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Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement. [ABSTRACT FROM AUTHOR]

Background: Little is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline. Objectives: This study is to assess HRQoL progression and identify factors affecting SCA patients' HRQoL. Methods: Longitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006–2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients' socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression. Results: HRQoL significantly decreased over one (− 0.014, p = 0.095), two (− 0.028, p = 0.003), and three years (− 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = − 0.589; rsPHQ-9 = − 0.507). HRQoL more intensively declined in male (ß = − 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = − 0.010, p ≤ 0.001), mental health problems (ß = − 0.012, p < 0.001), and higher BMI (ß = − 0.003, p = 0.029) caused more severe decline of patients' HRQoL over time. Discussion: In absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients' HRQoL, especially in male patients with early disease onset. [ABSTRACT FROM AUTHOR]

Although health-related quality of life (HRQoL) has developed into a crucial outcome parameter in clinical research, evidence of the EQ-5D-3L validation performance is lacking in patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The objective of this study is to assess the acceptability, validity, reliability, and responsiveness of the EQ-5D-3L. For n = 842 predominantly European SCA patients of two longitudinal cohort studies, the EQ-5D-3L, PHQ-9 (Patient Health Questionnaire), and ataxia-specific clinical assessments (SARA: Scale for Assessment and Rating of Ataxia; ADL: activities of daily living as part of Friedreich's Ataxia Rating Scale; INAS: Inventory of Non-Ataxia Signs) were assessed at baseline and multiple annual follow-ups. The EQ-5D-3L was evaluated regarding acceptability, distribution properties, convergent and known-groups validity, test-retest reliability, and effect size measures to analyze health changes. The non-item response was low (EQ-5D-3L index: 0.8%; EQ-VAS: 3.4%). Ceiling effects occurred in 9.9% (EQ-5D-3L) and 3.0% (EQ-VAS) with a mean EQ-5D-3L index of 0.65 ± 0.21. In total, convergent validity showed moderate to strong Spearman's rho (rs > 0.3) coefficients comparing EQ-5D-3L and EQ-VAS with PHQ-9, SARA, ADL, and INAS. EQ-5D-3L could discriminate between groups of age, SARA, ADL, and INAS. Intra-class correlation coefficients (EQ-5D-3LICC: 0.95/EQ-VASICC: 0.88) and Kappa statistics (range 0.44 to 0.93 for EQ-5D-3L items) indicated tolerable reliability. EQ-5D-3L shows small (effect size < 0.3) to moderate (effect size 0.3–0.59) health changes regarding ataxia severity. The analysis confirms an acceptable, reliable, valid, and responsive recommended EQ-5D-3L in SCA patients, measuring the HRQoL adequately, besides well-established clinical instruments. [ABSTRACT FROM AUTHOR]

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI's major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change. [ABSTRACT FROM AUTHOR]

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge. [ABSTRACT FROM AUTHOR]

The Ataxia Global Initiative (AGI) aims to serve as a platform to facilitate clinical trial readiness for the hereditary ataxias. Clinical trials for these diseases have been hampered by the lack of objective measures to study disease onset, progression, and treatment efficacy. While these issues are not unique to the genetic ataxias, the relative rarity of these diseases makes the need for such measures even more pressing to achieve statistical power in clinical trials. In this report, we have described the efforts of the AGI fluid biomarker working group (WG) in developing uniform protocols for biomarker sampling and storage, both for human and preclinical studies in mice. By reducing collection variability, we anticipate reduced noise in downstream biomarker analysis that will improve statistical power and minimize the necessary sample size. The emphasis has been on defining and standardizing the sampling and pre-analytical work-up of minimal set of biological samples, specifically blood plasma and serum, keeping in mind the need for harmonization of collection and storage that can be achieved with relatively limited cost and resources. An optional package is detailed for those centers that have the resources and commitment for additional biofluids/sample processing and storage. Finally, we have delineated similar standardized protocols for mice that will be important for preclinical studies in the field. [ABSTRACT FROM AUTHOR]

Abstract With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross‐species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock‐in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross‐sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock‐in mice, here also starting already at the presymptomatic stage, closely following ataxin‐3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross‐species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.

