Search

Despite a recent increase in FDA new drug approvals, leading pharmaceutical companies continue to face R&D productivity challenges. This highlights the need to better understand the context of their R&D concepts and related R&D outputs. Consequently, we conducted a systematic assessment of the impact of R&D expenditures, R&D intensities, mergers & acquisitions (M&A) deals and licensing agreements on new drug approvals of leading pharmaceutical companies between 2012 and 2021. Our analysis provides key insights into differentiating R&D factors: whereas R&D expenditures and the number of M&A deals correlate with the number of new drug approvals, our analysis shows no correlation with R&D intensity or the number of licensing agreements., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Previous analyses provide an industry benchmark of ∼10% for the success rate in clinical development. However, prior analyses were limited by a narrow timeframe, a diverse research focus, biases in phase-to-phase transition methodology or a focus on specific use cases. We calculated unbiased input:output ratios (Phase I to FDA new drug approval) to analyze the likelihood of first approval using data from clinicaltrials.gov, encompassing a total of 2092 active ingredients, 19 927 clinical trials conducted by 18 leading pharmaceutical companies (2006-2022) and 274 new drug approvals. Our study reveals an average likelihood of first approval rate of 14.3% across leading research-based pharmaceutical companies, broadly ranging from 8% to 23%., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The rapid development and distribution of mRNA COVID-19 vaccines has been essential in containing the SARS-CoV-2 epidemic around the globe. For ongoing and future immunization campaigns globally, there is a need to evaluate the impact of population demographics such as age and sex, on vaccine efficacy and safety., Methods: This systematic review (PROSPERO ID CRD42023328245) conducted according to PRISMA guidelines evaluates the impact of age and sex on the safety and efficacy of the mRNA COVID-19 vaccinations administrated in 15 studies that were chosen according to strict criteria. The ROBIS tool was applied to evaluate the robustness and the quality of the studies included in the review., Results: After screening, 15 studies satisfied the inclusion criteria. The results showed that the COVID-19 mRNA vaccines typically elicit robust immune responses, and that younger people have higher antibody levels. Comparing the sexes reveals that higher immunological responses were induced in females, and mild to moderate adverse effects (such as injection site discomfort, exhaustion, and headaches) were also more frequently reported in women. Despite these variations, COVID-19 vaccines have been found to be safe to use across diverse populations, which supports their extensive use in public health initiatives., Conclusion: Our results suggests that tailored vaccination may achieve maximum effectiveness and better tolerability depending on age and sex. Currently study results are rarely stratified by age and sex and this is a deficit in clinical trial publications. More research is needed to elucidate the biological mechanisms underlying the variations in vaccine responses according to age and sex., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Policy Points First, policymakers can strengthen the inherent trust-building effect of legislations on citizens by incorporating trust-building principles within health data-sharing legislations in a recognizable and comprehensive manner to explicitly signal public trust to policy implementers as one of the policy outcomes to be achieved in the implementation phase. Second, policymakers can use the proposed "public trust in health data sharing" framework as an initial guide to incorporate trust-building principles within health data-sharing legislations., Context: Public trust is critical to both system legitimacy and the successful implementation of data-driven health initiatives. Legislations are an essential instrument for building public trust, as they can have a dual effect on trust: a passive effect by reinforcing the public perception of an active regulatory system that upholds the rule of law and an active effect as a tool for policymakers to signal trust-building actions to be undertaken during the implementation phase. However, there is limited evidence on the extent to which health data-sharing legislations contain references to trust and trust-building principles for their practical implementation., Methods: By applying an evidence-based "public trust in health data sharing" framework, 36 legislations from the European Union (EU), Italy, France, and Switzerland on health data sharing were analyzed to assess 1) how the term "trust" is embedded in legislations, and 2) the presence and quality of trust-building principles within the selected legislations., Findings: Nine legislations incorporated references to "trust," mainly within the explanatory memorandum and preambles of EU legislations. The most prevalent trust-building principles were "agencies of accountability" (72%) and data "security" (70%). In contrast, the principles "public information" (14%) and "time" (6%) were the least presented. Moreover, the qualitative analysis showed that the majority of the trust-building principles were implicit in the legal text, with Swiss legislations having the highest number of explicit references., Conclusions: The limited and implicit use of "trust" and trust-building principles in EU, Italian, French, and Swiss legislation emphasizes the opportunity to raise policymakers' awareness of these principles. The proposed framework provides an initial guide for policymakers to incorporate trust-building principles within health data-sharing legislations in a recognizable and comprehensive manner. This ensures that policy implementers at various stages of the policy process can implement trust-building actions, contributing to public trust building in both European and national health data-sharing initiatives., (© 2024 The Author(s). The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)

Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near-infrared spectroscopy in neonates and 6- to 7-month-old infants to investigate the neural substrate supporting NAD learning and detection using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6- to 7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and serve as the foundation for the later engagement of these regions for NAD detection, thus, providing a neural basis for language acquisition., Competing Interests: SWT is a member of PLOS Biology’s Editorial Board. The other authors declare that no competing interests exist., (Copyright: © 2024 Cai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: An understanding of the complex nomenclature and 3D spatial relations between the cortical and white matter components of the retrocommissural portion of the hippocampal formation is essential for a successful outcome when performing surgery in the mediobasal temporal region. The goal of this study was to clarify the nomenclature related to the retrocommissural portion of the hippocampal formation and to provide a detailed description of its topography and inner structure from a relevant surgical perspective. This description can serve as an anatomical reference for approaching lesions in the mediobasal temporal region., Methods: Fiber microdissection was performed from the superolateral and inferior aspects on 20 previously frozen, formalin-fixed human brains. Three formalin-fixed plastinated brain specimens were then sectioned in the coronal, axial, and sagittal planes, and the relevant sections were studied., Results: Based on its relationship with the corpus callosum, the hippocampal formation is subdivided into precommissural, supracommissural, and retrocommissural sections. The retrocommissural portion of the hippocampal formation, a structure in the mediobasal temporal region, is a component of both the floor of the temporal horn and the medial surface of the cerebral hemisphere. It includes the hippocampus (Ammon's horn and the dentate gyrus), subiculum, and related white matter fibers. Step-by-step microdissection revealed the complex ventricular and cisternal relationships of the retrocommissural portion of the hippocampal formation in the mediobasal temporal region. This further allowed clear distinction of each component of this formation in order to understand their complex reciprocal relationships that comprise a unique internal architecture and external morphology., Conclusions: The fiber microdissection technique provides a valuable perspective for understanding the complex structure and relations of the components of the retrocommissural portion of the hippocampal formation. This study clarifies and supplements the information presently available in the literature by offering an anatomical reference essential for differentiating the topographic diagnosis and safer surgical planning for any lesion within this formation or the mediobasal temporal region.

