Men and women demonstrate comparable rates of failures and reoperations following primary osteochondral allograft transplantation of the knee, but women undergo reoperation sooner.

PURPOSE: To compare the differences between men and women who receive primary osteochondral allograft transplantation of the knee with regard to preoperative disease presentation, failures and reoperations. METHODS: A retrospective review of patients ≥18 years old who underwent primary osteochondral allograft transplantation between 2002 and 2020 by a single surgeon with a minimum of 2-year follow-up was performed. Demographic, preoperative, intraoperative and postoperative data were collected for all included patients. Patients were then assigned to two groups, either male or female, based on their reported sex. Statistical analysis was performed to assess sex-related differences in baseline characteristics, comparative survival analysis for determining survival probabilities, and regression analysis for determining variables associated with subsequent reoperation or failure. RESULTS: Among the 437 patients that were identified, 337 patients (77.1% follow-up, 161 men, 176 women) with a minimum of 2-year follow-up were included in our study. The mean age of included patients was 31.3 ± 9.9 years (range, 18.0-55.9), with a BMI of 26.7 ± 4.4 (range, 19.0-39.0) and a mean follow-up of 5.6 ± 2.6 years (range, 2.0-16.3). Male patients had significantly higher body mass index (BMI) (p ≤ 0.01), were more likely to have lesions on the medial femoral condyle (p = 0.041), and had larger lesions at the medial femoral condyle (p ≤ 0.01) and lateral femoral condyle (p ≤ 0.01). 36.8% of patients experienced subsequent reoperation (59 male, 65 female). Mean time to reoperation was 3.5 ± 2.8 years (range, 0.4-16.3 years) in males and 2.1 ± 1.9 years (range, 0.1-13.5 years) in females. No significant difference was found between the two groups with regard to reoperation rates (n.s.) or survivability free from reoperation (n.s.), but females were found to undergo reoperation sooner (p = 0.028). Sixty-three (18.7%) patients experienced subsequent graft failure (36 male, 27 female). No significant difference was found between the two groups in terms of failure rates, time to failure, survivability free from failure, or mode of failure (n.s. for all). CONCLUSIONS: Despite several differences in baseline demographics and intraoperative variables, no significant differences were found between men and women receiving primary osteochondral allograft transplantation of the knee with regard to failure or reoperation, with the exception that women underwent reoperation sooner. STUDY DESIGN: Retrospective Comparative Cohort Study. LEVEL OF EVIDENCE: Level III.

Why Symptoms Linger in Quiescent Crohn's Disease: Investigating the Impact of Sulfidogenic Microbes and Sulfur Metabolic Pathways.

Introduction: Even in the absence of inflammation, persistent symptoms in patients with Crohn's disease (CD) are prevalent and worsen quality of life. We previously demonstrated enrichment in sulfidogenic microbes in quiescent Crohn's disease patients with ( qCD+S ) vs. without persistent GI symptoms ( qCD-S ). Thus, we hypothesized that sulfur metabolic pathways would be enriched in stool while differentially abundant microbes would be associated with important sulfur-metabolic pathways in qCD+S. Methods: We performed a multi-center observational study nested within SPARC IBD. Quiescent inflammation was defined by fecal calprotectin level <150 mcg/g. Persistent symptoms were defined by CD-PRO2. Active CD ( aCD ) and non-IBD diarrhea-predominant irritable bowel syndrome ( IBS-D ) were included as controls. Results: Thirty-nine patients with qCD+S, 274 qCD-S, 21 aCD, and 40 IBS-D underwent paired shotgun metagenomic sequencing and untargeted metabolomic profiling. The fecal metabolome in qCD+S was significantly different relative to qCD-S and IBS-D but not aCD. Patients with qCD+S were enriched in sulfur-containing amino acid pathways, including cysteine and methionine, as well as serine, glycine, and threonine. Glutathione and nicotinate/nicotinamide pathways were also enriched in qCD+S relative to qCD-S, suggestive of mitochondrial dysfunction, a downstream target of H 2 S signaling. Multi-omic integration demonstrated that enriched microbes in qCD+S were associated with important sulfur-metabolic pathways. Bacterial sulfur-metabolic genes, including CTH , isfD , sarD , and asrC , were dysregulated in qCD+S. Finally, sulfur metabolites with and without sulfidogenic microbes showed good accuracy in predicting presence of qCD+S. Discussion: Microbial-derived sulfur pathways and downstream mitochondrial function are perturbed in qCD+S, which implicate H 2 S signaling in the pathogenesis of this condition. Future studies will determine whether targeting H 2 S pathways results in improved quality of life in qCD+S. Key Messages: What is Already Known Even in the absence of inflammation, persistent gastrointestinal symptoms are common in Crohn's disease.The microbiome is altered in quiescent Crohn's disease patients with persistent symptoms, but the functional significance of these changes is unknown. What is New Here Sulfur metabolites and sulfur metabolic pathways were enriched in stool in quiescent Crohn's disease patients with persistent symptoms.Multi-omic integration showed enriched microbes were associated with important sulfur metabolic pathways in quiescent Crohn's disease patients with persistent symptoms. How Can This Study Help Patient Care Strategies to decrease sulfidogenic microbes and associated sulfur metabolic pathways could represent a novel strategy to improve quality of life in quiescent Crohn's disease with persistent GI symptoms.

