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Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Background: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. Methods: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH−, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. Results: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. Conclusions: P-AscH− infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

IntroductionThis study explores the beliefs of pre-service mathematics teachers regarding the teaching and learning of mathematics.MethodsWe employed a mixed methods approach, combining quantitative Likert-scale surveys and Q methodology, an integrative quantitative and qualitative approach. A sample of 33 pre-service teachers participated in the study. Initially, Likert-scale surveys were used to ascertain general trends in belief orientations. Subsequently, the same participants engaged in a Q sort exercise, which allowed for a nuanced exploration of individual belief systems by prioritizing the same survey statements within a forced-choice grid. Qualitative interviews further enriched these findings.ResultsQ methodology analysis identified distinct belief profiles, characterized by their prioritization of specific educational practices and the contextual and subjective interpretations that underpin these preferences. The qualitative interviews provided deeper insight into the reasoning behind participants’ choices in the Q sort, illustrating the complex, sometimes contradictory nature of personally held beliefs that traditional Likert-scale approaches may obscure.DiscussionOur results underscore the utility of combining Q methodology with conventional teacher belief survey techniques to achieve a more holistic understanding of pre-service teachers’ beliefs. This approach reveals the complexity within individual belief systems and highlights the potential for mixed methods research to refine the measurement and interpretation of psychological constructs in educational settings.

Abstract Depressive symptoms in Parkinson’s disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment of depressive symptoms both in PD and DC should be improved.

This study focuses on a comparison of personal meanings that students from Finland (FIN) and Germany (GER) assign to (learning) mathematics. Participants are 256 Finnish and 276 German ninth graders. The survey consists of 18 scales that are based on the theory of personal meaning. The original German version was translated into Finnish. Using item response theory (IRT) partial credit models, the psychometric properties of the scales were found to be good. As statistical procedure, Differential Item Functioning (DIF) analysis and mean comparisons were conducted to compare the two groups' (FIN and GER) responses. Indicators of educational system and curriculum could be found in students' responses to explain similarities and differences between the two samples. In both countries, social inclusion is meaningful for most of the students ("Support by teacher," "Experience of relatedness," and "Emotional-affective relation to teacher"). In addition, it is personally meaningful for Finnish students to do well in mathematics. This shows a link to identity-related questions such as confirming important aspects of the self. Hence, personal meanings related to mathematics are more common in Finland than in Germany ("Active practice of mathematics," "Cognitive challenge," and "Self-perfection").

This Special Issue in International Journal on Math, Science and Technology Education (LUMAT) has a unique history. It is a collection of selected papers from the 27th International Conference on Mathematical Views (MAVI27), which took place in Bremen, Germany, from 15 to 17 September 2021.

Stenotrophomonas maltophilia is one of the most frequently isolated multidrug-resistant nosocomial opportunistic pathogens. It contributes to disease progression in cystic fibrosis (CF) patients and is frequently isolated from wounds, infected tissues, and catheter surfaces. On these diverse surfaces S. maltophilia lives in single-species or multispecies biofilms. Since very little is known about common processes in biofilms of different S. maltophilia isolates, we analyzed the biofilm profiles of 300 clinical and environmental isolates from Europe of the recently identified main lineages Sgn3, Sgn4, and Sm2 to Sm18. The analysis of the biofilm architecture of 40 clinical isolates revealed the presence of multicellular structures and high phenotypic variability at a strain-specific level. Further, transcriptome analyses of biofilm cells of seven clinical isolates identified a set of 106 shared strongly expressed genes and 33 strain-specifically expressed genes. Surprisingly, the transcriptome profiles of biofilm versus planktonic cells revealed that just 9.43% ± 1.36% of all genes were differentially regulated. This implies that just a small set of shared and commonly regulated genes is involved in the biofilm lifestyle. Strikingly, iron uptake appears to be a key factor involved in this metabolic shift. Further, metabolic analyses implied that S. maltophilia employs a mostly fermentative growth mode under biofilm conditions. The transcriptome data of this study together with the phenotypic and metabolic analyses represent so far the largest data set on S. maltophilia biofilm versus planktonic cells. This study will lay the foundation for the identification of strategies for fighting S. maltophilia biofilms in clinical and industrial settings.IMPORTANCE Microorganisms living in a biofilm are much more tolerant to antibiotics and antimicrobial substances than planktonic cells are. Thus, the treatment of infections caused by microorganisms living in biofilms is extremely difficult. Nosocomial infections (among others) caused by S. maltophilia, particularly lung infection among CF patients, have increased in prevalence in recent years. The intrinsic multidrug resistance of S. maltophilia and the increased tolerance to antimicrobial agents of its biofilm cells make the treatment of S. maltophilia infection difficult. The significance of our research is based on understanding the common mechanisms involved in biofilm formation of different S. maltophilia isolates, understanding the diversity of biofilm architectures among strains of this species, and identifying the differently regulated processes in biofilm versus planktonic cells. These results will lay the foundation for the treatment of S. maltophilia biofilms.

Abstract Low‐fouling materials are often generated by surface zwitterionization with polymers. In this context, poly‐N‐oxides have recently attracted considerable attention as biomimetic stealth coatings with low protein adsorption. Herein, this study reports that poly‐N‐oxides can be grafted from plasma‐activated plastic base materials. The resulting hydrophilic surfaces have low‐fouling properties in bacterial suspensions and suppress the formation of biofilms. Moreover, efficient antibacterial activity against Gram‐negative and Gram‐positive bacteria caused by release of reactive oxygen species is observed. The latter effect is specific for polymeric N‐oxides and is most likely triggered by a reductive activation of the N‐oxide functionality in the presence of bacteria. In contrast to other zwitterionic polymers, N‐oxides combine thus low‐fouling (stealth) properties with antibacterial activity. The bioactive N‐oxide groups can be regenerated after use by common oxidative disinfectants. Poly‐N‐oxides are thus attractive antibacterial coatings for many base materials with a unique combined mechanism of action.