Transition metal doped nanoparticles have potential for photodegradation, antibacterial activity, and water splitting. Co-doped SnO2 nanoparticles (CoxSn1−xO2−δ: x = 0–7%) with an average diameter of ≈ 32 nm are successfully synthesized using the coprecipitation method. The structural properties are investigated using an X-ray diffractometer (XRD) that shows tetragonal structure of the nanoparticles. Microstrain and average crystallite size of the nanoparticles are investigated using different XRD models. It is observed that 7% Co-doping reduces the optical bandgap down to 17% (3.04 eV). The nanoparticles show 75% photodegradation of methylene blue dye under sunlight exposure, and enhance antibacterial activity against both gram-positive and gram-negative bacteria. These results may provide pathways to utilize CoxSn1−xO2−δ nanoparticles as efficient photocatalysts, antibacterial agents for industrial wastewater treatment, and water-splitting applications as well. [ABSTRACT FROM AUTHOR]

Common carp (Cyprinus carpio) are a serious invasive species of riverine habitats in Australia and several control measures have been proposed. The strategy and potential success of any control measure will be influenced by carp population dynamics. Carp survival and distribution are driven by abiotic environmental factors (e.g., water flow rates and habitat availability), which vary greatly in space and time in Australian river systems. To inform realistic control strategies, we developed a mechanistic (process-based) carp metapopulation model with parameters explicitly linked to spatio-temporal estimates of habitat suitability. To demonstrate the use of this model, we evaluated how recovery times following a one-time management action (that results in population reduction) varied across five river catchments in the Murray-Darling Basin (MDB), eastern Australia, using reconstructed environmental conditions from the early 1990s to 2016. We found that recovery time at the catchment scale can be highly dependent on the flood-drought cycle, with recovery varying from to 2 to 10 years between wet and dry periods. In more stable catchments, however, ~ 6 years (range 4–8 years) is more likely. Our results are consistent with the paradigm that carp are a highly successful invasive species, with strong recovery potential, especially during periods of access to quality nursery habitat (i.e., during floodplain and wetland inundation). [ABSTRACT FROM AUTHOR]

Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago. [ABSTRACT FROM AUTHOR]

Abstract In Huntington disease (HD), polyglutamine expansion in the huntingtin protein causes specific neuronal death. The consequences of the presence of mutant huntingtin in other tissues are less well understood. Here we propose that mutant huntingtin influences breast cancer progression. Indeed, we show that mammary tumours appear earlier in mouse breast cancer models expressing mutant huntingtin as compared to control mice expressing wild‐type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern that reflects enhanced aggressiveness with the overexpression of genes favouring invasion and metastasis. In agreement, mutant huntingtin accelerates epithelial to mesenchymal transition and enhances cell motility and invasion. Also, lung metastasis is higher in HD conditions than in control mice. Finally, we report that in HD, the dynamin dependent endocytosis of the ErbB2/HER2 receptor tyrosine kinase is reduced. This leads to its accumulation and to subsequent increases in cell motility and proliferation. Our study may thus have important implications for both cancer and HD.

The current study analyzes the impacts of BISP's unconditional cash transfers on beneficiary households' well-being through various indicators including consumption and poverty. The analysis is conducted by using the 2019 cross-sectional data and panel data of 5 rounds conducted during the 2011–2019 period. A Quasi-experimental approach is adopted by applying both the regression discontinuity design (RDD) and difference-in-discontinuity techniques for cross-sectional and longitudinal data, respectively. The findings reveal that despite 8-years of the intervention, three-fourths of the beneficiary households are still below the poverty line and little impact is found on the consumption expenditures in general. Overall the unconditional cash transfers remained unsuccessful in eradicating extreme poverty which was one of the major objectives of the program. The analysis suggests that BISP needs to revisit its existing design, shifting towards conditional interventions for sustainably alleviating poverty. [ABSTRACT FROM AUTHOR]

Copyright of International Journal for the Semiotics of Law is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice. [ABSTRACT FROM AUTHOR]

