The chemical composition and sources of road dust, and of tire and road wear particles-A review.

To gain better understanding of how the transition to electric vehicles affects road dust (RD) composition, and potential health and environmental risks, it is crucial to analyze the chemical composition of RD and identify its sources. Sources of RD include wear of tire tread (TT), brake wear (BW) and road wear (RW). A relevant component of RD are tire and road wear particles (TRWPs). This literature review compiles data on the chemical bulk composition of RD sources, RD in Asia, Europe and North America and TRWP as a RD component. The focus is on elements such as Cd, Co, Cr, Cu, Ni, Pb, V, and Zn. Although the comparability of global RD data is limited due to differences in sampling and analytical methods, no significant differences in the composition from Asia, Europe, and North America were found for most of the investigated elements studied, except for Cd, Co, and V. Sources of RD were analyzed using elemental markers. On average TT, BW, and RW contributed 3 %, 1 %, and 96 %, respectively. The highest concentrations of TT (9 %) and BW (2 %) were observed in the particle size fraction of RD ≤ 10 µm. It is recommended that these results be verified using additional marker compounds. The chemical composition of TRWPs from different sources revealed that (i) TRWPs isolated from a tunnel dust sample are composed of 31 % TT, 6 % BW, and 62 % RW, and (ii) test material from tire test stands show a similar TT content but different chemical bulk composition likely because e.g., of missing BW. Therefore, TRWPs from test stands need to be chemically characterized prior to their use in hazard testing to validate their representativeness.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Policy responses to the COVID-19 pandemic in West Africa: a scoping review protocol.

INTRODUCTION: Four years after the devastating Ebola outbreak, governments in West Africa were quick to implement non-pharmaceutical interventions (NPIs) in response to the rapid spread of SARS-CoV-2. The NPIs implemented included physical distancing, closure of schools and businesses, restrictions on public gatherings and mandating the use of face masks among others. In the absence of widely available vaccinations, NPIs were the only known means to try to slow the spread of COVID-19. While numerous studies have assessed the effectiveness of these NPIs in high-income countries, less is known about the processes that lead to the adoption of policies and the factors that influence their implementation and adherence in low-income and middle-income countries. The objective of this scoping review is to understand the extent and type of evidence in relation to the policy formulation, decision-making and implementation stages of NPIs in West Africa. METHODS AND ANALYSIS: A scoping review will be undertaken following the guidance developed by Arskey and O'Malley, the Joanna Briggs Institute (JBI) methodology for scoping reviews and the PRISMA guidelines for Scoping Reviews. Both peer-reviewed and grey literature will be searched using Web of Science, Embase, Scopus, APA PsycInfo, WHO Institutional Repository for Information Sharing, JSTOR and Google Advanced Search, and by searching the websites of the WHO, and the West African Health Organisation. Screening will be conducted by two reviewers based on inclusion and exclusion criteria, and data will be extracted, coded and narratively synthesised. ETHICS AND DISSEMINATION: We started this scoping review in May 2023, and anticipate finishing by April 2024. Ethics approval is not required since we are not collecting primary data. This protocol was registered at Open Science Framework (https://osf.io/gvek2/). We plan to disseminate this research through publications, conference presentations and upcoming West African policy dialogues on pandemic preparedness and response.

Review of Validated Methods to Evaluate Diet History in Diet Therapy and Counselling: An Overview and Analysis of Screeners Based on Food-Based Dietary Guidelines.

Evidence-based dietetic practice calls for systematically developed assessment methods for nutritional assessment in dietetic counselling and therapy (DCT). Screeners can provide a quick and easy way to determine a client's diet quality and contribute to quality assurance in DCT. The aim of this systematic review was to give a comparative overview of screeners based on national food-based dietary guidelines (FBDGs) and to derive recommendations for developing an FBDG-based screener for DCT. The literature search in PubMed (MEDLINE), embase and Web of Science was conducted between May and July 2022, and updated in March 2023, in accordance with the consensus-based standards for the selection of health measurement instruments (COSMIN). The analysis focused on characteristics of screener design and measurement properties for screener testing. In total, 13 studies on 11 screeners based on FBDGs were included; 7 screeners were targeted to DCT. The content and scoring of screeners were based on the corresponding national FBDGs. The validity and/or reliability of screeners were investigated in 11 studies; responsiveness was not tested for any screener and practicality was considered in all studies. Based on the screeners reviewed, a systematic rationale to develop, enhance and test screeners based on national FBDGs was established.

Concept of an Intervention for Sustainable Weight Loss in Postmenopausal Women with Overweight-Secondary Analysis of a Randomized Dietary Intervention Study.

