Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1

Spinocerebellar ataxias are neurodegenerative diseases, the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells, the principal neurons of the cerebellar cortex, are the main cells affected in these disorders, but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of Purkinje cells dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to Purkinje cells dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1 (SCA1). Spatiotemporal characterization of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of Purkinje cells intrinsic excitability, which was followed by atrophy of Purkinje cells dendrite arborization and aberrant glutamatergic signalling, finally leading to disruption of Purkinje cells innervation of climbing fibres and loss of intrinsic plasticity of Purkinje cells. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of climbing fibre degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.</p

Cost-Effectiveness and Cost-Utility of Early Levodopa in Parkinson's Disease

Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start).Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study.Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up.Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of D 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated.Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.Neurological Motor Disorder

Development of a simple score based on HBeAg and ALT for selecting patients for HBV treatment in Africa.

BACKGROUND & AIMS: To eliminate hepatitis B virus (HBV) infection, it is essential to scale up antiviral treatment through decentralized services. However, access to the conventional tools to assess treatment eligibility (liver biopsy/Fibroscan®/HBV DNA) is limited and not affordable in resource-limited countries. We developed and validated a simple score to easily identify patients in need of HBV treatment in Africa. METHODS: As a reference, we used treatment eligibility determined by the European Association for the Study of the Liver based on alanine aminotransferase (ALT), liver histology and/or Fibroscan and HBV DNA. We derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of chronic HBV infection in The Gambia (n = 804). We subsequently validated the score in an external cohort of HBV-infected Africans from Senegal, Burkina Faso, and Europe (n = 327). RESULTS: Out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREAT-B). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79-0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-to-platelet ratio index (APRI) and ALT were 90% and 40%, respectively. CONCLUSIONS: A simple score based on HBeAg and ALT had a high diagnostic accuracy for the selection of patients for HBV treatment. This score could be useful in African settings. LAY SUMMARY: Limited access to the diagnostic tools used to assess treatment eligibility (liver biopsy/Fibroscan/hepatitis B virus DNA) has been an obstacle to the scale up of hepatitis B treatment programs in low- and middle-income countries. Using the data from African patients with chronic HBV infection, we developed and validated a new simple diagnostic score for treatment eligibility, which only consists of hepatitis B virus e antigen and alanine aminotransferase level. The diagnostic accuracy of the score for selecting patients for HBV treatment was high and could be useful in African settings

Twenty-three unsolved problems in hydrology (UPH) – a community perspective

This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through on-line media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focussed on process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come

