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Morphologic Achilles tendon properties obtained via diagnostic ultrasound imaging are valuable in understanding Achilles tendon health and injury. Currently, limited information exists regarding Achilles tendon morphological properties amongst active aging adults based upon Victorian Institute of Sport Assessment (VISA-A) scores. Achilles tendon morphologic properties defined by VISA-A score groupings allow clinicians and researchers to compare data values amongst current patients. Purpose: Comparison of physically active aging adults Achilles tendon morphological properties with various VISA-A scores or a previous Achilles tendon rupture. A convenience sample of 121 participants (71 females, 50 males) at least moderately active and 50 years old, were recruited. Participants completed a VISA-A survey, and assigned groups by scores (Group 1: 90-100, Group 2: 70-89, Group 3: 45-69, Group 4: Previous Achilles tendon tear). Achilles tendon ultrasound imaging occurred at the malleolar line (The apex of the medial and lateral malleolus). Following imaging Achilles tendon cross-sectional area (CSA), thickness, and elastography were measured and analyzed. Participants with a previous Achilles tendon rupture displayed significantly larger tendon CSA and thickness compared with other groups (p<0.05). Individuals with VISA-A scores from 45-69 displayed significantly larger tendon CSA and thickness than participants with scores greater than 90 (p<0.03). No significant differences were noted for elastography between groups (p>0.05). Achilles tendon morphological differences exist based upon pain level in physically active aging adults. Diagnostic ultrasound may be used during assessment and rehabilitation of injured tendon tissue to inform about current tendon tissue properties.

Objective: Prosthetic restorations require functional occlusal planes to ensure therapeutic success. The purpose of the present study was to develop a new Broadrick flag support for a semi-adjustable articulator and to investigate the effectiveness of occlusal planes drawn using the Broadrick flag method by inexperienced practitioners in complex situations such as skeletal class II relationships associated with edentulous areas. MÉTHODOLOGY: The Broadrick flag support was designed and manufactured by the additive technique and was adapted to the Quick Master articulator. The QR code of the manufacturing file of the Broadrick flag support is accessible to any practitioner. Thirty-seven third-year students (inexperienced practitioners) were randomised into two groups for drawing occlusal planes on two models either with or without the Broadrick flag method. A prosthodontic professor (experienced practitioner) drew occlusal planes on the models to serve as references. Each model was analysed using a standardised method to measure the distances between the occlusal planes drawn by experienced and inexperienced practitioners. RÉSULTS: Only the distance measured for the right second molar of the first model with the Broadrick flag method was significantly shorter than those measured without using this method (p < 0.05, Wilcoxon test). Visual observations showed that only the second molar drawings of the inexperienced practitioners were above the drawings of the experienced practitioner., Conclusion: The Broadrick flag method helped inexperienced practitioners to draw occlusal planes of models in complex skeletal class II relationships associated with edentulous areas with natural teeth located both anterior and posterior to them., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (P int <5.0e-9) not previously observed for lipids. Of interest, the ASPH locus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (P joint <5.0e-9 in combination with P int <6.6e-6). Of these, the SLC8A1 locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management., Competing Interests: Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.

Interferon-gamma (IFNG) is a pro-inflammatory cytokine secreted by the porcine conceptus (embryo and extra-embryonic membranes) during the peri-implantation period of pregnancy. IFNG modifies the endometrial inflammatory immune response and is required for the implantation and survival of the conceptus. It is not known how IFNG from the conceptus trophectoderm is transported across the endometrial luminal epithelium (LE). In the present study, immunofluorescence analyses detected immunoreactive IFNG protein in both the trophectoderm and endometrial LE on Day 15 of pregnancy, while our previous research localized IFNG mRNA only to conceptus trophectoderm. Using minced endometrial explants to disrupt the barrier posed by the intact endometrial LE, treatment with recombinant IFNG induced the expression of genes that were not induced when IFNG was infused into the uterine lumen in vivo by McLendon et al. (Biology of Reproduction. 2020;103(5):1018-1029). We hypothesized that during pregnancy extracellular vesicles (EVs) serve as intercellular signaling vehicles to transport conceptus-derived IFNG across the intact endometrial LE and into the stromal compartment of the uterus. Western blotting detected the presence of IFNG in EVs isolated from the uterine fluid of pregnant gilts, but not nonpregnant gilts. Real-time PCR demonstrated increased expression of IFNG-stimulated genes in EV-treated endometrial explants and EV-mediated IFNG transport was confirmed in whole uterine sections cultured with EVs from Day 15 of pregnancy. These results suggest that EVs are involved in IFNG transport across the endometrial LE to enable paracrine communication between the conceptus and cells within the endometrial stroma., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The primary aim of this study was to evaluate the indications and additional information provided by videourodynamic study (VUDS) over urodynamic studies (UDS) in men with spinal cord injury (SCI) and neurogenic lower urinary tract dysfunction (NLUTD). The secondary aim was to determine the added value of VUDS and its impact on bladder management., Materials and Methods: Single-centre retrospective study of all men with SCI who underwent VUDS between 2011 and 2021. Participant characteristics, clinical data and indications for UDS and VUDS as well as bladder management were recorded. The added value of VUDS was defined as additional information not provided by standard UDS that impacted on bladder management (choice of voiding mode, surgical indication or type of surgery)., Results: Eighty-eight men with a median age of 52 years were included. In 20 men who were unable to perform self-catheterisation, the VUDS clarified the nature and extent of the obstruction and enabled targeted surgery to achieve reflex bladder emptying in all of them. VUDS also clarified the type and level of obstruction in 28 patients, enabling targeted surgery in 24. In 11 men, VUDS was performed as part of the preoperative assessment for a Brindley procedure or after this operation if a complication occurred during follow-up to confirm the need for further surgery or to target surgical revision. Overall, VUDS had added value in 59 patients (67%)., Conclusions: VUDS had added value over UDS in specific situations; the additional information provided impacted on bladder management in men with SCI and NLUTD., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations., (© 2024. The Author(s).)

Background: Previous studies suggest an association between Post-concussion syndrome (PCS) and depression, both highly prevalent after mTBI., Objective: To assess the prevalence and risk-factors of depression among patients with PCS 1 month after mTBI., Methods: We prospectively screened 372 mTBI patients admitted in two academic Emergency Departments between 2017 and 2019. One month after mTBI, we administered the Rivermead Post-concussion symptoms Questionnaire (RPQ) and the Patient Health Questionnaire (PHQ-9) questionnaires over the telephone. PCS and depression were defined by RPQ ≥ 12 and PHQ-9 ≥ 10. Multivariate multinomial regression identified baseline factors associated with PCS and depression., Results: Two hundred and eight completed RPQ and PHQ-9. Forty-seven patients (22.5%) met criteria for PCS, among which 22 (46.8%) met criteria for depression (PCS+D+). Patients with PCS but without depression were less likely to present with an associated injury (Coefficient = -1.6, p  = 0.047) and to report initial sadness (Coefficient = -2.5, p  = 0.03). Initial sadness (Coefficient = -1.3, p  = 0.047), associated injury (Coefficient = -1.9, p  = 0.008), as well as initial nausea (Coefficient = -1.8, p  = 0.002), and male sex (Coefficient = 1.8, p  = 0.002), were associated with the absence of depression and PCS in comparison with PCS+D+ patients., Conclusion: Among patients with PCS 1 month after mTBI, those with depression are more likely to present with initial sadness and with an associated injury.