Spinal Cord Injury (SCI) presents a significant challenge in rehabilitation medicine, with recovery outcomes varying widely among individuals. Machine learning (ML) is a promising approach to enhance the prediction of recovery trajectories, but its integration into clinical practice requires a thorough understanding of its efficacy and applicability. We systematically reviewed the current literature on data-driven models of SCI recovery prediction. The included studies were evaluated based on a range of criteria assessing the approach, implementation, input data preferences, and the clinical outcomes aimed to forecast. We observe a tendency to utilize routinely acquired data, such as International Standards for Neurological Classification of SCI (ISNCSCI), imaging, and demographics, for the prediction of functional outcomes derived from the Spinal Cord Independence Measure (SCIM) III and Functional Independence Measure (FIM) scores with a focus on motor ability. Although there has been an increasing interest in data-driven studies over time, traditional machine learning architectures, such as linear regression and tree-based approaches, remained the overwhelmingly popular choices for implementation. This implies ample opportunities for exploring architectures addressing the challenges of predicting SCI recovery, including techniques for learning from limited longitudinal data, improving generalizability, and enhancing reproducibility. We conclude with a perspective, highlighting possible future directions for data-driven SCI recovery prediction and drawing parallels to other application fields in terms of diverse data types (imaging, tabular, sequential, multimodal), data challenges (limited, missing, longitudinal data), and algorithmic needs (causal inference, robustness)., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Re-evaluation of statistical analysis of the Randomised Badger Culling Trial (RBCT) by Torgerson et al. 2024 was rebutted by Mills et al. 2024 Parts I and II. The rebuttal defended the use of count rather than rate when considering bovine tuberculosis herd incidence. The defence makes biologically implausible use of Information Criterion for appraisal diagnostics; overfits data; and has erroneous Bayesian analyses. It favours 'goodness of fit' over 'predictive power', for a small data set, when the study was to inform application. Importantly, for 'total' bTB breakdown: ('confirmed' (OTF-W) +'unconfirmed' (OTF-S)), where modern interpretation of the main diagnostic bTB test better indicates the incidence rate of herd breakdown, there is no effect in cull and neighbouring areas, across all statistical models. The RBCT was a small, single experiment with unknown factors. With respect to the paradigm of reproducibility and the FAIR principles, the original RBCT analysis and recent efforts to support it are wholly unconvincing. The 2006 conclusion of the RBCT that " badger culling is unlikely to contribute positively to the control of cattle TB in Britain " is supported, but the route to such a position is revised in the light of modern veterinary understanding and statistical reappraisal.

Over the last two decades, proliferations of benthic cyanobacteria producing derivatives of anatoxin-a have been reported in rivers worldwide. Here, we follow up on such a toxigenic event happening in the Areuse river in Switzerland and investigate the diversity and genomics of major bloom-forming riverine benthic cyanobacteria. We show, using 16S rRNA-based community profiling, that benthic communities are dominated by Oscillatoriales. We correlate the detection of one Microcoleus sequence variant matching the Microcoleus anatoxicus species with the presence of anatoxin-a derivatives and use long-read metagenomics to assemble complete circular genomes of the strain. The main dihydro-anatoxin-a-producing strain in the Areuse is distinct from strains isolated in New Zealand, the USA, and Canada, but forms a monophyletic strain cluster with them with average nucleotide identity values close to the species threshold. Compared to the rest of the Microcoleus genus, the toxin-producing strains encode a 15 % smaller genome, lacking genes for the synthesis of some essential vitamins. Toxigenic mats harbor a distinct microbiome dominated by proteobacteria and bacteroidetes, which may support cyanobacterial growth by providing them with essential nutrients. We recommend that strains closely related to M. anatoxicus be monitored internationally in order to help predict and mitigate similar cyanotoxic events., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Diego Gonzalez reports financial support was provided by Swiss National Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The fungal community of the skin microbiome is dominated by a single genus, Malassezia . Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro , while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo . In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies., Competing Interests: COMPETING INTERESTS The authors declare that they have no conflicts of interest to disclose.

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability.

