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Previous studies from our lab suggest that transportation of early adulthood ducks can have long lasting physiological effects. To better understand how transportation affects the ducks' physiology, we evaluated several central and peripheral parameters. Thirty-six, 23-week-old ducks were collected at a commercial breeder facility and randomly assigned to one of three treatment groups (n = 6/sex/treatment): 1) caught and euthanized (control), 2) caught and put in a crated in the pen for 90 min (crate), or 3) caught, crated, and transported in a truck for 90 min (transport) to simulate actual transportation. Blood was collected for serum corticosterone and blood smear analyses. Brains were hemisected and each half was dissected into three brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), and diencephalon (DI). Mass spectrometry was run on the right half of the brain, and gene expression of TPH1, TPH2, TH, CRH, and NPY were measured on the left half of brain using qRT-PCR. Serum corticosterone levels were increased (p = 0.01) in crated hens and in transported hens and drakes (p = 0.0084) when compared to control. HLR was increased (p = 0.035) in crated hens and transported hens and drakes compared to control. No differences in serotonin turnover were observed in drakes but increased in hens within the CM and RM from control to crate (p = 0.01) and crate to transport (p = 0.016). There were no differences in DA turnover or in gene expression for all brain areas for drakes and CM and RM for hens. Within the DI, hens showed a decrease (p = 0.03) in TPH1 for transport compared to crate. Overall, transportation elicits an acutely stressful event that increases corticosterone and HLR in a sex dependent manner where hens appear to be more reactive to the stressor than drakes. Our data supports that when assessing a stress response, care must be given to the sex of the bird and to the relative timepoint of sampling compared to the perceived onset of the stressor., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Preening cups are a semi-open water source for Pekin duck enrichment. To evaluate the ducks' affective state, we combined measuring welfare by walking a transect in the barn with mass spectrometry and qRT-PCR to measure brain neurotransmitter levels and gene expression for serotonin (5-HT) and dopamine (DA) synthesis and metabolism. 5-HT and DA have been established as indicators of mental state and emotions. We visited 4 standard commercial barns that housed approximately 6000-9000 ducks (one preening cup per 1500 ducks) and collected samples on d21 prior to preening cup placement, d28 one week after preening cup placement, and d35 one day prior to processing. Litter samples (n = 3/barn/day) were collected and transect walks were conducted to evaluate the welfare of the birds. Brain samples (n = 8/day/barn) were collected from two locations: ducks actively using the preening cups (PC) and ducks across the barn not actively using the preening cups (CON). The brains were hemisected and dissected in three brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), and diencephalon (DI). Litter samples showed no significant differences between collection dates. The transect showed significant differences in feather quality, feather cleanliness, and eye due to age, but not preening cups. The right hemisphere showed no differences in 5-HT turnover. For DA turnover, there are differences in CM (p < 0.05) and DI (p < 0.001) over time, but no differences between PC and CON. The left hemisphere measured TPH1, TPH2, and TH. CM and DI brain areas are not significantly different. Within the RM, there is a significant increase in TPH1 expression for ducks on d35 when compared to ducks on d28 and d21. These results suggest that 5-HT and DA do not differ due to duck location. However, DA activity increases as these ducks age. DA is an important neurotransmitter and activity increases as an animal grows allowing for behavioral development. Our data shows that commercial preening cups do not negatively impact ducks' welfare or affective state., Competing Interests: Disclosures The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Root resorption consists of complex, multistep processes that involve cell signalling caused by inflammation and stromal cells, which promotes the secretion of receptor activator of nuclear factor κB ligand/ macrophage-colony stimulating factor (RANKL/M-CSF) resulting in a resorptive process., Objective: The aim of this narrative review was to analyse the literature related to root resorption resulting from microbial infection and to comparing it with non-microbial infection., Methods: An electronic literature search was performed using the PubMed database and applying keywords of articles published in English. Eligible papers were reviewed to reveal the descriptions of bone and root resorption processes. The abstracts were searched manually to identify articles about infection-stimulating bone and root resorption., Results: Three main types of root resorption were identified, two associated with primary bacterial infection and one secondary to bacterial infection. These include external inflammatory resorption, internal inflammatory resorption and external cervical (invasive) resorption., Discussion: The magnitude of cytokine involvement that promotes resorption and M-CSF/RANKL production depends on multiple factors, including pathogen virulence, site of infection and host genetic factors that activate the inflammation at the infection site. Two mechanisms activate the resorption mechanisms-the canonical and non-canonical pathways that can activate clastic cells independently of the RANKL/RANK canonical pathways., Conclusions: Two pathways of root resorption co-exist in the body. When resorption is caused by infection, chronic inflammation due to bacterial infection prolongs the secretions of pro-inflammatory cytokines that intensify root and bone resorption. The second pathway is bacterial independent of the non-infection root resorption that is part of the wound healing process, which is limited in time due to its innate ability., (© 2024 The Author(s). International Endodontic Journal published by John Wiley & Sons Ltd on behalf of British Endodontic Society.)

Background and Objectives: This study aimed to investigate the risk and mechanisms of air entry into the extracorporeal membrane oxygenation (ECMO) circuit through the central venous catheter (CVC) in a veno-venous configuration. The primary goal was to assess the impact of different air volumes on ECMO circuit performance at varying pump speeds. Material and Methods: The study utilized a circuit model to simulate ECMO conditions and evaluate the potential entry points of air, specifically through the unprotected lumen of the CVC. Various interventions, such as the use of a closed three-way stopcock or clave, were implemented to assess their efficacy in preventing air entry. Results: The unprotected lumen of the central venous catheter posed a significant risk for air entry into the ECMO circuit. The introduction of a closed three-way stopcock or clave proved effective in preventing air ingress through the central venous catheter. Auditory cues, such as a distinct hissing sound, served as an early warning sign of air presence in the circuit. The study demonstrated that even small volumes of air, as minimal as 1 mL, could pass through the oxygenator at specific pump speeds, and larger volumes could lead to pump dysfunction. Conclusions: The study identified the unprotected lumen of the central venous catheter as a potential entry point for air into the ECMO circuit. The use of a closed three-way stopcock or one-way valve was found to be a reliable protective measure against air infiltration. Early detection through the observation of a hissing sound in the circuit provided a valuable warning sign. These findings contribute to enhancing the safety and performance of ECMO systems by minimizing the risk of air embolism.