Objective: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia., Methods: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes., Results: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocytes and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for β-glucuronidase (GUSB) as a promising new actor in adipocyte lipolysis., Conclusions: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment., 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 Author(s). Published by Elsevier GmbH.. All rights reserved.)

Obesity is a risk factor for many diseases, such as type 2 diabetes and cardiovascular diseases. In line with the need for precision medicine, the search for biomarkers reporting the progression of obesity- and diet-associated disorders is urgent. We used NMR to determine the metabolomics profile of key organs (lung, liver, heart, skeletal muscle, kidney, and brain) and serum from male C57Bl/6J mice (5 weeks old) fed for 6, 10, and 14 weeks on a high-fat and high-sucrose diet (HFHSD) vs. a standard diet (STD). We determined metabolite concentrations in the organs at each time point, which allowed us to discriminate age- and diet-related effects as well as the interactions between both, highlighting the need to evaluate the influence of age as a confounding factor on metabolic signatures. Notably, the analysis revealed the influence of time on metabolite concentrations in the STD condition, probably reflecting the juvenile-to-adult transition. Variations impacted the liver and lung metabolites, revealing the strong influence of the HFHS diet on normal metabolism maturation during youth.

The ability of cells to mount an interferon response to virus infections depends on intracellular nucleic acid sensing pattern recognition receptors (PRRs). RIG-I is an intracellular PRR that binds short double-stranded viral RNAs to trigger MAVS-dependent signalling. The RIG-I/MAVS signalling complex requires the coordinated activity of multiple kinases and E3 ubiquitin ligases to activate the transcription factors that drive type I and type III interferon production from infected cells. The linear ubiquitin chain assembly complex (LUBAC) regulates the activity of multiple receptor signalling pathways in both ligase-dependent and -independent ways. Here, we show that the three proteins that constitute LUBAC have separate functions in regulating RIG-I signalling. Both HOIP, the E3 ligase capable of generating M1-ubiquitin chains, and LUBAC accessory protein HOIL-1 are required for viral RNA sensing by RIG-I. The third LUBAC component, SHARPIN, is not required for RIG-I signalling. These data cement the role of LUBAC as a positive regulator of RIG-I signalling and as an important component of antiviral innate immune responses., (© 2023. The Author(s).)

Aims: Surgical Antibiotic Prophylaxis (SAP) in Nigeria is often not evidence based. The aim of this study is to test if the GADSA application can change prescription behaviour of surgeons in Nigeria. In addition, the study aims to identify AMS strategies and policies for the future., Methods: The GADSA gamified decision support app uses WHO and Sanford prescribing guidelines to deliver real-time persuasive technology feedback to surgeons through an interactive mentor. The app can advise on whether clinician's decisions align with SAP recommendations and provides the opportunity for clinicians to make adjustments. Twenty surgeons actively participated in a 6-month pilot study in three hospitals in Nigeria. The surgeons determined the risk of infection of a surgical procedure, and the need, type and duration of SAP. The study used a longitudinal approach to test whether the GADSA app significantly changed prescribing behaviour of participating surgeons by analysing the reported prescription decisions within the app., Results: 321 SAP prescriptions were recorded. Concerning the surgical risk decision, 12% of surgeons changed their decision to be in line with guidelines after app feedback (p < 0.001) and 10% of surgeons changed their decision about the need for SAP (p = 0.0035) to align with guidelines. The change in decision making for SAP use in terms of "type" and "duration" to align with guidelines was similar with 6% and 5% respectively (both p-values < 0.001)., Conclusion: This study suggests that the GADSA app, with its game based and feedback feature, could significantly change prescribing behaviour at the point of care in an African setting, which could help tackle the global challenge of antibiotic resistance., (© 2023. The Author(s).)

Background: Rheumatoid arthritis (RA) considerably impacts patients' lives. Patients' confidence in their ability to manage this impact, or self-efficacy, can be supported with self-management interventions. One approach is to use mobile health (mHealth) applications, which can additionally provide insight into disease impact by remotely monitoring patient-reported outcomes. However, user engagement with mHealth-apps is variable, and concerns exist that remote monitoring might make patients overly attentive to symptoms., Methods: App-based Education and GOal setting in RA (AEGORA) is a multicentre, pragmatic randomised controlled trial investigating an mHealth-based self-management intervention to improve self-efficacy and remotely monitor disease impact in patients with RA. The intervention is provided via an adapted version of the application Sidekick (Sidekick Health, Reykjavik, Iceland) and consists of education, goal setting, lifestyle advice, and remote assessment of the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire. Across two centres, 120 patients will be recruited and randomised (2:1:1) to usual care or intervention group A/B (study app with weekly/monthly prompts to complete the RAID, respectively). Outcomes are assessed at baseline and after 4-6 months. The primary endpoint is a clinically important improvement (≥ 5.5/110) in the Arthritis Self-Efficacy Scale in the combined intervention group compared to usual care. Secondary endpoints are (a) non-inferiority regarding pain catastrophising, as a measure of symptom hypervigilance; (b) superiority regarding the RAID, sleep quality, and physical activity; and (c) participant engagement with the study app. Finally, the relationship between engagement, prompted frequency of RAID questionnaires, and the primary and secondary outcomes will be explored., Discussion: The AEGORA trial aims to study the effectiveness of mHealth-based, multicomponent self-management support to improve self-efficacy in the context of RA, while providing potentially valuable insights into temporal disease activity dynamics and the feasibility and possible negative effects of remote symptom monitoring in this population., Trial Registration: Clinicaltrials.gov NCT05888181. Retrospectively registered on March 23, 2023. Study inclusion started on March 3, 2023., (© 2023. The Author(s).)

Introduction: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH., Methods: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded., Results: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L., Conclusion: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading., 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 B.V. All rights reserved.)

Background: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis., Methods: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APC Min/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells., Results: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APC Min/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020)., Conclusions: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Purpose: We assess the efficacy, safety, and predictive factors for failure of synthetic mid-urethral slings for the treatment of urinary incontinence in a large cohort of women with neurogenic lower urinary tract dysfunction., Materials and Methods: Women aged 18 years or older who received a synthetic mid-urethral sling for stress urinary incontinence or mixed urinary incontinence in 3 centers between 2004 and 2019 and who had a neurological disorder were included. Exclusion criteria were less than 1 year of follow-up, concomitant pelvic organ prolapse repair, previous synthetic sling implantation, and no baseline urodynamics. The primary outcome was surgical failure, defined as recurrence of stress urinary incontinence during follow-up. Kaplan-Meier analysis was used to estimate the 5-year failure rate. Adjusted Cox proportional hazard model was used to identify factors associated with surgical failure. Complications and reoperations during the follow-up have also been reported., Results: A total of 115 women with a median age of 53 years were included . The median follow-up duration was 75 months. The 5-year failure rate was 48% (95 CI 46%-57%). Age above 50 years, negative tension-free vaginal tape test and transobturator route were associated with surgical failure. Thirty-six patients (31.3%) underwent at least 1 reoperation for complications or failure, and 2 required definitive intermittent catheterization., Conclusions: Synthetic mid-urethral slings may be an acceptable alternative to autologous slings or artificial urinary sphincters for the treatment of stress urinary incontinence in a selected group of patients with neurogenic lower urinary tract dysfunction.