Background: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed., Method: Here, we propose a machine learning-based approach to detect the key metabolites and proteins involved in MCI progression to AD using data from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Study. Proteins and metabolites were evaluated separately in multiclass models (controls, MCI and AD) and together in MCI conversion models (MCI stable vs converter). Only features selected as relevant by 3/4 algorithms proposed were kept for downstream analysis., Results: Multiclass models of metabolites highlighted nine features further validated in an independent cohort (0.726 mean balanced accuracy). Among these features, one metabolite, oleamide, was selected by all the algorithms. Further in-vitro experiments in rodents showed that disease-associated microglia excreted oleamide in vesicles. Multiclass models of proteins stood out with nine features, validated in an independent cohort (0.720 mean balanced accuracy). However, none of the proteins was selected by all the algorithms. Besides, to distinguish between MCI stable and converters, 14 key features were selected (0.872 AUC), including tTau, alpha-synuclein (SNCA), junctophilin-3 (JPH3), properdin (CFP) and peptidase inhibitor 15 (PI15) among others., Conclusions: This omics integration approach highlighted a set of molecules associated with MCI conversion important in neuronal and glia inflammation pathways., Competing Interests: Declaration of competing interest SL is named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past five years has advised for Optum labs, Merck, SomaLogic and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AL has served at scientific advisory boards of Fujirebio Europe, Eli Lilly, Novartis, Nutricia and Otsuka and is the inventor of a patent on synaptic markers in CSF (all unrelated to this study). JP has served at scientific advisory boards of Fujirebio Europe, Eli Lilly and Nestle Institute of Health Sciences, all unrelated to this study. SE has received unrestricted research grants from Janssen Pharmaceutica and ADx Neurosciences and has served at scientific advisory boards of Biogen, Eisai, Novartis, Nutricia/Danone, all unrelated to this study. FB is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD, all unrelated to this study. CLQ has received funding related to this study from Pfizer and via the IMI funding scheme, in the past five years has been the recipient of funding from Novo Nordisk, unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The link between schizophrenia and homicide has long been the subject of research with significant impact on mental health policy, clinical practice, and public perception of people with psychiatric disorders. The present study investigates factors contributing to completed homicides committed by offenders diagnosed with schizophrenia referred to a Swiss forensic institution, using machine learning algorithms. Data were collected from 370 inpatients at the Centre for Inpatient Forensic Therapy at the Zurich University Hospital of Psychiatry. A total of 519 variables were explored to differentiate homicidal and other (violent and non-violent) offenders. The dataset was split employing variable filtering, model building, and selection embedded in a nested resampling approach. Ten factors regarding criminal and psychiatric history and clinical factors were identified to be influential in differentiating between homicidal and other offenders. Findings expand the research on influential factors for completed homicide in patients with schizophrenia. Limitations, clinical relevance, and future directions are discussed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Paraneoplastic retinopathy (PNR) is a rapid-onset photoreceptor and post-photoreceptor dysfunction triggered by a cross-reaction between antigens expressed by the underlying tumour and retinal proteins. The present study aims to determine the electrodiagnostic biomarkers that support the diagnosis of PNR and evaluate the effect of treatment., Methods: A retrospective observational case-controlled study including 25 patients with suspected PNR, of which 11 patients were diagnosed with PNR. The presence of PNR was confirmed based on clinical examination, supported by colour fundus photography, fundus autofluorescence imaging, optical coherence tomography, fluorescein angiography, retinal vessel oximetry, colour test, full-field electroretinogram (ffERG), on-/off ERG, S-cone ERG, and multifocal ERG (mfERG). The relationships between the clinical symptomatology and the effect of therapy were evaluated., Results: All PNR patients (Nr: 11) presented with subjective symptoms of newly reported central vision or visual field deterioration. Posterior segment findings showed a severe patchy-like retinal atrophy, attenuation of the retinal vessels, and a waxy optic disc. Optical coherence tomography revealed a discontinued ISe line, and multiple hyperreflective foci. Retinal vessel oxygen saturation was increased. Multifocal ERG revealed reduced central and paracentral responses and ffERG severely attenuated scotopic-, photopic-, on-/off- and S-cone responses. The colour vision test revealed a tritan-tetartan-weakness. Two of the PNR patients underwent rituximab therapy with no further progression and even recovery of electrodiagnostic responses.In 1 nPNR (non-paraneoplastic retinopathy) patient (total Nr: 14) pseudoxanthoma elasticum-related retinopathy was the reason for impaired vision. In 3 of 13 patients with bronchopulmonary cancer a MEK- and FGFR-inhibitor- drug toxicity was the reason for the visual deterioration., Conclusion: Careful investigation for signs of central and/or peripheral visual field deterioration must be performed in the presence of history of a co-existing malignancy. The possibility of PNR should be taken into account. The electrodiagnostic biomarkers, suggested in this study, may help to promptly recognise PNR and also to evaluate the effect of implemented therapy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The influence of baseline severity on the efficacy of Silexan, a proprietary essential oil from Lavandula angustifolia , in anxiety disorders has not been investigated in a pooled dataset. We report on an individual patient data analysis of all five double-blind, randomized, placebo-controlled trials with Silexan in anxiety disorders. Eligible participants received Silexan 80 mg/d or placebo for 10 weeks. Analyses were based on the Hamilton Anxiety Rating Scale (HAMA), its psychic and somatic anxiety subscores, and the Clinical Global Impressions (CGI) scale. To correlate baseline severity with outcome, patients were segregated into mild, moderate, and severe cases. Altogether 1,172 patients (Silexan, n = 587; placebo, n = 585) were analyzed. For the HAMA total score, we found a significant association between the score at baseline and the treatment effect of Silexan versus placebo at week 10 ( p  < 0.001). HAMA items from the somatic domain scored lower at baseline and showed less improvement than items from the psychic domain, particularly in patients with mild or moderate baseline symptoms. For CGI item 2 (global improvement), significant efficacy favoring Silexan were observed in mild, moderate, and severe baseline symptom severity. Although significant improvements were found for all subsets, the more severe the initial symptoms, the greater the treatment effects documented by the HAMA. Overall this analysis confirms that Silexan is an effective treatment option in early or mild stages of anxiety disorder. Given its favorable safety profile, Silexan can thus fill a therapeutic gap in the treatment of (subsyndromal) anxiety disorders.

Background: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events., Methods: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO 2 ) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate., Results: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P <0.001) for recurrent ischemic stroke., Conclusions: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR., Competing Interests: Disclosures The device used in this study was developed by Thornhill Medical, Inc (TMI) a for-profit spin-off from the University Health Network, University of Toronto, to enable cerebrovascular reactivity studies. It is not a commercial product and is made available to academic centers for certified research under ethics board approval. Drs Fisher and Mikulis are appointees at the University of Toronto and employees of, and own shares in, TMI. Dr Katant is a consultant for AstraZeneca and Brahms GmbH, and receives funding from Bayer Healthcare, both of which are not related to the current article. Currently, Dr Katant has a dual appointment at the University Hospital of Zürich and the University Hospital Basel. Dr Wegener receives funding through the following institutes: Baugarten Stiftung, the Betty and David Koetser Foundation, Hartmann Müller-Stiftung für Medizinische Forschung, and the Swiss National Science Foundation and is the co-applicant of the UZH CRPP Stroke of the University Hospital of Zürich. Dr Luft is a consultant for Amgen, Boehringer Ingelheim, and Moleac Ltd. Dr Kulcsár is a consultant for Johnson and Johnson International, Medtronic, and Stryker. The other authors report no conflicts.

Advanced Practice Nurse (APN) roles in Switzerland include Clinical Nurse Specialist (CNS), Nurse Practitioner (NP) and blended roles. The variety contributes to unclear profiles and scope of practice. Background: To describe a) the performance of APN tasks according to Hamric's competencies, b) job satisfaction, and c) barriers and facilitators to role performance. Aim: Nationwide cross-sectional survey among clinically working APNs. Inclusion criteria: academic degree, role with advanced nursing competency. Analysis of quantitative and qualitative data using inferential statistics and content analysis. Methods: Of the 222 APNs, 49% (n = 108) described themselves as CNSs, 37% (n = 81) as working in a blended role, and 15% (n = 33) as NP. APNs provided the greatest proportion of their tasks in the competency direct clinical practice and the least in ethical decision-making. Group comparisons between roles revealed significant differences in the competencies: direct clinical practice, guidance and coaching, leadership, and evidence-based practice. Job satisfaction was high (76%, n = 165), most often described by the category work content/role (e.g., defined scope of practice). The most frequent barrier to role performance was the category scope of practice (e.g., unclear responsibilities); the most frequent facilitator was the category professional recognition (e.g., respect). Results: The study highlights current APN scope of practice and can support the advancement of the role through clinical practice, educational institutions, and research.Conclusion: The study highlights current APN scope of practice and can support the advancement of the role through clinical practice, educational institutions, and research.

