Structures of TGF-ß with betaglycan and the signaling receptors reveal the mechanism whereby betaglycan potentiates receptor complex assembly and signaling.

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-ß (TGF-ß) family of signaling ligands. It is essential for embryonic development and tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-ß isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-ßs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-ß bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed novel binding interfaces that differ from those described for the closely related co-receptor of the TGF-ß family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-ß signal potentiation.

Resolution of a chronic occipital wound with exposed skull bone with a fish skin graft: a successful treatment approach.

Chronic skin defects in the head, face and neck pose challenges for closure, especially after multiple surgeries or radiation therapy. We report the case of a woman in her 70s with a chronic occipital wound following squamous cell carcinoma resections, resulting in exposed skull bone. Despite various options, we successfully treated the 4 cm x 5 cm wound with a Kerecis fish skin graft (FSG), observing significant improvement within a week. The FSG promoted granulation tissue formation, enabling subsequent full-thickness skin grafting from the patient's groin. Complete wound closure was achieved within 2 weeks, indicating FSG's efficacy in complex wound management. Our experience highlights FSG's potential as a valuable tool in wound healing and reconstruction, particularly in challenging cases involving the head and neck.

Postoperative outcomes and trends in computer-navigated and robotic-assisted total hip arthroplasty.

INTRODUCTION: As the volume of technology-assisted total hip arthroplasty (THA) increases, there is a need to characterise the outcomes of robotic-assisted (RA) and computer-navigated (CN) THA. The goal of this study was to assess outcomes and opioid consumption following CN-THA and RA-THA compared to conventionally-instrumented (CON) THA. METHODS: The Premier Database was queried for all patients who underwent primary, elective THA from 2015-2020. Patients were divided into 3 groups: CN, RA, or CON-THA. Yearly usage trends were assessed. Univariate and multivariate analyses were performed to assess the 90-day risk of postoperative complications. Opioid consumption was reported in morphine milligram equivalents (MME) for postoperative days (POD) 0 and 1. RESULTS: Overall, 474,707 elective THAs were identified (95.7% CON, 2.1% CN, 2.2% RA. After accounting for confounders, CN-THA patients were at decreased risk for periprosthetic joint infection (PJI) (aOR: 0.55, p < 0.001) and dislocation (aOR 0.45, p < 0.001), but increased risk for blood transfusion (aOR 1.97, <0.001) compared to CON-THA. RA-THA patients were at decreased risk of dislocation (aOR:0.66, p < 0.001) but increased risk for transfusion (aOR 1.20, p < 0.001), prosthesis breakage (aOR 3.88, p < 0.001), and periprosthetic fracture (aOR 1.72, p < 0.001). Opioid consumption for CN-THA patients was lower on POD1 and lower for RA-THA patients POD0 and 2 compared to CON-THA. DISCUSSION: CN-THA was associated with reduced rates of PJI and dislocation, but increased rates of blood transfusion while RA-THA was associated with decreased rates of dislocation, but increased rates of blood transfusion, prosthesis complications, and periprosthetic fracture compared to CON-THA. Technology-assisted THA was associated with lower postoperative opioid consumption.

Career trajectories, transition rates, and birthdate distributions: the rocky road from youth to senior level in men's European football.

This study aimed to assess youth-to-senior transition rates, quantify the magnitude of relative age effect (RAEs), and evaluate how RAEs affect these transitions in 9,527 men's national football players of England, France, Germany, Italy, and Spain. Regardless of national team, only -15%, 25%, and 40% of U17, U19, and U21 players successfully transitioned to the senior team, respectively, whilst -14%-24% progressed to senior level without being selected during youth. Data suggested a skewed birthdate distribution favouring relatively older players at U17, U19, and U21 levels across all countries, whereas RAEs were also present in England, Italy, and Spain at senior level. Youth-to-senior transition rates were modulated by birthdate at U17 and U19, whereby Q4 players were -2 and 1.5 times more likely to successfully transition at senior level than Q1 players, respectively. Selection at youth international level does not guarantee selection at senior level, but does make it more likely. Moreover, relatively younger athletes are disadvantaged in youth categories, although are more likely to transition to senior level once they have entered the pathway.