This paper presents inserexs , an open-source computer program that aims to pre-evaluate the different reflections for resonant elastic X-ray scattering (REXS) diffraction experiments. REXS is an extremely versatile technique that can provide positional and occupational information about the atoms present in a crystal. inserexs was conceived to help REXS experimentalists know beforehand which reflections to choose to determine a parameter of interest. Prior work has already proven this to be useful in the determination of atomic positions in oxide thin films. inserexs allows generalization to any given system and aims to popularize resonant diffraction as an alternative technique to improve the resolution of crystalline structures., (© Antonio Peña Corredor et al. 2023.)

The usual Lewinnek orientation for cup positioning in total hip arthroplasty is not suitable for all patients as it does not consider the patient mobility. We propose an ultrasound-based approach to compute a Functional Safe Zone (FSZ) considering daily positions. Our goal was to validate it, and to evaluate how the input parameters impact the FSZ size and barycentre. The accuracy of the FSZ was first assessed by comparing the FSZ computed by the proposed approach and the true FSZ determined by 3D modelling. Then, the input parameters' impact on the FSZ was studied using a principal component analysis. The FSZ was estimated with errors below 0.5° for mean anteversion, mean inclination, and at edges. The pelvic tilts and the neck orientation were found correlated to the FSZ mean orientation, and the target ROM and the prosthesis dimensions to the FSZ size. Integrated into the clinical workflow, this non-ionising approach can be used to easily determine an optimal patient-specific cup orientation minimising the risks of dislocation., (© 2022 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to assess midterm functional outcomes and complications of robot-assisted laparoscopic cystectomy with non-continent urinary diversion in patients with neurogenic lower urinary tract dysfunction., Materials and Methods: We performed a retrospective single center study including all patients who underwent robot-assisted laparoscopic cystectomy with non-continent urinary diversion between January 2008 and December 2018 for neurogenic lower urinary tract dysfunction. Perioperative data, early and late complications, reoperation rate, renal function, and patient satisfaction (PGI-I) were evaluated., Results: One hundred and forty patients were included (70 multiple sclerosis, 37 spinal cord injuries, 33 others) with a median follow-up of 29 months (12-49). The main indication for surgery was an inability to perform intermittent self-catheterization (n = 125, 89%). The early complication rate (<30 days) was 41% (n = 58), including 72% (n = 45) minor complications (Clavien I-II) and 29% (n = 17) major complications (Clavien III-V). Three patients died in the early postoperative period. Late complications appear in 41% (n = 57), with 9% (n = 13) being ureteroileal anastomotic stricture. The overall reintervention rate was 19% (n = 27), mainly for lithiasis surgery. Pre- and postoperative renal function were comparable. Most of patients reported an improvement in their quality of life following their surgery (PGI-I 1-2)., Conclusion: Robot-assisted laparoscopic cystectomy with non-continent urinary diversion may be of particular interest in patients with neurogenic lower urinary tract dysfunction who are unable to benefit from conservative treatment, as it provides midterm protection of the upper urinary tract and an improvement in quality of life., (© 2023 Wiley Periodicals LLC.)

Background Total joint arthroplasty (TJA) has moved to a value-based care model that emphasizes increased quality and decreased costs. Preoperative patient selection and optimization significantly improve postoperative outcomes, improve quality, and decrease systemic costs. We introduced a readmission risk assessment tool (RRAT) previously verified in the literature at a large, private practice, multispecialty hospital to determine if implementation could improve outcomes and decrease our readmission rates. Methods All patients were administered the RRAT scoring tool prior to surgery. All staff was trained prior by a team consisting of multiple orthopedic surgeons, internal medicine and cardiac specialists, and anesthesiologists. If the score received by the patient was greater or equal to 4, a letter was sent immediately to the operative physician to work on optimization and a list of options for optimization was provided. No patients were expressly denied surgery. Results All 4912 patients from September 2017 to March 2020 were screened using the RRAT tool. A total of 228 patients had an RRAT score greater than 4 and required notification of the index surgeon. The overall readmission rate was 2.61% for all patients. We noted a readmission rate of 2.35% for those with a score of <4, 4.27% for those between 4-6, and 13.64% for those with a readmission rate >6. The odds ratio of those readmitted with an RRAT score >6 was 6.5488 (1.9080-22.4775, 95% CI). The American Society of Anesthesiologists (ASA) score and RRAT score were significantly correlated (Spearman Rho =0.324, P<0.001). Thirty-day readmission rates across the system decreased from 3.7% to 2.61% (p<0.05) when compared to the readmission rate in the year prior to the application of RRAT (September 2016 - August 2017). Conclusion The preoperative RRAT score is significantly correlated with 30-day readmission rates. Notification of the surgeon preoperatively of risk factors with modification options significantly lowered readmission rates in our study. Preoperative optimization leads to a decreased readmission rate and surgeon involvement is paramount to adherence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Dundon et al.)

Introduction: The use of serum and family oral fluids for porcine reproductive and respiratory syndrome virus (PRRSV) surveillance in weaning-age pigs has been previously characterized. Characterizing more sample types similarly offers veterinarians and producers additional validated sample options for PRRSV surveillance in this subpopulation of pigs. Oral swab sampling is relatively easy and convenient; however, there is sparse information on how it compares to the reference sample type for PRRSV surveillance under field conditions. Therefore, this study's objective was to compare the PRRSV reverse-transcription real-time polymerase chain reaction (RT-rtPCR) test outcomes of oral swabs (OS) and sera samples obtained from weaning-age pig litters., Method: At an eligible breeding herd, six hundred twenty-three weaning-age piglets from 51 litters were each sampled for serum and OS and tested for PRRSV RNA by RT-rtPCR., Results and Discussion: PRRSV RT-rtPCR positivity rate was higher in serum samples (24 of 51 litters, 83 of 623 pigs, with a mean cycle threshold (Ct) value of RT-rtPCR-positive samples per litter ranging from 18.9 to 32.0) compared to OS samples (15 of 51 litters, 33 of 623 pigs, with a mean Ct of RT-rtPCR positive samples per litter ranging from 28.2 to 36.9); this highlights the importance of interpreting negative RT-rtPCR results from OS samples with caution. Every litter with a positive PRRSV RT-rtPCR OS had at least one viremic piglet, highlighting the authenticity of positive PRRSV RT-rtPCR tests using OS; in other words, there was no evidence of environmental PRRSV RNA being detected in OS. Cohen's kappa analysis (Ck = 0.638) indicated a substantial agreement between both sample types for identifying the true PRRSV status of weaning-age pigs., Competing Interests: CL was employed by Carthage Veterinary Services, Limited. 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 © 2023 Osemeke, VanKley, LeFevre, Peterson and Linhares.)

