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The National Institute of Mental Health created the National Database for Autism Research (NDAR) to accelerate autism knowledge through data sharing and collaboration. However, our experience using NDAR reveals systematic challenges across several aspects of data submission, selection, management, and analysis that limit utility of this resource. We describe our NDAR experience in an ongoing project examining autism intervention outcomes among marginalized racial, ethnic, and gender groups. For this study, we planned to gather data from NDAR to conduct an individual participant data meta-analysis. Eighteen studies met inclusion criteria and reported data on participants at more than one point in time on the Vineland Adaptive Behavior Scales (Vineland) and the Autism Diagnostic Observation Schedule (ADOS). The difficulties with submitting, selecting, downloading, and managing data from NDAR posed limitations on data availability and analysis. Of the 3,850 unique participants in the selected studies, data at multiple time points were available for 312 participants on the Vineland and 278 on the ADOS. No participants had data on all assessment domains. To accelerate autism research via data sharing and collaboration with NDAR necessitates improving the processes for submitting, selecting, and managing data., Competing Interests: Declarations Competing Interests Dr. Scahill has served as a consultant to Roche, Janssen, Impel. He has received royalties from American Psychological Association, Guilford and Oxford University Press and licensing fees from Cogstate, Abbvie, Yamo. The remaining authors have no relevant financial or non-financial interests to disclose. Ethical Approval The Boston University Medical Campus Institutional Review Board approved this project as exempt. Consent to Participate Data for this commentary were drawn from the National Database for Autism Research (NDAR) data repository, available on National Institute of Mental Health National Data Archive. All participants were consented at the time of data collection in the original study before deposition in NDAR., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The recent advances of large language models (LLMs) have opened a wide range of opportunities, but at the same time, they pose numerous challenges and questions that research needs to answer. One of the main challenges are the quality and correctness of the output of LLMs as well as the overreliance of students on the output without critically reflecting on it. This poses the question of the quality of the output of LLMs in educational tasks and what students and teachers need to consider when using LLMs for creating educational items. In this work, we focus on the quality and characteristics of conceptual items developed using ChatGPT without user-generated improvements., Methods: For this purpose, we optimized prompts and created 30 conceptual items in kinematics, which is a standard topic in high-school level physics. The items were rated by two independent experts. Those 15 items that received the highest rating were included in a conceptual survey. The dimensions were designed to align with the ones in the most commonly used concept inventory, the Force Concept Inventory (FCI). We administered the designed items together with the FCI to 172 first-year university students. The results show that ChatGPT items have a medium difficulty and discriminatory index but they overall exhibit a slightly lower average values as the FCI. Moreover, a confirmatory factor analysis confirmed a three factor model that is closely aligned with a previously suggested expert model., Results and Discussion: In this way, after careful prompt engineering, thorough analysis and selection of fully automatically generated items by ChatGPT, we were able to create concept items that had only a slightly lower quality than carefully human-generated concept items. The procedures to create and select such a high-quality set of items that is fully automatically generated require large efforts and point towards cognitive demands of teachers when using LLMs to create items. Moreover, the results demonstrate that human oversight or student interviews are necessary when creating one-dimensional assessments and distractors that are closely aligned with students' difficulties., 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., (Copyright © 2024 Küchemann, Rau, Schmidt and Kuhn.)

Background: Loneliness represents a significant health risk and is associated with numerous mental and physical conditions. The aim of this paper was to describe the prevalence of loneliness in Bavaria before and during the COVID-19 pandemic with respect to socio-demographic attributes., Methods: Data sources were the German Ageing Survey (DEAS) and the Socio-Economic Panel (SOEP). Univariate statistical analyses were carried out for different socio-demographic attributes, such as age, gender, type of household, education, and financial resources., Results: According to the SOEP, the proportion of adults who are often or very often lonely increased from 2.3% in 2017 to 16.2% in 2021. In 2021, women had a higher prevalence of loneliness than men (21.0% vs. 11.3%), and younger adults had the highest prevalence of loneliness (18 to 25 years: 31.7%) compared to the other age groups., Discussion and Conclusions: During the COVID-19 pandemic, loneliness increased in almost every population subgroup in Bavaria. Further studies are needed to examine whether this development is temporary or represents a long-term effect even after the measures to prevent the spread of COVID-19 have been lifted., (© 2024. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