Diagnostic and treatment indication for patients with chronic Hepatitis B

Weltweit sind etwa 257 Millionen Menschen chronisch mit dem Hepatitis B Virus (HBV) infiziert, die meisten davon leben in den Regionen des globalen Südens mit mittlerem oder geringem Einkommen. Die Weltgesundheitsorganisation (WHO) formuliert das Ziel, die chronische Hepatitis B bis zum Jahre 2030 zu eliminieren und hat dieses Ziel an diagnostische und therapeutische Kriterien geknüpft. Folglich sind die Kenntnis der regionalen Epidemiologie sowie einfache diagnostische Methoden zum Erreichen dieser Ziele unerlässlich. Diese kumulativ konzipierte Promotionsschrift beschäftigt sich mit nur unzureichend bekannten Fragen der Diagnostik und der Therapieindikationsstellung für Patienten mit chronischer HBV-Infektion. Konkrete Fragestellungen sind: 1.) Wer sind die Patient*innen mit HBV in Deutschland, wo kommen sie her und wie dringend benötigen sie eine antivirale Therapie? 2.) Westafrika zählt zu den Regionen der Erde mit der höchsten HBV-Prävalenz und weist zudem eine hohe Migrationsrate nach Europa bzw. Deutschland auf. Können kostengünstige Serummarker bereits in den Heimatländern Anwendung finden, um eine HBV-Therapieindikation festzustellen? Zur Bearbeitung der ersten Frage konnte ich in meiner ersten Publikation in einer retrospektiven Analyse 301 Patient*innen mit chronischer Hepatitis B aus einer infektiologischen Schwerpunktpraxis in Berlin einschließen. 61 % der Patient*innen hatten einen Migrationshintergrund und 26 % bei Erstpräsentation bereits eine Indikation für den Beginn einer medikamentösen Therapie. Für 76 Patient*innen konnte bei Erstdiagnose eine Leberfibrose und für 20 Patient*innen bereits eine schwere Fibrose oder Leberzirrhose diagnostiziert werden. Zur Auseinandersetzung mit der zweiten Fragestellung wurden die Patient*innen aus Subsahara-Afrika in eine internationale Kohorte mit 1131 afrikanischen Patient*innen eingespeist. Anhand dieser Kohorte wurde der „Treat-B-Score“ entwickelt, der lediglich aus HBeAg Status und der Höhe der ALT mit einer Sensitivität von 85% und Spezifität von 77% die Empfehlungen für eine antivirale Therapie vorhersagen konnte. Abschließend wurde in einer dritten Publikation in der retrospektiven Analyse von 944 afrikanischen Patient*innen mit chronischer Hepatitis B der Nutzen von quantitativem HBsAg zur Bestimmung der Schwere der Erkrankung oder der Indikation zum Beginn einer medikamentösen Therapie untersucht. Leider erwies sich dieser günstige Parameter als ungeeignet, Patienten für eine Therapie zu klassifizieren. Als Einschränkung dieser Arbeit ist die einzeitige Beobachtung der Patient*innen zu nennen. Longitudinale Verläufe konnten nicht präsentiert werden und bieten einen Ansatzpunkt für weitere Forschungsprojekte. Des Weiteren fand eine Bestimmung der Hepatitis B Genotypen nur begrenzt statt und Mutationen wurden nicht betrachtet. Diese Arbeit liefert eine weitere für die Deutschland wichtige Beschreibung der epidemiologischen Situation. Für (West)-afrikanische Patient*innen konnten wir zur Weiterentwicklung dringend benötigter nichtinvasiver und kostenreduzierender Diagnostik beitragen.Around 257 million people worldwide are chronically infected with the hepatitis B virus, most of them live in the regions of the global south in low an middle income countries (LMIC). The World Health Organization aims the goal of eliminating chronic hepatitis B by 2030 and has linked it to diagnostic and therapeutic criteria. Consequently, knowledge of the regional epidemiology and simple diagnostic methods are essential to achieve these goals. This doctoral thesis consists of cumulative publications. The subjects are the diagnostic assessments as well as the eligibility for treatment for patients with chronic HBV infection. Specific questions are: 1.) Who are the patients with HBV in Germany, where do they come from and how urgently do they need antiviral therapy? 2.) West Africa is one of the regions with the highest HBV prevalence and has a high rate of migration to Europe and Germany. Can inexpensive serum markers be used in home countries to determine the need of drug therapy? To answer the first question, in my first publication I analyzed 301 patients with chronic hepatitis B in Berlin. Of these patients 61% had a migrant background and 26% met the criteria for the start of drug therapy at the first presentation. Liver fibrosis was diagnosed for 76 patients and severe fibrosis or cirrhosis for 20 patients. To address the second question, the patients from sub-Sahara Africa were merged into an international cohort of 1,131 African patients. Based on this, the “Treat-B-Score” was developed, which consist of the HBeAg status and the level of ALT and could predict the recommendations for the start of antiviral therapy of the EASL with a sensitivity of 85% and specificity of 77%. In a third publication a retrospective analysis of 944 African patients with chronic hepatitis B examined the benefit of quantitative HBsAg for determining the severity of the disease or the indication to start drug therapy. This parameter turned out to be unsuitable for classifying patients for therapy. One limitation of this work is the one-time observation of the patients. Longitudinal courses could not be presented and offer a starting point for further research projects. Furthermore, the determination of the hepatitis B genotypes was limited and mutations were not considered. This work provides another important description of the epidemiological situation in Germany. For (West-) African patients we were able to contribute to the further development of urgently needed non-invasive and cost-reducing diagnostics

Choice-Based Evaluation for the Improvement of Upper-Extremity Function Compared With Other Impairments in Tetraplegia

Objectives To assess preference of reconstructive treatment of upper extremities in subjects with tetraplegia compared with preference of treatment of 3 other impairments and to determine the effect of subjects’ characteristics on preference of upper-extremity reconstruction. Design Survey. Setting Two specialized spinal cord injury centers in the Netherlands. Participants A consecutive sample of 47 patients with tetraplegia in stable condition. Interventions Not applicable. Main Outcome Measure The quality weight of 5 tetraplegic health states determined with the time trade-off technique and expressed as a single value (the “utility”) on a scale between 0 (worst possible situation) and 1 (best possible situation). Results The response rate was 92%. The utility of tetraplegia ± standard deviation was .57±.30. The utilities of tetraplegia without impairment in one of the following functions were .69±.33 for sexuality, .69±.33 for standing/walking, .63±.31 for bladder and bowel function, and .65±.32 for upper-extremity function. The differences between these utilities and the utility of tetraplegia were significant (P<.05). No significant differences were found between the utilities of the impairments. Improvement of a specific impairment contributed between 14% and 28% to the potential overall gain in the tetraplegic health state utility. Conclusions The combination of impairments determines the low utility of the tetraplegic health state. No priority for improvement of any of the investigated impairments was found. This emphasizes the need for the meticulous selection of patients for treatment of specific conditions. Further research should try to determine the crucial factors in the decision-making process of patients for specific intervention