Koordination, Kognition und Lebensqualität von Patienten mit idiopathischen Normaldruckhydrozephalus - eine prospektive Beobachtung

Neurodegenerative diseases such as idiopathic normal pressure hydrocephalus play an increasing role due to the steadily aging population. This disease is characterized by the Hakim-Triad, with symptoms of gait disturbance, urinary incontinence as well as dementia. Among other things, a clear enlargement of the lateral ventricles as well as of the third ventricle in the imaging is pathognomonic. The treatment of choice for this disease is the surgical implantation of a ventriculoperitoneal shunt. In the daily clinical practice, the greatest attention is paid to gait disturbance. This is undoubtedly a tribute to its easy and quick assessability. By doing so, idiopathic normal pressure hydrocephalus symptoms were insufficiently characterized. Other factors such as quality of life and neuropsychology play an important role as well. A more comprehensive assessment of the symptoms of normal pressure hydrocephalus would describe the everyday situation of these patients better. So far, a comprehensive characterization of these aspects of idiopathic normal pressure hydrocephalus is missing, especially in regard to surgical intervention via shunt implantation. Thus, the main focus of this work was to assess how quality of life, neuropsychological and motor skills are affected by shunt placement in idiopathic normal pressure hydrocephalus patients as compared to an age-appropriate, healthy control group. In the present study, 40 patients with idiopathic normal pressure hydrocephalus who were treated with a shunt between January 2020 and October 2021 were included. Another 40 individuals, not suffering from idiopathic normal pressure hydrocephalus, served as a reference group. In order to allow a valid comparison between those two groups, they were matched according to age, gender, level of education and previous illnesses. To assess quality of life, neuropsychological and motor skills, a broad test battery was used. Concerning quality of life, the Rankin Scale, Stein and Langfitt Grading, bladder function grading, Kiefer Score as well as EQ-5D were conducted. For detailed examination of neuropsychology, the Mini Mental State Examination, the Dementia Detection Test, the Stroop Test A and B, the Digit Span Test A and B and the Trail Making Test A and B as well as the Rey Auditory Verbal Learning Test were selected. Motor skills were tested via a ten-meter walk, 360 degree turns, finger-tapping test and the grooved pegboard test. This test battery was carried out preoperatively as well as six weeks, three and six months postoperatively. In summary, the present study shows that patients clearly benefited from shunting in all aspects. In comparison between the preoperative testing and the six-month follow-up, almost all tests with regard to quality of life showed a significant improvement. Concerning neuropsychology, the Mini Mental State Examination, the Dementia Detection Test, the Stroop Test A and B and the Digit Span Test A and B showed a significant improvement after six months as well. Nonetheless, in further tests, particularly the Rey Auditory Verbal Learning Test and the Trail Making Test A and B, no significant neuropsychological improvement was detected. The evaluation of the motor skills showed a significant improvement in all tests after six months. When compared to the reference group, it was shown that for most tests, idiopathic normal pressure hydrocephalus patients did not reach the performance level of the reference individuals even six months postoperatively. For some tests however, in particular EQ-5D, Rey Auditory Verbal Learning Test, Stroop Test A and B and Digit Span Test A and B, patients improved to an extent where no statistically significant difference between patients and reference group was detected six months postoperatively. The results underline the fact that the idiopathic normal pressure hydrocephalus is not characterized by a gait disorder alone. Within the first six months, the shunt placement showed a significant reduction in symptoms in the areas of quality of life and neuropsychology, as well as gait disorders. This improvement occurred much earlier than reported in the literature. In some areas, the patient's level of performance even increased to the level of healthy individuals.Zusammenfassung 1.1. Deutsche Fassung Durch eine stetig alternde Bevölkerung spielen neurodegenerative Erkrankungen, wie die des idiopathischen Normaldruckhydrozephalus, eine