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Objective: Remote self-assessment of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) using digital data capture was investigated for its feasibility as an add-on to ALSFRS-R assessments during multidisciplinary clinic visits. Methods: From August 2017 to December 2021, at 12 ALS centers in Germany, an observational study on remote assessment of the ALSFRS-R was performed. In addition to the assessment of ALSFRS-R during clinic visits, patients were offered a digital self-assessment of the ALSFRS-R - either on a computer or on a mobile application ('ALS-App'). Results: An estimated multicenter cohort of 4,670 ALS patients received care at participating ALS centers. Of these patients, 971 remotely submitted the ALSFRS-R, representing 21% of the multicenter cohort. Of those who opted for remote assessment, 53.7% (n = 521) completed a minimum of 4 ALSFRS-R per year with a mean number of 10.9 assessments per year. Different assessment frequencies were found for patients using a computer (7.9 per year, n = 857) and mobile app (14.6 per year, n = 234). Patients doing remote assessments were more likely to be male and less functionally impaired but many patients with severe disability managed to complete it themselves or with a caregiver (35% of remote ALSFRS-R cohort in King's Stage 4). Conclusions: In a dedicated ALS center setting remote digital self-assessment of ALSFRS-R can provide substantial data which is complementary and potentially an alternative to clinic assessments and could be used for research purposes and person-level patient management. Addressing barriers relating to patient uptake and adherence are key to its success.

An expansion of the GGGGCC hexanucleotide in the non-coding region of C9orf72 represents the most common cause of familial amyotrophic lateral sclerosis. The objective was to describe and analyse the clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations in a large population. Between November 2011 and December 2020, clinical and genetic characteristics of n = 248 patients with amyotrophic lateral sclerosis carrying C9orf72 mutations were collected from the clinical and scientific network of German motoneuron disease centres. Clinical parameters included age of onset, diagnostic delay, family history, neuropsychological examination, progression rate, phosphorylated neurofilament heavy chain levels in CSF and survival. The number of repeats was correlated with the clinical phenotype. The clinical phenotype was compared to n = 84 patients with SOD1 mutations and n = 2178 sporadic patients without any known disease-related mutations. Patients with C9orf72 featured an almost balanced sex ratio with 48.4% (n = 120) women and 51.6% (n = 128) men. The rate of 33.9% patients (n = 63) with bulbar onset was significantly higher compared to sporadic (23.4%, P = 0.002) and SOD1 patients (3.1%, P < 0.001). Of note, 56.3% (n = 138) of C9orf72, but only 16.1% of SOD1 patients reported a negative family history (P < 0.001). The GGGGCC hexanucleotide repeat length did not influence the clinical phenotypes. Age of onset (58.0, interquartile range 52.0–63.8) was later compared to SOD1 (50.0, interquartile range 41.0–58.0; P < 0.001), but earlier compared to sporadic patients (61.0, interquartile range 52.0–69.0; P = 0.01). Median survival was shorter (38.0 months) compared to SOD1 (198.0 months, hazard ratio 1.97, 95% confidence interval 1.34–2.88; P < 0.001) and sporadic patients (76.0 months, hazard ratio 2.34, 95% confidence interval 1.64–3.34; P < 0.001). Phosphorylated neurofilament heavy chain levels in CSF (2880, interquartile range 1632–4638 pg/ml) were higher compared to sporadic patients (1382, interquartile range 458–2839 pg/ml; P < 0.001). In neuropsychological screening, C9orf72 patients displayed abnormal results in memory, verbal fluency and executive functions, showing generally worse performances compared to SOD1 and sporadic patients and a higher share with suspected frontotemporal dementia. In summary, clinical features of patients with C9orf72 mutations differ significantly from SOD1 and sporadic patients. Specifically, they feature a more frequent bulbar onset, a higher share of female patients and shorter survival. Interestingly, we found a high proportion of patients with negative family history and no evidence of a relationship between repeat lengths and disease severity.