Treatment of Hip Cartilage Defects in Athletes.

Chondral defects in the athlete's hip are a relatively common occurrence, often presenting with debilitating pain and activity limitation. Preoperative identification of cartilage defects is challenging and there are many different modalities for treatment. Nonsurgical interventions, including activity modification, physical therapy, and injections, play a vital role, especially in less severe cases and as adjuncts to surgical intervention. Treating surgeons must be familiar with the cartilage restoration procedures available, including debridement, microfracture, and various implantation and transplantation options. Safe and effective management of cartilage defects is imperative to an athlete's return to sport. It is also imperative that surgeons are aware of all these various treatment options to determine what modality is best for their patients. This review serves to outline these options, cover the published literature, and provide general guidelines for surgeons when they encounter chondral defects in the office and the operating room.

Permissible HLA mismatches in 9/10 unrelated donor pediatric stem cell transplants using HLA-EMMA, an EBMT IEWP Study.

HSCT with mismatched unrelated donors (MMUD) is associated with inferior outcome compared to matched unrelated donors. We aimed to identify permissible mismatches using HLA-EMMA, which determines permissibility by analyzing amino-acid (AA) sequences, in a single center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. AA matching was evaluated for the whole HLA protein, the α-helices, and the ß-sheets, in both Host versus Graft (HvG) and Graft vs Host (GvH) direction. Superior EFS was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year, p=0.009), and in 21 patients matched for AA on the α-helices (αHvG, 90% vs 53%, p=0.002), similar to EFS with 10/10 MUDs (90% vs 80%, p=0.60). EFS was not related to ß-sheet AA matching, nor to matching in the GvH direction. OS trended similarly as EFS for AA mismatches (totalHvG, 92% vs 74%, p=0.075 and αHvG90% vs 71%, p=0.072). These findings were reproduced in an EBMT inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG-AA matching on the α-helices identifies 9/10 MMUD with permissible mismatches correlated with a favorable transplant outcome similar to matched donors.

Correction: Gender differences in quality of life in coronary artery disease patients with comorbidities undergoing coronary revascularization.

[This corrects the article DOI: 10.1371/journal.pone.0234543.].

Endovascular Treatment for Complex Vascular Pathologies in the Pediatric Population: Experience from a Center with Dual-Trained Neurosurgeons.

OBJECTIVE: Endovascular treatment of complex vascular pathologies in the pediatric population is often performed by nonpediatric subspecialists with adaptation of equipment and techniques developed for adult patients. We aimed to report our center's experience with safety and outcomes of endovascular treatments for pediatric vascular pathologies. METHODS: We performed a retrospective review of our endovascular database. All patients ≤18 years who underwent endovascular treatment between January 1, 2004 and December 1, 2022 were included. RESULTS: During the study time frame, 118 cerebral angiograms were performed for interventional purposes in 55 patients. Of these patients, 8(14.5%) had intracranial aneurysms, 21(38.2%) had intracranial arteriovenous malformations, 6(10.9%) had tumors, 5(9.1%) had arterial occlusions (n = 3) or dissections (n = 2), 8(14.5%) had vein of Galen malformations, and 7(12.7%) had other cerebrovascular conditions. Of the total 118 procedures, access-site complications occurred in 2(1.7%), intraprocedural complications occurred in 3(2.5%), and transient neurological deficits were observed after 2(1.7%). Treatment-related mortality occurred in 1(1.8%) patient. CONCLUSIONS: Neurointervention in pediatric patients was safe and effective in our experience.

Assessing expert reliability in determining intracranial EEG channel quality and introducing the automated bad channel detection algorithm.