Introduction: Non-unions are fractures that do not heal properly, resulting in a false joint formation at the fracture site. This condition leads to major health issues and imposes a burden on national healthcare systems. The etiology of non-unions is still not fully understood; therefore, we aimed to identify potential systemic factors that may contribute to their formation., Materials and Methods: We conducted a cross-sectional concomitant proteomic and metabolomic pilot study of blood plasma in patients with non-unions (N = 11) and compared them with patients with bone fracture in the normal active healing phase (N = 12)., Results: We found five significantly upregulated proteins in the non-union group: immunoglobulin heavy variable 3-74, immunoglobulin lambda variable 2-18, low-density lipoprotein receptor-related protein 4, zinc-alpha-2-glycoprotein, and serum amyloid A-1 protein; and we found one downregulated protein: cystatin-C. The metabolomic study found differences in alanine, aspartate and glutamate metabolism pathways between two groups., Conclusions: The combined results of proteomic and metabolomic analyses suggest that the dysregulation of lipid metabolism may contribute to non-union formation.

This article presents SmartRoutes, (version 1) a sensory navigation system designed for the localization and guidance of individuals with cognitive disabilities in both indoor and outdoor environments. The platform facilitates route generation in both contexts and provides detailed instructions, enabling effective task execution and seamless integration into daily activities or high-stress situations, such as emergency evacuations. SmartRoutes aims to enhance users' independence and quality of life by offering comprehensive support for navigation across various settings. The platform is specifically designed to manage routes in both indoor and outdoor environments, targeting individuals with cognitive disabilities that affect orientation and the ability to follow instructions. This solution seeks to improve route learning and navigation, facilitating the completion of routine tasks in work and social contexts. Additionally, in exceptional situations such as emergencies, SmartRoutes ensures that users do not become disoriented or blocked. The application effectively guides users to the most appropriate exit or evacuation point. This combination of route generation and detailed instructions underscores the platform's commitment to inclusion and accessibility, ultimately contributing to the well-being and autonomy of individuals with cognitive disabilities.

Background and Aims: The pathophysiology of haemophilic arthropathy (HA) is complex and largely undefined. Proteomic analyses provide insights into the intricate mechanisms of the HA.Our study aimed to identify differentially expressed proteins in relation to the severity of HA, explore their pathophysiological roles, and evaluate their potential as HA biomarkers., Methods: Our cross-sectional observational study encompassed 30 HA patients and 15 healthy subjects. Plasma samples were pooled into three groups of 15 samples from those with severe haemophilic arthropathy (sHA), mild haemophilic arthropathy (mHA) and healthy controls. Proteomic analysis was performed using liquid chromatography-mass spectrometry. The severity of HA was assessed using the World Federation of Haemophilia Physical Examination Score and ultrasonography following the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) guidelines., Results: A total of 788 proteins were identified, with 97% of the uniquely identified proteins being expressed in all analysed groups. We identified several up and downregulated proteins across the groups that were mainly related to inflammatory and immunity-modulating processes, as well as joint degeneration. We highlighted ten proteins relevant for the development of HA: cathepsin G, endoplasmic reticulum aminopeptidase 2, S100-A9, insulin-like growth factor I, apolipoprotein (a), osteopontin, pregnancy zone protein, cartilage oligomeric matrix protein, CD44, and cadherin-related family member 2., Conclusion: Our analysis identified several proteins that shed further light on the distinctive pathogenesis of HA and could serve for biomarker research. However, these results need to be validated on a larger patient group., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus , we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations., Competing Interests: MS Inventor on a relevant patentapplication held by Harvard University (PCT/US2021/012626), BC, HF, KP, ZI, TL, AK, SK, ML, SL, RM, SM, JM, MP, AS, KS, KS, DD, TP, JY, JP, DW, ZH, CH, JC, OP, JS, EW, MS No competing interests declared, EG Inventor on a relevant patentapplication held by Harvard University (PCT/US2021/012626). Hold equity in and is employed by Unravel Biosciences, Inc, TT Inventor on a relevant patent807 application held by Harvard University (PCT/US2021/012626), KA, EC, RL, IC, ZM, IJ, RV, LB Employee of Vascular Perfusion Solutions, ML Inventor on a relevant patent application held by Harvard University (PCT/US2021/012626). Hold equity in and is a member of the scientific advisory board of Unravel Biosciences, Inc, RN Inventor on a relevant patent application held by Harvard University (PCT/US2021/012626). Holds equity in, is a member of the board of directors, and is a current employee of Unravel Biosciences, Inc, DI Founder, board member and Scientific Advisory Board chair of, and holds equity in, Emulate Inc Inventors on a relevant patent application held by Harvard University (PCT/US2021/012626). Holds equity and is a member of the board of directors of Unravel Biosciences, Inc Member of the scientific advisory board of Vascular Perfusion Solutions

In December 2021 the U.S. Government announced a new, whole-of-government $1.8 billion effort, the Initiative for Global Vaccine Access (Global VAX) in response to the global COVID-19 pandemic. Using the foundation of decades of U.S. government investments in global health and working in close partnership with local governments and key global and multilateral organizations, Global VAX enabled the rapid acceleration of the global COVID-19 vaccine rollout in selected countries, contributing to increased COVID-19 vaccine coverage in some of the world's most vulnerable communities. Through Global VAX, the U.S. Government has supported 125 countries to scale up COVID-19 vaccine delivery and administration while strengthening primary health care systems to respond to future health crises. The progress made by Global VAX has paved the way for a stronger global recovery and improved global health security., 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., (Published by Elsevier Ltd.)

Achieving a reversible decrease of metabolism and other physiological processes in the whole organism, as occurs in animals that experience torpor or hibernation, could contribute to increased survival after serious injury. Using a Bayesian network tool with transcriptomic data and chemical structure similarity assessments, we predicted that the Alzheimer's disease drug donepezil (DNP) could be a promising candidate for a small molecule drug that might induce a torpor-like state. This was confirmed in a screening study with Xenopus laevis tadpoles, a nonhibernator whole animal model. To improve the therapeutic performance of the drug and minimize its toxicity, we encapsulated DNP in a nanoemulsion formulated with low-toxicity materials. This formulation is composed of emulsified droplets <200 nm in diameter that contain 1.250 mM DNP, representing ≥95% encapsulation efficiency. The DNP nanoemulsion induced comparable torpor-like effects to those produced by the free drug in tadpoles, as indicated by reduced swimming motion, cardiac beating frequency, and oxygen consumption, but with an improved biodistribution. Use of the nanoemulsion resulted in a more controlled increase of DNP concentration in the whole organism compared to free DNP, and to a higher concentration in the brain, which reduced DNP toxicity and enabled induction of a longer torpor-like state that was fully reversible. These studies also demonstrate the potential use of Xenopus tadpoles as a high-throughput in vivo screen to assess the efficacy, biodistribution, and toxicity of drug-loaded nanocarriers.