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02–2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12–0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Das KrWG ist ein hybrides Gesetz. Sein Konzept beruht darauf, aus ökonomischer Sicht unvereinbare Systeme der freien Marktwirtschaft und der staatlich regulierten Planwirtschaft unter dem übergreifenden Ziel einer Bewältigung wachsender Abfallströme zusammenzuführen. Der hybride Gesetzescharakter folgt unmittelbar aus dem Gesetzesziel, weil abgesehen von nachgefragten Abfallstoffen wie Holz, Glas, Papier und Metall Abfallstoffe keine Wirtschaftsgüter sind. Ihre umfassende Einbeziehung in ein vom Gesetzgeber konzipiertes Kreislaufwirtschaftssystem erfordert umfangreiche planerische Interventionen und Vorkehrungen, die nur vom Gesetzgeber, nicht vom Markt gewährleistet werden können. Jede Kritik am Planungscharakter des KrWG ist vom Ansatz her verfehlt. Die wesentlichen Ziele des KrWG der Abfallvermeidung und der Abfallverwertung sind richtig. In drei Punkten ist der Gesetzgeber mit dem KrWG 2012 Illusionen erlegen, die nicht realisierbar sind. (1) Der Illusion einer unbegrenzten stofflichen Rückführbarkeit von Abfällen in den allgemeinen Wirtschaftskreislauf durch Recycling. Das kann aus physikalischen Gründen nicht gelingen. (2) Der Illusion einer Erreichbarkeit der Ziele des KrWG durch Privatisierung der kommunalen Abfallbeseitigungshoheit, sowie der Illusion (3) das gesetzlich im KrWG vorgegebene Ziel einer Vermeidung von Abfällen könne im Rahmen und mit den Instrumenten des KrWG erreicht werden.

Objective: Motor-assisted movement exercisers (MME) enable device-assisted physical therapy delivered in domestic settings. This observational study captures the frequency of MME use, subjective experience of the therapy provided and MME recommendation. Method: The prospective cohort study was implemented at ten ALS centres (02/2019-10/2020) and coordinated by the research platform Ambulanzpartner. Participants assessed symptom severity, frequency of use and subjective benefit of therapy on a numerical rating scale (NRS, 0 to 10 points). The likelihood of recommending the MME was determined by the Net Promotor Score (NPS). Results: Data for 144 participants were analysed. Weekly MME applications ranged from 1 to 4 in 41%, 5 to 7 in 42% and >7 in 17% of participants. Particularly positive results were achieved in the following domains: amplification of a sense of achievement (67%), diminution of the feeling of having rigid limbs (63%), diminution of the feeling of being immobile (61%), improvement of general wellbeing (55%) and reduction of muscle stiffness (52%). Participants with more pronounced self-rated muscle weakness were more likely to note a beneficial effect on preservation and improvement of muscle strength under MME treatment (p Conclusion: High-frequency MME-assisted treatment (defined as a minimum of five sessions a week) was administered in the majority of participants (59%) in addition to physical therapy. Most patients stated to have achieved their individual objectives of MME intervention as evidenced by a high level of satisfaction. The results underline the justification for extended MME treatment as part of the ALS care concept.

Ciliopathies often comprise retinal degeneration since the photoreceptors outer segment is an adapted primary cilium. CEP162 is a distal end centriolar protein required for proper transition zone assembly during ciliogenesis and whose loss causes ciliopathy in zebrafish. CEP162 has so far not been implicated in human disease. Here, we identified a homozygous CEP162 frameshift variant, c.1935dupA (p.(E646R*5)), in retinitis pigmentosa patients from two unrelated Moroccan families, likely representing a founder allele. We found that even though mRNA levels were reduced, the truncated CEP162-E646R*5 protein was expressed and localized to the mitotic spindle during mitosis, but not at the basal body of the cilium. In CEP162 knockdown cells, expression of the truncated CEP162-E646R*5 protein is unable to restore ciliation indicating its loss of function at the cilium. In patient fibroblasts, cilia overcome the absence of CEP162 from the primary cilium by delaying ciliogenesis through the persistence of CP110 at the mother centriole. The patient fibroblasts are ultimately able to extend some abnormally long cilia that are missing key transition zone components. Defective transition zone formation likely disproportionately affects the long-living ciliary outer segment of photoreceptors resulting in retinal dystrophy. CEP162 is expressed in human retina, and we show that wild-type CEP162, but not truncated CEP162-E646R*5, specifically localizes to the distal end of centrioles of mouse photoreceptor cilia. Together, our genetic, cell-based, and in vivo modeling establish that CEP162 deficiency causes retinal ciliopathy in humans. SIGNIFICANCE STATEMENTCiliopathies often comprise retinal degeneration since the photoreceptors outer segment is an adapted primary cilium. CEP162 is a basal body protein required for proper transition zone assembly during ciliogenesis and has so far not been implicated in human disease. Using genetic, cell-based, and in vivo studies, we show that a biallelic mutation of CEP162 causes late-onset human retinal degeneration. This mutation specifically hinders CEP162 function at the cilia, leading to impaired transition zone assembly and delayed formation of dysmorphic cilia. Studies in mouse photoreceptors support that absence of CEP162 could lead to defective outer segments. The discovery of novel ciliopathy genes, such as CEP162, advances our insight into cell-specific functions of the primary cilium.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required., publishedVersion