We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA. [ABSTRACT FROM AUTHOR]

Variability in neurodegenerative disease progression poses great challenges for the evaluation of potential treatments. Identifying the persons who will experience significant progression in the short term is key for the implementation of trials with smaller sample sizes. We apply here disease course mapping to forecast biomarker progression for individual carriers of the pathological CAG repeat expansions responsible for Huntington disease. We used data from two longitudinal studies (TRACK-HD and TRACK-ON) to synchronize temporal progression of 15 clinical and imaging biomarkers from 290 participants with Huntington disease. We used then the resulting HD COURSE MAP to forecast clinical endpoints from the baseline data of 11,510 participants from ENROLL-HD, an external validation cohort. We used such forecasts to select participants at risk for progression and compute the power of trials for such an enriched population. HD COURSE MAP forecasts biomarkers 5 years after the baseline measures with a maximum mean absolute error of 10 points for the total motor score and 2.15 for the total functional capacity. This allowed reducing sample sizes in trial up to 50% including participants with a higher risk for progression ensuring a more homogeneous group of participants. [ABSTRACT FROM AUTHOR]

Aim: Our primary study objective was to identify risk factors for serious psychological distress (SPD) within the lesbian, gay, and bisexual (LGB) population, while accounting for the differences across these groups compared to heterosexual adults. We hypothesized that LGB adults had a higher risk for SPD compared to heterosexual adults, and that variation existed in SPD risk factors between LGB groups. Methods: National Health Interview Survey data collected from 2013 to 2018 were pooled to examine risk factors for SPD among gay men (n = 1752), bisexual men (n = 509), lesbian women (n = 1421), bisexual women (n = 1235), heterosexual men (n = 80,191) and heterosexual women (n = 97,909). A multivariate logistic regression model estimated SPD risk factors. Results: Bisexual women were at higher risk for SPD [adjusted odds ratio (AOR)= 2.5; 95% CI 1.8, 3.5]compared to heterosexual women. Bisexual (AOR = 3.8; 95% CI 1.9, 7.4) and gay men (AOR = 2.0; 95% CI 1.4, 3.0) were at increased risk for SPD compared to heterosexual men. Younger vs older adults were more likely to identify as bisexual or gay (18–25 years vs 65 years and older identifying as gay men 17.0% vs 9.5%; bisexual men 33.4% vs 8.0%; lesbian 18.0% vs 8.6% and bisexual women 37.7% vs 3.5%). Gay men were more likely to live alone compared to other groups (34.5% vs 16.9% heterosexual men, 31.8% bisexual men, 17.6% heterosexual women, 20.7% lesbian, 19.7% bisexual women). Living alone increased risk for SPD among men (AOR = 2.2; 95% CI 1.6, 3.0). Conclusion: Sexual minorities have increased mental health risks compared to heterosexual adults. Word Count: 248. [ABSTRACT FROM AUTHOR]

Western flower thrips (Frankliniella occidentalis; Thysanoptera: Thripidae), or WFT, are a global pest of commercial crops, particularly those grown in greenhouses. Current management recommendations often involve judicious use of pesticides to which WFT have evolved multiple resistance phenotypes. Essential oils (EOs) have shown promise as a less toxic alternative for WFT greenhouse management. However, challenges remain in predicting which EOs are most likely to be insecticidal to WFT and ensuring that the efficacy of EOs under bioassay conditions reflect performance in whole-plant application scenarios. To address these challenges, 9 EOs were tested for contact toxicity against WFT in small container assays, then gas chromatography–mass spectroscopy (GC–MS) profiles of each EO were used to quantify concentrations of 22 chemicals shared by at least 5 or more of the plant species. Of these, 13 compounds were positively correlated with thrips mortality. Effective compounds were a mixture of sesquiterpenes, cyclic monoterpenes, and noncyclic monoterpenes. Interestingly, no bicyclic monoterpenes shared among the essential oils tested correlated with thrips mortality. Whole-plant assays of the four best EOs from the container assay showed significant reduction in the number of thrips per plant, although mortality in EO treatments in the whole plant assay was lower than in the container assay. In addition, all four EOs were as efficacious as the conventional insecticide flonicamid. Identifying other EOs with high concentrations of the efficacious compounds that were identified in this study and using container assays to screen these oils for WFT thrip mortality and phytotoxicity could help integrated pest management (IPM) practitioners and greenhouse staff to more rapidly accumulate a suite of EOs as low toxicity alternatives for management of WFT in greenhouse settings. [ABSTRACT FROM AUTHOR]

