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Background: Radiomics is a quantitative approach to medical imaging, aimed to extract features into large datasets. By using artificial intelligence (AI) methodologies, large radiomic data can be analysed and translated into meaningful clinical applications. In rhinology, there is heavy reliance on computed tomography (CT) imaging of the paranasal sinus for diagnostics and assessment of treatment outcomes. Currently, there is an emergence of literature detailing radiomics use in rhinology., Objective: This systematic review aims to assess the current techniques used to analyze radiomic data from paranasal sinus CT imaging., Methods: A systematic search was performed using Ovid MEDLINE and EMBASE databases from January 1, 2019 until March 16, 2024 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist and Cochrane Library Systematic Reviews for Diagnostic and Prognostic Studies. The QUADAS-2 and PROBAST tools were utilized to assess risk of bias., Results: Our search generated 1456 articles with 10 articles meeting eligibility criteria. Articles were divided into 2 categories, diagnostic (n = 7) and prognostic studies (n = 3). The number of radiomic features extracted ranged 4 to 1409, with analysis including non-AI-based statistical analyses (n = 3) or machine learning algorithms (n = 7). The diagnostic or prognostic utility of radiomics analyses were rated as excellent (n = 3), very good (n = 2), good (n = 2), or not reported (n = 3) based upon area under the curve receiver operating characteristic (AUC-ROC) or accuracy. The average radiomics quality score was 36.95%., Conclusion: Radiomics is an evolving field which can augment our understanding of rhinology diseases, however there are currently only minimal quality studies with limited clinical utility., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Richard J Harvey is a consultant/advisory board with Medtronic, Novartis, GSK and Meda pharmaceuticals. Research grant funding received from Glaxo-Smith-Kline. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Astra-Zeneca, Meda Pharmaceuticals and Seqirus. Janet Rimmer has honoraria with Sanofi Aventis, Novartis, Mundipharma, BioCSL, Stallergenes. Larry Kalish is on the speakers’ bureau for Care Pharmaceuticals, Mylan and Seqirus Pharmaceuticals. Raymond Sacks is a consultant for Medtronic. Antonio Di Ieva has received research funding from B Braun, Abbott, Servier, and BrainLab. All other authors have no financial disclosures or conflicts of interest.

Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2 -/- ) and knock-in (Atp6v0a2 RQ/RQ ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2 -/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2 RQ/RQ . Atp6v0a2 RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2 RQ/RQ . Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2 -/- and 6.25 in Atp6v0a2 RQ/RQ . Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway., Competing Interests: Declaration. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: Permissions for animal breeding and experiments were obtained from the Landesamt für Gesundheit und Soziales (LAGeSo) in Berlin, Germany (No. G0346/13, G0176/19), and the Landesamt für Verbraucherschutz und Lebensmittelsicherheit (LAVES) in Oldenburg, Germany (No. 20/3483). Consent to publish: This study does not contain any human materials or data., (© 2024. The Author(s).)