Introduction: Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD)., Materials and Methods: Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups., Results: We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH., Discussion and Conclusion: We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pastrovic 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: Elicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination., Methods: We randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine., Findings: CD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group., Interpretation: This study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans., Funding: National Institute of Allergy and Infectious Diseases, NIH., Competing Interests: Declaration of interests MAA is employed by NIAID, the funder of the study. HVT, KJB, SAK, AFG, LC, GDT, NF, NG, SCDR reports receiving institutional grants from the NIH. IF reports institutional grants and participation on Boards of Gilead and Viiv; LB reports institutional grants and participation on Boards of the FDA and NIAID; MJM reports institutional grants, participation on Boards of Ragon Institute, Keystone Symposia and NIH VRC, and a patent on HIV immunogens. The rest of the authors as well as HVTN 085 Study Team declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: To determine the characteristics of patients who experienced muscle fasciculations and migraine auras without headache after BNT162b2 immunization., Methods: In January 2022, we published a case report that described a 48-year-old female patient who experienced muscle twitching and migraine auras without headache following BNT162b2 immunization. A self-administered online survey was sent to people who had written to us and complained of similar symptoms described in the case report (N=20)., Results: The survey was completed by 11 participants, of whom 10 reported muscle twitching following BNT162b2 immunization lasting a median of 14 (4-36.5) days. Five of these participants (50%) reported migraine auras without headache. Participants further reported on self-identified triggers that altered the intensity of their symptoms, such as anxiety or caffeine. Fifty percent of participants who got an acute SARS-CoV-2 infection (3/6) experienced increased muscle symptom intensity during the acute phase of the disease., Conclusion: To the best of our knowledge, our survey is the first to summarize patients' experiences of these phenomena occurring after BNT162b2 immunization. It is important to note that no causal relationship between vaccination and these phenomena can be inferred.

Participatory exposure research, which tracks behaviour and assesses exposure to stressors like air pollution, traditionally relies on time-activity diaries. This study introduces a novel approach, employing machine learning (ML) to empower laypersons in human activity recognition (HAR), aiming to reduce dependence on manual recording by leveraging data from wearable sensors. Recognising complex activities such as smoking and cooking presents unique challenges due to specific environmental conditions. In this research, we combined wearable environment/ambient and wrist-worn activity/biometric sensors for complex activity recognition in an urban stressor exposure study, measuring parameters like particulate matter concentrations, temperature, and humidity. Two groups, Group H (88 individuals) and Group M (18 individuals), wore the devices and manually logged their activities hourly and minutely, respectively. Prioritising accessibility and inclusivity, we selected three classification algorithms: k-nearest neighbours (IBk), decision trees (J48), and random forests (RF), based on: (1) proven efficacy in existing literature, (2) understandability and transparency for laypersons, (3) availability on user-friendly platforms like WEKA, and (4) efficiency on basic devices such as office laptops or smartphones. Accuracy improved with finer temporal resolution and detailed activity categories. However, when compared to other published human activity recognition research, our accuracy rates, particularly for less complex activities, were not as competitive. Misclassifications were higher for vague activities (resting, playing), while well-defined activities (smoking, cooking, running) had few errors. Including environmental sensor data increased accuracy for all activities, especially playing, smoking, and running. Future work should consider exploring other explainable algorithms available on diverse tools and platforms. Our findings underscore ML's potential in exposure studies, emphasising its adaptability and significance for laypersons while also highlighting areas for improvement.

Introduction: Papillary thyroid carcinomas (PTC) are the most common thyroid malignancies that are often diagnosed as microcarcinomas when the tumor is less than one centimetre in diameter. Currently, there are no valid stratification strategies that would reliably assess the risk of lateral neck metastases and optimize surgical treatment., Materials and Methods: Aiming to find potential tissue biomarkers of metastatic potential, we conducted a cross-sectional proteomic pilot study on formalin-fixed paraffin-embedded tissues of metastatic (N = 10) and non-metastatic (N = 10) papillary thyroid microcarcinoma patients. Samples were analysed individually using liquid chromatography/mass spectrometry, and the differentially expressed proteins (DEP) were functionally annotated., Results: We identified five overexpressed DEPs in the metastatic group (EPB41L2, CSE1L, GLIPR2, FGA and FGG) with a known association to tumour biology. Using bioinformatic-based tools, we found markedly different profiles of significantly enriched biological processes between the two groups., Conclusions: The identified DEPs might have a role as potential tissue biomarkers for PTC metastases. However, further prospective research is needed to confirm our findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The mechanism of action of root resorption in a permanent tooth can be classified as infection-related (e.g., microbial infection) or non-infection-related (e.g., sterile damage). Infection induced root resorption occurs due to bacterial invasion. Non-infection-related root resorption stimulates the immune system through a different mechanism., Objectives: The aim of this narrative review is to describe the pathophysiologic process of non-infection-related inflammatory processes involved in root resorption of permanent teeth., Methods: A literature search on root resorption was conducted using Scopus (PubMed and Medline) and Google Scholar databases to highlight the pathophysiology of bone and root resorption in non-infection-related situations. The search included key words covering the relevant category. It included in vitro and in vivo studies, systematic reviews, case series, reviews, and textbooks in English. Conference proceedings, lectures and letters to the editor were excluded., Results: Three types of root resorption are related to the non-infection mechanism of action, which includes surface resorption due to either trauma or excessive orthodontic forces, external replacement resorption and external cervical resorption. The triggers are usually damage associated molecular patterns and hypoxia conditions. During this phase macrophages and clastic cells act to eliminate the damaged tissue and bone, eventually enabling root resorption and bone repair as part of wound healing., Discussion: The resorption of the root occurs during the inflammatory phase of wound healing. In this phase, damaged tissues are recognized by macrophages and neutrophiles that secrete interlaukines such as TNF-α, IL-1, IL-6, IL-8. Together with the hypoxia condition that accelarates the secretion of growth factors, the repair of the damaged perioduntiom, including damaged bone, is initiated. If the precementum and cementoblast are injured, root resorption can occur., Conclusions: Wound healing exhibits different patterns of action that involves immune stimulation in a bio-physiological activity, that occurs in the proper sequence, with overlapping phases. Two pathologic conditions, DAMPs and hypoxia, can activate the immune cells including clastic cells, eliminating damaged tissue and bone. Under certain conditions, root resorption occurs as a side effect., (© 2023 The Authors. International Endodontic Journal published by John Wiley & Sons Ltd on behalf of British Endodontic Society.)

Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp -/- mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S rRNA gene in fecal samples collected from separately housed mice revealed apparent dysbiosis in Shp -/- mice. Cohousing Shp -/- mice with WT mice during a Western diet regimen impaired their metabolic improvement and effectively disrupted their distinctive microbiome structure, which became indistinguishable from that of WT mice. While the Western diet challenge significantly increased lipopolysaccharide and phenylacetic acid (PAA) levels in the blood of WT mice, their levels were not increased in Shp -/- mice. PAA was strongly associated with hepatic peroxisome proliferator-activated receptor gamma isoform 2 (Pparg2) activation in mice, which may represent the basis of the molecular mechanism underlying the association of gut bacteria and hepatic steatosis. Shp deletion reshapes the gut microbiota possibly by altering BAs. While lipopolysaccharide and PAA are the major driving forces derived from gut microbiota for NASH development, Shp deletion decreases these signaling molecules via dysbiosis, thereby partially protecting mice from diet-induced metabolic disorders., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Misfolded protein oligomers are of central importance in both the diagnosis and treatment of Alzheimer's and Parkinson's diseases. However, accurate high-throughput methods to detect and quantify oligomer populations are still needed. We present here a single-molecule approach for the detection and quantification of oligomeric species. The approach is based on the use of solid-state nanopores and multiplexed DNA barcoding to identify and characterize oligomers from multiple samples. We study α-synuclein oligomers in the presence of several small-molecule inhibitors of α-synuclein aggregation as an illustration of the potential applicability of this method to the development of diagnostic and therapeutic methods for Parkinson's disease.

To gain a comprehensive understanding of the effects of air pollution on human health, it is imperative to assess exposure at an individual level. This necessitates the use of personal monitoring equipment that can record exposure in real-time while simultaneously capturing relevant biometric data and the activities being undertaken by the individual. The dataset presented herein encompasses data from five distinct sources, collected in Ljubljana, Slovenia: (a) Questionnaire filled out by all participants for general information, i.e., age, height, weight. (b) Time Activity Diaries maintained by participants. (a) A personal particulate matter sensing unit that recorded data on PM 1 , PM 2.5 , PM 10 , ambient temperature, relative humidity, and geographical location coordinates. (b) A wrist-worn Smart Activity Tracker that captures heart rate and movement data. (c) An Indoor Air Quality sensing unit, specifically the uHoo device, which measures parameters such as Temperature, Relative Humidity, CO 2 , TVOC, PM 2.5 , CO, O 3 , NO 2 , and Air Pressure. Participants were equipped with these sensors for two separate 1-week durations in 2019, specifically during a heating season and a non-heating season, as part of the ICARUS H2020 project. Throughout these periods, data was recorded at a 1-minute resolution. Additionally, based on the collected data, an inhalation rate was determined, and an inhalation adjusted exposure (or intake dose) was computed. The richness and granularity of this dataset not only offer insights into the direct health implications of air pollution exposure but also provide a valuable resource for urban planners, environmental scientists, and policymakers aiming to design healthier living environments and implement effective air quality regulations., (© 2023 The Author(s).)

Small heterodimer partner (SHP, Nr0b2) is an orphan nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Shp -/- mice are resistant to diet-induced obesity and hepatic steatosis. In this study, we explored the potential role of SHP in the development of nonalcoholic steatohepatitis (NASH). A 6-month Western diet (WD) regimen was used to induce NASH. Shp deletion protected mice from NASH progression by inhibiting inflammatory and fibrotic genes, oxidative stress, and macrophage infiltration. WD feeding disrupted the ultrastructure of hepatic mitochondria in WT mice but not in Shp -/- mice. In ApoE -/- mice, Shp deletion also effectively ameliorated hepatic inflammation after a 1 week WD regimen without an apparent antisteatotic effect. Moreover, Shp -/- mice resisted fibrogenesis induced by a methionine- and choline-deficient diet. Notably, the observed protection against NASH was recapitulated in liver-specific Shp -/- mice fed either the WD or methionine- and choline-deficient diet. Hepatic cholesterol was consistently reduced in the studied mouse models with Shp deletion. Our data suggest that Shp deficiency ameliorates NASH development likely by modulating hepatic cholesterol metabolism and inflammation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Background: We consider two key challenges that early-stage biotechnology firms face in developing a sustainable financing strategy and a sustainable business model: developing a valuation model for drug compounds, and choosing an appropriate operating model and corporate structure. We use the specific example of Unravel Biosciences-a therapeutics platform company that identifies novel drug targets through off-target mechanisms of existing drugs and then develops optimized new molecules-throughout the paper and explore a specific scenario of drug repurposing for rare genetic diseases., Results: The first challenge consists of producing a realistic financial valuation of a potential rare disease repurposed drug compound, in this case targeting Rett syndrome. More generally, we develop a framework to value a portfolio of pairwise correlated rare disease compounds in early-stage development and quantify its risk profile. We estimate the probability of a negative return to be [Formula: see text] for a single compound and [Formula: see text] for a portfolio of 8 drugs. The probability of selling the project at a loss decreases from [Formula: see text] (phase 3) for a single compound to [Formula: see text] (phase 3) for the 8-drug portfolio. For the second challenge, we find that the choice of operating model and corporate structure is crucial for early-stage biotech startups and illustrate this point with three concrete examples., Conclusions: Repurposing existing compounds offers important advantages that could help early-stage biotech startups better align their business and financing issues with their scientific and medical objectives, enter a space that is not occupied by large pharmaceutical companies, and accelerate the validation of their drug development platform., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Background and Objectives: Bone resection and endoprosthetic reconstruction (EPR) in the setting of soft tissue sarcoma (STS) management is rare and incurs unique challenges. We aim to report on the surgical and oncological outcomes of this relatively previously undocumented cohort., Methods: This is a single-center retrospective review of prospectively collected data for patients who required EPRs following resection of STSs of the lower extremity. Following inclusion criteria, we assessed 29 cases of EPR for primary STS of the lower limb., Results: The mean age was 54 years (range 18-84). Of the 29 patients, there were 6 total femur, 11 proximal femur, 4 intercalary, and 8 distal femur EPRs. Fourteen of 29 patients (48%) underwent re-operations for surgical complications, with 9 relating to infection (31%). When a matched cohort analysis was performed comparing our cohort to STSs that did not necessitate EPR, a reduced rate of overall survival and metastasis-free survival was found in those requiring EPR., Conclusion: This series identifies a high rate of complication from EPRs performed for STS. Patients should be cautioned about the high rate of infection, surgical complications, and lower overall survival in this setting., (© 2023 Wiley Periodicals LLC.)