Le présent article s'intéresse aux stratégies discursives et linguistiques qui ont permis d'ancrer la vision du monde national-socialiste dans le discours politique, philosophique et juridique en Allemagne dans les années 1939–1945. A partir de la notion d'authenticité d'extraction heideggérienne, il sera montré que le renversement politique et juridique ayant conduit in fine à l'extermination des Juifs d'Europe a été fondé et légitimé par un corpus d'idées philosophiques et de concepts juridiques qui ont inscrit leur anéantissement dans le discours. Il sera également montré que l'introduction du critère racial dans le discours philosophique et juridique a profondément bouleversé la signification des concepts en modifiant leur grammaire d'usage de sorte qu'ils ont été vidés de leur sens. L'élaboration de ce corpus et les bouleversements dans l'usage des mots et des concepts ont donné lieu à l'émergence d'un langage spécifique, à la fois cryptique, élusif et équivoque. Ce langage a joué un double rôle: il a permis d'exclure d'emblée certaines catégories de la population, jugées indignes de faire partie de la communauté du peuple germanique, d'une part, et d'autre part, il a permis de justifier le génocide des Juifs après 1945. Méthodologiquement, la notion de formule sera mobilisée pour mettre en exergue la manipulation linguistique à l'œuvre dans le discours de l'authenticité. Enfin, les difficultés posées par la traduction de ce type de discours seront brièvement abordées. [ABSTRACT FROM AUTHOR]

Purpose of this Review: We discuss the role of observational studies and cardiac registries during the COVID-19 pandemic. We focus on published cardiac registries and highlight contributions to the field that have had clinical implications. Recent Findings: We included observational studies of COVID-19 patients published in peer-reviewed medical journals with defined inclusion and exclusion criteria, defined study design, and primary outcomes. A PubMed and MEDLINE literature review results in 437 articles, of which 52 include patients with COVID-19 with cardiac endpoints. From July 2020 to December 2021, the average time from last data collected to publication was 8.9 ± 4.1 months, with an increasing trend over time (R = 0.9444, p < 0.0001). Of the 52 articles that met our inclusion criteria, we summarize main findings of 4 manuscripts on stroke, 14 on acute coronary syndrome, 4 on cardiac arrest, 7 on heart failure, 7 on venous thromboembolism, 5 on dysrhythmia, and 11 on different populations at risk for cardiovascular. Summary: Registries are cost effective, not disruptive to essential health services, and can be rapidly disseminated with short intervals between last data point collected and publication. In less than 2 years, cardiac registries have filled important gaps in knowledge and informed the care of COVID-19 patients with cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV) belongs to the Pneumoviridae family and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors. We characterize the antibodies' germline usage, epitopes, neutralization potencies, and binding specificities. We find that unlike RSV-F specific mAbs, antibody responses to hMPV F are less dominant against the apex of the antigen, and the majority of the potent neutralizing mAbs recognize epitopes on the side of hMPV F. Furthermore, neutralizing epitopes that differ from previously defined antigenic sites on RSV F are identified, and multiple binding modes of site V and II mAbs are discovered. Interestingly, mAbs that bind preferentially to the unprocessed prefusion F show poor neutralization potency. These results elucidate the immune recognition of hMPV infection and provide novel insights for future hMPV antibody and vaccine development. Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the infectious disease COVID-19, which has rapidly become an international pandemic with significant impact on healthcare systems and the global economy. To assist antiviral therapy and vaccine development efforts, we performed a natural history/time course study of SARS-CoV-2 infection in ferrets to characterise and assess the suitability of this animal model. Ten ferrets of each sex were challenged intranasally with 4.64 × 104 TCID50 of SARS-CoV-2 isolate Australia/VIC01/2020 and monitored for clinical disease signs, viral shedding, and tissues collected post-mortem for histopathological and virological assessment at set intervals. We found that SARS-CoV-2 replicated in the upper respiratory tract of ferrets with consistent viral shedding in nasal wash samples and oral swab samples up until day 9. Infectious SARS-CoV-2 was recovered from nasal washes, oral swabs, nasal turbinates, pharynx, and olfactory bulb samples within 3–7 days post-challenge; however, only viral RNA was detected by qRT-PCR in samples collected from the trachea, lung, and parts of the gastrointestinal tract. Viral antigen was seen exclusively in nasal epithelium and associated sloughed cells and draining lymph nodes upon immunohistochemical staining. Due to the absence of clinical signs after viral challenge, our ferret model is appropriate for studying asymptomatic SARS-CoV-2 infections and most suitable for use in vaccine efficacy studies. [ABSTRACT FROM AUTHOR]