Background: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome., Methods: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T 1 -weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z -scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale., Results: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10 -5 ) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10 -7 ) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10 -4 ). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control., Conclusions: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

Recent evidence suggests that infection with the Epstein Barr virus (EBV) initiates a prodromal phase of multiple sclerosis (MS) in individuals with genetic and environmental predispositions for this autoimmune disease. In the context of the main genetic risk factor, the major histocompatibility complex (MHC) class II molecule HLA-DRB1*1501, EBV infection is less well controlled in a preclinical mouse model. CD4 + T cells that are primed during EBV infection and recognize EBV transformed B cells in an HLA-DRB1*1501 restricted fashion, cross-react more frequently with myelin autoantigens that are thought to mediate MS. While EBV emerges as an important, possibly essential trigger of MS, more mechanistic insights into this connection are required to understand if targeting of EBV infection itself or of cross-reactive immune responses that recognize both viral and autoantigens might prevent or even allow to treat MS., Competing Interests: Declaration of Competing Interest My laboratory is supported by research contract grants from Roche, Novartis and Viracta. Furthermore, I consult currently for Pfizer, Moderna and Roche. Finally, I am president past of the Swiss Society of Allergology and Immunology (SSAI). None of these have influenced the content of this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Background and Objectives: Heterozygous variants in RAR-related orphan receptor B ( RORB ) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants., Methods: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB . To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology., Results: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB , including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function., Discussion: In most patients, the phenotype of the RORB -related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

The willingness to exert effort for reward is essential but comes at the cost of fatigue. Theories suggest fatigue increases after both physical and cognitive exertion, subsequently reducing the motivation to exert effort. Yet a mechanistic understanding of how this happens on a moment-to-moment basis, and whether mechanisms are common to both mental and physical effort, is lacking. In two studies, participants reported momentary (trial-by-trial) ratings of fatigue during an effort-based decision-making task requiring either physical (grip-force) or cognitive (mental arithmetic) effort. Using a novel computational model, we show that fatigue fluctuates from trial-to-trial as a function of exerted effort and predicts subsequent choices. This mechanism was shared across the domains. Selective to the cognitive domain, committing errors also induced momentary increases in feelings of fatigue. These findings provide insight into the computations underlying the influence of effortful exertion on fatigue and motivation, in both physical and cognitive domains., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. In order to improve health care of FD-patients, knowledge of its predictors is important. The aim of our study was to evaluate health-related quality of life (HrQol) in FD and to identify its independent determinants by exploring a wide range of demographic, social and clinical parameters., Results: In this cross-sectional multicenter study, 135 adult patients with FD were recruited at three specialized European centers in Germany and Switzerland. Demographics, social status and clinical parameters as well as data on HrQol (EQ5D, EQ VAS) and depression were collected by means of self-reporting questionnaires and confirmed by medical records. HrQol and its predictors were evaluated by univariate and multivariate regression analyses. The study population consisted of 78 female and 57 male FD patients (median age 48 yrs) of whom 80.7% (N = 109) were on enzyme replacement therapy (ERT) and 10.4% (N = 14) were on chaperone treatment. Univariate analysis revealed various factors reducing HrQol such as age > 40 years, classic phenotype, organ involvement (kidney and heart disease, stroke/transient ischemic attack (TIA), gastrointestinal disturbances), depression, and burning limb pain. However, only the following factors were identified as independent predictors of decreased HrQol: classic phenotype, kidney and heart disease, stroke/TIA, depression, and burning limb pain. ERT and chaperone therapy were independent determinants of increased HrQol., Conclusions: Modifiable factors, such as burning limb pain and depression, identified as independent predictors of HrQol-deterioration should be addressed in programs aiming to improve HrQol in FD. A multidisciplinary approach is essential in FD-patients since diverse organ involvement prominently compromises HrQol in affected patients. Our findings showed that the classic phenotype is a strong predictor of worsening HrQol., Competing Interests: Declaration of Competing Interest YW reports honoraria for educational presentations and consultations from Arvelle Therapeutics, Bayer AG, BIAL, Bioprojet Pharma, Eisai, Eythpharm GmbH, LivaNova, Novartis and UCB Pharma, which were not related to the topic of this study. AN received speaker honoraria and research grants from Amicus, Shire/Takeda and Sanofi Genzyme. ML received research grants and speaker honoraria from Amicus Therapeutics, Sanofi Genzyme and Shire/Takeda and consultation honoraria from Avrobio. EB received research grants and speaker honoraria from Amicus Therapeutics, Sanofi Genzyme, Shire/Takeda as well as honoraria for educational presentations and consultations from Chiesi and Greenovation/Eleva., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Post-tuberculosis (TB) radiological changes and symptoms can mimic TB. PCR-based diagnostic tests can show positive results, suggesting the presence of Mycobacterium tuberculosis DNA in the absence of viable bacteria. We present a case with two episodes of previous TB. Despite workup including trace to low positive PCR results, after performing sputum analysis, bronchoalveolar lavage analysis, cyto-brush and 18F-FDG PET/CT guided transthoracic biopsy, no culturable mycobacteria were detected. 18F-FDG PET/CT showed a high metabolic activity of the biopsied lesions. More accurate strategies and tools in patients with previous TB and positive PCR results are required to make appropriate treatment decisions., Competing Interests: No conflict of interest, (© 2023 The Authors.)