Epidemiological and exposure studies concerning particulate matter (PM) often rely on data from sparse governmental stations. While low-cost personal monitors have some drawbacks, recent developments have shown that they can provide fairly accurate and fit-for-purpose data. Comparing a stochastic, i.e., agent-based model (ABM), with environmental, biometric and activity data, collected with personal monitors, could provide insight into how the two approaches assess PM exposure and dose. An ABM was constructed, simulating a PM exposure/dose assessment of 100 agents. Their actions were governed by inherent probabilities of performing an activity, based on population data. Each activity was associated with an intensity level, and a PM pollution level. The ABM results were compared with real-world results. Both approaches had comparable results, showing similar trends and a mean dose. Discrepancies were seen in the activities with the highest mean dose values. A stochastic model, based on population data, does not capture well some specifics of a local population. Combined, personal sensors could provide input for calibration, and an ABM approach can help offset a low number of participants. Implementing a function of agents influencing others transport choice, increased the importance of cycling/walking in the overall dose estimate. Activists, agents with an increased transport influence, did not play an important role at low PM levels. As concentrations rose, higher shares of activists (and their influence) caused the dose to increase. Simulating a person's PM exposure/dose in different scenarios and activities in a virtual environment provides researchers and policymakers with a valuable tool., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Urban stressors pose a health risk, and individual-level assessments provide necessary and fine-grained insight into exposure. An ever-increasing amount of research literature on individual-level exposure to urban stressors using data collected with personal monitors, has called for an integrated assessment approach to identify trends, gaps and needs, and provide recommendations for future research. To this end, a scoping review of the respective literature was performed, as part of the H2020 URBANOME project. Moreover, three specific aims were identified: (i) determine current state of research, (ii) analyse literature according with a waterfall methodological framework and identify gaps and needs, and (iii) provide recommendations for more integrated, inclusive and robust approaches. Knowledge and gaps were extracted based on a systematic approach, e.g., data extraction questionnaires, as well as through the expertise of the researchers performing the review. The findings were assessed through a waterfall methodology of delineating projects into four phases. Studies described in the papers vary in their scope, with most assessing exposure in a single macro domain, though a trend of moving towards multi-domain assessment is evident. Simultaneous measurements of multiple stressors are not common, and papers predominantly assess exposure to air pollution. As urban environments become more diverse, stakeholders from different groups are included in the study designs. Most frequently (per the quadruple helix model), civil society/NGO groups are involved, followed by government and policymakers, while business or private sector stakeholders are less frequently represented. Participants in general function as data collectors and are rarely involved in other phases of the research. While more active involvement is not necessary, more collaborative approaches show higher engagement and motivation of participants to alter their lifestyles based on the research results. The identified trends, gaps and needs can aid future exposure research and provide recommendations on addressing different urban communities and 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Resection of soft-tissue sarcomas from the adductor compartment is associated with significant complications. Free/pedicled flaps often are used for wound closure, but their effect on healing is unclear. We compared wound complications, oncologic, and functional outcomes for patients undergoing flap reconstruction or primary closure following resection of adductor sarcomas., Methods: A total of 177 patients underwent resection of an adductor sarcoma with primary closure (PrC) or free/pedicled flap reconstruction (FR). Patient, tumor, and treatment characteristics were compared, as well as wound complications, oncologic, and functional outcomes (TESS/MSTS87/MSTS93). To examine the relative benefit of flap reconstruction, number needed to treat (NNT) was calculated., Results: In total, 143 patients underwent PrC and 34 had FR, 68% of which were pedicled. There were few differences in demographic, tumor, or treatment characteristics. No significant difference was found in the rate of wound complications. Length of stay was significantly longer in FR (18 days vs. PrC 8 days; p < 0.01). Oncologic and functional outcomes were similar over 5 years follow-up. Uncomplicated wound healing occurred more often in FR compared with PrC for tumors with ≥15 cm (NNT = 8.4) or volumes ≥ 800 ml (NNT = 8.4). Tumors ≤ 336 ml do not benefit from a flap, whereas those > 600 ml are 1.5 times more likely to heal uneventfully after flap closure., Conclusions: Although flap use prolonged hospitalization, it decreased wound healing complications for larger tumors, and in all sized tumors, it demonstrated similar functional and oncologic outcomes to primary closure. Our size-based treatment criteria can help to identify patients with large adductor sarcomas who could benefit from flap reconstruction., Level of Evidence Iii: (Retrospective cohort study)., (© 2023. Society of Surgical Oncology.)

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: R.N. and D.E.I. hold equity in Unravel Biosciences, Inc and are members of its board of directors; D.E.I. is a member of its scientific advisory board; and R.N. is a current employee of the company. The remaining authors declare no competing interests., (Copyright: © 2023 Sperry 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.)

Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Acute and chronic kidney diseases are an evolving continuum for which reliable biomarkers of early disease are lacking. The potential use of glycosidases, enzymes involved in carbohydrate metabolism, in kidney disease detection has been under investigation since the 1960s. N-acetyl-beta-D-glucosaminidase (NAG) is a glycosidase commonly found in proximal tubule epithelial cells (PTECs). Due to its large molecular weight, plasma-soluble NAG cannot pass the glomerular filtration barrier; thus, increased urinary concentration of NAG (uNAG) may suggest injury to the proximal tubule. As the PTECs are the workhorses of the kidney that perform much of the filtration and reabsorption, they are a common starting point in acute and chronic kidney disease. NAG has previously been researched, and it is widely used as a valuable biomarker in both acute and chronic kidney disease, as well as in patients suffering from diabetes mellitus, heart failure, and other chronic diseases leading to kidney failure. Here, we present an overview of the research pertaining to uNAG's biomarker potential across the spectrum of kidney disease, with an additional emphasis on environmental nephrotoxic substance exposure. In spite of a large body of evidence strongly suggesting connections between uNAG levels and multiple kidney pathologies, focused clinical validation tests and knowledge on underlining molecular mechanisms are largely lacking.