INTRODUCTION: The approach of an individual diet has great potential for sustainable weight reduction. Social support, participation and empowerment are also key factors for high motivation and compliance. So, the impact of an individual diet in combination with group sessions on weight loss in postmenopausal women with overweight was investigated. METHODS: In this reanalysis of a controlled intervention study, postmenopausal women (n = 54; BMI 30.9 ± 3.4 kg/m2; 59 ± 7 years) were recruited receiving an energy restricted diet for 12 weeks, followed by a six-month follow-up phase. The women received 51 individual meal plans based on their habits and were trained in four group sessions. RESULTS: Forty-six women completed the intervention phase, and 29 completed the follow-up. Average weight loss was -5.8 ± 3.0 kg (p < 0.001) after 12 weeks and was still significant at follow-up (-4.9 ± 5.4 kg, p < 0.001). Also, decreases in fat-free mass (-1.1 ± 1.2 kg, p < 0.001) and resting energy expenditure (-1096 ± 439 kJ/24 h, p < 0.001) were observed. CONCLUSIONS: The individual nutrition approach with a focus on nutritype in combination with group sessions was effective for long-lasting weight loss in postmenopausal women. An important factor is close individual and group support.

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

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.

Clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations.

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.

Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers.

BACKGROUND: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum. METHODS: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status. FINDINGS: Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60). INTERPRETATION: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers. FUNDING: This work was an investigator-initiated trial. On the German side, there was no institutional or industrial funding. On the Swedish side, this work was supported by grants from the Swedish Brain Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310, 2020-0353), the Swedish Research Council (grants nr. 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the Ulla-Carin Lindquist Foundation, Umeå University (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the Västerbotten County Council (grants nr 56103-7002829), King Gustaf V:s and Queen Victoria's Freemason's Foundation.

Integrative genetic analysis illuminates ALS heritability and identifies risk genes.

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10-03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

A novel homozygous p.Ser69Pro SOD1 mutation causes severe young-onset ALS with decreased enzyme activity.

BACKGROUND: The dose-effect of various SOD1 mutations on SOD1 enzymatic activity offers valuable insights into ALS pathogenesis with possible therapeutic implications. Homozygous SOD1 mutations, yet scarce, are of special interest. We report a novel homozygous SOD1 mutation with decreased enzymatic activity and severe early onset ALS phenotype. METHODS: Whole exome sequencing and targeted screening of commonly implicated genes were conducted. Repeat-primed PCR and fragment length analysis were used for C9orf72. Bi-directional Sanger sequencing was used for SOD1 and other genes. SOD1 activity was measured by direct spectrophotometry. Serum neurofilament light chain level was measured by the ELLA immunoassay system. RESULTS: The homozygous patient for a novel SOD1 variant p.Ser69Pro showed poor SOD1 enzymatic activity (16% of controls) and an early onset ALS phenotype predominantly affecting lower motor neurons with rapid involvement of the trunk, upper limbs and bulbar muscles. The asymptomatic heterozygous relatives had at least 68% of normal enzyme activity. Level of serum neurofilament light chain was much higher (148 pg/ml) in the patient than the relatives who had normal levels (6-10 pg/ml). CONCLUSION: This novel mutation adds knowledge to the ALS genotype-phenotype spectrum and supports the strong dose-effect of SOD1 mutations associated with severely decreased enzymatic activity.

Human ß-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling.

Acute graft-versus-host disease (aGVHD), which is driven by allogeneic T cells, has a high mortality rate and limited treatment options. Human ß-defensin 2 (hBD-2) is an endogenous epithelial cell-derived host-defense peptide. In addition to its antimicrobial effects, hBD-2 has immunomodulatory functions thought to be mediated by CCR2 and CCR6 in myeloid cells. In this study, we analyzed the effect of recombinant hBD-2 on aGVHD development. We found that intestinal ß-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal ß-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency.

Methylome analysis of ALS patients and presymptomatic mutation carriers in blood cells.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with a monogenic cause in approximately 10% of cases. However, familial clustering of disease without inheritance in a Mendelian manner and the broad range of phenotypes suggest the presence of epigenetic mechanisms. Hence, we performed an epigenome-wide association study on sporadic, symptomatic and presymptomatic familial ALS cases with mutations in C9ORF72 and FUS and healthy controls studying DNA methylation in blood cells. We found differentially methylated DNA positions (DMPs) and regions embedding DMPs associated with either disease status, C9ORF72 or FUS mutation status. One DMP reached methylome-wide significance and is attributed to a region encoding a long non-coding RNA (LOC389247). Furthermore, we could demonstrate co-localization of DMPs with an ALS-associated GWAS region near the SCN7A/SCN9A and XIRP2 genes. Finally, a classifier model that predicts disease status (ALS, healthy) classified all but one presymptomatic mutation carrier as healthy, suggesting that the presence of ALS symptoms rather than the presence of ALS-associated genetic mutations is associated with blood cell DNA methylation.

[Promotion of oral health in nursing-An interprofessional expert standard]. / Förderung der Mundgesundheit in der Pflege ­ ein interprofessioneller Expertenstandard.