The collagen superfamily, as the major structural component of the extracellular matrix, encompasses 28 distinct subtypes, with type-I and -III forming fibrils crucial for the matrix scaffold. During collagen biogenesis, trimers of type-I and -III procollagen are secreted into the extracellular matrix. The N- and C-terminal propeptides of these trimers are proteolytically cleaved from procollagen during secretion, initiating collagen fibril formation. The propeptides are released into extracellular space and, therefore, have been used to quantify collagen biogenesis. But high-throughput methods for the quantification of these biomarkers are still lacking. This study presents a state-of-the-art multiplexed approach for the simultaneous quantification of PINP, PICP, PIIINP and PIIICP from cell culture supernatants. The ability of targeted proteomics to quantify these propeptides from cell culture samples was assessed in this study. Using tryptic digestion and solid phase extraction, we were able to accurately quantify precollagen propeptides in a range of 3-1000 ng/mL. The assay showed an average inter-assay variance of 6.86 % with an overall recovery ranging from 92 to 98 %. The assay was validated using recombinant protein standards diluted in surrogate matrix and tested using transforming growth factor β1 mediated induction of normal human dermal fibroblasts. In summary, the assay presented in this paper offers a novel, robust, and precise high-throughput method for measuring human collagen propeptides in cell culture supernatants, empowering researchers to assess collagen biogenesis effectively in in vitro experiments., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Myocardial infarction (MI) is a cardiovascular disease caused by necrosis of the myocardium, which places a heavy burden on patients. In France, the proportion of daily smokers remains high, reaching at 25.5% in 2020. We evaluated the impact of smoking reduction scenarios on the projection of MI prevalence, mean age of incident cases and number of MI prevented cases until 2035., Methods and Results: The French government has introduced smoking cessation policies that have led to an annual decrease in smoking prevalence. Based on this annual decline, we implemented three scenarios (SC) simulating an annual decrease in the proportion of smokers aged over 35 (SC1: 1%, ie, natural evolution without intervention, SC2: 2%, SC3: 9.87%) and a fourth scenario (SC4) in which there is a complete discontinuation of smoking from 2024 onwards using MI hospitalization and demographic data, estimations for the proportion of daily smokers between 35 and 95 years and multi-state models. Between 2023 and 2035, MI prevalence increased from 3.18% to 4.23% in males and from 1.00% to 1.46% in females under SC1. MI prevalence was equal to 4.21%, 4.06%, and 3.82% in males and 1.45%, 1.40%, and 1.34% in females in 2035 according to SC2, SC3, and SC4, respectively. Compared with SC1, 0.68% MI cases would be prevented with SC2, 4.52% with SC3 and 10.34% with SC4, with almost half of cases being prevented before 65 years of age. The increase in the mean age of MI incident cases ranged from 3 to 4 years among males and from 1 to 2 years among females., Conclusion: While reducing tobacco use could substantially reduce the number of MI cases prevented, its prevalence would continue to increase due to the ageing population. An integrated prevention strategy that includes the leading cardiovascular risk factors should more efficiently reduce the future burden of MI., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024 Kuhn et al.)

Amid the SARS-CoV-2 pandemic, concerns surfaced regarding the spread of the virus to wildlife. Switzerland lacked data concerning the exposure of free-ranging animals to SARS-CoV-2 during this period. This study aimed to investigate the potential exposure of Swiss free-ranging wildlife to SARS-CoV-2. From 2020 to 2023, opportunistically collected samples from 712 shot or found dead wild mustelids (64 European stone and pine martens, 13 European badgers, 10 European polecats), canids (449 red foxes, 41 gray wolves, one golden jackal) and felids (56 Eurasian lynx, 18 European wildcats), as well as from 45 captured animals (39 Eurasian lynx, 6 European wildcats) were tested. A multi-step serological approach detecting antibodies to the spike protein receptor binding domain (RBD) and N-terminal S1 subunit followed by surrogate virus neutralization (sVNT) and pseudotype-based virus neutralization assays against different SARS-CoV-2 variants was performed. Additionally, viral RNA loads were quantified in lung tissues and in oronasal, oropharyngeal, and rectal swabs by reverse transcription polymerase chain reactions (RT-qPCRs). Serologically, SARS-CoV-2 exposure was confirmed in 14 free-ranging Swiss red foxes (prevalence 3.1%, 95% CI: 1.9-5.2%), two Eurasian lynx (2.2%, 95% CI: 0.6-7.7%), and one European wildcat (4.2%, 95% CI: 0.2-20.2%). Two positive foxes exhibited neutralization activity against the BA.2 and BA.1 Omicron variants. No active infection (viral RNA) was detected in any animal tested. This is the first report of SARS-CoV-2 antibodies in free-ranging red foxes, Eurasian lynx, and European wildcats worldwide. It confirms the spread of SARS-CoV-2 to free-ranging wildlife in Switzerland but does not provide evidence of reservoir formation. Our results underscore the susceptibility of wildlife populations to SARS-CoV-2 and the importance of understanding diseases in a One Health Concept.

Competing Interests: Die Autoren geben an, dass kein Interessenskonflikt besteht.

The pond loach (Misgurnus anguillicaudatus) is an important aquaculture freshwater species, used as an ornamental fish, food source for humans and angling bait. Pond loaches are resistant to fasting and extreme environmental conditions, including temperature and low oxygen levels. Little is known about how these factors affect the feeding physiology and the endocrine regulation of feeding of loaches. In this study, we examined the effects of fasting, as well as increased temperature and decreased oxygen levels on food intake and transcript levels of appetite regulators. Fasted fish had lower blood glucose levels, and lower expression levels of intestine CCK and PYY, and brain CART1, but had higher levels of brain orexin and ghrelin than fed fish. Fish held at 30 °C had higher food intake, glucose levels, and mRNA levels of intestine CCK and PYY, and brain CART2, but lower brain orexin levels than fish at 20 °C. Fish held at low oxygen levels had a lower food intake, higher intestine CCKa and ghrelin, and brain orexin, CART2 and ghrelin mRNA expression levels than fish held at high O 2 levels. Our results suggest that fasting and high temperatures increase the expression of orexigenic and anorexigenic factors respectively, whereas the increase in expression of both orexigenic and anorexigenic factors in low O 2 environments might not be related to their role in feeding, but possibly to protection from tissue damage. The results of our study might shed new light on how pond loaches are able to cope with extreme environmental conditions such as low food availability, extreme temperatures and hypoxia., 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 © 2024 Elsevier Inc. All rights reserved.)