Purpose of Review: This review aims to summarize the recent findings about the contribution of the gut microbiome to muscle pathophysiology and discuss molecular pathways that may be involved in such process. Related findings in the context of cancer cachexia are outlined., Recent Findings: Many bacterial metabolites have been reported to exert a beneficial or detrimental impact on muscle physiology. Most of the evidence concentrates on short-chain fatty acids (SCFAs), with an emerging role for bile acids, bacterial amino acid metabolites (bAAms), and bacterial polyphenol metabolites. Other molecular players worth considering include cytokines, hormones, lipopolysaccharides, and quorum sensing molecules. The current literature clearly establishes the ability for the gut microbiome to modulate muscle function and mass. The understanding of the mechanisms underlying this gut-muscle axis may lead to the delivery of novel therapeutic tools to tackle muscle wasting in cancer cachexia, chronic kidney disease, liver fibrosis, and age-related sarcopenia., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support., (© 2022. The Author(s).)

Background: In Nigeria, the prescription of surgical antibiotic prophylaxis for prevention of surgical site infection tends to be driven by local policy rather than by published guidelines (e.g. WHO and Sanford)., Objectives: To triangulate three datasets and understand key barriers to implementation using a behavioural science framework., Methods: Surgeons ( N  = 94) from three teaching hospitals in Nigeria participated in an online survey and in focus group discussions about barriers to implementation. The theoretical domains framework (TDF) was used to structure question items and interview schedules. A subgroup ( N  = 20) piloted a gamified decision support app over the course of 6 months and reported barriers at the point of care., Results: Knowledge of guidelines and intention to implement them in practice was high. Key barriers to implementation were related to environmental context and resources and concern over potential consequences of implementing recommendations within the Nigerian context applicable for similar settings in low-to-middle-income countries., Conclusions: The environmental context and limited resource setting of Nigerian hospitals currently presents a significant barrier to implementation of WHO and Sanford guidelines. Research and data collected from the local context must directly inform the writing of future international guidelines to increase rates of implementation., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objective: Monitoring of viral loads (VL) for hepatitis B and C viruses (HBV; HCV) is essential to evaluate disease progression and treatment response. Automated, random-access rapid systems are becoming standard to provide clinicians with reliable VL. The aim of this study was to evaluate the analytical performances of the recently launched NeuMoDx™ for HBV-DNA and HCV-RNA quantification., Methods: Clinical samples routinely quantified on the Beckman-Veris system were either retrospectively (frozen samples; HBV n = 178, HCV n = 249), or in parallel (fresh primary tubes; HBV n = 103, HCV n = 117) tested using NeuMoDx™. Linearity range was assessed on serial dilutions of high-titre plasmas containing different genotypes for HBV (A-E, n = 9) and HCV (1a,1b,2-5, n = 12)., Results: Overall test failure, mostly internal control amplification failure, was 2.3% and was not influenced by matrix types (fresh or frozen). For HBV VL, κ agreement was 74%, with 27 (12.6%) discrepancies. Correlation between HBV assays on 72 quantified samples by both methods was excellent (r = 0.963) with a mean bias (NeuMoDx™-Veris) of 0.21 log IU/mL. For HCV VL, κ agreement reached 94%, with 9 (2.8%) discrepancies. The r correlation factor between assays on 104 samples was 0.960 with a mean bias of -0.14 log IU/mL (NeuMoDx™-Veris). Serial dilutions confirmed the claimed linear ranges for all analysed HBV and HCV genotypes. The mean turnaround time was 72 minutes (range 55-101 minutes) for HBV and 96 minutes (range 78-133 minutes) for HCV., Conclusion: Results obtained on the NeuMoDx™ confirmed the overall good functionality of the system with a short turn-around-time, full traceability and easy handling. These results on HBV and HCV VL look promising and should be challenged with further comparisons., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Evacuation of infected fluid in pleural infections is essential. To date, the use of an intrapleural fibrinolytic agent such as urokinase and DNase has not yet been assessed in infections managed by repeated therapeutic thoracentesis (RTT)., Methods: We performed a retrospective comparative study of two successive cohorts of consecutive patients with pleural infections from 2001 to 2018. Between 2001 and 2010, patients had RTT with intrapleural urokinase (RTT-U). After 2011, patients received intrapleural urokinase and DNase with RTT (RTT-UD). Data were collected through a standardized questionnaire., Results: One hundred and thirty-three patients were included: 93 were men and the mean age was 59 years (standard deviation 17.2). Eighty-one patients were treated with a combination of intrapleural urokinase and DNase, and 52 were treated with intrapleural urokinase only. In the RTT-UD, RTT failure occurred in 14 patients (17%) compared to 10 (19%) in the RTT-U group (P = 0.82). There was no difference between the two groups in intensive care unit admission, surgical referrals or in-hospital mortality. RTT-UD was associated with faster time to apyrexia (aOR = 0.51, 95%CI [0.37-0.72]), a reduced length of hospital stay (aOR = 0.61, 95%CI [0.52-0.73]) and a higher volume of total pleural fluid retrieved (aOR = 1.38, 95%CI [1.02-1.88]). Complications were rare with only one hemothorax in the RTT-UD group and no pneumothorax requiring drainage in either group., Conclusion: Compared to urokinase only, intrapleural use of urokinase and DNase in RTT was associated with quicker defervescence, shorter hospital stay and increased volumes of pleural fluid drained. Randomized controlled trials evaluating urokinase and DNase with RTT technique would be required to confirm these results., Competing Interests: The authors reported no conflict of interest related to this work. DLP, BB, PC, FP, ML, MK, CL, BD, JL, PT have nothing to disclose. SJ reports personal fees from Actelion, personal fees from AIRB, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Galecto, personal fees from Gilead, personal fees from GlaxoSmithKline, personal fees from LVL, personal fees from Mundipharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Savara-Serendex, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade., Competing Interests: DECLARATION OF INTERESTS LV, MB, SC, SLM, ML, IS, MT, GR, SP, MC, FC, CL, KB, MK, IG, CSF, VV, FC, WHF, and FLL: Nothing to disclose AB, JPG, and CR: Employees of Immusmol/Explicyte EO, AS: Employees of Astra Zeneca AI: Received research grants from Astra Zeneca, Bayer, BMS, Chugai, Merck, MSD, Pharmamar, Novartis, Roche, and received personal fees from Epizyme, Bayer, Lilly, Roche, and Springworks BB: Received grants from AstraZeneca , Pfizer , Eli Lilly , Onxeo , Bristol Myers Squibb , Inivata , Abbvie , Amgen , Blueprint Medicines , Celgene , GlaxoSmithKline , Ignyta , Ipsen , Merck KGaA , MSD Oncology , Nektar , PharmaMar , Sanofi , Spectrum Pharmaceuticals , Takeda , Tiziana Therapeutics , Cristal Therapeutics , Daiichi Sankyo , Janssen Oncology , OSE Immunotherapeutics , BeiGene , Boehringer Ingelheim , Genentech , SERVIER , Tolero Pharmaceuticals YL: Received grants and personal fees from Janssen, during the conduct of the study; personal fees and non-financial support from Astellas, grants and personal fees from Sanofi, personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from MSD, personal fees and non-financial support from BMS, personal fees from Clovis , personal fees and non-financial support from Seattle Genetics, personal fees from Incyte, personal fees from Pfizer. AM: Received research grants from Mersu, Bristol-Myers Squibb, Boehringer Ingelheim, Transgene, MSD and received personal fees from Bristol-Myers Squibb, AstraZeneca, MedImmune, Oncovir, Merieux JCS: Has received consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pharma Mar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda.