zunehmende Rolle. Dieses Krankheitsbild ist durch die Hakim-Trias gekennzeichnet, welche die Symptome Gangunsicherheit, Urininkontinenz sowie Demenz umfasst. Bildgebend ist unter anderem eine deutliche Erweiterung der Seitenventrikel, als auch des dritten Ventrikels pathognomonisch. Therapie der Wahl dieser Erkrankung ist die operative Anlage eines ventrikuloperitonealen Shunts. Im klinischen Alltag wird meist der Gangproblematik die größte Aufmerksamkeit in der Beurteilung des Krankheitsverlaufs geschenkt. Dies liegt ohne Zweifel an ihrer einfachen und schnellen Beurteilbarkeit. Dabei wird aber verkannt, dass der Normaldruckhydrozephalus durch weit mehr als nur die oben genannten Symptome charakterisiert ist. Vielmehr spielen weitere Faktoren, wie Lebensqualität und Neuropsychologie eine wichtige Rolle. Eine umfassende Charakterisierung dieser Aspekte des Normaldruckhydrozephalus fehlt bisher, insbesondere im Hinblick auf eine chirurgische Intervention mittels Shuntanlage. Zentrales Thema der vorliegenden Arbeit war daher die Frage, wie sich Lebensqualität, Neuropsychologie sowie Motorik bei idiopathischen Normaldruckhydrozephalus -Patienten im Verlauf vor sowie nach Shuntanlage, als auch gegenüber einer altersentsprechenden, gesunden Referenzgruppe charakterisieren. In der vorliegenden Arbeit wurden 40 Patienten mit idiopathischem Normaldruckhydrozephalus eingeschlossen, die im Zeitraum von Januar 2020 bis Oktober 2021 mittels Shunt versorgt wurden. Weitere 40, nicht an einem idiopathischen Normaldruckhydrozephalus erkrankte Individuen, dienten als Referenzgruppe. Um einen validen Vergleich zwischen beiden Gruppen zu ermöglichen, wurden diese nach Alter, Geschlecht, Bildungsstand sowie Vorerkrankungen verglichen. Die Erhebung der Lebensqualität, der Neuropsychologie sowie der Motorik erfolgte mittels einer Testbatterie. Bezüglich der Lebensqualität wurden die Rankin Skala, die Stein und Langfitt Graduierung, die Blasenfunktions-Graduierung, die Kiefer Graduierung sowie der EQ-5D Test durchgeführt. Zur detaillierten Prüfung der Neuropsychologie wurden der Mini Mental State Examination, der Demenz Detektions Test, der Stroop Test A und B, der Digit Span Test A und B sowie der Trail Making Test A und B und der Rey Auditory Verbal Learning Test ausgewählt. Die Prüfung der Motorik erfolgte mittels zehn Meter Gehstrecke, 360 Grad Wendung, Finger-Tapping-Test sowie dem Grooved Pegboard Test. Diese Testbatterie wurde präoperativ sowie im Verlauf nach sechs Wochen, drei- und sechs Monaten durchgeführt. Zusammenfassend konnte in der vorliegenden Arbeit festgestellt werden, dass die Patienten im Verlauf in allen Teilbereichen deutlich von der Shuntanlage profitierten. Im Vergleich zwischen der präoperativen Testung und dem sechs Monats Follow-Up zeigten nahezu alle Tests hinsichtlich der Lebensqualität eine Besserung auf Signifikanzniveau. In Hinblick auf die Neuropsychologie zeigten der Mini Mental State Examination, der Demenz Detektions Test, der Stroop Test A und B sowie der Digit Span Test A und B eine signifikante Besserung nach sechs Monaten. Hingegen konnten in weiteren Tests, nämlich im Rey Auditory Verbal Learning Test sowie dem Trail Making Test A und B keine signifikante neuropsychologische Besserung nachgewiesen werden. Die Evaluation der Motorik zeigte in allen Tests eine signifikante Besserung nach sechs Monaten. Im Vergleich mit den Referenzindividuen konnte darlegt werden, dass die Normaldruckhydrozephalus Patienten trotz deutlicher Steigerung im Verlauf dennoch in den meisten Tests nicht das Level der Referenzgruppe erreichen konnten. Beim EQ-5D Test, Rey Auditory Verbal Learning Test, Stroop Test A und B, Digit Span Test A und B sowie der Zeit für die 10 Meter Gehstrecke und dem Grooved Pegboard Test näherte sich die Leistung der Normaldruckhydrozephalus Patienten der Referenzgruppe so an, dass kein signifikanter Unterschied mehr festgestellt werden konnte. Die Ergebnisse unterstreichen die Erkenntnis, dass der idiopathische Normaldruckhydrozephalus nicht alleine durch eine Gangstörung charakterisiert ist. Dabei zeigte die Shuntanlage innerhalb der ersten sechs Monate eine deutliche Symptomreduktion in den Bereichen Lebensqualität und Neuropsychologie sowie eine Linderung der Gangstörung. Dieser Effekt zeigte sich deutlich früher als in der Literatur berichtet. In Teilbereichen stieg das Leistungsniveau der Patienten gar auf das Niveau gesunder Individuen an

Motor skills, cognitive impairment, and quality of life in normal pressure hydrocephalus: early effects of shunt placement