Hyperpolarization has become a powerful tool to enhance the sensitivity of magnetic resonance. A universal tool to hyperpolarize small molecules in solution, however, has not yet emerged. Transferring hyperpolarized, labile protons between molecules is a promising approach towards this end. Therefore, hydrogenative parahydrogen-induced polarization (PHIP) was recently proposed as a source to polarize exchanging protons (PHIP-X). Here, we identified four key components that govern PHIP-X: adding the spin order, polarizing the labile proton, proton exchange, and polarization of the target nucleus. We investigated the last two steps experimentally and using simulations. We found optimal exchange rates and field cycling methods to polarize the target molecules. We also investigated the influence of spin relaxation of exchanging protons on the target polarization. It was found experimentally that transferring the polarization from protons directly bound to the target X-nucleus (here 13 C) of lactate and methanol using a pulse sequence was more efficient than applying a corresponding sequence to the labile proton. Furthermore, varying the concentrations of the transfer and target molecules yielded a distinct maximum 13 C polarization. We believe this work will further help to understand and optimize PHIP-X towards a broadly applicable hyperpolarization method., (© 2024. The Author(s).)

Objective: Subclinical hyperthyroidism (SCH) is common and associated with atrial fibrillation (AF) risk in the elderly. Current guidelines rely on a low level of evidence., Methods: Randomized clinical trial including patients 50 years and older, with TSH <0.4 mU/L and normal thyroid hormone concentrations. All patients showed autonomy on thyroid scan. They were randomized either to receive radioiodine (I131) or to be monitored and treated only if they underwent AF or evolved towards overt hyperthyroidism. Primary outcome was the onset of new AF. Secondary outcomes were treatment-induced hypothyroidism rate and health-related quality of life., Results: 144 patients (mean age 65.3±8.9y, 76% female) were randomized, 74 to surveillance and 70 to treatment. Four patients in the surveillance group and one in the treatment group developed AF (p=0.238). However, the patient who developed AF in the treatment group maintained TSH <0.4 mU/L at AF onset. A post-hoc analysis was carried out and showed that when normalization of TSH was considered, the risk of AF was significantly reduced (p=0.0003). In the surveillance group, several patients showed no classical characteristics associated with AF risk, including age>65y or TSH<0.1mU/L. Of 94 patients treated using radioiodine, 25% developed hypothyroidism during follow-up., Conclusions: Due to recruitment difficulties this study failed to demonstrate that SCH treatment can reduce significantly the incidence of AF in patients older than 50 years with thyroid autonomy even if all the patients who developed AF maintained TSH <0.4 mU/L. This result must be balanced with the increased risk of radioiodine-induced hypothyroidism.

Adults with no knowledge of sign languages can perceive distinctive markers that signal event boundedness (telicity), suggesting that telicity is a cognitively natural semantic feature that can be marked iconically (Strickland et al., 2015). This study asks if non-signing children (5-year-olds) can also link telicity to iconic markers in sign. Experiment 1 attempted three close replications of Strickland et al. (2015) and found only limited success. However, Experiment 2 showed that children can both perceive the relevant visual feature and can succeed at linking the visual property to telicity semantics when allowed to filter their answer through their own linguistic choices. Children's performance demonstrates the cognitive naturalness and early availability of the semantics of telicity, supporting the idea that telicity helps guide the language acquisition process., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate., Methods: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region., Results: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression., Conclusions: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Nuclear migration through narrow constrictions is important for development, metastasis, and proinflammatory responses. Studies performed in tissue culture cells have implicated linker of nucleoskeleton and cytoskeleton (LINC) complexes, microtubule motors, the actin cytoskeleton, and nuclear envelope repair machinery as important mediators of nuclear movements through constricted spaces. However, little is understood about how these mechanisms operate to move nuclei in vivo. In Caenorhabditis elegans larvae, six pairs of hypodermal P cells migrate from lateral to ventral positions through a constricted space between the body wall muscles and the cuticle. P-cell nuclear migration is mediated in part by LINC complexes using a microtubule-based pathway and by an independent CDC-42/actin-based pathway. However, when both LINC complex and actin-based pathways are knocked out, many nuclei still migrate, suggesting the existence of additional pathways. Here, we show that FLN-2 functions in a third pathway to mediate P-cell nuclear migration. The predicted N-terminal actin-binding domain in FLN-2 that is found in canonical filamins is dispensable for FLN-2 function; this and structural predictions suggest that FLN-2 does not function as a filamin. The immunoglobulin-like repeats 4-8 of FLN-2 were necessary for P-cell nuclear migration. Furthermore, in the absence of the LINC complex component unc-84, fln-2 mutants had an increase in P-cell nuclear rupture. We conclude that FLN-2 functions to maintain the integrity of the nuclear envelope in parallel with the LINC complex and CDC-42/actin-based pathways to move P-cell nuclei through constricted spaces., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America. 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.)

The functionality and efficiency of proteins within a biological membrane are highly dependent on both the membrane lipid composition and the physiochemical properties of the solution. Lipid mesophases are directly influenced by changes in temperature, pH, water content or due to individual properties of single lipids such as photoswitchability. In this work, we were able to induce light- and temperature-driven mesophase transitions in a model membrane system containing a mixture of 1,2-dipalmitoyl-phosphatidylcholine phospholipids and azobenzene amphiphiles. We observed reversible and reproducible transitions between the lamellar and Pn3m cubic phase after illuminating the sample for 5 min with light of 365 and 455 nm wavelengths, respectively, to switch between the cis and trans states of the azobenzene N=N double bond. These light-controlled mesophase transitions were found for mixed complexes with up to 20% content of the photosensitive molecule and at temperatures below the gel-to-liquid crystalline phase transition temperature of 33°C. Our results demonstrate the potential to design bespoke model systems to study the response of membrane lipids and proteins upon changes in mesophase without altering the environment and thus provide a possible basis for drug delivery systems., (open access.)