Background: Shifting tasks from General practitioners (GPs) to practice nurses (PNs) could help address the shortage of GPs in Europe. Internationally, PN-led care (PNLC) is feasible and offers similar health outcomes to usual care. However, PN-led consultations (PN-cons) or as PN-led dosage changes for permanent medication (PN-DCPM) are uncommon in German general practice offices (GPO)., Objective: To explore GPs' and PNs' views on the feasibility and acceptability of PN-cons and PN-DCPM in GPOs., Methods: In this exploratory, qualitative online focus group study, we recruited GPs, GP trainees, PNs and specialized PNs (APN) currently working in German GPO using a qualitative sampling plan. We used a semi-structured self-developed interview guide. Separate focus groups (FGs) were performed for each profession, with audio and video recordings, and the transcripts were analysed using thematic analysis., Results: Two FGs comprising 15 GPs and three FGs with 26 PNs revealed four major themes: (i) Attitudes towards PN-cons and PN-DCPM, revealing that participants were generally open towards a PN-cons, but were more reserved towards PN-DCPM. (ii) Acceptable reasons for encounters for PN-cons, e.g. diabetes or hypertension, and acceptable medications for PN-DCPM, e.g. antidiabetics, antihypertensive drugs. (iii) Conditions mentioned for implementing PN-led care were e.g. adequate qualification and supervision concepts. (iv) Perceived chances were e.g. time savings and increased quality of care and perceived risks were e.g. fear of treatment errors., Conclusion: Participants showed openness towards PN-cons and were more reserved towards PN-DCPM in German GPO. Further quantitative studies should assess how acceptance and rejection of PN-led care are distributed among patients, GPs, and PNs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To analyze waste from intraocular lens (IOL) packaging across a variety of brands., Setting: Private clinical practice., Design: Prospective weight and composition analysis of all elements of unopened packages of IOLs sold in the United States-both preloaded and non-preloaded., Methods: Samples were collected from multiple IOL companies in 2023. The primary end point for comparison was the total weight of each IOL package, because this generally correlates with the carbon footprint. The percentage of total weight contributed by paper, plastic, Tyvek, foil, sterile saline solution (fluid), metal, or glossy paper material was also calculated., Results: The non-preloaded IOL package weights ranged from 29 g (Zeiss Lucia) to 80 g (RxSIGHT LAL). Most of the weight was attributable to paper, including the box and instructions for use (IFUs) pamphlet. The latter was generally the largest component within the box. The weights of preloaded IOL packages were generally higher than those of their non-preloaded counterparts and ranged from 67 g (Hoya iSert) to 116 g (Rayner RayOne Spheric)., Conclusions: Meaningful differences in IOL packaging weight and waste were noted across different models and manufacturers. Electronic IFUs linked to QR codes could replace the need for an IFU pamphlet within every box, significantly reducing the box's size, weight, and carbon footprint. Pairing preloaded IOL cartridges with autoclavable injectors could reduce associated waste. Because of the enormous global volume of IOL implantation, these waste-reducing strategies should be prioritized by IOL manufacturers., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Based on the relevance of an established and broad foundation of physical activity in healthcare, this position paper of the DNVF working group Physical Activity-Related Health Services research presents current conceptual approaches to physical activity-related health services in Germany and highlights the need for interprofessional and interdisciplinary approaches. Three central positions are outlined and elaborated in order to integrate the evidence on health benefits of physical activity and exercise more strongly into healthcare and to show that, against the background of the challenges in the German healthcare system, physical activity-related health services can make a cost-effective and high-quality contribution to improve healthcare. These three positions include 1) the integration of all professional groups involved in healthcare into physical activity-related health services, 2) the greater integration of physical activity professions and physical activity interventions into all healthcare contexts and 3) the systematic consideration of physical activity- and exercise-related expertise in clinical guidelines., Competing Interests: JW ist Konsortialführer des genannten MOVE-ONKO Projektes und Koordinator der S3-Leitlinie Bewegungstherapie bei onkologischen Erkrankungen. JW und KE haben an der S2k-Leitlinie in der pädiatrischen Onkologie mitgearbeitet. GS ist Konsortialpartner des genannten ImPuls-Projekts. SP ist Mitarbeiter im DVGS e. V., der als Fachverband Bewegungsfachkräfte qualifiziert, für die qualitätsgesicherte Umsetzung von Bewegung in allen Versorgungskontexten eintritt und Mandatstragende für die Mitarbeit an Leitlinien entsendet. CT ist Professor für Physiotherapie an der Hochschule für Gesundheit Bochum, die einen primärqualifizierenden Bachelor-Studiengang „Physiotherapie“ anbietet und für die Vollakademisierung der Physiotherapie eintritt. BW ist im Präsidium der Deutschen Vereinigung für Sportwissenschaft (dvs) und vertritt im Ressort „Gesundheit und Bewegung“ die Interessen der Sportwissenschaft. Alle Autorinnen und Autoren haben Projekterfahrung mit der Entwicklung, Implementierung und/oder Evaluation von bewegungsbezogenen Interventionen in verschiedenen Versorgungskontexten. AS, CT, LG und SP sind im Sprecherrat der AG bewegungsbezogene Versorgungsforschung und verweisen auf die Darlegung ihrer entsprechenden Interessen (https://dnvf.de/gruppen/ag-bewegungsbezogene-versorgungsforschung.html). Alle anderen Autorinnen und Autoren sind Mitglied der AG Bewegungsbezogenen Versorgungsforschung und geben an, keine Interessenkonflikte zu haben., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Physical activity (PA) plays a vital role in maintaining the functional ability that enables well-being in older age (healthy aging), potentially also saving costs for the healthcare system and society. The aim of this study was to examine the association between PA and healthcare and societal costs in a sample of very mild to moderately frail older adults., Methods: This cross-sectional study is a secondary analysis using baseline data from the PromeTheus randomized-controlled trial, which included 385 very mild to moderately frail community-dwelling older adults (70 + years) from Germany. Participants self-reported their health-related resource use in the previous 6 months (FIMA questionnaire), which was monetarily valued using standardized unit costs. PA was also self-reported using the German Physical Activity Questionnaire for middle-aged and older adults (German-PAQ-50+) and categorized as 'insufficient'/'sufficient' or 'insufficient'/'moderate'/'high' in accordance with the World Health Organization guidelines for PA. Mean and median healthcare costs (including outpatient, inpatient, rehabilitation, formal care, and medication costs) and societal costs (healthcare costs plus informal care costs) for different PA groups were estimated using generalized linear models and quantile regression, with sociodemographic variables and physical capacity (Short Physical Performance Battery) as covariates., Results: Of the sample, 24% were classified as insufficiently, 23% as moderately, and 54% as highly active. Sufficient PA, especially high PA, was associated with lower costs in the 6 months prior to data collection compared to insufficient PA (-€6,237, 95% CI [-10,656; -1,817] and -€8,333, 95% CI [-12,183; -4,483], respectively). The cost difference between PA intensity groups was largely driven by differences in informal care costs and decreased substantially when physical capacity was accounted for in the analyses; e.g., the mean difference in societal costs between sufficient and insufficient PA decreased from -€7,615 (95% CI [-11,404; -3,825]) to -€4,532 (95% CI [-7,930; -1,133])., Conclusion: Promoting PA throughout the lifespan as a means of promoting healthy aging and reducing dependency in old age could potentially provide economic benefits and help to mitigate the economic consequences of an aging population with increasing health and long-term care needs. Future longitudinal studies should attempt to disentangle the mediating and confounding role of physical capacity and health status in the association between PA and costs., (© 2024. The Author(s).)

The large number of different analytical choices used by researchers is partly responsible for the challenge of replication in neuroimaging studies. For an exhaustive robustness analysis, knowledge of the full space of analytical options is essential. We conducted a systematic literature review to identify the analytical decisions in functional neuroimaging data preprocessing and analysis in the emerging field of cognitive network neuroscience. We found 61 different steps, with 17 of them having debatable parameter choices. Scrubbing, global signal regression, and spatial smoothing are among the controversial steps. There is no standardized order in which different steps are applied, and the parameter settings within several steps vary widely across studies. By aggregating the pipelines across studies, we propose three taxonomic levels to categorize analytical choices: 1) inclusion or exclusion of specific steps, 2) parameter tuning within steps, and 3) distinct sequencing of steps. We have developed a decision support application with high educational value called METEOR to facilitate access to the data in order to design well-informed robustness (multiverse) analysis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Diagnosing Congenital Disorders of Glycosylation (CDG) is challenging due to clinical heterogeneity and the limited sensitivity of the classic serum transferrin isoelectric focusing (IEF) or capillary zone electrophoresis test. This study investigates the potential of using the glycoprotein carnosinase 1 (CN1) activity as a diagnostic marker for CDG patients. CN1 activity was measured photometrically in serum from 81 genetically confirmed CDG patients and healthy individuals. While the IEF transferrin method detected 77 patients, four remained undetected. In healthy individuals, serum CN1 activity ranged from 0.1 to 6.4 μmol/ml/h depending on age, with mean CN1 activities up to four-fold higher than in CDG patients. CDG patients´ CN1 activities never exceeded 2,04 μmol/ml/h. Using the 25th percentile to differentiate between groups, the test performance varied by age. For children over 10 years old, the sensitivity and specificity were 96 % and 83 %, respectively. For those under 10, sensitivity and specificity dropped to 71 % and to 64 %. However, CN1 activity successfully identified three of four patients with normal IEF patterns. Although mean CN1 activity in CDG patients is significantly lower than in healthy controls, the test's reliability for classic CDG diagnosis is limited, as the diagnosis is usually made at a young age. Nevertheless, it is a simple, cost-effective assay that can complement classic tests, especially in settings with limited access to complex methods or for patients with normal transferrin patterns but suspicious for CDG., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare different types of activity trackers recording physical activity energy expenditure (PAEE) and examine their criterion validity against indirect calorimetry (IC) as the gold standard in adults over 60 years of age with a special focus on women with cardiovascular risk., Design: Synchronous registrations of PAEE were performed with up to four different devices to determine criterion validity against IC while participants performed a protocol of simulated activities in a laboratory setting., Method: Thirty-four participants (25 women, 9 men) with at least a light cardiac risk performed a protocol of simulated activities in a laboratory setting (daily living activities, cycle ergometer test). PAEE was simultaneously assessed by IC, two research-grade activity trackers (ActiGraph-wGT3X-BT and Actiheart-4) and two consumer-level activity trackers (OMRON pedometer and Fitbit Charge-3). Tracker-derived PAEE was compared with PAEE calculated from IC descriptively and by Bland-Altman plots., Results: The ActiGraph (0.7 ± 0.4 kcal/min), the Actiheart (1.1 ± 0.6 kcal/min) and the OMRON (0.8 ± 0.6 kcal/min) underestimated, while the Fitbit (3.4 ± 1.2 kcal/min) overestimated PAEE compared to IC-PAEE (2.0 ± 0.5 kcal/min). The Bland-Altman limits of agreement (LoA) against IC were +0.5/+2.2 kcal/min for the ActiGraph, -0.3/+2.1 kcal/min for the Actiheart, -3.7/+1.0 kcal/min for the Fitbit, and -0.5/+2.9 kcal/min for the OMRON. The magnitude of the deviation varied considerably depending on the activity (e.g. walking, cleaning, cycle ergometer test)., Conclusions: The research-grade activity trackers estimated PAEE with higher validity than the commercially available activity trackers. The partly very wide LoA have to be critically considered when assessing PAEE in the context of health service research, as individual Physical Activity behaviour may be under- or overestimated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rieckmann 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.)