Background: Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper clinical and genetic diagnosis may allow an individual prognosis, accurate genetic counselling, and the optimal choice of low vision aids. The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM., Methods: A retrospective analysis was performed in 8 patients from non-related families (5 ♀,3 ♂); age at diagnosis: 3 - 56 y, mean 18.13 (SD ± 18.22). Clinical phenotyping, supported by colour vision test, fundus photography-, autofluorescence- (FAF), infra-red- (IR), OCT imaging and electroretinography provided information on the current status and the course of the disease over the years. In addition, genetic examinations were performed with ACHM relevant testing ( CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and the transcription factor ATF6 )., Results: All patients suffered photophobia and reduced visual acuity (mean: 0.16 [SD ± 0.08]). Nystagmus was identified in 7 from 8 subjects and in one patient a head-turn right helped to reduce the nystagmus amplitude. Colour vision testing confirmed complete achromatopsia in 7 out of 8 patients. Electrophysiology found severely reduced photopic- but also scotopic responses. Thinning and interruption of the inner segment ellipsoid (ISe) line within the macula but also FAF- and IR abnormalities in the fovea and/or parafovea were characteristic in all ACHM patients. Identification of pathogenic mutations in 7 patients helped to confirm the diagnosis of ACHM (3 adults, 4 children; 3 ♀ and 4 ♂). Achromatopsia was linked to CNGA3 (2 ♀, 1 ♂) and CNGB3 variants (2 ♀, 3 ♂). The youngest patient (♀, 10 y) had 3 different CNGB3 variants on different alleles. In a patient (♂, 29 y) carrying 2 pathogenic digenic-triallelic CNGA3 - and CNGB3 -mutations, a severe progression of ISe discontinuity to coloboma-like macular atrophy was observed during the 12-year follow-up. The oldest female (67 y) showed a compound homozygous CNGA3 - and heterozygous CNGB3 -, as well as a heterozygous GUCY2D variants. The destruction of her ISe line was significantly enlarged and represented a progressive cone-rod phenotype in comparison to other ACHM patients. In a patient (♂, 45 y) carrying a pathogenic CNGB3 and USH2 mutation, a severe macular oedema and a rod-cone phenotype was observed. In addition, two variants in C2ORF71 considered as VOS were found. One patient showed the rare ATF6 mutation, where a severe coloboma-like macular atrophy was observed on the left eye as early as at the age of three years., Conclusion: Combining multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM helps in characterizing the disease and associated modifiers, and is therefore strongly recommended for such patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: The association of body mass index (BMI) with diastolic dysfunction (DD) is well described in the literature. However, there is conflicting evidence and long-term follow-up data regarding effects of BMI on preclinical DD and left atrial (LA) function are scarce, highlighting the importance of early detection tools, such as myocardial strain., Purpose: The aim of our study was to prospectively analyze the impact of clinical and demographic parameters, especially of BMI, on worsening of diastolic function and left atrial strain (LAS) in an urban population of women with a low prevalence of cardiovascular risk factors., Methods and Results: An extensive clinical and echocardiographic assessment comprising the analysis of phasic LAS using two-dimensional speckle-tracking echocardiography (2D STE) was performed in 258 participants of the Berlin Female Risk Evaluation (BEFRI) trial between October 2019 and December 2020 after a mean follow-up period of 6.8 years. We compared clinical and echocardiographic parameters stratifying women by BMI < or ≥25 kg/m 2 , and we analyzed the impact of demographic characteristics on the worsening of DD and LA mechanics in the longer-term follow-up using univariate and multivariate regression analyses. 248 women were suitable for echocardiographic analysis of LAS using 2D STE. After a mean follow-up time of 6.8 years, LA reservoir strain (LASr) and LA conduit strain (LAScd) were significantly reduced in participants with a BMI ≥25 kg/m 2 compared with women with a BMI <25 kg/m 2 at baseline (30 ± 8% vs. 38 ± 9%, p  < 0.0001; -14 ± 7% vs. -22 ± 8%, p  < 0.0001). 28% of the overweighted women presented a deterioration of diastolic function at the time of follow-up in contrast with only 7% of the group with a BMI <25 kg/m 2 ( p  < 0.0001). BMI remained significantly associated with LAS reductions after adjustment for other risk factors in multivariate regression analyses., Conclusion: Overweight and obesity are related to impaired LAS and to a worsening of diastolic function after a long-term follow-up in a cohort of randomly selected women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Romero Dorta, Wolf, Hübscher, Blaschke-Waluga, Seeland, Crayen, Bischoff, Mattig, Dreger, Stangl, Regitz-Zagrosek, Landmesser, Knebel, Stangl and Brand.)

Introduction: The aim of this systematic review was to assess the literature reporting on the failure rates, survival rates and complication rates and patient reported outcome measures (PROMs) of anterior full (FC) or partial (PC) coverage single tooth restorations after a mean observation period of at least 3 years., Methods: Systematic search was conducted using the electronic databases: MEDLINE, EMBASE and Cochrane library. Data regarding survival (restoration failure) and complication rates and PROMs were extracted and presented descriptively., Results: Altogether 42 studies were included in the analysis (28 with FC, 12 with PC and 2 with both types of restorations). For FC restorations the estimated annual failure rate was 0.72 (95%CI: 0.33-1.57), resulting in a 5-year survival rate of 96.4% (95%CI: 92.4-98.3). For PC restorations, the estimated annual failure rate was 0.62 (95%CI: 0.27-1.46), resulting in a 5-year survival rate of 96.9% (95%CI: 93.0-98.7). There was no significant difference between the groups regarding survival or technical complications, while significantly fewer biological complications were observed with PC compared to FC restorations (test for subgroup differences, p=0.01)., Conclusions: FC and PC restorations showed high 5-year survival rates but the teeth restored with FC restorations may be more prone to biological complications., (Copyright© 2023 Dennis Barber Ltd.)

Aims of the Study: Remdesivir has shown benefits against COVID-19. However, it remains unclear whether, to what extent, and among whom remdesivir can reduce COVID-19-related mortality. We explored whether the treatment response to remdesivir differed by patient characteristics., Methods: We analysed data collected from a hospital surveillance study conducted in 21 referral hospitals in Switzerland between 2020 and 2022. We applied model-based recursive partitioning to group patients by the association between treatment levels and mortality. We included either treatment (levels: none, remdesivir within 7 days of symptom onset, remdesivir after 7 days, or another treatment), age and sex, or treatment only as regression variables. Candidate partitioning variables included a range of risk factors and comorbidities (and age and sex unless included in regression). We repeated the analyses using local centring to correct the results for the propensity to receive treatment., Results: Overall (n = 21,790 patients), remdesivir within 7 days was associated with increased mortality (adjusted hazard ratios 1.28-1.54 versus no treatment). The CURB-65 score caused the most instability in the regression parameters of the model. When adjusted for age and sex, patients receiving remdesivir within 7 days of onset had higher mortality than those not treated in all identified eight patient groups. When age and sex were included as partitioning variables instead, the number of groups increased to 19-20; in five to six of those branches, mortality was lower among patients who received early remdesivir. Factors determining the groups where remdesivir was potentially beneficial included the presence of oncological comorbidities, male sex, and high age., Conclusions: Some subgroups of patients, such as individuals with oncological comorbidities or elderly males, may benefit from remdesivir.

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant., Competing Interests: Competing Interests M.L.S. is equity holder, scientific co-founder and advisory board member of Immunitas Therapeutics. M.M. holds equity in MapLight Therapeutics.