Classical statistical analysis of data can be complemented or replaced with data analysis based on machine learning. However, in certain disciplines, such as education research, studies are frequently limited to small datasets, which raises several questions regarding biases and coincidentally positive results. In this study, we present a refined approach for evaluating the performance of a binary classification based on machine learning for small datasets. The approach includes a non-parametric permutation test as a method to quantify the probability of the results generalising to new data. Furthermore, we found that a repeated nested cross-validation is almost free of biases and yields reliable results that are only slightly dependent on chance. Considering the advantages of several evaluation metrics, we suggest a combination of more than one metric to train and evaluate machine learning classifiers. In the specific case that both classes are equally important, the Matthews correlation coefficient exhibits the lowest bias and chance for coincidentally good results. The results indicate that it is essential to avoid several biases when analysing small datasets using machine learning., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Steinert 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.)

Background: How best to improve the early detection of autism spectrum disorder (ASD) is the subject of significant controversy. Some argue that universal ASD screeners are highly accurate, whereas others argue that evidence for this claim is insufficient. Relatedly, there is no clear consensus as to the optimal role of screening for making referral decisions for evaluation and treatment. Published screening research can meaningfully inform these questions-but only through careful consideration of children who do not complete diagnostic follow-up., Methods: We developed two simulation models that re-analyze the results of a large-scale validation study of the M-CHAT-R/F by Robins et al. (2014, Pediatrics, 133, 37). Model #1 re-analyzes screener accuracy across six scenarios, each reflecting different assumptions regarding loss to follow-up. Model #2 builds on this by closely examining differential attrition at each point of the multi-step detection process., Results: Estimates of sensitivity ranged from 40% to 94% across scenarios, demonstrating that estimates of accuracy depend on assumptions regarding the diagnostic status of children who were lost to follow-up. Across a range of plausible assumptions, data also suggest that children with undiagnosed ASD may be more likely to complete follow-up than children without ASD, highlighting the role of clinicians and caregivers in the detection process., Conclusions: Using simulation modeling as a quantitative method to examine potential bias in screening studies, analyses suggest that ASD screening tools may be less accurate than is often reported. Models also demonstrate the critical importance of every step in a detection process-including steps that determine whether children should complete an additional evaluation. We conclude that parent and clinician decision-making regarding follow-up may contribute more to detection than is widely assumed., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Candida parapsilosis has recently emerged as a major threat due to the worldwide emergence of fluconazole-resistant strains causing clonal outbreaks in hospitals and poses a therapeutic challenge due to the limited antifungal armamentarium. Here, we used precise genome editing using CRISPR-Cas9 to gain further insights into the contribution of mutations in ERG11 , ERG3 , MRR1 , and TAC1 genes and the influence of allelic dosage to antifungal resistance in C. parapsilosis . Seven of the most common amino acid substitutions previously reported in fluconazole-resistant clinical isolates (including Y132F in ERG11 ) were engineered in two fluconazole-susceptible C. parapsilosis lineages (ATCC 22019 and STZ5). Each mutant was then challenged in vitro against a large array of antifungals, with a focus on azoles. Any possible change in virulence was also assessed in a Galleria mellonella model. We successfully generated a total of 19 different mutants, using CRISPR-Cas9. Except for R398I ( ERG11 ), all remaining amino acid substitutions conferred reduced susceptibility to fluconazole. However, the impact on fluconazole in vitro susceptibility varied greatly according to the engineered mutation, the stronger impact being noted for G583R acting as a gain-of-function mutation in MRR1 . Cross-resistance with newer azoles, non-medical azoles, but also non-azole antifungals such as flucytosine, was occasionally noted. Posaconazole and isavuconazole remained the most active in vitro . Except for G583R, no fitness cost was associated with the acquisition of fluconazole resistance. We highlight the distinct contributions of amino acid substitutions in ERG11 , ERG3 , MRR1 , and TAC1 genes to antifungal resistance in C. parapsilosis .