Objective.To evaluate the inter- and intra-rater reliability for the identification of bad channels among neurologists, EEG Technologists, and naïve research personnel, and to compare their performance with the automated bad channel detection (ABCD) algorithm for detecting bad channels.Approach.Six Neurologists, ten EEG Technologists, and six naïve research personnel (22 raters in total) were asked to rate 1440 real intracranial EEG channels as good or bad. Intra- and interrater kappa statistics were calculated for each group. We then compared each group to the ABCD algorithm which uses spectral and temporal domain features to classify channels as good or bad.Main results.Analysis of channel ratings from our participants revealed variable intra-rater reliability within each group, with no significant differences across groups. Inter-rater reliability was moderate among neurologists and EEG Technologists but minimal among naïve participants. Neurologists demonstrated a slightly higher consistency in ratings than EEG Technologists. Both groups occasionally misclassified flat channels as good, and participants generally focused on low-frequency content for their assessments. The ABCD algorithm, in contrast, relied more on high-frequency content. A logistic regression model showed a linear relationship between the algorithm's ratings and user responses for predominantly good channels, but less so for channels rated as bad. Sensitivity and specificity analyses further highlighted differences in rating patterns among the groups, with neurologists showing higher sensitivity and naïve personnel higher specificity.Significance.Our study reveals the bias in human assessments of intracranial electroencephalography (iEEG) data quality and the tendency of even experienced professionals to overlook certain bad channels, highlighting the need for standardized, unbiased methods. The ABCD algorithm, outperforming human raters, suggests the potential of automated solutions for more reliable iEEG interpretation and seizure characterization, offering a reliable approach free from human biases.

Frequency-Chirped Magic Angle Spinning Dynamic Nuclear Polarization Combined with Electron Decoupling.

Magic angle spinning (MAS) dynamic nuclear polarization (DNP) increases the signal intensity of solid-state nuclear magnetic resonance. DNP typically uses continuous wave (CW) microwave irradiation close to the resonance frequency of unpaired electron spins. In this study, we demonstrate that frequency-chirped microwaves improve DNP performance under MAS. By modulating the gyrotron anode potential, we generate a train of microwave chirps with a maximum bandwidth of 310 MHz and a maximum incident power on the spinning sample of 18 W. We characterize the efficiency of chirped DNP using the following polarizing agents: TEMTriPol-1, AsymPolPOK, AMUPol, and Finland trityl. The effects of different chirp widths and periods are analyzed at different MAS frequencies and microwave powers. Furthermore, we show that chirped DNP can be combined with electron decoupling to improve signal intensity by 59%, compared to CW DNP without electron decoupling, using Finland trityl as a polarizing agent.

Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer.

BACKGROUND: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. METHODS: ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

Managing Cluster Headache in Patients with Medical, Psychiatric, and Surgical Comorbidities.

PURPOSE OF REVIEW: What should a provider know about medications and other treatments in patients with cluster headache who have medical, psychiatric, and surgical comorbidities? What conversations should providers have with patients about living with and managing cluster headache? RECENT FINDINGS: While the number of treatments used in cluster headache is relatively small, numerous considerations were identified related to managing patients with comorbidities. Many of these touch on cardiac, cardiovascular, and cerebrovascular health, but full histories are needed to guide safe and effective treatment. Both older and newer treatments may be contraindicated in certain patients with cluster headache or should be considered carefully. In addition to incorporating medical, psychiatric, and surgical histories in the management plan, collaboration with other providers may be beneficial. Providers should also inquire about patient practices and discuss participation in clinical trials that might be a good fit for the individual.

Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy.

Background: Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis. Methods: WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint. Results/Conclusions: At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.

Primary Hip Arthroscopy is Associated with Earlier Achievement of Substantial Clinical Benefit Compared to Revision Hip Arthroscopy for Femoroacetabular Impingement Syndrome.