A digital diary in the form of a mobile messenger service offers a novel method for data collection in cancer research. Little is known about the things to consider when using this data collection method in clinical research for patients with cancer. In this Viewpoint paper, we discuss the lessons we learned from using a qualitative digital diary method via a mobile messenger service for data collection in oncology care. The lessons learned focus on three main topics: (1) data quality, (2) practical aspects, and (3) data protection. We hope to provide useful information to other researchers who consider this method for their research with patients. First, in this paper, we argue that the interactive nature of a digital diary via a messenger service is very well suited for the phenomenological approach and produces high-quality data. Second, we discuss practical issues of data collection with a mobile messenger service, including participant and researcher interaction. Third, we highlight corresponding aspects around technicalities, particularly those regarding data security. Our views on data privacy and information security are summarized in a comprehensive checklist to inform fellow researchers on the selection of a suitable messenger service for different scenarios. In our opinion, a digital diary via a mobile messenger service can provide high-quality data almost in real time and from participants' daily lives. However, some considerations must be made to ensure that patient data are sufficiently protected. The lessons we learned can guide future qualitative research using this relatively novel method for data collection in cancer research., (©Eleonore Baum, Christian Thiel, Andrea Kobleder, Daniela Bernhardsgrütter, Ramona Engst, Carola Maurer, Antje Koller. Originally published in JMIR Cancer (https://cancer.jmir.org), 29.07.2024.)

The DNVF Memorandum: Objectives and Methods of Physical Activity-Related Health Services Research summarizes, for the first time, the highly interdisciplinary and interprofessional field of physical activity-based health care in the German healthcare system. In addition to providing a conceptual framework and definition of key measures and concepts in physical activity-related health care research, existing research gaps and needs are identified, and methods for advancing this relatively young field of research are described. A particular focus of this study is the relevant outcome parameters and their standardized assessment using established and valid measurement tools. The memorandum aims to establish a general understanding of the complex subject of promoting physical activity and sports therapy in the context of healthcare, to give an impulse to new research initiatives, and to integrate the currently available strong evidence on the effectiveness of physical activity and exercise into healthcare., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences., Methods: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics., Results: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9)., Discussion: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks., (© 2024. The Author(s).)

Background and Objectives: Hexokinase 1 (encoded by HK1 ) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals., Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype., Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile., Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings., Competing Interests: Several authors of this publication are members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN) - Project ID No 739543. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Various heterozygous cytoskeletal γ-actin mutations have been shown to cause Baraitser-Winter cerebrofrontofacial syndrome, non-syndromic hearing loss, or isolated eye coloboma. Here, we report the biochemical characterization of human cytoskeletal γ-actin carrying mutation E334Q, a mutation that leads to a hitherto unspecified non-muscle actinopathy. Following expression, purification, and removal of linker and thymosin β4 tag sequences, the p.E334Q monomers show normal integration into linear and branched actin filaments. The mutation does not affect thermal stability, actin filament nucleation, elongation, and turnover. Model building and normal mode analysis predict significant differences in the interaction of p.E334Q filaments with myosin motors and members of the ADF/cofilin family of actin-binding proteins. Assays probing the interactions of p.E334Q filaments with human class 2 and class 5 myosin motor constructs show significant reductions in sliding velocity and actin affinity. E334Q differentially affects cofilin-mediated actin dynamics by increasing the rate of cofilin-mediated de novo nucleation of actin filaments and decreasing the efficiency of cofilin-mediated filament severing. Thus, it is likely that p.E334Q-mediated changes in myosin motor activity, as well as filament turnover, contribute to the observed disease phenotype., Competing Interests: JG, AM, RH, TR, CT, ND, MT, DM No competing interests declared, (© 2023, Greve et al.)

Purpose: Congenital disorders of glycosylation (CDG) are one of the fastest growing groups of inborn errors of metabolism. Despite the availability of next-generation sequencing techniques and advanced methods for evaluation of glycosylation, CDG screening mainly relies on the analysis of serum transferrin (Tf) by isoelectric focusing, HPLC or capillary electrophoresis. The main pitfall of this screening method is the presence of Tf protein variants within the general population. Although reports describe the role of Tf variants leading to falsely abnormal results, their significance in confounding diagnosis in patients with CDG has not been documented so far. Here, we describe two PMM2-CDG cases, in which Tf variants complicated the diagnostic., Experimental Design: Glycosylation investigations included classical screening techniques (capillary electrophoresis, isoelectric focusing and HPLC of Tf) and various confirmation techniques (two-dimensional electrophoresis, western blot, N-glycome, UPLC-FLR/QTOF MS with Rapifluor). Tf variants were highlighted following neuraminidase treatment. Sequencing of PMM2 was performed., Results: In both patients, Tf screening pointed to CDG-II, while second-line analyses pointed to CDG-I. Tf variants were found in both patients, explaining these discrepancies. PMM2 causative variants were identified in both patients., Conclusion and Clinical Relevance: We suggest that a neuraminidase treatment should be performed when a typical CDG Tf pattern is found upon initial screening analysis., (© 2023 Wiley-VCH GmbH.)