Functionalized nanoparticles have been developed for use in nanomedicines for treating life threatening diseases including various cancers. To ensure safe use of these new nanoscale reagents, various assays for biocompatibility or cytotoxicity in vitro using cell lines often serve as preliminary assessments prior to in vivo animal testing. However, many of these assays were designed for soluble, colourless materials and may not be suitable for coloured, non-transparent nanoparticles. Moreover, cell lines are not always representative of mammalian organs in vivo. In this work, we use non-invasive impedance sensing methods with organotypic human liver HepaRG cells as a model to test the toxicity of PEG-Fe 3 O 4 magnetic nanoparticles. We also use Coherent anti-Stokes Raman Spectroscopic (CARS) microscopy to monitor the formation of lipid droplets as a parameter to the adverse effect on the HepaRG cell model. The results were also compared with two commercial testing kits (PrestoBlue and ATP) for cytotoxicity. The results suggested that the HepaRG cell model can be a more realistic model than commercial cell lines while use of impedance monitoring of Fe 3 O 4 nanoparticles circumventing the uncertainties due to colour assays. These methods can play important roles for scientists driving towards the 3Rs principle - Replacement, Reduction and Refinement., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Longer durations of warmer weather, altered precipitation, and modified streamflow patterns driven by climate change are expected to impair ecosystem resilience, exposing freshwater ecosystems and their biota to a severe threat worldwide. Understanding the spatio-temporal temperature variations and the processes governing thermal heterogeneity within the riverscape are essential to inform water management and climate adaptation strategies. We combined UAS-based imagery data of aquatic habitats with meteorological, hydraulic, river morphology and water quality data to investigate how key factors influence spatio-temporal stream heterogeneity on a diurnal basis within different thermal regions of a large recently restored Danube floodplain. Diurnal temperature ranges of aquatic habitats were larger than expected and ranged between 14.2 and 28.0 °C (mean = 20.7 °C), with peak median temperatures (26.1 °C) around 16:00 h. The observed temperature differences in timing and amplitude among thermal regions were unexpectedly high and created a mosaic pattern of temperature heterogeneity. For example, cooler groundwater-influenced thermal regions provided several cold water patches (CWP, below 19.0 °C) and potential cold water refuges (CWRs) around 12:00 h, at the time when other habitats were warmer than 21.0 °C, exceeding the ecological threshold (20.0 °C) for key aquatic species. Within the morphological complexity of the restored floodplain, we identified groundwater influence, shading and river morphology as the key processes driving thermal riverscape heterogeneity. Promoting stream thermal refuges will become increasingly relevant under climate change scenarios, and river restoration should consider both measures to physically prevent habitat from excessive warming and measures to improve connectivity that meet the temperature requirements of target species for conservation. This requires restoring mosaics of complex and dynamic temperature riverscapes., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: After an acute infection with the corona virus 10-20% of those affected suffer from ongoing or new symptoms. A causal therapy for the phenomenon known as Long/Post-COVID is still lacking and specific therapies addressing psychosocial needs of these patients are imperatively needed. The aim of the PsyLoCo-study is developing and piloting a psychotherapeutic manual, which addresses Long/Post-COVID-related psychosocial needs and supports in coping with persistent bodily symptoms as well as depressive or anxiety symptoms., Methods and Analysis: This pilot trial implements a multi-centre, 2-arm (N=120; allocation ratio: 1:1), parallel group, randomised controlled design. The pilot trial is designed to test the feasibility and estimate the effect of 1) a 12-session psychotherapeutic intervention compared to 2) a wait-list control condition on psychosocial needs as well as bodily and affective symptoms in patients suffering from Long/Post-COVID. The intervention uses an integrative, manualized, psychotherapeutic approach. The primary study outcome is health-related quality of life. Outcome variables will be assessed at three timepoints, pre-intervention (t1), post-intervention (t2) and three months after completed intervention (t3). To determine the primary outcome, changes from t1 to t2 are examined. The analysis will be used for the planning of the RCT to test the efficacy of the developed intervention., Discussion: The pilot study will evaluate a 12-session treatment manual for Long/Post-COVID sufferers and the therapy components it contains. The analysis will provide insights into the extent to which psychotherapeutic treatment approaches improve the symptoms of Long/Post-COVID sufferers. The treatment manual is designed to be carried out by psychotherapists as well as people with basic training in psychotherapeutic techniques. This approach was chosen to enable a larger number of practitioners to provide therapeutic support for Long/Post-COVID patients. After completion of the pilot study, it is planned to follow up with a randomized controlled study and to develop a treatment guideline for general practitioners and interested specialists., Trial Registration: The pilot trial has been registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien; Trial-ID: DRKS00030866; URL: https://drks.de/search/de/trial/DRKS00030866) on March 7, 2023., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Allwang, Frank, Bruckmann, Dinkel, Binneboese, Wallis, Elgner, Giel, Schurr, Gündel, Wedekind, Kuhn, Lahmann, Müller, Beckmann, Massag, Mikolajczyk and Junne.)

Telehealth was instrumental in NC Medicaid's ability to pro-vide health care during the COVID-19 pandemic. Analyses of utilization and survey data and interviews with key Medicaid payors and providers reveal trends in beneficiary access to and utilization of services, presenting NC Medicaid with opportunities to build upon lessons learned., Competing Interests: Acknowledgments: The authors have no conflicts of interest to disclose. The authors would like to acknowledge Dr. Marisa Domino and the Cecil G. Sheps Center for Health Services Research for their support in developing this article., (Copyright ©2024 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.)

Background: Deep brain stimulation (DBS) of the thalamus can effectively reduce tics in severely affected patients with Tourette syndrome (TS). Its effect on cortical oscillatory activity is currently unknown., Objective: We assessed whether DBS modulates beta activity at fronto-central electrodes. We explored concurrent EEG sources and probabilistic stimulation maps., Methods: Resting state EEG of TS patients treated with thalamic DBS was recorded in repeated DBS-on and DBS-off states. A mixed linear model was employed for statistical evaluation. EEG sources were estimated with eLORETA. Thalamic probabilistic stimulation maps were obtained by assigning beta power difference scores (DBS-on minus DBS-off) to stimulation sites., Results: We observed increased beta power in DBS-on compared to DBS-off states. Modulation of cortical beta activity was localized to the midcingulate cortex. Beta modulation was more pronounced when stimulating the thalamus posteriorly, peaking in the ventral posterior nucleus., Conclusion: Thalamic DBS in TS patients modulates beta frequency oscillations presumably important for sensorimotor function and relevant to TS pathophysiology., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Xylosyltransferase-I and -II (XT-I, -II) possess a central role during the glycosylation of proteoglycans (PGs). They catalyze the formation of an O-glycosidic bond between the xylosyl residue of uridinediphosphate-xylose and the core protein of a PG. Thereafter, three following glycosyltransferases lead to the generation of a tetrasaccharide linker, which connects the PG core protein to the respective glycosaminoglycan. The selective quantification of XT-I and XT-II activity is of biological and clinical interest due to their association with fibrotic processes and skeletal dysplasia. There is no assay available to date that simultaneously determines the activity of the two XT isoforms. Although an XT-I selective UPLC MS/MS-based assay was published by Fischer et al., in 2021, the determination of XT-II activity can only be performed simultaneously by the improved assay presented here. To establish the assay, two synthetic peptides, selectively xylosylated by the respective isoform, were identified and the associated measurement parameters for the mass spectrometer were optimized. In addition, the quantitative range of the xylosylated peptides were validated, and the incubation time of the enzyme reaction was optimized for cell culture samples and human sera. The specific enzyme kinetics (K M and V max ) of the respective XT isoform for the two peptides were also determined. Subsequently, a mathematical model was developed, allowing the simultaneous determination of XT-I and XT-II activity from the chromatographic results. Summarized, a mass spectrometric method suitable for the simultaneous analysis of XT-I and XT-II activity in cell culture lysates, supernatants and human sera was successfully developed., 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: 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.