The aim of this work is to evaluate the performance of a novel algorithm that combines dynamic wavefront aberrometry data and descriptors of the retinal image quality from objective autorefractor measurements to predict subjective refraction. We conducted a retrospective study of the prediction accuracy and precision of the novel algorithm compared to standard search-based retinal image quality optimization algorithms. Dynamic measurements from 34 adult patients were taken with a handheld wavefront autorefractor and static data was obtained with a high-end desktop wavefront aberrometer. The search-based algorithms did not significantly improve the results of the desktop system, while the dynamic approach was able to simultaneously reduce the standard deviation (up to a 15% for reduction of spherical equivalent power) and the mean bias error of the predictions (up to 80% reduction of spherical equivalent power) for the handheld aberrometer. These results suggest that dynamic retinal image analysis can substantially improve the accuracy and precision of the portable wavefront autorefractor relative to subjective refraction. [ABSTRACT FROM AUTHOR]

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Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD. [ABSTRACT FROM AUTHOR]

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate. [ABSTRACT FROM AUTHOR]

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In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in—easily accessible—peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions. [ABSTRACT FROM AUTHOR]

An imbalanced dataset is commonly found in at least one class, which are typically exceeded by the other ones. A machine learning algorithm (classifier) trained with an imbalanced dataset predicts the majority class (frequently occurring) more than the other minority classes (rarely occurring). Training with an imbalanced dataset poses challenges for classifiers; however, applying suitable techniques for reducing class imbalance issues can enhance classifiers' performance. In this study, we consider an imbalanced dataset from an educational context. Initially, we examine all shortcomings regarding the classification of an imbalanced dataset. Then, we apply data-level algorithms for class balancing and compare the performance of classifiers. The performance of the classifiers is measured using the underlying information in their confusion matrices, such as accuracy, precision, recall, and F measure. The results show that classification with an imbalanced dataset may produce high accuracy but low precision and recall for the minority class. The analysis confirms that undersampling and oversampling are effective for balancing datasets, but the latter dominates. [ABSTRACT FROM AUTHOR]

Background: Friedreich's ataxia (FRDA) is a cerebellar ataxia due to GAA repeat expansions in the FXN gene, and in affected patients, lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. We aimed to identify patients likely to develop worsening LVEF at an early stage. Methods: We included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years. Results: At baseline, left ventricular (LV) hypertrophy was present in 53%, with LVEF 65 ± 7%, LV end diastolic diameter (LVEDD) 43 ± 5 mm, septal wall thickness (SWT) 11.8 ± 2.7 mm, and posterior wall thickness 11.1 ± 2.5 mm. After a mean follow-up of 13 ± 6 years, LVEF ≤ 50% was observed in 12 patients. The main determinants of LVEF ≤ 50% were GAA repeat number on the shorter allele (odds ratio [OR] 1.007, 95% confidence interval [CI] 1.003–1.012, p = 0.002), LVEDD (OR 1.217, 95% CI 1.058–1.399, p = 0.006), and SWT (OR 1.352, 95% CI 1.016–1.799, p = 0.04). High-risk patients were predicted 5 years before LVEF ≤ 50% occurred: area under the curve of 0.91, 95% CI 0.85–0.97. Patients with GAA repeats > 800 were categorized as high risk, patients with 500 < GAA < 800 were high risk if LVEDD was ≥ 52.6 mm and SWT was ≥ 13.3 mm, and patients with GAA < 500 were low risk if LVEDD was < 52.6 mm and SWT was < 13.3 mm. Conclusions: Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions. [ABSTRACT FROM AUTHOR]