Protein glycosylation is an essential post-translational modification in all domains of life. Its impairment in humans can result in severe diseases named congenital disorders of glycosylation (CDGs). Most of the glycosyltransferases (GTs) responsible for proper glycosylation are polytopic membrane proteins that represent challenging targets in proteomics. We established a multiple reaction monitoring (MRM) assay to comprehensively quantify GTs involved in the processes of N -glycosylation and O - and C -mannosylation in the endoplasmic reticulum. High robustness was achieved by using an enriched membrane protein fraction of isotopically labeled HEK 293T cells as an internal protein standard. The analysis of primary skin fibroblasts from eight CDG type I patients with impaired ALG1 , ALG2 , and ALG11 genes, respectively, revealed a substantial reduction in the corresponding protein levels. The abundance of the other GTs, however, remained unchanged at the transcript and protein levels, indicating that there is no fail-safe mechanism for the early steps of glycosylation in the endoplasmic reticulum. The established MRM assay was shared with the scientific community via the commonly used open source Skyline software environment, including Skyline Batch for automated data analysis. We demonstrate that another research group could easily reproduce all analysis steps, even while using different LC-MS hardware.

The global decline of terrestrial species is largely due to the degradation, loss and fragmentation of their habitats. The conversion of natural ecosystems for cropland, rangeland, forest products and human infrastructure are the primary causes of habitat deterioration. Due to the paucity of data on the past distribution of species and the scarcity of fine-scale habitat conversion maps, however, accurate assessment of the recent effects of habitat degradation, loss and fragmentation on the range of mammals has been near impossible. We aim to assess the proportions of available habitat within the lost and retained parts of mammals' distribution ranges, and to identify the drivers of habitat availability. We produced distribution maps for 475 terrestrial mammals for the range they occupied 50 years ago and compared them to current range maps. We then calculated the differences in the percentage of 'area of habitat' (habitat available to a species within its range) between the lost and retained range areas. Finally, we ran generalized linear mixed models to identify which variables were more influential in determining habitat availability in the lost and retained parts of the distribution ranges. We found that 59% of species had a lower proportion of available habitat in the lost range compared to the retained range, thus hypothesizing that habitat loss could have contributed to range declines. The most important factors negatively affecting habitat availability were the conversion of land to rangeland and high density of livestock. Significant intrinsic traits were those related to reproductive timing and output, habitat breadth and medium body size. Our findings emphasize the importance of implementing conservation strategies to mitigate the impacts caused by human activities on the habitats of mammals, and offer evidence indicating which species have the potential to reoccupy portions of their former range if other threats cease to occur., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

We present a genome assembly from an individual male Muscardinus avellanarius (the hazel dormouse; Chordata; Mammalia; Rodentia; Gliridae). The genome sequence is 2,497.5 megabases in span. Most of the assembly is scaffolded into 24 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 16.73 kilobases in length., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Böhne A et al.)

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD).

Moment-to-moment variations in hearing and speech perception have long been observed. Depending on the researcher's theoretical position, the observed fluctuations have been attributed to measurement error or to internal, nonsensory factors such as fluctuations in attention. While cognitive performance has been shown to fluctuate from day to day over longer time, such fluctuations have not been quantified for speech perception, despite being well-recognized by clinical audiologists and hearing-impaired patients. In three studies, we aimed to explore and quantify the magnitude of daily variability in speech perception and to investigate whether such variability goes beyond test unreliability. We also asked whether intraindividual variability depends on overall speech perception performance as observed in different groups of individuals. Older adults with objective hearing impairment and mostly hearing aids (N₁ = 45), with subjective hearing problems but no hearing aids (N₂ = 113), and younger adults without hearing problems (N₃ = 20) participated in three ecological momentary assessment studies. They performed a digit-in-noise test two to three times a day for several weeks. Variance heterogeneous linear mixed-effects models indicated reliable intraindividual variability in speech perception and substantial individual differences in daily variability. A protective factor against daily fluctuations is a higher average speech perception. These studies show that day-to-day variations in speech perception cannot simply be attributed to test unreliability and pave the way for investigating how psychological states that do not vary from moment-to-moment, but rather from day to day, predict variations in speech perception. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Purpose: This study determined the evolution of performance and pacing for each winner of the men's Olympic 1500-m running track final from 1924 to 2020., Methods: Data were obtained from publicly available sources. When official splits were unavailable, times from sources such as YouTube were included and interpolated from video records. Final times, lap splits, and position in the peloton were included. The data are presented relative to 0 to 400 m, 400 to 800 m, 800 to 1200 m, and 1200 to 1500 m. Critical speed and D' were calculated using athletes' season's best times., Results: Performance improved ∼25 seconds from 1924 to 2020, with most improvement (∼19 s) occurring in the first 10 finals. However, only 2 performances were world records, and only one runner won the event twice. Pacing evolved from a fast start-slow middle-fast finish pattern (reverse J-shaped) to a slower start with steady acceleration in the second half (J-shaped). The coefficient of variation for lap speeds ranged from 1.4% to 15.3%, consistent with a highly tactical pacing pattern. With few exceptions, the eventual winners were near the front throughout, although rarely in the leading position. There is evidence of a general increase in both critical speed and D' that parallels performance., Conclusions: An evolution in the pacing pattern occurred across several "eras" in the history of Olympic 1500-m racing, consistent with better trained athletes and improved technology. There has been a consistent tactical approach of following opponents until the latter stages, and athletes should develop tactical flexibility, related to their critical speed and D', in planning prerace strategy.

Background: The US health care system is the second largest contributor of trash. Approximately 20% to 70% of waste is produced by operating rooms, and very few of this waste is recycled. The purpose of this study is to quantify the opened but unused disposable supplies and generate strategies to reduce disposable waste., Methods: A single-center prospective study to evaluate the cost of opened but unused single-use operating room supplies was completed by counting the number of wasted disposable products at the end of hand surgery cases. We used χ 2 test, t test, Wilcoxon rank-sum test, and simple linear regression to assess the associations between patient and case variables and the total cost of wasted items. Environmentally Extended Input Output Life Cycle Assessment methods were used to convert the dollar spent to kilograms of carbon dioxide equivalent (CO 2 -e), a measure of greenhouse gas emissions., Results: Surgical and dressing items that were disposed of and not used during each case were recorded. We included 85 consecutive cases in the analysis from a single surgeon's practice. Higher cost from wasted items was associated with shorter operative time ( P = .010). On average, 11.5 items were wasted per case (SD: 3.6 items), with a total of 981 items wasted over the 85 cases in the study period. Surgical sponges and blades were 2 of the most unused items. Wasted items amounted to a total of $2193.5 and 441 kg of CO 2 -e during the study period., Conclusions: This study highlights the excessive waste of unused disposable products during hand surgery cases and identifies ways of improvement., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.P. and C.T. are paid consultants for Stryker corporation, E.M. is a paid consultant for NewClip and Axogen. D.B., R.B., and A.M. have no conflict of interests.