Youth with intellectual and/or developmental disabilities (IDD) often struggle with depression and anxiety, which adversely impacts transition to adulthood. Integrated behavioral health care coordination, wherein care coordinators and behavioral health specialists collaborate to provide systematic, cost-effective, patient-centered care, is a promising strategy to improve access to behavioral health services and address factors that impact transition to adulthood, including depression/anxiety symptoms. Current care coordination models (e.g., Title V Maternal and Child Health Bureau [MCHB]) do not include behavioral health services. The CHECK (Coordinated HealthCarE for Complex Kids) mental health model, hereby refined and renamed BEhavioral Health Stratified Treatment (B.E.S.T.), is a behavioral health intervention delivery program designed for integration into care coordination programs. This study aims to determine whether an integrated behavioral health care coordination strategy (i.e., MCHB care coordination plus B.E.S.T.) would be more acceptable and lead to better youth health and transition outcomes, relative to standard care coordination (i.e., MCHB care coordination alone). Results would guide future investment in improving outcomes for youth with IDD. This study is a two-arm randomized clinical trial of 780 transition-aged youth with IDD (13-20 years) to evaluate the comparable efficacy of MCHB Care Coordination alone vs. MCHB Care Coordination plus B.E.S.T. on the following outcomes: 1) decreased symptoms and episodes of depression and anxiety over time; 2) improved health behaviors, adaptive functioning and health related quality of life; 3) increased health care transition (HCT) readiness; and 4) improved engagement and satisfaction with care coordination among stakeholders., 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 Elsevier Inc. All rights reserved.)

Purpose: Deliberate reflection on initial diagnosis has been found to repair diagnostic errors. We investigated the effectiveness of teaching students to use deliberate reflection on future cases and whether their usage would depend on their perception of case difficulty., Method: One-hundred-nineteen medical students solved cases either with deliberate-reflection or without instructions to reflect. One week later, all participants solved six cases, each with two equally likely diagnoses, but some symptoms in the case were associated with only one of the diagnoses ( discriminating features ). Participants provided one diagnosis and subsequently wrote down everything they remembered from it. After the first three cases, they were told that the next three would be difficult cases. Reflection was measured by the proportion of discriminating features recalled (overall; related to their provided diagnosis; related to alternative diagnosis)., Results: The deliberate-reflection condition recalled more features for the alternative diagnosis than the control condition ( p  = .013) regardless of described difficulty. They also recalled more features related to their provided diagnosis on the first three cases ( p  = .004), but on the last three cases (described as difficult), there was no difference., Conclusion: Learning deliberate reflection helped students engage in more reflective reasoning when solving future cases.

Background: Internationally, a variety of definitions for public health interventions (PHI) exist. In the German-speaking countries, however, a definition is still outstanding. Therefore, the aim of this study was to derive consensus criteria for the definition of PHI from the expert perspective of science and practice., Methods: A Delphi survey with two online rounds was conducted from December 2022 to February 2023. Six criteria were formulated by a working group and posed for consensus: 1) the intention of the intervention, 2) potential conflicts of interest of the initiators of the intervention, 3) primary vs. secondary/tertiary prevention, 4) costs, 5) targeting, and 6) the reach of the intervention. In both Delphi rounds, experts from academia and practice were recruited through relevant networks and associations throughout the German-speaking world. The judgments were asked about standardized rating scales with the possibility of open justification., Results: In the first Delphi round, n = 52 and in the second round n = 43 experts from research, care and administration/management in health care participated. Consensus was reached on four of the six criteria after the second Delphi round: the intention of the intervention, possible conflicts of interest of the initiators of the intervention, primary vs. secondary/tertiary prevention, and the scope of the intervention. From the perspective of the experts interviewed, these are the criteria that distinguish PHI., Discussion and Conclusion: Based on the consensus criteria, PHI can be defined more concretely. Thus, the results contribute to a better inter- and transdisciplinary understanding. Ideally, the criteria will make it easier to assign interventions to the public health sector in the future, even if a precise examination will be necessary in individual cases, among other things because the experts disagreed on the criteria of costs and how to address the target group., (Copyright © 2023. Published by Elsevier GmbH.)

Neonicotinoids, systemic insecticides that are distributed into all plant tissues and protect against pests, have become a common part of crop production, but can unintentionally also affect non-target organisms, including pollinators. Such effects can be direct effects from insecticide exposure, but neonicotinoids can affect plant physiology, and effects could therefore also be indirectly mediated by changes in plant phenology, attractiveness and nutritional value. Under controlled greenhouse conditions, we tested if seed treatment with the neonicotinoid clothianidin affected oilseed rape's production of flower resources for bees and the content of the secondary plant products glucosinolates that provide defense against herbivores. Additionally, we tested if seed treatment affected the attractiveness of oilseed rape to flower visiting bumblebees, using outdoor mesocosms. Flowers and leaves of clothianidin-treated plants had different profiles of glucosinolates compared with untreated plants. Bumblebees in mesocosms foraged slightly more on untreated plants. Neither flower timing, flower size nor the production of pollen and nectar differed between treatments, and therefore cannot explain any preference for untreated oilseed rape. We instead propose that this small but significant preference for untreated plants was related to the altered glucosinolate profile caused by clothianidin. Thereby, this study contributes to the understanding of the complex relationships between neonicotinoid-treated crops and pollinator foraging choices, by suggesting a potential mechanistic link by which insecticide treatment can affect insect behavior., (© 2023. The Author(s).)