PURPOSE: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy. PATIENTS AND METHODS: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). RESULTS: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. CONCLUSIONS: P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Purpose: Neurogenic lower urinary tract dysfunction (NLUTD) is highly prevalent among patients with neurologic disorders. Some studies have demonstrated that implantable neuromodulation can improve symptoms of NLUTD. We seek to describe our experience with sacral and pudendal neuromodulation in patients with NLUTD. Methods: A retrospective chart review of patients with "neurogenic bladder" ICD-9/10 (International Classification of Diseases, Ninth Revision/10th Revision) code was performed at a single institution. This included patients from 2008 to 2020 who underwent stage 1 neuromodulation trial. Demographic and clinical information was collected, including neurologic diagnosis, the character of patients' voiding symptoms, the presence or absence of fecal incontinence, the need for intermittent catheterization, and whether patients had sufficient (>50%) improvement in their symptoms to undergo stage 2 implantable pulse generator (IPG) placement. Results: We identified 82 patients with neurologic diagnoses who underwent stage 1 neuromodulation. The most common diagnoses were diabetic cystopathy (17.07%), spinal surgery (17.07%), and spinal cord injury (12.20%). The most commonly reported symptoms were urinary urgency, and urge urinary incontinence. Overall, 59 patients (71.95%) advanced to stage 2 IPG placement including 72% of patients with sacral leads and 76% with pudendal leads. Conclusions: Neuromodulation is feasible and effective in the treatment of NLUTD. Further investigation into its utilization is warranted. [ABSTRACT FROM AUTHOR]

Background: Despite considerable heritability, previous smaller genome‐wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large‐scale GWAS in a well‐characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array‐based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome‐wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single‐nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence‐based GWASs (eg, by whole‐genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Until recently, about three‐quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype–phenotype relationships at a global scale. Objective: To identify the multi‐ancestry spectrum of monogenic PD. Methods: The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD‐causing genes. In contrast, the Global Parkinson's Genetics Program's Monogenic Network took a different approach by targeting PD centers underrepresented or not yet represented in the medical literature. Results: In this article, we describe combining both efforts in a merger project resulting in a global monogenic PD cohort with the buildup of a sustainable infrastructure to identify the multi‐ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expressivity of monogenic PD. Conclusions: This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

In ancient DNA research, the degraded nature of the samples generally results in poor yields of highly fragmented DNA; targeted DNA enrichment is thus required to maximize research outcomes. The three commonly used methods – array-based hybridization capture and in-solution capture using either RNA or DNA baits – have different characteristics that may influence the capture efficiency, specificity and reproducibility. Here we compare their performance in enriching pathogen DNA of Mycobacterium leprae and Treponema pallidum from 11 ancient and 19 modern samples. We find that in-solution approaches are the most effective method in ancient and modern samples of both pathogens and that RNA baits usually perform better than DNA baits.

Abstract Neurological long-term sequelae are increasingly considered an important challenge in the recent COVID-19 pandemic. However, most evidence for neurological symptoms after SARS-CoV-2 infection and central nervous system invasion of the virus stems from individuals severely affected in the acute phase of the disease. Here, we report long-lasting cognitive impairment along with persistent cerebrospinal fluid anti-SARS-CoV-2 antibodies in a female patient with unremarkable standard examination 6 months after mild COVID-19, supporting the implementation of neuropsychological testing and specific cerebrospinal fluid investigation also in patients with a relatively mild acute disease phase.

Hypoglycin A (HGA) in seeds of Acer spp. is suspected to cause seasonal pasture myopathy in North America and equine atypical myopathy (AM) in Europe, fatal diseases in horses on pasture. In previous studies, this suspicion was substantiated by the correlation of seed HGA content with the concentrations of toxic metabolites in urine and serum (MCPA-conjugates) of affected horses. However, seed sampling was conducted after rather than during an outbreak of the disease. The aim of this study was to further confirm the causality between HGA occurrence and disease outbreak by seed sampling during an outbreak and the determination of i) HGA in seeds and of ii) HGA and MCPA-conjugates in urine and serum of diseased horses. Furthermore, cograzing healthy horses, which were present on AM affected pastures, were also investigated. AM-pastures in Germany were visited to identify seeds of Acer pseudoplatanus and serum (n = 8) as well as urine (n = 6) from a total of 16 diseased horses were analyzed for amino acid composition by LC-ESI-MS/MS, with a special focus on the content of HGA. Additionally, the content of its toxic metabolite was measured in its conjugated form in body fluids (UPLC-MS/MS). The seeds contained 1.7-319.8 μg HGA/g seed. The content of HGA in serum of affected horses ranged from 387.8-8493.8 μg/L (controls < 10 μg/L), and in urine from 143.8-926.4 μg/L (controls < 10 μg/L), respectively. Healthy cograzing horses on AM-pastures showed higher serum (108.8 ± 83.76 μg/L) and urine concentrations (26.9 ± 7.39 μg/L) compared to control horses, but lower concentrations compared to diseased horses. The range of MCPA-carnitine and creatinine concentrations found in diseased horses in serum and urine were 0.17-0.65 mmol/L (controls < 0.01), and 0.34-2.05 μmol/mmoL (controls < 0.001), respectively. MCPA-glycine levels in urine of cograzing horses were higher compared to controls. Thus, the causal link between HGA intoxication and disease outbreak could be further substantiated, and the early detection of HGA in cograzing horses, which are clinically normal, might be a promising step in prophylaxis.