Porcine epidemic diarrhea virus is a swine pathogen that has been responsible for significant animal and economic losses worldwide in recent years. In this manuscript, we report the generation of a reverse genetics system C(RGS) for the highly virulent US PEDV strain Minnesota (PEDV-MN; GenBank accession number KF468752), which was based on the assembly and cloning of synthetic DNA, using vaccinia virus as a cloning vector. Viral rescue was only possible following the substitution of 2 nucleotides within the 5'UTR and 2 additional nucleotides within the spike gene, based on the sequence of the cell culture-adapted strains. Besides displaying a highly pathogenic phenotype in newborn piglets, in comparison with the parental virus, the rescued recombinant PEDV-MN was used to confirm that the PEDV spike gene has an important role in PEDV virulence and that the impact of an intact PEDV ORF3 on viral pathogenicity is modest. Moreover, a chimeric virus with a TGEV spike gene in the PEDV backbone generated with RGS was able to replicate efficiently in vivo and could be readily transmitted between piglets. Although this chimeric virus did not cause severe disease upon the initial infection of piglets, there was evidence of increasing pathogenicity upon transmission to contact piglets. The RGS described in this study constitutes a powerful tool with which to study PEDV pathogenesis and can be used to generate vaccines against porcine enteric coronaviruses. IMPORTANCE PEDV is a swine pathogen that is responsible for significant animal and economic losses worldwide. Highly pathogenic variants can lead to a mortality rate of up to 100% in newborn piglets. The generation of a reverse genetics system for a highly virulent PEDV strain originating from the United States is an important step in phenotypically characterizing PEDV. The synthetic PEDV mirrored the authentic isolate and displayed a highly pathogenic phenotype in newborn piglets. With this system, it was possible to characterize potential viral virulence factors. Our data revealed that an accessory gene (ORF3) has a limited impact on pathogenicity. However, as it is also now known for many coronaviruses, the PEDV spike gene is one of the main determinants of pathogenicity. Finally, we show that the spike gene of another porcine coronavirus, namely, TGEV, can be accommodated in the PEDV genome background, suggesting that similar viruses can emerge in the field via recombination., Competing Interests: The authors declare no conflict of interest.

Objective: The authors report on a large, consecutive, single-surgeon series of patients undergoing microsurgical removal of midbrain gliomas. Emphasis is put on surgical indications, technique, and results as well as long-term oncological follow-up., Methods: A retrospective analysis was performed of prospectively collected data from a consecutive series of patients undergoing microneurosurgery for midbrain gliomas from March 2006 through June 2022 at the authors' institution. According to the growth pattern and location of the lesion in the midbrain (tegmentum, central mesencephalic structures, and tectum), one of the following approaches was chosen: transsylvian (TS), extreme anterior interhemispheric transcallosal (eAIT), posterior interhemispheric transtentorial subsplenial (PITS), paramedian supracerebellar transtentorial (PST), perimedian supracerebellar (PeS), perimedian contralateral supracerebellar (PeCS), and transuvulotonsillar fissure (TUTF). Clinical and radiological data were gathered according to a standard protocol and reported according to common descriptive statistics. The main outcomes were rate of gross-total resection; extent of resection; occurrence of any complications; variation in Karnofsky Performance Status score at discharge, 3 months, and last follow-up; progression-free survival (PFS); and overall survival (OS)., Results: Fifty-four patients (28 of them pediatric) met the inclusion criteria (6 with high-grade and 48 with low-grade gliomas [LGGs]). Twenty-two tumors were in the tegmentum, 7 in the central mesencephalic structures, and 25 in the tectum. In no instance did the glioma originate in the cerebral peduncle. TS was performed in 2 patients, eAIT in 6, PITS in 23, PST in 16, PeS in 4, PeCS in 1, and TUTF in 2 patients. Gross-total resection was achieved in 39 patients (72%). The average extent of resection was 98.0% (median 100%, range 82%-100%). There were no deaths due to surgery. Nine patients experienced transient and 2 patients experienced permanent new neurological deficits. At a mean follow-up of 72 months (median 62, range 3-193 months), 49 of the 54 patients were still alive. All patients with LGGs (48/54) were alive with no decrease in their KPS score, whereas 42 showed improvement compared with their preoperative status., Conclusions: Microneurosurgical removal of midbrain gliomas is feasible with good surgical results and long-term clinical outcomes, particularly in patients with LGGs. As such, microneurosurgery should be considered as the first therapeutic option. Adequate microsurgical technique and anesthesiological management, along with an accurate preoperative understanding of the tumor's exact topographic origin and growth pattern, is crucial for a good surgical outcome.

Objectives: The ambient lighting condition has been identified as an important factor that influences the accuracy of intraoral scanners (IOSs). The purpose of this study was to evaluate the influence of 12 different ambient lighting conditions on the accuracy of a confocal based IOS (PrimeScan)., Materials and Methods: A typodont was digitized using a laboratory scanner (L2i) to obtain a reference standard tessellation language (STL r ) file. A restorative dentist recorded the scans using an IOS (PrimeScan) under 12 different ambient lighting conditions where the luminosity was measured using a light meter (LX1330B Light Meter). Twelve groups were created, namely 0-, 500-, 1000-, 2000-, 3000-, 4000-, 5000-, 6000-, 7000-, 8000-, 9000-, and 10 000 lux groups. Ten STL files were recorded per group. The STL r file was used as a reference with which to compare the distortion of the 120 STL files obtained using a software program (Meshlab). The normality Shapiro-Wilk test indicated that the distributions were not normal. Therefore, the nonparametric Kruskal-Wallis and pairwise multicomparison tests were used to analyze the data (α = 0.05)., Results: The group with the 1000 lux lighting condition obtained the smallest median ±interquartile range (IQR) with scanning distortion values of 69.5 ± 97.4 µm, followed by the 8000 lux group with a median ±IQR of 166.5 ± 318.1 µm. The 0 lx group presented the highest distortion values with a mean ±IQR of 355.5 ± 488.0 µm (p < 0.05)., Conclusions: Ambient lighting conditions influenced the accuracy of the IOS tested. The highest accuracy values were obtained with 1000 lux. The lowest scanning accuracy was obtained with 0 lux., Competing Interests: Declaration of Competing Interest The authors did not have any conflict interest, financial or personal, in any of the materials described in this study., (Copyright © 2023. Published by Elsevier Ltd.)

Background In view of the rising global burden of severe symptomatic aortic stenosis, its early recognition and treatment is key. Although patients with classical low-flow, low-gradient (C-LFLG) aortic stenosis have higher rates of death after transcatheter aortic valve implantation (TAVI) when compared with patients with high-gradient (HG) aortic stenosis, there is conflicting evidence on the death rate in patients with severe paradoxical low-flow, low-gradient (P-LFLG) aortic stenosis. Therefore, we aimed to compare outcomes in real-world patients with severe HG, C-LFLG, and P-LFLG aortic stenosis undergoing TAVI. Methods and Results Clinical outcomes up to 5 years were addressed in the 3 groups of patients enrolled in the prospective, national, multicenter SwissTAVI registry. A total of 8914 patients undergoing TAVI at 15 heart valve centers in Switzerland were analyzed for the purpose of this study. We observed a significant difference in time to death at 1 year after TAVI, with the lowest observed in HG (8.8%) aortic stenosis, followed by P-LFLG (11.5%; hazard ratio [HR], 1.35 [95% CI, 1.16-1.56]; P <0.001) and C-LFLG (19.8%; HR, 1.93 [95% CI, 1.64-2.26]; P <0.001) aortic stenosis. Cardiovascular death showed similar differences between the groups. At 5 years, the all-cause death rate was 44.4% in HG, 52.1% in P-LFLG (HR, 1.35 [95% CI, 1.23-1.48]; P <0.001), and 62.8% in C-LFLG aortic stenosis (HR, 1.7 [95% CI, 1.54-1.88]; P <0.001). Conclusions Up to 5 years after TAVI, patients with P-LFLG have higher death rates than patients with HG aortic stenosis but lower death rates than patients with C-LFLG aortic stenosis.