When choosing between rewards that differ in temporal proximity (intertemporal choice), human preferences are typically stable, constituting a clinically relevant transdiagnostic trait. Here we show, in female and male human patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder, that long-term chronic (but not phasic) DBS disrupts intertemporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of intertemporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not because of range restriction, the presence of obsessive-compulsive disorder symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human NAcc region to intertemporal preference stability over time. SIGNIFICANCE STATEMENT Choosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation of the human anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder disrupts the stability of intertemporal preferences. These findings show that chronic stimulation of one of the brain's central motivational hubs can disrupt preferences thought to depend on this circuit., (Copyright © 2023 the authors.)

Background: Healthcare-associated infections in long-term care are associated with substantial morbidity and mortality. While infection prevention and control (IPC) guidelines are well-defined in the acute care setting, evidence of effectiveness for long-term care facilities (LTCF) is missing. We therefore performed a systematic literature review to examine the effect of IPC measures in the long-term care setting., Methods: We systematically searched PubMed and Cochrane libraries for articles evaluating the effect of IPC measures in the LTCF setting since 2017, as earlier reviews on this topic covered the timeframe up to this date. Cross-referenced studies from identified articles and from mentioned earlier reviews were also evaluated. We included randomized-controlled trials, quasi-experimental, observational studies, and outbreak reports. The included studies were analyzed regarding study design, type of intervention, description of intervention, outcomes and quality. We distinguished between non-outbreak and outbreak settings., Results: We included 74 studies, 34 (46%) in the non-outbreak setting and 40 (54%) in the outbreak setting. The most commonly studied interventions in the non-outbreak setting included the effect of hand hygiene (N = 10), oral hygiene (N = 6), antimicrobial stewardship (N = 4), vaccination of residents (N = 3), education (N = 2) as well as IPC bundles (N = 7). All but one study assessing hand hygiene interventions reported a reduction of infection rates. Further successful interventions were oral hygiene (N = 6) and vaccination of residents (N = 3). In outbreak settings, studies mostly focused on the effects of IPC bundles (N = 24) or mass testing (N = 11). In most of the studies evaluating an IPC bundle, containment of the outbreak was reported. Overall, only four articles (5.4%) were rated as high quality., Conclusion: In the non-outbreak setting in LTCF, especially hand hygiene and oral hygiene have a beneficial effect on infection rates. In contrast, IPC bundles, as well as mass testing seem to be promising in an outbreak setting., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Exposure to particulate matter (PM) has been associated with a wide range of adverse health effects, but it is still unclear how particles from various transport modes differ in terms of toxicity and associations with different human health outcomes. This literature review aims to summarize toxicological and epidemiological studies of the effect of ultrafine particles (UFPs), also called nanoparticles (NPs, <100 nm), from different transport modes with a focus on vehicle exhaust (particularly comparing diesel and biodiesel) and non-exhaust as well as particles from shipping (harbor), aviation (airport) and rail (mainly subway/underground). The review includes both particles collected in laboratory tests and the field (intense traffic environments or collected close to harbor, airport, and in subway). In addition, epidemiological studies on UFPs are reviewed with special attention to studies aimed at distinguishing the effects of different transport modes. Results from toxicological studies indicate that both fossil and biodiesel NPs show toxic effects. Several in vivo studies show that inhalation of NPs collected in traffic environments not only impacts the lung, but also triggers cardiovascular effects as well as negative impacts on the brain, although few studies compared NPs from different sources. Few studies were found on aviation (airport) NPs, but the available results suggest similar toxic effects as traffic-related particles. There is still little data related to the toxic effects linked to several sources (shipping, road and tire wear, subway NPs), but in vitro results highlighted the role of metals in the toxicity of subway and brake wear particles. Finally, the epidemiological studies emphasized the current limited knowledge of the health impacts of source-specific UFPs related to different transport modes. This review discusses the necessity of future research for a better understanding of the relative potencies of NPs from different transport modes and their use in health risk assessment., 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 Inc. All rights reserved.)

Understanding scientific concepts is a fundamental aim of science education. Conceptual understanding can be fostered through inquiry learning with experiments. However, during the Covid-19 pandemic school closures hands-on experiments could hardly be realized. Fortunately, digital technologies allow for conducting experiments virtually by using interactive simulations or observing video recordings of hands-on experiments. In the present study, 154 seventh graders in remote schooling were involved in inquiry learning using either a combination of virtual and video experiments in two different orders or only virtual experiments. We hypothesized that in general inquiry learning fosters students' conceptual understanding in physics, which could be confirmed. Moreover, we expected the combinations to be more effective than learning with virtual experiments only due to the complementary roles of the prior, which was, however, not the case. We conclude that virtual and video experiments can be recommended to teachers if hands-on experimentation is not possible., Competing Interests: None., (© 2023 The Authors.)

Following the reaction of biological membranes to external stimuli reveals fundamental insights into cellular function. Here, self-assembled lipid monolayers act as model membranes containing photoswitchable azobenzene glycolipids for investigating structural response during isomerization by combining Langmuir isotherms with X-ray scattering. Controlled in-situ trans/cis photoswitching of the azobenzene N = N double bond alters the DPPC monolayer structure, causing reproducible changes in surface pressure and layer thickness, indicating monolayer reorientation. Interestingly, for monolayers containing azobenzene glycolipids, along with the expected DPPC phase transitions an additional discontinuity is observed. The associated reorintation represents a crossover point, with the surface pressure and layer thickness changing in opposite directions above and below. This is evidence that the azobenzene glycolipids themselves change orientation within the monolayer. Such behaviour suggests that azobenzene glycolipids can act as a bidirectional switch in DPPC monolayers providing a tool to investigate membrane structure-function relationships in depth., (© 2023. The Author(s).)