Background: The SAME device (i-SEP, France) is an innovative filtration-based autotransfusion device able to salvage and wash both red blood cells and platelets. This study evaluated the device performances using human whole blood with the hypothesis that the device will be able to salvage platelets while achieving a erythrocyte yield of 80% and removal ratios of 90% for heparin and 80% for major plasma proteins without inducing signification activation of salvaged cells., Methods: Thirty healthy human whole blood units (median volume, 478 ml) were diluted, heparinized, and processed by the device in two consecutive treatment cycles. Samples from the collection reservoir and the concentrated blood were analyzed. Complete blood count was performed to measure blood cell recovery rates. Flow cytometry evaluated the activation state and function of platelets and leukocytes. Heparin and plasma proteins were measured to assess washing performance., Results: The global erythrocyte yield was 88.1% (84.1 to 91.1%; median [25th to 75th]) with posttreatment hematocrits of 48.9% (44.8 to 51.4%) and 51.4% (48.4 to 53.2%) for the first and second cycles, respectively. Ektacytometry did not show evidence of erythrocyte alteration. Platelet recovery was 36.8% (26.3 to 43.4%), with posttreatment counts of 88 × 109/l (73 to 101 × 109/l) and 115 × 109/l (95 to 135 × 109/l) for the first and second cycles, respectively. Recovered platelets showed a low basal P-selectin expression at 10.8% (8.1 to 15.2%) and a strong response to thrombin-activating peptide. Leukocyte yield was 93.0% (90.1 to 95.7%) with no activation or cell death. Global removal ratios were 98.3% (97.8 to 98.9%), 98.2% (96.9 to 98.8%), and 88.3% (86.6 to 90.7%) for heparin, albumin, and fibrinogen, respectively. The processing times were 4.4 min (4.2 to 4.6 min) and 4.4 min (4.2 to 4.7 min) for the first and second cycles, respectively., Conclusions: This study demonstrated the performance of the SAME device. Platelets and red blood cells were salvaged without significant impact on cell integrity and function. In the meantime, leukocytes were not activated, and the washing quality of the device prevented reinfusion of high concentrations of heparin and plasma proteins., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

Red blood cell production, or erythropoiesis, is a proliferative process that requires tight regulation. Erythropoietin (Epo) is a glycoprotein cytokine that plays a major role in erythropoiesis by triggering erythroid progenitors/precursors of varying sensitivity. The concentration of Epo in bone marrow is hypothesized to be suboptimal, and the survival of erythroid cells has been suggested to depend on Epo sensitivity. However, the key factors that control Epo sensitivity remain unknown. Two types of transferrin receptors (TfRs), TfR1 and TfR2, are known to play a role in iron uptake in erythroid cells. Here, we hypothesized that TfRs may additionally modulate Epo sensitivity during erythropoiesis by modulating Epo receptor (EpoR) signaling. Using an Epo-sensitive UT-7 (UT7/Epo) erythroid cell and human erythroid progenitor cell models, we report that iron-loaded transferrin, that is, holo-transferrin (holo-Tf), synergizes with suboptimal Epo levels to improve erythroid cell survival, proliferation, and differentiation. This is accomplished via the major signaling pathways of erythropoiesis, which include signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide-3-kinase (PI3K)/AKT. Furthermore, we found that this cooperation is improved by, but does not require, the internalization of TfR1. Interestingly, we observed that loss of TfR2 stabilizes EpoR levels and abolishes the beneficial effects of holo-Tf. Overall, these data reveal novel signaling properties of TfRs, which involve the regulation of erythropoiesis through EpoR signaling., Competing Interests: Conflict of interest disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Mesenchymal stem cells from healthy adipose tissue are adipocytes progenitors with immunosuppressive potential that are used for years in cell therapy. Whether adipose stem cells (ASC) may prevent inflammation in early obesity is not known. To address this question, we performed a kinetic study of high-fat (HF) diet induced obesity in mice to follow the immune regulating functions of adipose stem cells (ASC) isolated from the subcutaneous (SAT) and the visceral adipose tissue (VAT). Our results show that, early in obesity and before inflammation was detected, HF diet durably and differently activated ASC from SAT and VAT. Subcutaneous ASC from HF-fed mice strongly inhibited the proliferation of activated T lymphocytes, whereas visceral ASC selectively inhibited TNFα expression by macrophages and simultaneously released higher concentrations of IL6. These depot specific differences may contribute to the low-grade inflammation that develops with obesity in VAT while inflammation in SAT is delayed. The mechanisms involved differ from those already described for naïve cells activation with inflammatory cytokines and probably engaged metabolic activation. These results evidence that adipose stem cells are metabolic sensors acquiring an obesity-primed immunocompetent state in answer to depot-specific intrinsic features with overnutrition, placing these cells ahead of inflammation in the local dialog with immune cells., (© 2021 Federation of American Societies for Experimental Biology.)

Thin deposits of aligned semiconducting titanium oxide and of zinc oxide nanowires are prepared by grazing incidence spraying on transparent substrates. By measuring the transmittance of linearly polarized light of these anisotropic assemblies as compared to that of randomly oriented nanowires and of spherical nanoparticles, we find that titanium oxide nanowires exhibit an orientation-dependent variation of the apparent optical band gap energy at room temperature (>100 meV), depending on the direction of the polarization of the light with respect to the direction of alignment of the nanowires.

Spinal cord injury (SCI) is a complex disease that affects not only sensory and motor pathways below the neurological level of injury (NLI) but also all the organs and systems situated below this NLI. This multisystem impairment implies comprehensive management in dedicated SCI specialized centers, by interdisciplinary and multidisciplinary teams, able to treat not only the neurological impairment, but also all the systems and organs affected. After a brief history of the Spinal Cord Medicine, the author describes how to determine the level and severity of a SCI based on the International Standards for Neurological Classification of Spinal Cord Injury and the prognosis factors of recovery. This article provides also a review of the numerous SCI-related impairments (except for urinary, sexual problems and pain treated separately in this issue), their principles of management and related complications., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Assessing the role of lactogenic hormones in human mammary gland development is limited due to issues accessing tissue samples and so development of a human in vitro three-dimensional mammosphere model with functions similar to secretory alveoli in the mammary gland can aid to overcome this shortfall. In this study, a mammosphere model has been characterised using human mammary epithelial cells grown on either mouse extracellular matrix or agarose and showed insulin is essential for formation of mammospheres. Insulin was shown to up-regulate extracellular matrix genes. Microarray analysis of these mammospheres revealed an up-regulation of differentiation, cell-cell junctions, and cytoskeleton organisation functions, suggesting mammosphere formation may be regulated through ILK signalling. Comparison of insulin and IGF-1 effects on mammosphere signalling showed that although IGF-1 could induce spherical structures, the cells did not polarise correctly as shown by the absence of up-regulation of polarisation genes and did not induce the expression of milk protein genes. This study demonstrated a major role for insulin in mammary acinar development for secretory differentiation and function indicating the potential for reduced lactational efficiency in women with obesity and gestational diabetes.