PURPOSE: To compare time to achievement of clinically significant outcomes (CSOs) between patients undergoing primary and revision hip arthroscopy (HA) for femoroacetabular impingement syndrome (FAIS). METHODS: Patients undergoing primary and revision HA for FAIS with complete 6-month, 1-year, and 2-year Hip Outcome Score - Activities of Daily Living (HOS-ADL) and Sport Subscale (HOS-SS) were identified. Revision patients were propensity matched 1:4 to primary HA patients, controlling for age, sex, and body mass index (BMI). Time to achievement of minimal clinically important difference (MCID) and substantial clinical benefit (SCB) were compared alongside cumulative CSO achievement at 6, 12, and 24 months. Hazard ratios (HR) for predictors of earlier CSO achievement were identified with multivariate Cox regressions. RESULTS: Fifty revision HA patients were propensity-matched to 200 primary HA patients of similar age, sex, and BMI. Primary HA patients demonstrated a greater prevalence of regular preoperative physical activity (87% vs. 59%, p<0.001). Primary HA patients showed significantly greater SCB achievement for HOS-ADL at 6, 12, and 24 months (p<0.001) and significantly greater SCB achievement for HOS-SS at 12 and 24 months (p≤0.001) compared to revision HA patients. Primary HA patients achieved SCB for HOS-ADL (p<0.001) and HOS-SS (p=0.015) quicker than revision HA patients. Predictors of earlier CSO achievement included preoperative PRO score (HR: 0.98-1.02, p≤0.007), lower BMI (HR: 0.97, p=0.038), presence of physical activity (HR: 1.51, p=0.038), and absence of revision status (HR: 0.52-0.56, p≤0.019). CONCLUSIONS: Primary HA patients showed a quicker time to SCB achievement for HOS-ADL and HOS-SS compared to revision HA patients. Preoperative PRO score, lower BMI, regular physical activity, and primary HA status predicted earlier CSO achievement. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

Substrate complexity buffers negative interactions in a synthetic community of leaf litter degraders.

Leaf litter microbes collectively degrade plant polysaccharides, influencing land-atmosphere carbon exchange. An open question is how substrate complexity-defined as the structure of the saccharide and the amount of external processing by extracellular enzymes-influences species interactions. We tested the hypothesis that monosaccharides (i.e. xylose) promote negative interactions through resource competition, and polysaccharides (i.e. xylan) promote neutral or positive interactions through resource partitioning or synergism among extracellular enzymes. We assembled a three-species community of leaf litter-degrading bacteria isolated from a grassland site in Southern California. In the polysaccharide xylan, pairs of species stably coexisted and grew equally in coculture and in monoculture. Conversely, in the monosaccharide xylose, competitive exclusion and negative interactions prevailed. These pairwise dynamics remained consistent in a three-species community: all three species coexisted in xylan, while only two species coexisted in xylose, with one species capable of using peptone. A mathematical model showed that in xylose these dynamics could be explained by resource competition. Instead, the model could not predict the coexistence patterns in xylan, suggesting other interactions exist during biopolymer degradation. Overall, our study shows that substrate complexity influences species interactions and patterns of coexistence in a synthetic microbial community of leaf litter degraders.

Humans forage for reward in reinforcement learning tasks.

How do we make good decisions in uncertain environments? In psychology and neuroscience, the classic answer is that we calculate the value of each option and then compare the values to choose the most rewarding, modulo some exploratory noise. An ethologist, conversely, would argue that we commit to one option until its value drops below a threshold, at which point we start exploring other options. In order to determine which view better describes human decision-making, we developed a novel, foraging-inspired sequential decision-making model and used it to ask whether humans compare to threshold ("Forage") or compare alternatives ("Reinforcement-Learn" [RL]). We found that the foraging model was a better fit for participant behavior, better predicted the participants' tendency to repeat choices, and predicted the existence of held-out participants with a pattern of choice that was almost impossible under RL. Together, these results suggest that humans use foraging computations, rather than RL, even in classic reinforcement learning tasks.