In this article, we provide detailed protocols on using optogenetic dimerizers to acutely perturb activities of guanine nucleotide exchange factors (GEFs) specific to Ras, Rac or Rho small GTPases of the migratory networks in various mammalian and amoeba cell lines. These GEFs are crucial components of signal transduction networks which link upstream G-protein coupled receptors to downstream cytoskeletal components and help cells migrate through their dynamic microenvironment. Conventional approaches to perturb and examine these signaling and cytoskeletal networks, such as gene knockout or overexpression, are protracted which allows networks to readjust through gene expression changes. Moreover, these tools lack spatial resolution to probe the effects of local network activations. To overcome these challenges, blue light-inducible cryptochrome- and LOV domain-based dimerization systems have been recently developed to control signaling or cytoskeletal events in a spatiotemporally precise manner. We illustrate that, within minutes of global membrane recruitment of full-length GEFs or their catalytic domains only, widespread increases or decreases in F-actin rich protrusions and cell size occur, depending on the particular node in the networks targeted. Additionally, we demonstrate localized GEF recruitment as a robust assay system to study local network activation-driven changes in polarity and directed migration. Altogether, these optical tools confirmed GEFs of Ras superfamily GTPases as regulators of cell shape, actin dynamics, and polarity. Furthermore, this optogenetic toolbox may be exploited in perturbing complex signaling interactions in varied physiological contexts including mammalian embryogenesis., 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., (Copyright © 2023 Pal, Lin, Zhan, Banerjee, Kuhn, Providence and Devreotes.)

Objective: Part C Early Intervention (EI) services have been shown to reduce autism symptoms and promote healthy development among young children. However, EI participation remains low, particularly among children from structurally marginalized communities. We investigated whether family navigation (FN) improved EI initiation following positive primary care screening for autism compared to conventional care management (CCM)., Methods: We conducted a randomized clinical trial among 339 families of children (ages 15-27 months) who screened as having an increased likelihood for autism at 11 urban primary care sites in 3 cities. Families were randomized to FN or CCM. Families in the FN arm received community-based outreach from a navigator trained to support families to overcome structural barriers to autism evaluation and services. EI service records were obtained from state or local agencies. The primary outcome of this study, EI service participation, was measured as the number of days from randomization to the first EI appointment., Results: EI service records were available for 271 children; 156 (57.6%) children were not engaged with EI at study enrollment. Children were followed for 100 days after diagnostic ascertainment or until age 3, when Part C EI eligibility ends; 65 (89%, 21 censored) children in the FN arm and 50 (79%, 13 censored) children in the CCM arm were newly engaged in EI. In Cox proportional hazards regression, families receiving FN were approximately 54% more likely to engage EI than those receiving CCM (1.54 (95% confidence interval: 1.09-2.19), P = .02)., Conclusions: FN improved the likelihood of EI participation among urban families from marginalized communities., Competing Interests: Declaration of Competing Interest Amanda Bennett reports a relationship with National Institute of Mental Health that includes: funding grants. Amanda Bennett reports a relationship with Autism Speaks that includes: funding grants. Nathan Blum reports a relationship with Health Resources and Services Administration that includes: funding grants. Nathan Blum reports a relationship with Elsevier that includes: consulting or advisory. Sarabeth Broder-Fingert reports a relationship with EarliTech Dx, Inc. that includes: board membership. Emily Feinberg reports a relationship with National Institutes of Health that includes: funding grants. Emily Feinberg reports a relationship with Richard and Susan Smith Family Foundation that includes: funding grants. Emily Feinberg reports a relationship with Klarman Family Foundation that includes: funding grants. Ada Fenick reports a relationship with Bristol Myers Squibb Co that includes: equity or stocks. Carol Weitzman reports a relationship with Journal of Developmental and Behavioral Pediatrics that includes: consulting or advisory. Carol Weitzman reports a relationship with Up to Date that includes: consulting or advisory. Carol Weitzman reports a relationship with Helios that includes: board membership. Carol Weitzman reports a relationship with Meliora Health that includes: board membership. Dr. Bennett’s spouse is employed at Pfizer but not in a field relevant to this research., (Copyright © 2023 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation., Materials and Methods: To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase., Results: 36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase., Conclusions: In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.

Arthrofibrosis following total knee arthroplasty is a fibroproliferative joint disorder marked by dysregulated biosynthesis of extracellular matrix proteins, such as collagens and proteoglycans. The underlying cellular events remain incompletely understood. Myofibroblasts are highly contractile matrix-producing cells characterized by increased alpha-smooth muscle actin expression and xylosyltransferase-I (XT-I) secretion. Human XT-I has been identified as a key mediator of arthrofibrotic remodeling. Primary fibroblasts from patients with arthrofibrosis provide a useful in vitro model to identify and characterize disease regulators and potential therapeutic targets. This study aims at characterizing primary synovial fibroblasts from arthrofibrotic tissues (AFib) regarding their molecular and cellular phenotype by utilizing myofibroblast cell culture models. Compared to synovial control fibroblasts (CF), AFib are marked by enhanced cell contractility and a higher XT secretion rate, demonstrating an increased fibroblast-to-myofibroblast transition rate during arthrofibrosis. Histochemical assays and quantitative gene expression analysis confirmed higher collagen and proteoglycan expression and accumulation in AFib compared to CF. Furthermore, fibrosis-based gene expression profiling identified novel modifier genes in the context of arthrofibrosis remodeling. In summary, this study revealed a unique profibrotic phenotype in AFib that resembles some traits of other fibroproliferative diseases and can be used for the future development of therapeutic interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ly 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.)