Background: Total knee arthroplasty (TKA) is an option for the treatment of knee osteoarthritis (OA). Patients have high expectations regarding the benefits of the actual operation. Patients can seek a second opinion on the indication for TKA. In a study, less than half of recommended TKAs were confirmed by the second opinion and conservative treatments are not fully utilized. Informed consent forms that are used in Germany usually do not meet the requirements to support informed decision-making. Our aim was to describe the process from the diagnosis of knee OA through the decision-making process to the informed consent process for TKA, and to understand when, how, and by whom decisions are made. Moreover, we wanted to describe patients' information needs and preferences about knee OA and its treatment, including TKA, and find out what information is provided. We also wanted to find out what information was important for decision-making and identify barriers and facilitators for the optimal use of evidence-based informed consent forms in practice., Methods: We chose a qualitative approach and conducted semi-structured interviews with patients who were going to receive, have received, or have declined TKA, and with general practitioners (GP), office-based as well as orthopaedists and anaesthesiologists in clinics who obtain informed consent. The interviews were audio-recorded, transcribed and analysed using qualitative content analysis., Results: We conducted interviews with 13 patients, three GPs, four office-based orthopaedists and seven doctors in clinics who had obtained informed consent. Information needs were modelled on subjective disease theory and information conveyed by the doctors. Patients in this sample predominantly made their decisions without having received sufficient information. Trust in doctors and experiences seemed to be more relevant in this sample than fact-based information. Office-based (GPs, orthopaedists) and orthopaedists in clinics had different understandings of their roles and expectations in terms of providing information., Conclusions: We were able to identify structural barriers and assumptions that hinder the implementation of evidence-based informed consent forms., (© 2023. BioMed Central Ltd., part of Springer Nature.)

PMM2-CDG is the most prevalent type of congenital disorders of glycosylation (CDG). It is caused by pathogenic variants in the gene encoding phosphomannomutase 2 (PMM2), which converts mannose-6-phosphate to mannose-1-phosphate and thus activates this saccharide for further glycosylation processes. Defective glycosylation can lead to an abnormal accumulation of unfolded proteins in endoplasmic reticulum (ER) and cause its stress. The ER is a key compartment for glycosylation, and its connection and communication with mitochondria has been described extensively in literature. Their crosstalk is important for cell proliferation, calcium homeostasis, apoptosis, mitochondrial fission regulation, bioenergetics, autophagy, lipid metabolism, inflammasome formation and unfolded protein response. Therefore, in the present study we posed a question, whether defective glycosylation leads to bioenergetic disruption. Our data reveal possible chronic stress in ER and activated unfolded protein response via PERK pathway in PMM2-CDG fibroblasts. Presumably, it leads to bioenergetic reorganization and increased assembly of respiratory chain complexes into supercomplexes together with suppressed glycolysis in PMM2-CDG patient cells. These changes cause alterations in Krebs cycle, which is tightly connected to electron transport system in mitochondria. In summary, we present data showing metabolic adaptation of cells to glycosylation defect caused by various pathogenic variants in PMM2., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) can affect speech as well as emotion processing. We employ whole-brain graph-theoretical network analysis to determine how the speech-processing network (SPN) changes in PD, and assess its susceptibility to emotional distraction. Functional magnetic resonance images of 14 patients (aged 59.6 ± 10.1 years, 5 female) and 23 healthy controls (aged 64.1 ± 6.5 years, 12 female) were obtained during a picture-naming task. Pictures were supraliminally primed by face pictures showing either a neutral or an emotional expression. PD network metrics were significantly decreased (mean nodal degree, p < 0.0001; mean nodal strength, p < 0.0001; global network efficiency, p < 0.002; mean clustering coefficient, p < 0.0001), indicating an impairment of network integration and segregation. There was an absence of connector hubs in PD. Controls exhibited key network hubs located in the associative cortices, of which most were insusceptible to emotional distraction. The PD SPN had more key network hubs, which were more disorganized and shifted into auditory, sensory, and motor cortices after emotional distraction. The whole-brain SPN in PD undergoes changes that result in (a) decreased network integration and segregation, (b) a modularization of information flow within the network, and (c) the inclusion of primary and secondary cortical areas after emotional distraction., (© 2023 Massachusetts Institute of Technology.)

Purpose: Practice nurse (PN)-led patient consultations and PN-led dosage adjustments of permanent medication are uncommon and not well studied in general practice (GP) in Germany. We investigated the perspectives of patients with common chronic diseases in Germany, diabetes mellitus (DM) type 2 and/or arterial hypertension (AT), on PN-led patient consultations and dosage adjustments of permanent medications in GP., Patients and Methods: In this exploratory qualitative study, online focus groups were conducted using a semi-structured interview guide. Patients were recruited from collaborating GPs according to a predefined sampling plan. Patients were eligible for this study if they had DM or AT treated by their GP, were on at least one permanent medication and were aged 18 years or older. Focus group transcripts were analyzed using thematic analyses., Results: Analyses of two focus groups, involving a total of 17 patients, revealed four main themes: (1) openness to the PN-led care and perceived benefits, eg because of patients' confidence in PNs' skills, or patients' impression that PN-led care would better meet their needs and increase their compliance. Some patients had (2) reservations and perceived risks, especially for PN-led medication changes eg feeling that medication adjustments were a GP's issue. Patients identified (3) reasons for encounters where they were likely to accept PN-led consultation and medication advice, eg management of DM, AT and thyroid disease. Patients also saw several important general requirements for the implementation of PN-led care in German general practice (4)., Conclusion: There is a potential for openness towards PN-led consultation and PN-led medication adjustment for permanent medication in patients with DM or AT. This study is the first qualitative study to investigate PN-led consultations and medication advice in German general practice. If the implementation of PN-led care is planned, our findings add the patients' perspectives of acceptable reasons for encounter for PN-led care and their general requirements., Competing Interests: Dr Solveig Weise reports grants from Foundation for Perspectives in General Practice, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Weise et al.)

Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice ( Cndp1 -KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) ( n = 10/group), with streptozocin (STZ)-induced type-1 diabetes ( n = 21-23/group), were studied for 32 weeks. Independent of diet, Cndp1 -KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1 -KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1 -KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1 -KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1 -KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD.