A year-long design project is a typical requirement for an undergraduate engineering degree. However, the abbreviated, two-semester format limits most projects from reaching appropriate maturity for obtaining intellectual property (IP) protection, external funding, and/or peer-reviewed publications. The traditional model may be associated with some dissatisfaction with the abrupt ending of the work, as projects are often just completing their initial proof-of-concept testing after 1 year. This study reports the results of a pilot experiment that allowed such design projects to extend through a second year. We investigated three different mechanisms for continuation: research credits, a second-year curricular course (Advanced Design Teams), and extracurricular support. Students in this program continued to engage with an advisory board of clinicians, engineers, and other professionals, many of whom had assisted with the project during the first year. We investigated whether continuing the projects in a curricular fashion may provide a better avenue for productivity than extracurricular mechanisms. Based on the results of this pilot study, our department has formalized a curriculum to support teams beyond the first year, in which continuing students from the first-year teams can apply to continue their projects for credit toward their degrees. [ABSTRACT FROM AUTHOR]

Breast cancer is the most commonly diagnosed malignancy in females, the etiology being multifactorial and includes the role of lifestyle exposure to DNA-damaging chemicals such as dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Both compounds require cytochrome P450 (CYP)-mediated metabolic activation to DNA-damaging species, and both induce transcriptional responses through the nuclear receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The objective of this work was to investigate the molecular toxicology and local activation of BaP and PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24 h) of cells with BaP (10 nM-10 µM) and PhIP (100 nM-100 µM) significantly induced genetic damage (micronuclei formation) in a dose-dependent manner in both cell lines. This effect was potentiated in the presence of human IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6 treatment failed to induce micronuclei frequency above the control levels in these cells. Compared to BaP or PhIP treatment alone, IL-6 plus BaP or PhIP selectively induced CYP1B1 significantly in both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically CYP1B1 via miR27b, is responsible for this effect. [ABSTRACT FROM AUTHOR]

The NC-LINK Project initiated both clinic-based retention services and state public health bridge counselor-based (SBCs) re-engagement services to retain and re-engage people living with HIV infection (PLWH) in care. The goal of this project is to compare efforts between clinic-based retention and SBC re-engagement services to determine whether patients are more or less likely to remain in HIV care services. Clinic appointment data were used to identify patients who were last seen more than 6-9 months prior. Patients either received clinic-based retention services only or were subsequently referred to the SBC re-engagement intervention if the retention services were unsuccessful. The frequency of re-engagement in care (180 days) and HIV suppression (VLS, within 1 year) was examined for patients in these two groups. The SBC group was less likely to have VLS at the visit prior to referral (adjusted OR 2.04, 95% CI 1.53, 2.72). Patients who were referred to the SBC were less likely to re-engage in care within 180 days as compared to those who received clinic-based retention services only (adjusted OR 0.29, 95% CI 0.21, 0.41). [ABSTRACT FROM AUTHOR]