Background Traditionally, clinical fndings of normal pressure hydrocephalus are mainly characterized by the Hakim triad. The aim of this study is to evaluate the performance of patients sufering from idiopathic normal pressure hydrocephalus (iNPH) in a more holistic manner regarding motor skills, cognitive impairment, and quality of life. Methods In total, 30 individuals diagnosed with iNPH as well as a reference group with another 30 individuals were included. The iNPH patients and the reference group were age, educational, and morbidity matched. A standardized test battery for psychomotor skills, gait, neuropsychological abilities as well as questionnaires for quality of life was applied. The iNPH group was tested prior to surgery, at 6 weeks, and 3 months postoperatively. The reference group was tested once. Results Patients showed a signifcant improved performance in various items of the test battery during the frst 3 months postoperatively. This included neuropsychological evaluation, motor skills including gait and upper motor function as well as the quality of life of the patients. Compared to reference individuals, neuropsychological aspects and quality of life of iNPH patients improved in some parts nearly to normal values. Conclusion Our fndings underline that shunt surgery does not only improve the symptoms in iNPH patients but also ame liorates the quality of life to a great extent close to those of age and comorbidity matched reference individuals. This data enables an optimized counseling of iNPH patients regarding the expectable outcome after shunt surgery especially regarding cognitive performance, motor skills as well as life quality

Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only.

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signalswithin this high-density datasetare enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinementapproach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation

Identification of domains in Plasmodium falciparum proteins of unknown function using DALI search on AlphaFold predictions

Abstract Plasmodium falciparum, the causative agent of malaria, poses a significant global health challenge, yet much of its biology remains elusive. A third of the genes in the P. falciparum genome lack annotations regarding their function, impeding our understanding of the parasite's biology. In this study, we employ structure predictions and the DALI search algorithm to analyse proteins encoded by uncharacterized genes in the reference strain 3D7 of P. falciparum. By comparing AlphaFold predictions to experimentally determined protein structures in the Protein Data Bank, we found similarities to known domains in 353 proteins of unknown function, shedding light on their potential functions. The lowest-scoring 5% of similarities were additionally validated using the size-independent TM-align algorithm, confirming the detected similarities in 88% of the cases. Notably, in over 70 P. falciparum proteins the presence of domains resembling heptatricopeptide repeats, which are typically involvement in RNA binding and processing, was detected. This suggests this family, which is important in transcription in mitochondria and apicoplasts, is much larger in Plasmodium parasites than previously thought. The results of this domain search provide a resource to the malaria research community that is expected to inform and enable experimental studies

Physical condition, nutritional status, fatigue, and quality of life in oncological out-patients

Objective: Early detection of limited physical activity and nutritional deficiencies in cancer survivors could contribute to early treatment and preservation of quality of life. The aim of this study is to describe the association of physical condition and nutritional status with fatigue and quality of life in oncological out-patients. Methods: Data in this descriptive study was collected on bioelectrical impedance analysis, postural stability (stability index), body mass index, Karnofsky Index, quality of life (Short-Form 36-Item Health Survey) and fatigue (multidimensional fatigue inventory-20) in a consecutive sample of 203 oncological out-patients. Phase angle was calculated from bioelectrical impedance analysis. Values were intercorrelated and compared to appropriate standard values. Results: Phase angle and stability index outcomes were far below the values of a healthy population of similar age (p < 0.001). Quality of life was significantly lower than in the normal population (p < 0.001), and the level of fatigue was significantly higher (p < 0.001). Phase angle correlated with Karnofsky Index (p = 0.002) and Short-Form 36-Item Health Survey Summary physical function (p < 0.001). Furthermore, multidimensional fatigue inventory-20 scales ‘physical fatigue’ and ‘reduced activity’ were significantly associated with phase angle (p = 0.04, p = 0.005). Stability indices correlated with Short-Form 36-Item Health Survey physical function. Conclusion: The physical condition and the nutritional status are key components determining the individual quality of life of oncological out-patients. These variables also showed an association with the manifestation of fatigue. Results highlight the need for interdisciplinary cooperation to detect physical, nutritional and psychological deficiencies in oncological out-patients

Self-management for patients on ventricular assist device support: a national, multicentre study: protocol for a 3-phase study

