularly, the integrity of the actin cytoskeleton is crucial as ...cytoskeletal damage associated with foot process effacement and loss of slit diaphragms constitutes a major aspect of proteinuria. Previously, the mammalian target of rapamycin (mTOR) was linked to actin regulation and aberrant activity of the kinase was associated with renal disease. In this study, actin-related effects of mTOR inhibition by the immunosuppressant everolimus (EV) were investigated in human podocytes using an in vitro model of puromycin aminonucleoside (PAN) induced proteinuria. EV substantially recovered aberrant podocyte behavior by re-establishing a stationary phenotype with decreased migration efficiency, enhanced cell adhesion and recovery of actin stress fibers. Biochemical studies revealed substantial increase in the activity of RhoA and the effector pathway Rho-associated protein kinase (ROCK) and myosin light chain (MLC) by EV, all known regulators of stress fiber generation. Taken together, we show for the first time cytoskeleton stabilizing effects of the mTOR inhibitor EV and establish RhoA signaling as a key mediator in this process.
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