Background: Infections are a common medical complication in hemorrhagic stroke patients, with vancomycin commonly used as empiric therapy. The purpose of this study was to evaluate the pharmacokinetic parameters of vancomycin in hemorrhagic stroke patients.Methods: This was a retrospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted between May 2010 and February 2015 who received vancomycin. Predicted pharmacokinetic parameters based on population data were compared with calculated pharmacokinetic parameters based on serum trough concentrations.Results: Eighty aSAH patients and 66 ICH patients met inclusion criteria. In the aSAH group, the mean dosing regimen was 17.6 ± 4 mg/kg every 12 (8-12) h. The mean measured trough concentration was lower than the predicted trough concentration (9.9 ± 4.1 vs. 19 ± 8.7 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.135 ± 0.04 vs. 0.092 ± 0.03 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (5.7 ± 1.8 vs. 8.3 ± 2.9 h; p < 0.001). In the ICH group, the mean dosing regimen was 15.9 ± 4.3 mg/kg every 12 (8-12) h. Similarly, the mean measured trough concentration was lower than the predicted trough concentration (10.7 ± 4.6 vs. 17.5 ± 8.5 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.106 ± 0.03 vs. 0.079 ± 0.02 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (7.2 ± 2.3 vs. 9.6 ± 3.2 h; p < 0.001).Conclusions: Patients with hemorrhagic stroke exhibited pharmacokinetic alterations favoring increased elimination of vancomycin when compared to predicted pharmacokinetic parameters based on population data. This may result in underexposure to vancomycin, leading to treatment failure and other medical complications. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (B(a)P) is a major cancer-causing contaminant present in food such as cooked meats and cereals, and is ubiquitous in the environment in smoke derived from the combustion of organic material. Exposure to B(a)P is epidemiologically linked with the incidence of breast cancer. Although B(a)P is recognized as a complete genotoxic carcinogen, thought to act primarily via CYP-mediated metabolic activation to DNA-damaging species, there is also evidence that B(a)P exposure elicits other biological responses that promote development of the cancer phenotype. Here in mechanistic studies using human mammary cells MCF-7 and MDA-MB-231, we have explored mechanisms whereby B(a)P (10− 8 to 10− 5M) promotes inflammation pathways via TNF-α and NFκB leading to IL-6 upregulation, microRNA (Let7a, miR21 and miR29b) dysregulation and activation of VEGF. The miRNA dysregulation is associated with altered expression of inflammation mediators and increased migration and invasive potential of human mammary cancer cells. Our data suggest that mammary cell exposure to B(a)P results in perturbation of inflammation mediators and dysregulation of tumorigenic miRNAs, leading to an inflammation microenvironment that facilitates migration and invasion of mammary epithelial cells. These properties of B(a)P, together with its well-established metabolic activation to DNA-damaging species, offer mechanistic insights into its carcinogenic mode of action. [ABSTRACT FROM AUTHOR]

Introduction: To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6.Methods: To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington’s Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS).Results: UHDRS-IV [SCA1: − 1.35 (0.12); SCA2: − 1.15 (0.11); SCA3: − 1.16 (0.11); SCA6: − 0.99 (0.12)] and EQ-5D [SCA1: − 2.88 (0.72); SCA2: − 1.97 (0.49); SCA3: − 2.06 (0.55); SCA6: − 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473-0.707) and EQ-5D VAS (0.053-0.184) were lower than that of SARA (0.404-0.979). In SCA1, higher SARA scores [− 0.0288 (0.01), p = 0.0251], longer repeat expansions [− 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [− 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [− 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396].Conclusions: In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials. [ABSTRACT FROM AUTHOR]

Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10−7-10−4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α−) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10−3-10−1 M) with PhIP (10−7-10−4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices. [ABSTRACT FROM AUTHOR]

Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits. [ABSTRACT FROM AUTHOR]

Following the footprints of Bill Gates, Steve Jobs and Mark Zuckerberg, there has been a misconception that students are better off quitting their studies to bring to life their ideas, create jobs and monetize their inventions. Having historically transitioned from manpower to mind power, we live in one of the most rapidly changing times in human history. As a result, academic institutions that are supposed to be pioneers and educators of the next generations have started to realize that they need to adapt to a new system, and change their policies to be more flexible towards patent ownership and commercialization. There is an infrastructure being developed towards students starting their own businesses while continuing with their studies. This paper aims to provide an overview of the existing landscape, the exciting rewards as well as risks awaiting a student entrepreneur, the challenges of the present ecosystem, and questions to consider prior to embarking on such a journey. Various entities influencing the start-up environment are considered, specifically for the medical technology sector. These parties include but are not limited to: scientists, clinicians, investors, academic institutions and governments. A special focus will be set on the seemingly unbridgeable gap between founding a company and a scientific career. [ABSTRACT FROM AUTHOR]