Background: Individuals with sarcoidosis are at higher risk for infection owing to underlying disease pathogenesis and need for immunosuppressive treatment. Current knowledge as to how subjects with sarcoidosis respond to different forms of vaccination is limited. We examined quantitative and functional antibody response to COVID-19 vaccination in infection-naive subjects with and without sarcoidosis., Methods: Our prospective cohort study recruited 14 subjects with biopsy-proven sarcoidosis and 27 age-sex matched controls who underwent a two-shot series of the BNT162b2 mRNA vaccine at the University of Illinois at Chicago. Baseline, 4-week and 6-month trimer spike protein IgG and neutralising antibody (nAb) titres were assessed. Correlation and multivariate regression analysis was conducted., Results: Sarcoidosis subjects had a significant increase in short-term antibody production to a level comparable to controls; however, IgG titres significantly declined back to baseline levels by 6 months. Corresponding neutralising assays revealed robust nAb titres in sarcoidosis subjects that persisted at 6 months. A significant and strong correlation between IgG and nAb titres across all time points was observed in the control group. However within the sarcoidosis group, a significant but weak correlation between antibody levels was found. Overall, IgG levels were poor predictors of nAb titres at short- or long-term time points., Conclusions: Sarcoidosis subjects exhibit nAb induced by the BNT162b2 mRNA SARS-CoV-2 vaccine at levels comparable to controls that persists at 6 months indicating conferred immunity. Trimer IgG levels are poor predictors of nAb in subjects with sarcoidosis. Studies of further antibody immunoglobulins and subtypes warrant investigation., Competing Interests: Conflict of interest: Richard M. Novak reports the following relationships outside the submitted work: grants or contracts received from Janssen; consulting fees received from Gilead and Viiv. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: The timing and magnitude of antiretroviral therapy-associated weight change attributions are unclear., Setting: HIV Outpatient Study participants., Methods: We analyzed 2007-2018 records of virally suppressed (VS) persons without integrase inhibitor (INSTI) experience who switched to either INSTI-based or another non-INSTI-based ART, and remained VS. We analyzed BMI changes using linear mixed models, INSTI- and tenofovir alafenamide (TAF) contributions to BMI change by linear mixed models-estimated slopes, and BMI inflection points., Results: Among 736 participants (5316 person-years), 441 (60%) switched to INSTI-based ART; the remainder to non-INSTI-based ART. The mean follow-up was 7.15 years for INSTI recipients and 7.35 years for non-INSTI. Preswitch, INSTI and non-INSTI groups had similar median BMI (26.3 versus 25.9 kg/m 2 , P = 0.41). INSTI regimens included raltegravir (178), elvitegravir (112), and dolutegravir (143). Monthly BMI increases postswitch were greater with INSTI than non-INSTI (0.0525 versus 0.006, P < 0.001). A BMI inflection point occurred 8 months after switch among INSTI users; slopes were similar regardless of TAF use immediately postswitch. Among INSTI + TAF users, during 8 months postswitch, 87% of BMI slope change was associated with INSTI use, 13% with TAF use; after 8 months, estimated contributions were 27% and 73%, respectively. For non-INSTI+TAF, 84% of BMI gain was TAF-associated consistently postswitch. Persons switching from TDF to TAF had greater BMI increases than others ( P < 0.001)., Conclusion: Among VS persons who switched ART, INSTI and TAF use were independently associated with BMI increases. During 8 months postswitch, BMI changes were greatest and most associated with INSTI use; afterward, gradual BMI gain was largely TAF-associated., Competing Interests: F.P. has been a consultant and/or on the Speakers' Bureau for Gilead Sciences, Janssen Pharmaceuticals, Merck and Co., and ViiV. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In vitro culture and differentiation of human-derived airway basal cells under air-liquid interface (ALI) into a pseudostratified mucociliated mucosal barrier has proven to be a powerful preclinical tool to study pathophysiology of respiratory epithelium. As such, identifying differentiation stage-specific biomarkers can help investigators better characterize, standardize, and validate populations of regenerating epithelial cells prior to experimentation. Here, we applied longitudinal transcriptomic analysis and observed that the pattern and the magnitude of OMG, KRT14, STC1, BPIFA1, PLA2G7, TXNIP, S100A7 expression create a unique biosignature that robustly indicates the stage of epithelial cell differentiation. We then validated our findings by quantitative hemi-nested real-time PCR from in vitro cultures sourced from multiple donors. In addition, we demonstrated that at protein-level secretion of BPIFA1 accurately reflects the gene expression profile, with very low quantities present at the time of ALI induction but escalating levels were detectable as the epithelial cells terminally differentiated. Moreover, we observed that increase in BPIFA1 secretion closely correlates with emergence of secretory cells and an anti-inflammatory phenotype as airway epithelial cells undergo mucociliary differentiation under air-liquid interface in vitro ., Competing Interests: KB is founder and holds equity in Pneumax, LLC. The remaining 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 © 2022 Clifton, Niemeyer, Novak, Can, Hainline and Benam.)

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KT has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); KK has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); AF has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); FMB has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); ZM has received honoraria for lectures and consultations and he also functions as medical director at CytoSorbents Europe (Berlin, Germany). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is the fastest way to restore circulation in refractory cardiogenic shock, however it cannot unload the failing left ventricle. There is a lack of consensus regarding optimal approach to left ventricular venting in V-A ECMO patients with severely depressed or absent left ventricular function., Methods: A computer model was developed in Matlab Simulink R20016b (MathWorks, Inc., Natick, MA, USA) to analyze different venting options as well as atrial septostomy in the setting of cardiogenic shock and V-A ECMO., Results: The model has shown an inverse linear relationship between left atrial pressure and either vent, Impella or atrial septum defect flow rate. The minimum vent flow required to prevent pulmonary edema in complete loss of left ventricular function needed to be higher than the bronchial blood flow. Atrial septostomy restored normal pulmonary blood flow with low left atrial pressure but induced stasis in the left ventricle. Venting the pulmonary artery induced stasis in the entire pulmonary circulation as well as left atrium and left ventricle. Venting the left ventricle directly with a cannula or Impella device avoided blood stasis., Conclusion: Our data suggest that reduction of left atrial pressure is linearly related to the vent, Impella or atrial septal defect flow rate. The preferred vent location is the left ventricle as it avoids stasis in the pulmonary circulation and cardiac chambers.

Bile acid-CoA: amino acid N-acyltransferase (BAAT) catalyzes bile acid conjugation, the last step in bile acid synthesis. BAAT gene mutation in humans results in hypercholanemia, growth retardation, and fat-soluble vitamin insufficiency. The current study investigated the physiological function of BAAT in bile acid and lipid metabolism using Baat -/- mice. The bile acid composition and hepatic gene expression were analyzed in 10-week-old Baat -/- mice. They were also challenged with a westernized diet (WD) for additional 15 weeks to assess the role of BAAT in bile acid, lipid, and glucose metabolism. Comprehensive lab animal monitoring system and cecal 16S ribosomal RNA gene sequencing were used to evaluate the energy metabolism and microbiome structure of the mice, respectively. In Baat -/- mice, hepatic bile acids were mostly unconjugated and their levels were significantly increased compared with wild-type mice. Bile acid polyhydroxylation was markedly up-regulated to detoxify unconjugated bile acid accumulated in Baat -/- mice. Although the level of serum marker of bile acid synthesis, 7α-hydroxy-4-cholesten-3-one, was higher in Baat -/- mice, their bile acid pool size was smaller. When fed a WD, the Baat -/- mice showed a compromised body weight gain and impaired insulin secretion. The gut microbiome of Baat -/- mice showed a low level of sulfidogenic bacteria Bilophila. Conclusion: Mouse BAAT is the major taurine-conjugating enzyme. Its deletion protected the animals from diet-induced obesity, but caused glucose intolerance. The gut microbiome of the Baat -/- mice was altered to accommodate the unconjugated bile acid pool., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis., (© 2022. The Author(s).)