Obesity is associated with both chronic and acute respiratory illnesses, such as asthma, chronic obstructive pulmonary disease (COPD) or increased susceptibility to infectious diseases. Anatomical but also systemic and local metabolic alterations are proposed contributors to the pathophysiology of lung diseases in the context of obesity. To bring perspective to this discussion, we used NMR to compare the obesity-associated metabolomic profiles of the lung with those of the liver, heart, skeletal muscles, kidneys, brain and serum from male C57Bl/6J mice fed with a high-fat and high-sucrose (HFHSD) diet vs. standard (SD) chow for 14 weeks. Our results showed that the lung was the second most affected organ after the liver, and that the two organs shared reduced one-carbon (1C) metabolism and increased lipid accumulation. Altered 1C metabolism was found in all organs and in the serum, but serine levels were increased only in the lung of HFHSD compared to SD. Lastly, tricarboxylic acid (TCA)-derived metabolites were specifically and oppositely regulated in the serum and kidneys but not in other organs. Collectively, our data highlighted that HFHSD induced specific metabolic changes in all organs, the lung being the second most affected organ, the main alterations affecting metabolite concentrations of the 1C pathway and, to a minor extend, TCA. The absolute metabolite quantification performed in this study reveals some metabolic specificities affecting both the liver and the lung, that may reveal common metabolic determinants to the ongoing pathological process.

Efficient erythropoiesis relies on the expression of the transferrin receptor type 2 (TFR2). In erythroid precursors, TFR2 facilitates the export of the erythropoietin receptor (EPOR) to cell surface, which ensures the survival and proliferation of erythroblasts. Although TFR2 has a crucial role in erythropoiesis regulation, its mechanism of action remains to be clarified. To understand its role better, we aimed at identifying its protein partners by mass-spectrometry after immunoprecipitation in erythroid cells. Here we report the kinase MRCKα (myotonic dystrophy kinase-related CDC42-binding kinase α) as a new partner of both TFR2 and EPOR in erythroblasts. We show that MRCKα is co-expressed with TFR2, and TFR1 during terminal differentiation and regulates the internalization of the two types of transferrin receptors. The knockdown of MRCKα by shRNA in human primary erythroblasts leads to a decreased cell surface expression of both TFR1 and TFR2, an increased cell-surface expression of EPOR, and a delayed differentiation. Additionally, knockout of Mrckα in the murine MEDEP cells also leads to a striking delay in erythropoiesis, showcasing the importance of this kinase in both species. Our data highlight the importance of MRCKα in the regulation of erythropoiesis., (© 2021 Wiley Periodicals LLC.)

Achromatium is a long known uncultured giant gammaproteobacterium forming intracellular CaCO 3 that impacts C and S geochemical cycles functioning in some anoxic sediments and at oxic-anoxic boundaries. While intracellular CaCO 3 granules have first been described as Ca oxalate then colloidal CaCO 3 more than one century ago, they have often been referred to as crystalline solids and more specifically calcite over the last 25 years. Such a crystallographic distinction is important since the respective chemical reactivities of amorphous calcium carbonate (ACC) and calcite, hence their potential physiological role and conditions of formation, are significantly different. Here, we analyzed the intracellular CaCO 3 granules of Achromatium cells from Lake Pavin using a combination of Raman microspectroscopy and scanning electron microscopy. Granules in intact Achromatium cells were unequivocally composed of ACC. Moreover, ACC spontaneously transformed into calcite when irradiated at high laser irradiance during Raman analyses. Few ACC granules also transformed spontaneously into calcite in lysed cells upon cell death and/or sample preparation. Overall, the present study supports the original claims that intracellular Ca-carbonates in Achromatium are amorphous and not crystalline. In that sense, Achromatium is similar to a diverse group of Cyanobacteria and a recently discovered magnetotactic alphaproteobacterium, which all form intracellular ACC. The implications for the physiology and ecology of Achromatium are discussed. Whether the mechanisms responsible for the preservation of such unstable compounds in these bacteria are similar to those involved in numerous ACC-forming eukaryotes remains to be discovered. Last, we recommend to future studies addressing the crystallinity of CaCO 3 granules in Achromatium cells recovered from diverse environments all over the world to take care of the potential pitfalls evidenced by the present study., (© 2020 John Wiley & Sons Ltd.)

Objective: Use next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting., Design: A diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019., Setting: Inpatient and outpatient genetics service at two large academic centres in Singapore., Patients: Inclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay., Exclusion Criteria: patients with known genetic disorders, either after clinical assessment or investigations (such as karyotype or chromosomal microarray)., Interventions: Use of NGS technology-whole exome sequencing (WES) or whole genome sequencing (WGS)., Main Outcome Measures: (1) Diagnostic yield by sequencing type, (2) diagnostic yield by phenotypical categories, (3) reduction in time to diagnosis and (4) change in clinical outcomes and management., Results: We demonstrate a 37.8% diagnostic yield for WES (n=172) and a 33.3% yield for WGS (n=24). The yield was higher when sequencing was conducted on trios (40.2%), as well as for certain phenotypes (neuromuscular, 54%, and skeletal dysplasia, 50%). In addition to aiding genetic counselling in 100% of the families, a positive result led to a change in treatment in 27% of patients., Conclusion: Genomic sequencing is an effective method for diagnosing rare disease or previous 'undiagnosed' disease. The clinical utility of WES/WGS is seen in the shortened time to diagnosis and the discovery of novel variants. Additionally, reaching a diagnosis significantly impacts families and leads to alteration in management of these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Ti-modified LaFeO 3 /β-SiC alveolar foams were used as immobilized, highly robust dual catalysts with combined photocatalytic wet peroxide oxidation and photocatalytic activity under UV-A light. They were prepared by incipient wetness impregnation of a β-SiC foam support, by implementing a sol-gel Pechini synthesis at the foam surface in the presence of dried amorphous sol-gel titania as a titanium source. The physicochemical and catalytic features suggest the stabilization at the foam surface of a substituted La 1- x Ti x FeO 3 catalyst analogous to its powdery counterpart. Taking 4-chlorophenol removal in water as a model reaction, its dual nature enables both high reaction rates and full total organic carbon (TOC) conversion because of a synergy effect, while its macroscopic structure overcomes the drawback of working with powdery catalysts. Further, it yields photonic efficiencies for degradation and mineralization of ca. 9.4 and 38%, respectively, that strongly outperform those obtained with a reference TiO 2 P25/β-SiC foam photocatalyst. The enhancement of the catalyst robustness upon Ti modification prevents any Fe leaching to the solution, and therefore, the optimized macroscopic foam catalyst with 10 wt % catalyst loading operates through pure heterogeneous surface reactions, without any activity loss during reusability test cycles.