BACKGROUND: People in need of care or with severe disability have a worse oral health status compared to people without these needs. The increasing number of older people who are able to keep their own teeth requires specific steps to support oral health. Whereas in 1997 1 in 4 people between 65 and 74 years of age was toothless, in 2016 this figure had risen to 1 in 8. Special challenges in oral care arise for older people and people with dementia. The management requires an interprofessional approach. OBJECTIVE: Interprofessional development of an expert standard for the promotion of oral health by nurses and a focus on older people. METHODS: The expert standard is based on a systematic literature analysis. Based on this, members of an interprofessional expert working group consisting of nurses, dentists and a representative of those affected formulated recommendations to promote oral health of people in need of care. RESULTS: The interprofessional approach defines the selection of the guiding questions for the literature search, the evaluation of the literature and the formulation of the recommendations. Interventions to maintain and promote oral health were identified for the guiding questions of the expert standard, for example, in cases of oral fungal diseases, mucositis, gingivitis or accompanying symptoms, such as dry mouth and pain. DISCUSSION: Interventions to promote oral health of people in need of care or with severe disability could be focused more deeply within the nursing profession and formulated by an interprofessional group to guide their actions.

J wave syndromes in patients with spinal and bulbar muscular atrophy.

BACKGROUND: Males with X-linked recessive spinobulbar muscular atrophy (SBMA) are reported to die suddenly and a Brugada electrocardiography (ECG) pattern may be present. A hallmark of this pattern is the presence of ST segment elevations in right precordial leads associated with an increased risk of sudden cardiac death. OBJECTIVE: We aimed to detect subtle myocardial abnormalities using ECG and cardiovascular magnetic resonance imaging (CMR) in patients with SBMA. METHODS: 30 SBMA patients (55.7 ± 11.9 years) and 11 healthy male controls underwent 12-lead ECGs were recorded using conventional and modified chest leads. CMR included feature-tracking strain analysis, late gadolinium enhancement and native T1 and T2 mapping. RESULTS: Testosterone levels were increased in 6/29 patients. Abnormal ECGs were recorded in 70%, consisting of a Brugada ECG pattern, early repolarization or fragmented QRS. Despite normal left ventricular ejection fraction (66 ± 5%), SBMA patients exhibited more often left ventricular hypertrophy as compared to controls (34.5% vs 20%). End-diastolic volumes were smaller in SBMA patients (left ventricular volume index 61.7 ± 14.7 ml/m2 vs. 79.1 ± 15.5 ml/m2; right ventricular volume index 64.4 ± 16.4 ml/m2 vs. 75.3 ± 17.5 ml/m2). Tissue characterization with T1-mapping revealed diffuse myocardial fibrosis in SBMA patients (73.9% vs. 9.1%, device-specific threshold for T1: 1030 ms). CONCLUSION: SBMA patients show abnormal ECGs and structural abnormalities, which may explain an increased risk of sudden death. These findings underline the importance of ECG screening, measurement of testosterone levels and potentially CMR imaging to assess cardiac risk factors.

De novo mutations in SOD1 are a cause of ALS.

OBJECTIVE: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS. METHODS: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature. RESULTS: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved. CONCLUSIONS: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees.

Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype. We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype-phenotype correlation analysis of FUS/TBK1 double-mutant patients. We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families. We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients. FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals. In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way. Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation.

Probing the chemical complexity of tires: Identification of potential tire-borne water contaminants with high-resolution mass spectrometry.

Tire wear particles are not only the type of polymer particles most prevalent in the environment but also act as source of various organic micropollutants, many of which are likely still unknown. We extracted particles prepared from nine tires in artificial freshwater (28 d) with the goal to characterize leachables (max intensity >105 in artificial freshwater), which are tire-borne water contaminants. A subsequent extraction of these particles with acetone (3 h) was used to assess the long-term leaching potential. A suspect and nontarget screening in aliquots of each extract led to the detection of 214 organic substances of which 145 were classified as leachables. The intrinsic polarity of some leachables (mean log D (pH 7.4) 3.9), which facilitates an increased aquatic mobility, highlights their potential as environmental water contaminants. With N,N'-diphenylguanidine (DPG) and benzothiazole, two of the ten unequivocally identified leachables, are classified as potential persistent, mobile and toxic substance by the German Environment Agency. Of the identified chemicals DPG showed the highest intensities in aqueous extracts and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD), the precursor of 6-PPD-quinone, in acetone extracts. A comparison between the 69 detected suspects and 174 high-intensity signals (>106) detected in the nontarget screening led to an overlap of only 29 features. A detailed investigation of the remaining high-intensity suspects revealed the presence of 13 proposed DPG reaction products, further highlighting the chemical complexity of tires. Consequently, we conclude that there are many, often still unrecognized chemicals entering the aquatic environment through leaching from tire wear particles.