Air pollution exposure is harmful to human health and reducing it at the level of an individual requires measurements and assessments that capture the spatiotemporal variability of different microenvironments and the influence of specific activities. In this paper, activity-specific and general indoor and outdoor exposure during and after a period of high concentrations of particulate matter (PM), e.g., an atmospheric thermal inversion (ATI) in the Ljubljana subalpine basin, Slovenia, was assessed. To this end, personal particulate matter monitors (PPM) were used, worn by participants of the H2020 ICARUS sampling campaigns in spring 2019 who also recorded their hourly activities. ATI period(s) were determined based on data collected from two meteorological stations managed by the Slovenian Environmental Agency (SEA). Results showed that indoor and outdoor exposure to PM was significantly higher during the ATI period, and that the difference between mean indoor and outdoor exposure to PM was much higher during the ATI period (23.0 µg/m3) than after (6.5 µg/m3). Indoor activities generally were associated with smaller differences, with cooking and cleaning even having higher values in the post-ATI period. On the other hand, all outdoor activities had higher PM values during the ATI than after, with larger differences, mostly >30.0 µg/m3. Overall, this work demonstrated that an individual-level approach can provide better spatiotemporal resolution and evaluate the relative importance of specific high-exposure events, and in this way provide an ancillary tool for exposure assessments.

Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. Computational transcriptomics and Xenopus laevis embryos are used to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling leads to definition of a 20-gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, are found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF-1α agonist (1,4-DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multiomics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Importance: Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit., Objectives: To test if different statins differ in their ability to exert protective effects based on molecular computational predictions and electronic medical record analysis., Main Outcomes and Measures: A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2, with a total of 2,436 drugs investigated. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus., Results: Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells., Conclusions and Relevance: Different statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

Introduction: Osteoarthritis (OA) and haemophilic arthropathy (HA) are clinically similar, but pathologically distinct conditions which result in joint pain and loss of function. Distinguishing their disease mechanisms is therefore a key step in the development of curative therapy, as opposed to current symptomatic treatments. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 is a metzincin-family member proteoglycan with known local involvement in OA pathogenesis., Aim: To investigate the potential differences and discriminatory potential of ADAMTS-4 between OA and HA patients., Methods: We determined ADAMTS-4 plasma concentrations by ELISA in patients with HA and OA. This pilot cross-sectional study included N = 40 male participants equally divided across four subgroups: haemophilia patients with severe or mild HA and control subjects with severe or mild/no OA., Results: Our study showed a striking elevation in plasma ADAMTS-4 expression levels in HA patients as compared to OA, as well as an increase in patients with severe as compared to mild HA. By performing the binomial logistical analysis and fitting the receiver-operator curve (ROC) (cut-off probability .5), ADAMTS-4 had a sensitivity of 95% and specificity of 50% in discriminating between HA and OA among our study participants., Conclusion: Uncovering the marked differences in plasma levels of ADAMTS-4 in patients with HA versus OA potentially sheds new light on the mechanisms of HA pathogenesis and could foster more research into the roles ADAMTS-4 and other matrix metalloproteinases (MMPs) play in HA versus OA., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Chronic kidney disease (CKD) is the progressive loss of renal function. Although advances have been made in understanding the progression of CKD, key molecular events in complex pathophysiological mechanisms that mark each stage of renal failure remain largely unknown. Changes in plasma protein profiles in different disease stages are important for identification of early diagnostic markers and potential therapeutic targets. The goal of this study was to determine the molecular profile of each CKD stage (from 1 to 5), aiming to specifically point out markedly expressed or downregulated proteins. We performed a cross-sectional shotgun-proteomic study of pooled plasma across CKD stages and compared them to healthy controls. After sample pooling and heparin-column purification we analysed proteomes from healthy to CKD stage 1 through 5 participants' plasma by liquid-chromatography/mass-spectrometry. We identified 453 proteins across all study groups. Our results indicate that key events, which may later affect the course of disease progression and the overall pathophysiological background, are most pronounced in CKD stage 2, with an emphasis on inflammation, lipoprotein metabolism, angiogenesis and tissue regeneration. We hypothesize that CKD stage 2 is the tipping point in disease progression and a suitable point in disease course for the development of therapeutic solutions.

Togo has reported seasonal meningitis outbreaks caused by non-Neisseria meningitidis serogroup A (NmA) pathogens since the introduction of meningococcal serogroup A conjugate vaccine (MACV, MenAfriVac) in 2014. From 2016 to 2017, NmW caused several outbreaks. In early 2019, a NmC outbreak was detected in the Savanes region of Togo and its investigation is described here. Under case-based surveillance, epidemiological and clinical data, and cerebrospinal fluid specimens were collected for every suspected case of meningitis. Specimens were tested for meningitis pathogens using confirmatory microbiological and molecular methods. During epidemic weeks 9 to 15, 199 cases were reported, with 179 specimens being available for testing and 174 specimens (97.2%) were tested by at least one confirmatory method. The NmC was the predominant pathogen confirmed (93.9%), belonging to sequence type (ST)-9367 of clonal complex (CC) 10217. All NmC cases were localized to the West Kpendjal district of the Savanes region with attack rates ranging from 4.1 to 18.8 per 100,000 population and case fatality rates ranging up to 2.2% during weeks 9 to 15. Of the 93 NmC confirmed cases, 63.4% were males and 88.2% were in the 5 to 29 age group. This is the first report of a NmC meningitis outbreak in Togo. The changing epidemiology of bacterial meningitis in the meningitis belt post-MACV highlights the importance of monitoring of emerging strain and country preparedness for outbreaks in the region. IMPORTANCE The recent emergence of an invasive NmC strain in Togo is an example of the changing bacterial meningitis epidemiology in the meningitis belt post-MACV. The current epidemiology includes the regional circulation of various non-NmA serogroups, which emphasizes the need for effective molecular surveillance, laboratory diagnosis, and a multivalent vaccine that is effective against all serogroups in circulation.

Radiation-associated sarcoma of the pelvis and/or sacrum (RASB) is a rare but challenging disease process associated with a poor prognosis. We hypothesized that patients with RASB would have worse surgical and oncologic outcomes than patients diagnosed with primary pelvic or sacral bone sarcomas. This was a retrospective, multi-institution, comparative analysis. We reviewed surgically treated patients from multiple tertiary care centers who were diagnosed with a localized RASB. We also identified a comparison group including all patients diagnosed with a primary localized pelvic or sacral osteosarcoma/spindle cell sarcoma of bone (POPS). There were 35 patients with localized RASB and 73 patients with POPS treated with surgical resection. Patients with RASB were older than those with POPS (57 years vs. 38 years, p < 0.001). Patients with RASB were less likely to receive chemotherapy (71% for RASB vs. 90% for POPS, p = 0.01). Seventeen percent of patients with RASB died in the perioperative period (within 90 days of surgery) as compared to 4% with POPS (p = 0.03). Five-year disease-specific survival (DSS) (31% vs. 54% p = 0.02) was worse for patients with RASB vs. POPS. There was no difference in 5-year local recurrence free survival (LRFS) or metastasis free survival (MFS). RASB and POPS present challenging disease processes with poor oncologic outcomes. Rates of perioperative mortality and 5-year DSS are worse for RASB when compared to POPS.