The faecal egg count reduction test (FECRT) remains the method of choice for establishing the efficacy of anthelmintic compounds in the field, including the diagnosis of anthelmintic resistance. We present a guideline for improving the standardization and performance of the FECRT that has four sections. In the first section, we address the major issues relevant to experimental design, choice of faecal egg count (FEC) method, statistical analysis, and interpretation of the FECRT results. In the second section, we make a series of general recommendations that are applicable across all animals addressed in this guideline. In the third section, we provide separate guidance details for cattle, small ruminants (sheep and goats), horses and pigs to address the issues that are specific to the different animal types. Finally, we provide overviews of the specific details required to conduct an FECRT for each of the different host species. To address the issues of statistical power vs. practicality, we also provide two separate options for each animal species; (i) a version designed to detect small changes in efficacy that is intended for use in scientific studies, and (ii) a less resource-intensive version intended for routine use by veterinarians and livestock owners to detect larger changes in efficacy. Compared to the previous FECRT recommendations, four important differences are noted. First, it is now generally recommended to perform the FECRT based on pre- and post-treatment FEC of the same animals (paired study design), rather than on post-treatment FEC of both treated and untreated (control) animals (unpaired study design). Second, instead of requiring a minimum mean FEC (expressed in eggs per gram (EPG)) of the group to be tested, the new requirement is for a minimum total number of eggs to be counted under the microscope (cumulative number of eggs counted before the application of a conversion factor). Third, we provide flexibility in the required size of the treatment group by presenting three separate options that depend on the (expected) number of eggs counted. Finally, these guidelines address all major livestock species, and the thresholds for defining reduced efficacy are adapted and aligned to host species, anthelmintic drug and parasite species. In conclusion, these new guidelines provide improved methodology and standardization of the FECRT for all major livestock species., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction/objectives: The aim of this study was to compare a novel small event recorder device, the Carnation Ambulatory Monitor (CAM), with a standard Holter., Animals: Nineteen adult dogs., Material and Methods: Comparative and explorative study. The two devices were simultaneously applied for approximately 24 h., Results: Analysis time (P=0.013) and percentage of artefacts (P<0.001) were greater for the CAM (110 min [40-264]; and 9% [0-34], respectively) compared to a standard Holter (30 min [18-270]; and 0.3% [0-9], respectively). The total number of beats (P=0.017) and maximum (P=0.02) and mean (P=0.037) heart rates were lower for the CAM (113,806 ± 23,619 beats; 227 ± 35 bpm; and 88 ± 22 bpm, respectively) compared to the standard Holter (131,640 ± 40,037 beats; 260 ± 64 bpm; and 92 ± 26 bpm, respectively). The minimal heart rate (P=0.725), number of pauses (P=0.078), duration of the longest pause (P=0.087), number of ventricular ectopic complexes (P=0.55), ventricular couplets (P=0.186), ventricular triplets (P=0.203), ventricular tachycardia (P=0.05), Lown grade (P=0.233), presence or absence of ventricular bigeminy, trigeminy, supraventricular tachycardia, and atrial fibrillation (P=0.98) did not differ. The CAM missed some relevant events, like complex ventricular arrhythmias, and the Lown grade did not match in 5/19 dogs when comparing the devices., Conclusions: Cardiac Ambulatory Monitor can be used to record ECG traces in dogs over a prolonged period, allowing to detect arrhythmias. Due to some clinically relevant limitations, including a higher percentage of artefacts, a longer reading time (which precludes quantitative counts of >300ventricular premature complexes), and underestimation of complex ventricular arrhythmias, the CAM appears not suitable for quantitative arrhythmia analysis in dogs., Competing Interests: Conflict of Interest Statement The authors do not have any conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Increasing numbers of women living with HIV transition through menopause. It is unclear whether this transition has an impact on treatment adherence, viral suppression, psychiatric comorbidities, or drug use. We aimed at examining adherence and viral suppression during the perimenopausal period and explored the influence of psychiatric comorbidities and active injection drug use (IDU)., Setting: Retrospective Swiss HIV Cohort Study analysis from January 2010 to December 2018., Methods: We explored perimenopausal and postmenopausal trends of viral blips, low-level viremia, viral failure, adherence, psychiatric comorbidities, and IDU using interrupted time series models., Results: Rates of depression and psychiatric care increased during perimenopause before decreasing afterward. Negative treatment outcomes such as viral blips, low-level viremia, viral failure, and low adherence steadily declined while transitioning through menopause-this was also true for subgroups of women with depression, psychiatric treatment, and active IDU., Conclusions: Increased rates of depression and psychiatric care while transitioning through menopause do not result in lower rates of adherence or viral suppression in women living with HIV in Switzerland., Competing Interests: None of the authors has declared a possible conflict of interest related to this study. A.H.'s institution has received travel grants, congress and advisory fees from MSD, ViiV, and Gilead, unrelated to this work. B.B. Flury has undertaken Advisory Boards or ad hoc consultancy for Merck/MSD, Melinta/Menarini, Shionogi, and Pfizer, and has received research grants from Melinta/Menarini unrelated to this work. K.E.A.D.'s institution has received research funding unrelated to this publication from Gilead and offered expert testimony for MSD. P.T.'s institution has received grants, advisory fees, and educational grants from Gilead, MSD, and ViiV outside the submitted work. K.A.-P.’s institution has received travel grants and advisory fees from MSD, Gilead, and ViiV healthcare unrelated to this work. I.A.A. is supported by the ProMedica Foundation., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