Objectives: Deep infiltrating endometriosis (DIE) of the rectosigmoid is associated with painful symptoms. When medical treatment is ineffective, surgical resection remains the standard treatment, despite significant risk of adverse events. High-intensity focused ultrasound (HIFU) is a minimally invasive ablative procedure. Focal One® is a transrectal HIFU (TR-HIFU) device used in prostate cancer treatment. The primary objective of this study was to confirm the feasibility of treatment with TR-HIFU in patients presenting with posterior DIE with rectosigmoid involvement. We also assessed its safety and clinical efficacy in this context., Methods: This was a non-controlled, prospective, Phase-I clinical trial in a French University Hospital which is a multidisciplinary center for management of endometriosis. Included were patients older than 25 years, without plans to conceive within 6 months, who presented with a single lesion of posterior DIE, with rectosigmoid invasion, after failure of hormonal therapy. All lesions were assessed preoperatively using transvaginal sonography and magnetic resonance imaging. Patients completed questionnaires on gynecological and intestinal symptoms (similar to a visual analog scale (VAS)), and on quality of life (Medical Outcomes Study 36-item short-form survey (SF-36) and, for the second half of patients recruited, symptom scoring system for constipation (KESS), female sexual function index (FSFI) and endometriosis health profile short-version score (EHP-5)), before, and at 1, 3 and 6 months after, TR-HIFU treatment with a Focal One real-time ultrasound-guided HIFU device., Results: Twenty-three consecutive patients were included in the study between September 2015 and October 2019. All 23 lesions were visualized, giving a detection rate of 100%. Twenty lesions were treated ('feasibility rate', 87.0%): in 13 the whole lesion was treated and in seven the lesion was treated partially. The mean duration of the TR-HIFU procedure was 55.6 min. We observed a significant improvement in VAS score at 6 months, with differences relative to preoperative scores as follows, for: dysmenorrhea (-3.6, P = 0.004), dyspareunia (-2.4, P = 0.006), diarrhea (-3.0, P = 0.006), constipation (-3.0, P = 0.002), dyschezia (-3.2, P = 0.003), false urge to defecate (-3.3, P = 0.007), posterior pelvic pain (-3.8, P = 0.002) and asthenia (-3.8, P = 0.002). There was also a significant improvement in the SF-36 score, with an increase at 6 months relative to the preoperative score in both the physical component summary (+ 9.3%, P = 0.002) and mental component summary (+ 10.9%, P = 0.017). No major complications occurred during or after any procedure., Conclusions: TR-HIFU therapy for posterior DIE is feasible. If its efficacy and safety are confirmed, it could be a minimally invasive alternative to surgery for the treatment of rectosigmoid endometriosis. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Background and Purpose: The effects of direct oral anticoagulants in nonvalvular atrial fibrillation should be assessed in actual conditions of use. France has near-universal healthcare coverage with a unified healthcare information system, allowing large population-based analyses. NAXOS (Evaluation of Apixaban in Stroke and Systemic Embolism Prevention in Patients With Nonvalvular Atrial Fibrillation) aimed to compare the safety, effectiveness, and mortality of apixaban with vitamin K antagonists (VKAs), rivaroxaban, and dabigatran, in oral anticoagulant-naive patients with nonvalvular atrial fibrillation., Methods: This was an observational study using French National Health System claims data and including all adults with nonvalvular atrial fibrillation who initiated oral anticoagulant between 2014 and 2016. Outcomes of interest were major bleeding events leading to hospitalization (safety), stroke and systemic thromboembolic events (effectiveness), and all-cause mortality. Four approaches were used for comparative analyses: matching on propensity score (PS; 1:n); as a sensitivity analysis, matching on high-dimensional PS; adjustment on PS; and adjustment on known confounders. For each outcome, cumulative incidence rates accounting for competing risks of death were estimated., Results: Overall, 321 501 patients were analyzed, of whom 35.0%, 27.2%, 31.1%, and 6.6% initiated VKAs, apixaban, rivaroxaban, and dabigatran, respectively. Apixaban was associated with a lower PS-matched risk of major bleeding compared with VKAs (hazard ratio [HR], 0.43 [95% CI, 0.40-0.46]) and rivaroxaban (HR, 0.67 [95% CI, 0.63-0.72]), but not dabigatran (HR, 0.93 [95% CI, 0.81-1.08]). Apixaban was associated with a lower risk of stroke and systemic thromboembolic event compared with VKAs (HR, 0.60 [95% CI, 0.56-0.65]), but not rivaroxaban (HR, 1.05 [95% CI, 0.97-1.15]) or dabigatran (HR, 0.93 [95% CI, 0.78-1.11]). All-cause mortality was lower with apixaban than with VKAs, but not lower than with rivaroxaban or dabigatran., Conclusions: Apixaban was associated with superior safety, effectiveness, and lower mortality than VKAs; with superior safety than rivaroxaban and similar safety to dabigatran; and with similar effectiveness when compared with rivaroxaban or dabigatran. These observational data suggest potentially important differences in outcomes between direct oral anticoagulants, which should be explored in randomized trials.

The anterior pelvic plane (APP) defined by both iliac spines and the pubic symphysis, is essential in total hip arthroplasty (THA) for the orientation of the prosthetic cup. However, the APP is nowadays still difficult to determine in computer assisted orthopedic surgery (CAOS). We propose to use a statistical shape model (SSM) of the pelvis to estimate the APP from ipsilateral anatomical landmarks, more easily accessible during surgery in computer assisted THA with the patient in lateral decubitus position. A SSM of the pelvis has been built from 40 male pelvises. Various ipsilateral anatomical landmarks have been extracted from these data and used to deform the SSM. Fitting the SSM to several combinations of these landmarks, we were able to reconstruct the pelvis with an accuracy between 2.8mm and 4.4mm, and estimate the APP inclination with an angular error between 1.3° and 2.8°, depending on the landmarks fitted. Results are promising and show that the APP could be acquired during the intervention from ipsilateral landmarks only.