Introduction: Hip and knee osteoarthritis are associated with functional limitations, pain and restrictions in quality of life and the ability to work. Furthermore, with growing prevalence, osteoarthritis is increasingly causing (in)direct costs. Guidelines recommend exercise therapy and education as primary treatment strategies. Available options for treatment based on physical activity promotion and lifestyle change are often insufficiently provided and used. In addition, the quality of current exercise programmes often does not meet the changing care needs of older people with comorbidities and exercise adherence is a challenge beyond personal physiotherapy. The main objective of this study is to investigate the short- and long-term (cost-)effectiveness of the SmArt-E programme in people with hip and/or knee osteoarthritis in terms of pain and physical functioning compared to usual care., Methods: This study is designed as a multicentre randomized controlled trial with a target sample size of 330 patients. The intervention is based on the e-Exercise intervention from the Netherlands, consists of a training and education programme and is conducted as a blended care intervention over 12 months. We use an app to support independent training and the development of self-management skills. The primary and secondary hypotheses are that participants in the SmArt-E intervention will have less pain (numerical rating scale) and better physical functioning (Hip Disability and Osteoarthritis Outcome Score, Knee Injury and Osteoarthritis Outcome Score) compared to participants in the usual care group after 12 and 3 months. Other secondary outcomes are based on domains of the Osteoarthritis Research Society International (OARSI). The study will be accompanied by a process evaluation., Discussion: After a positive evaluation, SmArt-E can be offered in usual care, flexibly addressing different care situations. The desired sustainability and the support of the participants' behavioural change are initiated via the app through audio-visual contact with their physiotherapists. Furthermore, the app supports the repetition and consolidation of learned training and educational content. For people with osteoarthritis, the new form of care with proven effectiveness can lead to a reduction in underuse and misuse of care as well as contribute to a reduction in (in)direct costs., Trial Registration: German Clinical Trials Register, DRKS00028477. Registered on August 10, 2022., (© 2023. The Author(s).)

A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R 2  = 0.18, p = 0.001; flexed: R 2  = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R 2  = 0.103, p = 0.017; flexed: R 2  = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420 ., (© 2023. The Author(s).)

Scientific interest in pacing goes back >100 years. Contemporary interest, both as a feature of athletic competition and as a window into understanding fatigue, goes back >30 years. Pacing represents the pattern of energy use designed to produce a competitive result while managing fatigue of different origins. Pacing has been studied both against the clock and during head-to-head competition. Several models have been used to explain pacing, including the teleoanticipation model, the central governor model, the anticipatory-feedback-rating of perceived exertion model, the concept of a learned template, the affordance concept, the integrative governor theory, and as an explanation for "falling behind." Early studies, mostly using time-trial exercise, focused on the need to manage homeostatic disturbance. More recent studies, based on head-to-head competition, have focused on an improved understanding of how psychophysiology, beyond the gestalt concept of rating of perceived exertion, can be understood as a mediator of pacing and as an explanation for falling behind. More recent approaches to pacing have focused on the elements of decision making during sport and have expanded the role of psychophysiological responses including sensory-discriminatory, affective-motivational, and cognitive-evaluative dimensions. These approaches have expanded the understanding of variations in pacing, particularly during head-to-head competition.

Speech production relies on the interplay of different brain regions. Healthy aging leads to complex changes in speech processing and production. Here, we investigated how the whole-brain functional connectivity of healthy elderly individuals differs from that of young individuals. In total, 23 young (aged 24.6 ± 2.2 years) and 23 elderly (aged 64.1 ± 6.5 years) individuals performed a picture naming task during functional magnetic resonance imaging. We determined whole-brain functional connectivity matrices and used them to compute group averaged speech production networks. By including an emotionally neutral and an emotionally charged condition in the task, we characterized the speech production network during normal and emotionally challenged processing. Our data suggest that the speech production network of elderly healthy individuals is as efficient as that of young participants, but that it is more functionally segregated and more modularized. By determining key network regions, we showed that although complex network changes take place during healthy aging, the most important network regions remain stable. Furthermore, emotional distraction had a larger influence on the young group's network than on the elderly's. We demonstrated that, from the neural network perspective, elderly individuals have a higher capacity for emotion regulation based on their age-related network re-organization., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dolichyl monophosphates (DolPs) are essential lipids in glycosylation pathways that are highly conserved across almost all domains of life. The availability of DolP is critical for all glycosylation processes, as these lipids serve as membrane-anchored building blocks used by various types of glycosyltransferases to generate complex post-translational modifications of proteins and lipids. The analysis of DolP species by reverse-phase liquid chromatography-mass spectrometry (RPLC-MS) remains a challenge due to their very low abundance and wide range of lipophilicities. Until now, a method for the simultaneous qualitative and quantitative assessment of DolP species from biological membranes has been lacking. Here, we describe a novel approach based on simple sample preparation, rapid and efficient trimethylsilyl diazomethane-dependent phosphate methylation, and RPLC-MS analysis for quantification of DolP species with different isoprene chain lengths. We used this workflow to selectively quantify DolP species from lipid extracts derived of Saccharomyces cerevisiae , HeLa, and human skin fibroblasts from steroid 5-α-reductase 3- congenital disorders of glycosylation (SRD5A3-CDG) patients and healthy controls. Integration of this workflow with global lipidomics analyses will be a powerful tool to expand our understanding of the role of DolPs in pathophysiological alterations of metabolic pathways downstream of HMG-CoA reductase, associated with CDGs, hypercholesterolemia, neurodegeneration, and cancer.

Aim To assess the efficacy of pain neuroscience education combined with physiotherapy for the management of migraine. Background Physiotherapy can significantly reduce the frequency of migraine, but the evidence is based only on a few studies. Pain neuroscience education might pose a promising treatment, as it addresses migraine as a chronic pain disease. Methods In this non-blinded randomized controlled trial, migraine patients received physiotherapy + pain neuroscience education or physiotherapy alone, preceded by a three-month waiting period. Primary outcomes were frequency of headache (with and without migraine features), frequency of migraine and associated disability. Results Eighty-two participants were randomized and analyzed. Both groups showed a decrease of headache frequency (p = 0.02, d = 0.46) at post-treatment (physiotherapy: 0.77 days, 95%CI: -0.75 to 2.29 and physiotherapy + pain neuroscience education: 1.25 days, 95%CI: -0.05 to 2.55) and at follow-up (physiotherapy: 1.93, 95%CI: 0.07 to 3.78 and physiotherapy + pain neuroscience education: 3.48 days, 95%CI: 1.89 to 5.06), with no difference between groups (p = 0.26, d = 0.26). Migraine frequency was reduced significantly in the physiotherapy + pain neuroscience education group, and not in the physiotherapy group, at post-treatment (1.28 days, 95%CI: 0.34 to 2.22, p = 0.004) and follow-up (3.05 days, 95%CI: 1.98 to 5.06, p < 0.0001), with a difference between groups at follow-up (2.06 days, p = 0.003). Migraine-related disability decreased significantly in both groups (physiotherapy: 19.8, physiotherapy + pain neuroscience education: 24.0 points, p < 0.001, d = 1.15) at follow-up, with no difference between groups (p = 0.583). Secondary outcomes demonstrated a significant effect of time with no interaction between time and group. No harm or adverse events were observed during the study. Conclusion In comparison to physiotherapy alone, pain neuroscience education combined with physiotherapy can further reduce the frequency of migraine, but had no additional effect on general headache frequency or migraine-related disability. Trial Registration The study was pre-registered at the German Clinical Trials Register (DRKS00020804).