Guided by affective events theory, the purpose of this study was to examine the temporal aspects of childcare teacher burnout, particularly as to how feelings of exhaustion throughout the day relate to perceptions of end-of-day job satisfaction and quitting intentions. A secondary purpose of the study was to explore the frequency and type of rejuvenation strategies childcare teachers use to relieve perceived stress throughout the day. Ecological momentary assessment procedures were employed for 1 week to assess exhaustion levels (3 times/day), frequencies and types of rejuvenation strategies (3 times/day), and end-of-day job satisfaction perceptions and quitting intentions (1 time/day) among 50 childcare teachers. Results indicated that childcare teachers' quitting intentions were positively predicted by emotional exhaustion (β = 0.52) and negatively predicted by overall job satisfaction (β = −0.28). Short (≤15 min), infrequently used (one to two times/day) physical or cognitive health reprieve strategies were reported by 86 % of teachers as the most effective for reducing daily stress. Findings suggest that daily accounts of burnout and quitting intentions have both exhaustive and restorative properties. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the narrowing of arteries due to the accumulation of macrophages overloaded with lipids resulting in foam cell formation, and these events occur preferentially at the branching points of arteries which are particularly susceptible to hyperlipidemic stress-induced inflammation and oxidative stress. The different stages of atherogenesis rely on oxidative stress, endothelial dysfunction, and inflammation, and hypertension or dyslipidemia can independently trigger these stages. Dyslipidemia and hypertension are pathological conditions that damage the endothelium, triggering cell proliferation, vascular remodeling, apoptosis, and increased cellular permeability with increased adhesion molecules that bind monocytes and T lymphocytes to create a vicious cocktail of pathophysiological factors. Correspondingly, the factors are redirected by chemo-attractants and pro-inflammatory cytokines into the intima of the vasculature, where monocytes differentiate into macrophages taking up oxidized LDL uncontrollably to form foam cells and atherosclerotic lesions. Moreover, endothelial damage also causes loss of vasomotor activity, disproportionate vascular contractility, and elevation of blood pressure in dyslipidemic patients, while in hypertensive patients, further elevation of blood pressure occurs, creating a self-perpetuating vicious cycle that aggravates the development and progression of atherosclerotic lesions. This review offers an in-depth analysis of atherosclerosis and the related interplay between dyslipidemia/hypertension and critically appraises the current diagnosis, etiology, and therapeutic options. [ABSTRACT FROM AUTHOR]

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [ K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) could treat chorea in Huntington's disease patients. The objectives of this study were to evaluate the efficacy of GPi-DBS to reduce abnormal movements of three patients with Huntington's disease and assess tolerability. Three non-demented patients with severe pharmacoresistant chorea underwent bilateral GPi-DBS and were followed for 30, 24, and 12 months, respectively. Primary outcome measure was the change of the chorea and total motor scores of the Unified Huntington's Disease Rating Scale between pre- and last postoperative assessments. Secondary outcome measures were motor changes between ventral versus dorsal and between on- and off- GPi-DBS. GPi neuronal activities were analyzed and compared to those obtained in patients with Parkinson's disease. No adverse effects occurred. Chorea decreased in all patients (13, 67 and 29 %) postoperatively. Total motor score decreased in patient 2 (19.6 %) and moderately increased in patients 1 and 3 (17.5 and 1.7 %), due to increased bradykinesia and dysarthria. Ventral was superior to dorsal GPi-DBS to control chorea. Total motor score increased dramatically off-stimulation compared to ventral GPi-DBS (70, 63 and 19 %). Cognitive and psychic functions were overall unchanged. Lower mean rate and less frequent bursting activity were found in Huntington's disease compared to Parkinson's disease patients. Ventral GPi-DBS sustainably reduced chorea, but worsened bradykinesia and dysarthria. Based on these results and previous published reports, we propose to select non-demented HD patients with severe chorea, and a short disease evolution as the best candidates for GPi-DBS. [ABSTRACT FROM AUTHOR]