Study Question: Do human granulosa cells (GCs) ingest and destroy apoptotic oocytes?, Summary Answer: Somatic GCs ingest and destroy apoptotic oocytes and other apoptotic substrates through unconventional autophagy-assisted phagocytosis., What Is Known Already: Most (99%) ovarian germ cells undergo apoptosis through follicular atresia. The mode of cleaning of atretic follicles from the ovary is unclear. Ovarian GCs share striking similarities with testicular Sertoli cells with respect to their origin and function. Somatic Sertoli cells are responsible for the elimination of apoptotic spermatogenic cells through unconventional autophagy-assisted phagocytosis., Study Design, Size, Duration: Human GCs were tested for the ability to ingest and destroy the apoptotic oocytes and other apoptotic substrates. A systemic study of the main phagocytosis steps has been performed at different time points after loading of apoptotic substrates into the GC., Participants/materials, Setting, Methods: Primary cultures of GC retrieved following controlled ovarian stimulation of five women for IVF/ICSI and a human granulosa KGN cell line were incubated with different apoptotic substrates: oocytes which underwent spontaneous apoptosis during the cultivation of immature germ cells for IVF/ICSI; apoptotic KGN cells; and apoptotic membranes from rat retinas. Cultured GC were analyzed for the presence of specific molecular markers characteristic of different steps of phagocytic and autophagy machineries by immunocytochemistry, confocal microscopy, transmission electron microscopy and western blotting, before and after loading with apoptotic substrates., Main Results and the Role of Chance: Incubation of human GC with apoptotic substrates resulted in their translocation in cell cytoplasm, concomitant with activation of the phagocytosis receptor c-mer proto-oncogene tyrosine kinase MERTK (P < 0.001), clumping of motor molecule myosin II, recruitment of autophagy proteins: autophagy-related protein 5 (ATG5), autophagy-related protein 6 (Beclin1) and the rise of a membrane form of microtubule-associated protein 1 light chain 3 (LC3-II) protein. Ingestion of apoptotic substrates was accompanied by increased expression of the lysosomal protease Cathepsin D (P < 0.001), and a rise of lysosomes in the GCs, as assessed by different techniques. The level of autophagy adaptor, sequestosome 1/p62 (p62) protein remained unchanged., Large Scale Data: N/A., Limitations, Reasons for Caution: The number of patients described here is limited. Also the dependence of phagocytosis on reproductive hormone status of patients should be analyzed., Wider Implications of the Findings: Removal of apoptotic oocytes by surrounding GC seems likely to be a physiological mechanism involved in follicular atresia. Proper functioning of this mechanism may be a new strategy for the treatment of ovarian dysfunctions associated with an imbalance in content of germ cells in the ovaries, such as premature ovarian failure and polycystic ovary syndrome., Study Funding/competing Interest(s): The study was funded by Rennes Metropole (AIS 2015) and Agence de BioMédecine. This work was supported by funding from Université de Rennes1, Institut National de la Santé et de la Recherche Médicale (INSERM) and CHU de Rennes. A.B. is funded in part by the program Actions Concertées Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. This work is supported by the Agence Nationale de la Recherche Grants ANR-17-CE14-0038 and ANR-10-LABX-73. The authors declare no competing interests., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Research Question: Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20-25% of cases. In rare cases, sequence variants of the NR5A1/SF-1 gene may result in POI, or in various disorders of gonadal development (DGD) or adrenal insufficiency., Design: This study describes the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound and genetic characteristics are reported., Results: The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified in one family: p.Cys283Phe (c.848G>T), and the NR5A1 sequence variant c.86G>C was found in the other family., Conclusion: Sequence variation of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variant is identified, genetic counselling is essential for the patient and his/her family., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Rationale: 3-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance derived from phencyclidine. Although it can lead to severe intoxications, the main manifestations and optimal management have not been well characterized. Here, we report 2 cases of 3-MeO-PCP intoxication in the same patient, and summarize the manifestations of this intoxication reported in literature., Patient Concerns: A 17-year-old male purchased a bag of 3-MeO-PCP on the Internet but took an oral dose (200 mg) that corresponds to the less active isomer 4-MeO-PCP. He developed high blood pressure (158/131 mm Hg), tachycardia (100 bpm), and neurological manifestations (confusion, hypertonia, nystagmus, and then agitation). A maculopapular rash appeared, although this may have been related to the administration of midazolam. Hyperlactatemia (2.6 mmol/L) was the main laboratory finding. Seven days later, he returned to the emergency department after sniffing 50 mg of 3-MeO-PCP. High blood pressure, tachycardia, and neurological manifestations (psychomotor impairment and dysarthria) were present but less severe than after the first intoxication., Diagnosis: In the first intoxication, the blood and urine 3-MeO-PCP concentrations were, respectively, 71.1 ng/mL and 706.9 ng/mL. Conventional toxicity tests were all negative. In the second intoxication, biological samples were not available., Interventions: In the first intoxication, treatment consisted of intravenous hydration and midazolam. The patient was transferred to an intensive care unit for monitoring. After the second intoxication, he was monitored for 12 hours., Outcomes: The patient's condition improved quickly in both cases., Lessons: These cases provide additional information on the manifestations of 3-MeO-PCP intoxication. These manifestations are mainly cardiovascular (high blood pressure, tachycardia) and neurological. The fact that second (50 mg) intoxication was less severe than the first (200 mg) is suggestive of a dose-effect relationship for 3-MeO-PCP. The first case also emphasizes the risk of dosing errors caused by the similarity between the names "3-MeO-PCP" and "4-MeO-PCP."

This study aimed to explore how social media is being used by sports nutritionists as part of service provision, as well as practitioners' experiences and opinions of its use in practice. An exploratory sequential mixed methods approach was used during this research. Forty-four sports nutritionists completed an online survey detailing their personal and professional social media use. Semi-structured follow-up interviews were conducted with 16 participants who volunteered to do so. Survey responses were collated and reported as descriptive statistics. Interviews were thematically analysed. Social media was used by 89% of sports nutritionists to support practice, of which 97% perceived its use to be beneficial. Platforms were used to deliver information and resources, and support athletes online via pages, groups and 1-2-1 messaging. Social media facilitated improved communication between the practitioner and the athlete, as well as facilitating mobile and visual learning. Lack of digital intervention training and time were reported as challenges to social media use in practice. Sports nutritionists have embraced social media as an extension of service provision. Professional education should now consider supporting nutritionists' in developing digital professionalism.

Context: High vertical ground reaction force (vGRF) when initiating ground contact during jump landing is one biomechanical factor that may increase risk of anterior cruciate ligament injury. Intervention programs have been developed to decrease vGRF to reduce injury risk, yet generating high forces is still critical for performing dynamic activities such as a vertical jump task., Objective: To evaluate if a jump-landing feedback intervention, cueing a decrease in vGRF, would impair vertical jump performance in a separate task (Vertmax)., Design: Randomized controlled trial. Patients (or Other Participants): Forty-eight recreationally active females (feedback: n = 31; 19.63 [1.54] y, 1.6 [0.08] cm, 58.13 [7.84] kg and control: n = 15; 19.6 [1.68] y, 1.64 [0.05] cm, 60.11 [8.36] kg) participated in this study., Intervention: Peak vGRF during a jump landing and Vertmax were recorded at baseline and 4 weeks post. The feedback group participated in 12 sessions over the 4-week period consisting of feedback provided for 6 sets of 6 jumps off a 30-cm box. The control group was instructed to return to the lab 28 days following the baseline measurements., Main Outcome Measures: Change scores (postbaseline) were calculated for peak vGRF and Vertmax. Group differences were evaluated for peak vGRF and Vertmax using a Mann-Whitney U test (P < .05)., Results: There were no significant differences between groups at baseline (P > .05). The feedback group (-0.5 [0.3] N/kg) demonstrated a greater decrease in vGRF compared with the control group (0.01 [0.3] N/kg) (t(46) = -5.52, P < .001). There were no significant differences in change in Vertmax between groups (feedback = 0.9 [2.2] cm, control = 0.06 [2.1] cm; t(46) = 0.46, P = .64)., Conclusions: While the feedback intervention was effective in decreasing vGRF when landing from a jump, these participants did not demonstrate changes in vertical jump performance when assessed during a different task. Practitioners should consider implementing feedback intervention programs to reduce peak vGRF, without worry of diminished vertical jump performance.