The KArlsruhe TRItium Neutrino experiment (KATRIN) aims to measure the effective electron anti-neutrino mass with an unprecedented sensitivity of 0.2 eV/c2, using β -electrons from tritium decay. Superconducting magnets will guide the electrons through a vacuum beamline from the windowless gaseous tritium source through differential and cryogenic pumping sections to a high resolution spectrometer. At the same time tritium gas has to be prevented from entering the spectrometer. Therefore, the pumping sections have to reduce the tritium flow by at least 14 orders of magnitude. This paper describes various simulation methods in the molecular flow regime used to determine the expected gas flow reduction in the pumping sections for deuterium (commissioning runs) and for radioactive tritium. Simulations with MolFlow+ and with an analytical model are compared with each other, and with the stringent requirements of the KATRIN experiment.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care., publishedVersion

The KArlsruhe TRItium Neutrino (KATRIN) experiment, which aims to make a direct and model-independent determination of the absolute neutrino mass scale, is a complex experiment with many components. More than 15 years ago, we published a technical design report (TDR) [https://publikationen.bibliothek.kit.edu/270060419] to describe the hardware design and requirements to achieve our sensitivity goal of 0.2 eV at 90% C.L. on the neutrino mass. Since then there has been considerable progress, culminating in the publication of first neutrino mass results with the entire beamline operating [arXiv:1909.06048]. In this paper, we document the current state of all completed beamline components (as of the first neutrino mass measurement campaign), demonstrate our ability to reliably and stably control them over long times, and present details on their respective commissioning campaigns., Comment: Added missing acknowledgement, corrected performance statement in chapter 4.2.5, updated author list and references

We report on the light sterile neutrino search from the first four-week science run of the KATRIN experiment in~2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are analyzed by a high-resolution MAC-E filter down to 40 eV below the endpoint at 18.57 keV. We consider the framework with three active neutrinos and one sterile neutrino of mass $m_{4}$. The analysis is sensitive to a fourth mass state $m^2_{4} \lesssim$ 1000 eV$^2$ and to active-to-sterile neutrino mixing down to $|U_{e4}|^2 \gtrsim 2\cdot10^{-2}$. No significant spectral distortion is observed and exclusion bounds on the sterile mass and mixing are reported. These new limits supersede the Mainz results and improve the Troitsk bound for $m^2_{4}, Comment: 8 pages, 4 figures

The DARWIN observatory is a proposed next-generation experiment to search for particle dark matter and for the neutrinoless double beta decay of $^{136}$Xe. Out of its 50$\,$t total natural xenon inventory, 40$\,$t will be the active target of a time projection chamber which thus contains about 3.6 t of $^{136}$Xe. Here, we show that its projected half-life sensitivity is $2.4\times10^{27}\,$yr, using a fiducial volume of 5t of natural xenon and 10$\,$yr of operation with a background rate of less than 0.2$~$events/(t$\cdot$yr) in the energy region of interest. This sensitivity is based on a detailed Monte Carlo simulation study of the background and event topologies in the large, homogeneous target. DARWIN will be comparable in its science reach to dedicated double beta decay experiments using xenon enriched in $^{136}$Xe., 12 pages, 9 figures

In Zeiten des „Beton-Goldes“ ist ein verlässlicher Partner im Immobilienrecht, der eine Grundlage für kluge Entscheidungen bietet, selbst Gold wert: Der Schreiber/Ruge (Hrsg.) behandelt konsequent das, was für Sie in der täglichen Arbeitspraxis relevant und wichtig ist. In 18 übersichtlichen Kapiteln, meinungsstark und sehr gut verständlich. Das Berliner Handbuch Immobilienrecht - jetzt in 4. Auflage! Der Wertermittlung von Immobilien widmet sich das neu hinzugekommene Kapitel 18, weil das Thema in vielfältigen juristischen Bezügen von großer praktischer Bedeutung ist und dennoch für viele eine Terra incognita. Fazit: In der sich rasch ändernden Landschaft des Immobilienrechts ist das Handbuch für alle Praktiker eine nützliche Arbeitshilfe und in seiner Art und Form konkurrenzlos!

In diesem Kapitel werden Managementinstrumente besprochen, welche helfen, im Matrixkontext ein hohes Mas an okonomischer und sozialer Effizienz zu erreichen („Erfolgsfaktoren“). Dargelegt wird eine grosere Zahl personenorientierter und technokratischer Erfolgsfaktoren. Zu den wichtigen technokratischen Erfolgsfaktoren gehort die Befolgung von Regeln, wie dies im Zuge der Entwicklung der regelbasierten Matrix vorgeschlagen worden ist.

Seit den siebziger Jahren ist die Zahl der Organisations-, Management-und Unternehmensfuhrungstheorien rasch angestiegen. In jedem der seither abgelaufenen Jahrzehnte wurden gleich mehrere Theorien vorgestellt und von Mitgliedern der Fachgemeinschaft zunachst euphorisch gefeiert, um dann teilweise ebenso schnell wieder fallen gelassen zu warden.