Purpose: Since their invention 40 years ago, totally implantable venous-access ports (TIVAPs) have become indispensable in cancer treatment. The aim of our study was to analyze complications under standardized operative and perioperative procedures and to identify risk factors for premature port catheter explantation., Methods: A total of 1008 consecutive TIVAP implantations were studied for success rate, perioperative, early, and late complications. Surgical, clinical, and demographic factors were analyzed as potential risk factors for emergency port catheter explantation., Results: Successful surgical TIVAP implantation was achieved in 1005/1008 (99.7%) cases. No intraoperative or perioperative complications occurred. A total of 32 early complications and 88 late complications were observed leading to explantation in 11/32 (34.4%) and 34/88 (38.6%) cases, respectively. The most common complications were infections in 4.7% followed by thrombosis in 3.6%. Parameters that correlated with unplanned TIVAP explantation were gender (port in situ: female 95% vs. male 91%, p = 0.01), underlying disease (breast cancer 97% vs. gastrointestinal 89%, p = 0.004), indication (chemotherapy 95% vs. combination of chemotherapy and parenteral nutrition 64%, p < 0.0001), and type of complication (infection 13.4% vs. TIVAP-related complication 54% and thrombosis 95%, p < 0.0001)., Conclusion: Standardized operative and perioperative TIVAP implantation procedures provide excellent results and low explantation rate., (© 2022. The Author(s).)

A 10-year-old female mixed breed dog was presented for thyroid scintigraphy due to a cervical mass. Apart from 99m-Technetium-pertechnetate (Tc-pertechnetate) scintigraphy, a second scintigraphy using 99m-Technetium sestamibi (Tc-MIBI) was performed because of additional hypothyroidism suspective for a "cold" nodule and as screening for metastases.Twenty minutes following intravenous injection of 38 MBq Tc-pertechnetate, a "hot" cervical as well as a "hot" intrathoracal nodule were seen with an uptake of 8.40 and 0.25 %, respectively. The second scintigraphy was performed 20 minutes after intravenous injection of 364 MBq Tc-MIBI and 70 minutes following the first. After subtraction of pertechnetate activity and decay correction, both nodules showed an uptake of 0.99 and 0.03 %. Additionally, both thyroid lobes were visible in the thyroid loge with a weak MIBI-uptake. For both lesions, the ratio Tc-uptake/Tc-MIBI-uptake was 8.48 and 8.33, respectively.Following the extirpation of the cervical mass, histopathology revealed atrophied healthy thyroid tissue almost completely displaced by a well-differentiated follicular thyroid carcinoma.This case report describes performance, utility and calculative correction of consecutive pertechnetate- and MIBI-scan, that enable a visualization of hypofunctional thyroid tissue.Therefore and because of their similar MIBI metabolic activity, both nodules were considered to be dystopic tissue/metastases so that this dog had to be classified as prognostically less favorable WHO stabe IV. Different from human patients, both scintigraphies should be performed shortly after another in dogs in order to avoid the necessity of a second anesthetic procedure. A reliable qualitative/visual evaluation of the MIBI-scan is therefore not possible, so that a quantitative assessment using the uptake after calculative correction of the pertechnetate activity is recommended., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Introduction: A novel multipurpose bipolar radiofrequency instrument, the Erbe Dissector (EDS), which simultaneously seals and cuts tissue, was developed. Ex vivo sealing rate and time, burst pressure, jaw temperature and thermal spread were studied in porcine renal arteries., Material and Methods: In vivo , 13 surgical tasks were performed in two pigs: beside sealing rate and time, overall performance in sharp and blunt dissection, tissue sticking, hemostasis, precision, etc., were evaluated by four surgeons compared with ENSEAL G2 (EG2) using surveys on a Likert scale (1 = very poor; 5 = very good)., Results: Ex vivo , the EDS sealing rate was 91.7% (33/36 arteries) at an average sealing time of 2.1 s (range 1.7-2.8) and a burst pressure of 1040 ± 350 mmHg. The maximum jaw temperature was 87 ± 4 °C and the mean lateral thermal spread was 0.8 ± 0.2 mm. In vivo , the sealing rate for arteries and veins was 92.6% (50/54) and the median seal and cut time was 1.6 s (range: 1.3-2.9). The average EDS performance score across all tasks was 4.4 ± 0.6 Likert points. For five shared tasks, EDS was better than EG2 (4.4 ± 0.5 versus 3.4 ± 0.6 Likert points; p  = 0.016)., Conclusions: EDS seals and cuts arteries and veins rapidly with good safety and user-friendliness.

Impaired emotion recognition is common in individuals with attention-deficit/hyperactivity disorder (ADHD) and may, via deficient emotion self-regulation, relate to the frequently co-occurring affective and social problems. The present study used an emotional face-matching task and functional magnetic resonance imaging (fMRI) to investigate neural responses during the processing of angry and fearful faces and visuo-spatial control stimuli. Additionally, measures for emotion dysregulation, ADHD type, and age were investigated in relation to the behavioral and neural fMRI data. We utilized a sample of 61 adolescents/young adults with ADHD and 51 age-matched healthy controls (age range: 12-28 years). Participants with ADHD had higher emotion dysregulation scores than controls. They also reacted slower and less accurate in response to emotional but not visuo-spatial control stimuli. Neural response differences between emotional and visuo-spatial trials were significantly smaller in cases, particularly in the left amygdala. While coupling between the right amygdala and bilateral ventromedial prefrontal cortex was stronger for emotional than visuo-spatial stimuli in control subjects, levels of positive coupling between the trial types did not significantly differ in participants with ADHD. Neither emotion dysregulation scores, nor ADHD type or age were related to the behavioral and neural processing alterations during the emotional face-matching task. Results indicate that emotion recognition deficits in ADHD are particularly associated with lower amygdala activation to emotional stimuli and alterations in the functional connections of the amygdala to medial prefrontal areas. Emotion recognition deficits and associated neural alterations were unrelated to emotion dysregulation, ADHD type, or age., (© 2021. The Author(s).)

Background: Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA., Objectives: To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication., Material and Methods: Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h., Results: Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival., Conclusions: Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.