Introduction Self-management (SM) may facilitate patient participation and involvement to become active and knowledgeable partners in the care of complex chronic conditions such as ventricular assist device (VAD) therapy. The ‘SM model for patients on VAD support’ will serve to distinguish between SM components, and will guide the development, implementation and evaluation of an evidence-based curriculum.Methods and analysis This is a 3-phase, multicentre study. In phase 1, a prevalence study will be performed. Phase 2 aims to develop an evidence-based, interprofessional curriculum for SM support for VAD patients. In phase 3, a non-blinded block-randomised controlled trial (RCT), allocation ratio 1:1, intervention group superiority, with an unblinded multifacetted intervention with assessments before (T1) and after (T2) the intervention, and two follow-up assessments at three (T3), and 12 (T4) months after VAD implantation, will be performed. The curriculum guides the intervention in the RCT. Patient recruitment will consider centre-related volume: power analyses require 384 patients for phase 1, and 142 patients for phase 3.Ethics and dissemination Ethical considerations will be continuously taken into account and approved by the institutional review boards. Central ethical review board approval has been obtained by the Albert-Ludwigs University Freiburg. This study will be performed in concordance with the Declaration of Helsinki and the European data protection law. Publications will exclusively report aggregated data and will be distributed in the scientific community, and patient support groups. Report languages will be German and English.Trial registration numbers NCT04234230 and NCT04526964; Pre-results

Delayed death in the malaria parasite Plasmodium falciparum is caused by disruption of prenylation-dependent intracellular trafficking.

Apicomplexan parasites possess a plastid organelle called the apicoplast. Inhibitors that selectively target apicoplast housekeeping functions, including DNA replication and protein translation, are lethal for the parasite, and several (doxycycline, clindamycin, and azithromycin) are in clinical use as antimalarials. A major limitation of such drugs is that treated parasites only arrest one intraerythrocytic development cycle (approximately 48 hours) after treatment commences, a phenotype known as the 'delayed death' effect. The molecular basis of delayed death is a long-standing mystery in parasitology, and establishing the mechanism would aid rational clinical implementation of apicoplast-targeted drugs. Parasites undergoing delayed death transmit defective apicoplasts to their daughter cells and cannot produce the sole, blood-stage essential metabolic product of the apicoplast: the isoprenoid precursor isopentenyl-pyrophosphate. How the isoprenoid precursor depletion kills the parasite remains unknown. We investigated the requirements for the range of isoprenoids in the human malaria parasite Plasmodium falciparum and characterised the molecular and morphological phenotype of parasites experiencing delayed death. Metabolomic profiling reveals disruption of digestive vacuole function in the absence of apicoplast derived isoprenoids. Three-dimensional electron microscopy reveals digestive vacuole fragmentation and the accumulation of cytostomal invaginations, characteristics common in digestive vacuole disruption. We show that digestive vacuole disruption results from a defect in the trafficking of vesicles to the digestive vacuole. The loss of prenylation of vesicular trafficking proteins abrogates their membrane attachment and function and prevents the parasite from feeding. Our data show that the proximate cause of delayed death is an interruption of protein prenylation and consequent cellular trafficking defects

The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites.

Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility of P. falciparum parasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in reduced susceptibility to ART. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites

Photoaging smartphone app promoting poster campaign to reduce smoking prevalence in secondary schools: the Smokerface Randomized Trial: design and baseline characteristics

Introduction: Smoking is the largest cause of preventable death globally. Most smokers smoke their first cigarette in early adolescence. We took advantage of the widespread availability of mobile phones and adolescents’ interest in appearance to develop a free photoaging app which is promoted via a poster campaign in secondary schools. This study aims to evaluate its effectiveness regarding smoking prevalence and students’ attitudes towards smoking. Methods and analysis A randomised controlled trial is conducted with 9851 students of both genders with an average age of 12 years in grades 6 and 7 of 126 secondary schools in Germany. At present, cigarette smoking prevalence in our sample is 4.7%, with 4.6% of the students currently using e-cigarettes (1.6% use both). The prospective experimental study design includes measurements at baseline and at 6, 12 and 24 months postintervention via a questionnaire plus a random cotinine saliva sample at 24 months postintervention. The study groups consist of randomised schools receiving the Smokerface poster campaign and control schools with comparable baseline data (no intervention). The primary end point is the difference of change in smoking prevalence in the intervention group versus the difference in the control group at 24 months follow-up. Longitudinal changes in smoking-related attitudes, the number of new smokers and quitters and the change in the number of never-smokers will be compared between the two groups as secondary outcomes. Ethics and dissemination Ethical approval was obtained from the ethics committee of the University of Gießen and the ministries of cultural affairs, both in Germany. Results will be disseminated at conferences, in peer-reviewed journals, on our websites and throughout the multinational Education Against Tobacco network. Trial registration number NCT02544360, Pre-results