In diesem Kapitel wird erlautert, warum die Matrixstruktur fur immer mehr Unternehmen geeignet ist. Es wird aufgezeigt, dass dies an den zunehmend multiperspektivischen und komplexen Strategien der Unternehmen liegt. Unter anderem ist die Nutzung der Matrixstruktur in der zunehmenden Bedeutung von Synergiepotenzialen, der haufiger werdenden Einsatz von mehrfach nutzbaren Werken und Anlagen sowie der erhohten Wichtigkeit von Key Accounts begrundet. Die Top-Manager mussen deshalb Entscheidungen treffen, die auf den Wert des Gesamtunternehmens und nicht nur auf dessen Teileinheiten ausgerichtet sind. Hierzu ist eine starke informationelle Verzahnung der Teileinheiten des Unternehmens erforderlich, wie dies die Matrixstruktur unterstutzt.

In diesem Kapitel wird die Frage behandelt, ob alle Funktionsbereiche, alle Produktbereiche bzw. alle regionenbezogenen Einheiten des Unternehmens in die Matrixstruktur einbezogen werden sollen oder ob eine Auswahl getroffen werden soll („Selektive Matrixbildung“). Auch wird geklart, ob das Doppelunterstellungssystem ausschlieslich zwischen der zweiten und der dritten Hierarchieebene des Unternehmens bestehen oder ob es auch auf darunterliegenden Hierarchieebenen zur Anwendung gelangen soll („Micro-Matrixing“).

In diesem Kapitel wird die grose Bedeutung hochrangiger Meetings fur das Gelingen der Matrix begrundet. Hochrangige Meetings sind nicht zuletzt deshalb erforderlich, weil in matrixstrukturierten Unternehmen typischerweise stark ausgepragte funktionsbereichs-, produktbereichs- und regionenubergreifende Interdependenzen vorliegen. Verschiedene Arten derartiger Meetings werden besprochen.

In diesem Kapitel wird das Ausmas des zwischen den Matrixmanagern und dem Two-boss-Manager typischerweise bestehenden Konflikts aufgezeigt und erlautert. Erstaunlicherweise scheinen nach unseren Forschungen Konflikte in matrixstrukturierten Unternehmen ein weitaus geringeres Ausmas aufzuweisen als gemeinhin vermutet. Auch wird dargelegt, bei welchen Themen Konflikte relativ wahrscheinlich sind. Auserdem werden Mechanismen (z. B. eingehende Diskussion sowie Eskalation) zur Losung bzw. Handhabung von Konflikten behandelt. Schlieslich wird die Einsatzhaufigkeit dieser Mechanismen in der Praxis beschrieben.

We detail the sensitivity of the liquid xenon (LXe) DARWIN observatory to solar neutrinos via elastic electron scattering. We find that DARWIN will have the potential to measure the fluxes of five solar neutrino components: $pp$, $^7$Be, $^{13}$N, $^{15}$O and $pep$. The precision of the $^{13}$N, $^{15}$O and $pep$ components is hindered by the double-beta decay of $^{136}$Xe and, thus, would benefit from a depleted target. A high-statistics observation of $pp$ neutrinos would allow us to infer the values of the weak mixing angle, $\sin^2\theta_w$, and the electron-type neutrino survival probability, $P_e$, in the electron recoil energy region from a few keV up to 200 keV for the first time, with relative precision of 5% and 4%, respectively, at an exposure of 300 ty. An observation of $pp$ and $^7$Be neutrinos would constrain the neutrino-inferred solar luminosity down to 0.2%. A combination of all flux measurements would distinguish between the high (GS98) and low metallicity (AGS09) solar models with 2.1-2.5$\sigma$ significance, independent of external measurements from other experiments or a measurement of $^8$B neutrinos through coherent elastic neutrino-nucleus scattering in DARWIN. Finally, we demonstrate that with a depleted target DARWIN may be sensitive to the neutrino capture process of $^{131}$Xe., Comment: 9 pages, 4 figures; for associated data files, see https://github.com/Physik-Institut-UZH/DARWIN-Sensitivity-Studies/tree/master/solar_neutrinos_electron_scattering

In diesem Kapitel geht es um die Aufgaben und Interaktionsmuster sowie das Fahigkeitsprofil des Two-boss-Managers. Der vorrangige Arbeitsinhalt des Two-boss-Managers scheint darin zu bestehen, die Interaktionsbeziehungen im Matrixdreieck und damit die Matrix selbst zu steuern sowie die getroffenen Entscheidungen hierarchieabwarts umzusetzen. Auch werden Fahigkeiten aufgezeigt, uber die ein Two-boss-Manager typischerweise verfugen sollte.