The objective of the present review is to synthesize all available research on the association between mobility capacity and incident disability in non-disabled older adults. MEDLINE, EMBASE and CINAHL databases were searched without any limits or restrictions until February 2021. Published reports of longitudinal cohort studies that estimated a direct association between baseline mobility capacity, assessed with a standardized outcome assessment, and subsequent development of disability, including initially non-disabled older adults were included. The risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Random-effect models were used to explore the objective. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The main outcome measures were the pooled relative risks (RR) per one conventional unit per mobility assessment for incident disability. A total of 40 reports (85,515 participants at baseline) were included. For usual and fast gait speed, the RR per -0.1 m/s was 1.23 (95% CI: 1.18-1.28; 26,638 participants) and 1.28 (95% CI: 1.19-1.38; 8161 participants), respectively. Each point decrease in Short Physical Performance Battery score increased the risk of incident disability by 30% (RR = 1.30, 95% CI: 1.23-1.38; 9183 participants). The RR of incident disability by each second increase in Timed Up and Go test and Chair Rise Test performance was 1.15 (95% CI: 1.09-1.21; 30,426 participants) and 1.07 (95% CI: 1.04-1.10; 9450 participants), respectively. The review concludes that among community-dwelling non-disabled older adults, poor mobility capacity is a potent modifiable risk factor for incident disability. Mobility impairment should be mandated as a quality indicator of health for older people., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Waste generated by health care includes harmful emissions and often disproportionately affects already vulnerable communities. Justly restructuring health care waste management involves better understanding key drivers of waste production, using sustainability as an ethical value to guide disposal decisions and practices, and reducing overall disposal quantity. Restructuring can be facilitated by making existing waste audit data transparent, incorporating waste accounting into social responsibility metrics used to evaluate health care organizational performance, and implementing policies that prioritize frontline workers' safety., (Copyright 2022 American Medical Association. All Rights Reserved.)

Re-directing attention to objects in working memory can enhance their representational fidelity. However, how this attentional enhancement of memory representations is implemented across distinct, sensory and cognitive-control brain network is unspecified. The present fMRI experiment leverages psychophysical modelling and multivariate auditory-pattern decoding as behavioral and neural proxies of mnemonic fidelity. Listeners performed an auditory syllable pitch-discrimination task and received retro-active cues to selectively attend to a to-be-probed syllable in memory. Accompanied by increased neural activation in fronto-parietal and cingulo-opercular networks, valid retro-cues yielded faster and more perceptually sensitive responses in recalling acoustic detail of memorized syllables. Information about the cued auditory object was decodable from hemodynamic response patterns in superior temporal sulcus (STS), fronto-parietal, and sensorimotor regions. However, among these regions retaining auditory memory objects, neural fidelity in the left STS and its enhancement through attention-to-memory best predicted individuals' gain in auditory memory recall precision. Our results demonstrate how functionally discrete brain regions differentially contribute to the attentional enhancement of memory representations., 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 © 2022. Published by Elsevier Inc.)

ALG9-CDG is a CDG-I defect within the group of Congenital Disorders of Glycosylation (CDG). We here describe the clinical symptoms of two new and unrelated ALG9-CDG patients, both carrying the novel homozygous missense variant c.1460 T > C (p.L487P) in the ALG9 gene which led to global developmental delay, psychomotor disability, facial dysmorphisms, brain and heart defects, hearing loss, hypotonia, as well as feeding problems. New clinical symptoms comprised West syndrome with hypsarrhythmia. Quantitative RT-PCR analysis revealed a significantly enhanced ALG9 mRNA transcript level, whereas the protein amount in fibroblasts was significantly reduced. This could be ascribed to a stronger degradation of the mutated ALG9 protein in patient fibroblasts. Lipid-linked oligosaccharide analysis showed an ALG9-CDG characteristic accumulation of Man 6 GlcNAc 2 -PP-dolichol and Man 8 GlcNAc 2 -PP-dolichol in patient cells. The clinical findings of our patients and of all previously published ALG9-CDG patients are brought together to further expand the knowledge about this rare N-glycosylation disorder. SYNOPSIS: Homozygosity for p.L487P in ALG9 causes protein degradation and leads to West syndrome., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Combining smartphone-assisted group activities in the neighbourhood and training in physical and cognitive skills may offer the potential to promote social participation and connectedness of older adults. This non-controlled proof-of-concept, retrospectively registered study aimed to determine the feasibility of such an intervention approach, including its evaluation., Methods: In two consecutive six-month intervention cycles, 39 community-dwelling adults were provided with weekly smartphone, physical and cognitive training by two tutors. Using a specifically designed app, the participants were also encouraged to join and later self-organise physically and cognitively stimulating activities related to hot spots in their Bochum neighbourhood. Indicators of feasibility were documented., Results: The recruitment and assessments took 3 hours per participant. Excluding smartphone support, the preparation and the implementation of the intervention amounted to nine person-hours per week. Six participants dropped out, and 13 did not complete one or more assessments. The participants attended 76 ± 15% of the weekly training sessions. The instructors deemed the programme feasible, but familiarisation with the smartphone and the app was very time-consuming. Twenty-seven of 29 participants reported high overall satisfaction, and 22 agreed that the programme helped them to establish social contacts. The smartphones attracted substantial interest and were used frequently, despite mixed satisfaction with the project-specific app. From baseline to follow-up, the six-minute walking distance, lower extremity strength and moderate to vigorous physical activity, as well as quality of life, were preserved at a high level, while balance performance was significantly improved. Of the 11 tests related to cognitive functioning, 4 tests (a memory test, the Stroop test and 2 tests of verbal fluency) indicated significant improvement. No moderate or serious adverse events occurred in relation to the assessments or the intervention., Conclusions: The multimodal approach seems safe and feasible and offers the potential to promote social connectedness, bonds in the residential neighbourhood and smartphone competency, as well as to preserve or improve physical and cognitive functions. Adaptations of the intervention and of the outcome assessments may contribute to better assessment and exploitation of the potential of this approach in a future study involving socially, physically and cognitively less active elderly persons., (© 2022. The Author(s).)

Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The United States health care industry is the second largest in the world, expending an estimated 479 million metric tons (MMT) of carbon dioxide per year, nearly 8 percent of the country's total emissions. The importance of carbon reduction in health care is slowly being accepted. However, efforts to "green" health care are incomplete since they generally focus on buildings and structures. Yet hospital care and clinical service sectors contribute the most carbon dioxide within the U.S. health care industry, with structures/equipment and pharmaceuticals ranking as the third and fourth highest emitters in the industry. Given the magnitude of health care carbon emissions-and the paucity of attention to the carbon of hospital care and clinical services-this essay identifies overuse of health care as a health threat with serious ethical implications, offers a data-driven action plan for carbon reduction in health care, and provides practical suggestions for more sustainable health care delivery in the United States., (© 2022 The Hastings Center.)