Background: We have previously shown that metzincin protease ADAMTS-4 accompanies renal fibrogenesis, as it appears in the blood of hemodialysis patients. Methods: Native kidney (NKB) and kidney transplant (TXCI) biopsy samples as well as plasma from patients with various stages of CKD were compared to controls. In paired analysis, 15 TXCI samples were compared with their zero-time biopsies (TX0). Tissues were evaluated and scored (interstitial fibrosis and tubular atrophy (IFTA) for NKB and Banff ci for TXCI). Immunohistochemical (IHC) staining for ADAMTS-4 and BMP-1 was performed. Plasma ADAMTS-4 was detected using ELISA. Results: ADAMTS-4 IHC expression was significantly higher in interstitial compartment (INT) of NKB and TXCI group in peritubular capillaries (PTC) and interstitial stroma (INT). Patients with higher stages of interstitial fibrosis (ci > 1 and IFTA > 1) expressed ADAMTS-4 in INT more frequently in both groups (p = 0.005; p = 0.013; respectively). In paired comparison, TXCI samples expressed ADAMTS-4 in INT and PTC more often than TX0. ADAMTS-4 plasma concentration varied significantly across CKD stages, being highest in CKD 2 and 3 compared to other groups (p = 0.0064). Hemodialysis patients had higher concentrations of ADAMTS-4 compared to peritoneal dialysis (p < 0.00001). Conclusion: ADAMTS-4 might have a significant role in CKD as a potential novel diagnostic indicator.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease in which bone tissue forms in extraskeletal sites, which is known as heterotopic ossification (HO). Extracellular vesicles (EVs) are small phospholipid-enclosed particles released by various cells which have an emerging, but not completely understood role in various (patho)physiological processes. In order to further study the pathophysiology of FOP we conducted a small observational study comparing the proteomic profiles of EV cargo, derived from pooled plasma of four patient groups: FOP patient ( N  = 1) during active disease phase (flare-up), FOP patients during remission ( N  = 2), patients after long bone fracture ( N  = 20) and healthy controls ( N  = 10). After isolation of EVs - their protein cargo was determined using liquid chromatography / mass spectrometry, after which a functional gene enrichment analysis was performed. Our results show a sizeable difference of the proteomics profiles in which EVs from the bone fracture group show significant activity of integrin interactions, Wnt, VEGF, IGF-1 and PDGF pathways; conversely, FOP patients' EVs indicate that HO occurs via processes of innate immunity and the Ephrin B signaling pathway. We hypothesize that the Ephrin B signaling (expressed in EVs) contributes to HO by aiding in mesenchymal stem cell recruitment and osteogenic differentiation, as well as by contributing to the inflammatory response, including macrophage chemotaxis and activation. This is, to our knowledge, the first published analysis of EV protein cargo in FOP., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors.)

Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This review focuses on the emerging role which ADAMTS-4 might play in vascular pathology, which has implications for atherosclerosis and vessel wall abnormalities, as well as for the resulting diseases, such as cardiovascular and cerebrovascular disease, aortic aneurysms, and dissections. Major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels. Good examples are versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy, which is why this metzincin protease was implicated in the pathophysiology of vascular diseases with an atherosclerotic background. Despite emerging evidence, it is important not to exaggerate the role of ADAMTS-4 as it is likely only a small piece of the complex atherosclerosis puzzle and one that could be functionally redundant due to its high structural similarity to other ADAMTS family members. The therapeutic potential of inhibiting ADAMTS-4 to halt the progression of vascular disease after initialization of treatment is unlikely. However, it is not excluded that it might find a purpose as a biomarker of vascular disease, possibly as an indicator in a larger cytokine panel., (© 2022 S. Karger AG, Basel.)

It is impossible to analyze human-specific host-microbiome interactions using animal models and existing in vitro methods fail to support survival of human cells in direct contact with complex living microbiota for extended times. Here we describe a protocol for culturing human organ-on-a-chip (Organ Chip) microfluidic devices lined by human patient-derived primary intestinal epithelium in the presence of a physiologically relevant transluminal hypoxia gradient that enables their coculture with hundreds of different living aerobic and anaerobic bacteria found within the human gut microbiome. This protocol can be adapted to provide different levels of oxygen tension to facilitate coculturing of microbiome from different regions of gastrointestinal tract, and the same system can be applied with any other type of Organ Chip. This method can help to provide further insight into the host-microbiome interactions that contribute to human health and disease, enable discovery of new microbiome-related diagnostics and therapeutics, and provide a novel approach to advanced personalized medicine., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Gas samples were collected from 25 m long horizontal boreholes drilled into the excavation field at 10° inclination to the longwall face in two mining areas, Pesje and Preloge, in the Velenje Coal Mine, Slovenia, from 2013 to 2018. The degassing mechanism of coalbed gas and its stable isotopic composition ( δ 13 C CO2 , δ 13 C CH4 , and δ 2 H CH4 ) were investigated in boreholes in advance of eight working faces. The major coalbed gas constituents were CO 2 and methane. Gas concentrations and isotope values revealed that the methane is biogenic in origin with δ 13 C CH4 values of -69.4 to -29.5 ‰, δ 2 H CH4 values of -301 to -222 ‰, and a fractionation factor (α CO2 - CH4 ) of 0.998-1.073, suggesting that methane derives from microbial acetate fermentation and CO 2 reduction. The carbon dioxide methane index values ranged from 50.0-98.3 vol.% and δ 13 C CO2 values from -11.8 to -0.5 ‰, indicating that CO 2 is biogenic and endogenic in origin. The degassing mechanism results in isotope fractionation of methane and CO 2 for carbon isotopes up to 39.9 ‰ and up to 8.5 ‰, respectively, depending on the position of the excavation fields in space, e.g. under pre-mined coal area, fresh overburden.

Using low-cost portable air quality (AQ) monitoring devices is a growing trend in personal exposure studies, enabling a higher spatio-temporal resolution and identifying acute exposure to high concentrations. Comprehension of the results by participants is not guaranteed in exposure studies. However, information on personal exposure is multiplex, which calls for participant involvement in information design to maximise communication output and comprehension. This study describes and proposes a model of a user-centred design (UCD) approach for preparing a final report for participants involved in a multi-sensor personal exposure monitoring study performed in seven cities within the EU Horizon 2020 ICARUS project. Using a combination of human-centred design (HCD), human-information interaction (HII) and design thinking approaches, we iteratively included participants in the framing and design of the final report. User needs were mapped using a survey ( n = 82), and feedback on the draft report was obtained from a focus group ( n = 5). User requirements were assessed and validated using a post-campaign survey ( n = 31). The UCD research was conducted amongst participants in Ljubljana, Slovenia, and the results report was distributed among the participating cities across Europe. The feedback made it clear that the final report was well-received and helped participants better understand the influence of individual behaviours on personal exposure to air pollution.