To compensate for decreased oxygen partial pressure, high-altitude residents increase hemoglobin concentrations [Hb]. The elevation varies between world regions, posing problems in defining cutoff values for anemia or polycythemia. The currently used altitude adjustments (World Health Organization [WHO]), however, do not account for regional differences. Data from The Demographic and Health Survey (DHS) Program were analyzed from 32 countries harboring >4% of residents at altitudes above 1000 m. [Hb]-increase, (ΔHb/km altitude) was calculated by linear regression analysis. Tables show 95% reference intervals (RIs) for different altitude ranges, world regions, and age groups. The prevalence of anemia and polycythemia was calculated using regressions in comparison to WHO adjustments. The most pronounced Δ[Hb]/km was found in East Africans and South Americans while [Hb] increased least in South/South-East Asia. In African regions and Middle East, [Hb] was decreased in some altitude regions showing inconsistent changes in different age groups. Of note, in all regions, the Δ[Hb]/km was lower in children than in adults, and in the Middle East, it was even negative. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. The distinct patterns of Δ[Hb] with altitude in residents from different world regions imply that one single, region-independent correction factor for altitude is not be applicable for diagnosing abnormal [Hb]. Therefore, we provide regression coefficients and reference-tables that are specific for world regions and altitude ranges to improve diagnosing abnormal [Hb]., Competing Interests: MUM is a HemaSphere editor. The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Despite the recognised need for education and training in laboratory animal science (LAS) and ethics in Africa, access to such opportunities has historically been limited. To address this, the Pan-African Network for Laboratory Animal Science and Ethics (PAN-LASE) was established to pioneer a support network for the development of education and training in LAS and ethics across the African continent.In the 4.5 years since the establishment of PAN-LASE, 3635 individuals from 28 African countries have participated in our educational activities. Returning to their home institutions, they have both established and strengthened institutional and regional hubs of knowledge and competence across the continent. Additionally, PAN-LASE supported the development of guidelines for establishment of institutional Animal Ethics Committees, a critical step in the implementation of ethical review processes across the continent, and in enhancing animal welfare and scientific research standards.Key challenges and opportunities for PAN-LASE going forward include the formalisation of the network; the sustainability of education and training programmes; implementation of effective hub-and-spoke models of educational provision; strengthening governance frameworks at institutional, national and regional levels; and the availability of Africa-centric open access educational resources.Our activities are enhancing animal welfare and the quality of animal research undertaken across Africa, enabling African researchers to undertake world-leading research to offer solutions to the challenges facing the continent. The challenges, successes and the lessons learnt from PAN-LASE's journey are applicable to other low- and middle-income countries across the world seeking to enhance animal welfare, research ethics and ethical review in their own country or region.

Purpose: To measure the flexural strength and Weibull characteristics of aged and nonaged printed interim dental material fabricated with different layer thickness., Material and Methods: Bars (25×2×2 mm) were additively fabricated by using a polymer printer (Asiga Max) and an interim resin (Nexdent C&B MFH). Specimens were fabricated with the same printing parameters and postprocessing procedures, but with 7 different layer thickness: 50 (control or 50-G group), 10 (10-G group), 25 (25-G group), 75 (75-G group), 100 (100-G group), 125 (125-G group), and 150 μm (150-G group). Two subgroups were created: nonaged and aged subgroups (n = 10). A universal testing machine was selected to measure flexural strength. Two-parameter Weibull distribution values were computed. Two-way ANOVA and Tukey tests were selected for statistical evaluation of the data (α = 0.05)., Results: Artificial aging methods (p < 0.001) were a significant predictor of the flexural strength computed. Aged specimens acquired less flexural strength than nonaged specimens. The Weibull distribution obtained the highest shape for nonaged 50-G and 75-G group specimens compared with those of other nonaged groups, while the Weibull distribution showed the highest shape for aged 125-G specimens., Conclusions: The flexural strength of the additively fabricated interim material examined was not influenced by the layer thickness at which the specimens were fabricated; however, artificial aging techniques reduced its flexural strength. Aged specimens presented lower Weibull distribution values compared with nonaged specimens, except for the 125-G specimens., (© 2022 by the American College of Prosthodontists.)

Periacetabular periprosthetic fractures are rare but potentially disastrous for the longevity of the adjacent implants, leading to multiple revision surgeries. It is of paramount importance to identify and treat intraoperative fractures, which will lead to satisfactory results. Postoperative fractures may be managed operatively or nonoperatively depending on the patient's pain and function, the fracture pattern, and the stability of the acetabular component., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Evolution has molded individual species' sensory capacities and abilities. In rodents, who mostly inhabit dark tunnels and burrows, the whisker-based somatosensory system has developed as the dominant sensory modality, essential for environmental exploration and spatial navigation. In contrast, humans rely more on visual and auditory inputs when collecting information from their surrounding sensory space in everyday life. As a result of such species-specific differences in sensory dominance, cognitive relevance and capacities, the evidence for analogous sensory-cognitive mechanisms across species remains sparse. However, recent research in rodents and humans yielded surprisingly comparable processing rules for detecting tactile stimuli, integrating touch information into percepts, and goal-directed rule learning. Here, we review how the brain, across species, harnesses such processing rules to establish decision-making during tactile learning, following canonical circuits from the thalamus and the primary somatosensory cortex up to the frontal cortex. We discuss concordances between empirical and computational evidence from micro- and mesoscopic circuit studies in rodents to findings from macroscopic imaging in humans. Furthermore, we discuss the relevance and challenges for future cross-species research in addressing mutual context-dependent evaluation processes underpinning perceptual learning., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polymers have the potential to replace metallic or bioprosthetic heart valve components due to superior durability and inertness while allowing for native tissue-like flexibility. Despite these appealing properties, certain polymers such as polyetheretherketone (PEEK) have issues with hemocompatibility, which have previously been addressed through assorted complex processes. In this paper, we explore the enhancement of PEEK hemocompatibility with polymer crystallinity. Amorphous, semi-crystalline and crystalline PEEK are investigated in addition to a highly crystalline carbon fiber (CF)/PEEK composite material (CFPEEK). The functional group density of the PEEK samples is determined, showing that higher crystallinity results in increased amount of surface carbonyl functional groups. The increase of crystallinity (and negatively charged groups) appears to cause significant reductions in platelet adhesion (33 vs. 1.5 % surface coverage), hemolysis (1.55 vs. 0.75 %∙cm -2 ), and thrombin generation rate (4840 vs. 1585 mU/mL/min/cm 2 ). In combination with the hemocompatibility study, mechanical characterization demonstrates that tailoring crystallinity is a simple and effective method to control both hemocompatibility and mechanical performance of PEEK. Furthermore, the results display that CFPEEK composite performed very well in all categories due to its enhanced crystallinity and complete carbon encapsulation, allowing the unique properties of CFPEEK to empower new concepts in cardiovascular device design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

No contemporary unifying framework has been provided for the study of non-ordinary states of consciousness (NSCs) despite increased interest in hypnosis, meditation, and psychedelics. NSCs induce shifts in experiential contents (what appears to the experiencer) and/or structure (how it appears). This can allow the investigation of the plastic and dynamic nature of experience from a multiscale perspective that includes mind, brain, body, and context. We propose a neurophenomenological (NP) approach to the study of NSCs which highlights their role as catalysts of transformation in clinical practice by refining our understanding of the relationships between experiential (subjective) and neural dynamics. We outline the ethical implications of the NP approach for standard conceptions of health and pathology as well as the crucial role of experience-based know-how in NSC-related research and application., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)