A Prospective, Randomized, Double-Blind Clinical Trial to Investigate the Efficacy of Autologous Bone Marrow Aspirate Concentrate During Arthroscopic Meniscectomy in Patients With Early Knee Osteoarthritis.

BACKGROUND: Despite being recognized as a safe procedure with minimal reported complications, injecting autologous bone marrow aspirate concentrate (BMAC) as an adjuvant to arthroscopic partial meniscectomy (APM) for symptomatic patients with meniscal tears and concomitant knee osteoarthritis (OA) has not been studied in randomized controlled trials. PURPOSE: To compare patient-reported outcome measure (PROM) scores and radiographic outcomes in symptomatic patients with meniscal tears and concomitant mild knee OA who underwent APM with and without an autologous BMAC injection administered at the time of surgery. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Enrolled patients aged ≥18 years determined to have a symptomatic meniscal tear with concomitant mild knee OA suitable for APM and meeting inclusion and exclusion criteria were randomized into 2 groups: BMAC and control (no BMAC). The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 1 year postoperatively. Secondary endpoints included radiographic outcomes (Kellgren-Lawrence grade) at 1 year postoperatively and various PROM scores, including those for the IKDC, Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale, and Veterans RAND 12-Item Health Survey, at 3 months, 6 months, 1 year, and 2 years after meniscectomy. RESULTS: Of the 95 enrolled patients, 83 (87.4%) were included for final analysis. No significant differences were found between the groups with regard to patient characteristics, intraoperative variables, concomitant procedures, preoperative PROM scores, or preoperative radiographic findings. At 1 year postoperatively, the BMAC group failed to demonstrate significantly better IKDC scores (P = .687) or radiographic outcomes (P > .05 for all radiographic measures) compared with the control group. Secondary PROM scores also did not significantly differ between the groups (P > .05 for all PROMs). However, there were higher achievement rates of the minimal clinically important difference for the KOOS Sport (100.0% vs 80.0%, respectively; P = .023) and KOOS Symptoms (92.3% vs 68.0%, respectively; P = .038) at 1 year postoperatively in the BMAC group than in the control group. All PROMs, excluding the VR-12 mental score, showed significant improvements compared with baseline at all postoperative time points for both the BMAC and control groups. CONCLUSION: The addition of an autologous BMAC injection during APM did not result in significant changes in IKDC scores or radiographic outcomes at the 1-year postoperative mark. Secondary PROM scores were generally comparable between the 2 groups, but there was higher minimal clinically important difference achievement for the KOOS Sport and KOOS Symptoms at 1 year postoperatively in the BMAC group. In patients with symptoms consistent with a meniscal tear who had concomitant mild OA, the addition of BMAC to arthroscopic debridement did not affect the outcome. REGISTRATION: NCT02582489 (ClinicalTrials.gov).

Quantitative susceptibility and T1 ρ mapping of knee articular cartilage at 3T.

T1 ρ and Quantitative Susceptibility Mapping (QSM) are evolving as substrates for quantifying the progressive nature of knee osteoarthritis. Objective: To evaluate the effects of spin lock time combinations on depth-dependent T1 ρ estimation, in adjunct to QSM, and characterize the degree of shared variance in QSM and T1 ρ for the quantitative measurement of articular cartilage. Design: Twenty healthy participants (10 â€‹M/10F, 22.2 â€‹± â€‹3.4 years) underwent bilateral knee MRI using T1 ρ MAPPS sequences with varying TSLs ([0-120] ms), along with a 3D spoiled gradient echo for QSM. Five total TSL combinations were used for T1 ρ computation, and direct depth-based comparison. Depth-wide variance was assessed in comparison to QSM as a basis to assess for depth-specific variation in T1 ρ computations across healthy cartilage. Results: Longer T1 ρ relaxation times were observed for TSL combinations with higher spin lock times. Depth-specific differences were documented for both QSM and T1 ρ , with most change found at ∼60% depth of the cartilage, relative to the surface. Direct squared linear correlation revealed that most T1 ρ TSL combinations can explain over 30% of the variability in QSM, suggesting inherent shared sensitivity to cartilage microstructure. Conclusions: T1 ρ mapping is subjective to the spin lock time combinations used for computation of relaxation times. When paired with QSM, both similarities and differences in signal sensitivity may be complementary to capture depth-wide changes in articular cartilage.

AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs.

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.

Predicting Response to Neuromodulators or Prokinetics in Patients With Suspected Gastroparesis Using Machine Learning: The "BMI, Infectious Prodrome, Delayed GES, and No Diabetes" Model.

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis (GP) have limited efficacy, and it is difficult to predict which patients will respond. In this study, we implemented a machine learning model to predict the response to prokinetics and/or neuromodulators in patients with GP-like symptoms. METHODS: Subjects with suspected GP underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their GP Cardinal Symptom Index at 6 months decreased by ≥1 from baseline. A machine learning model was trained using lasso regression, ridge regression, or random forest. Five-fold cross-validation was used to train the models, and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were nonresponders. A ridge regression model with the variables, such as body mass index, infectious prodrome, delayed gastric emptying scintigraphy, no diabetes, had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with gastric emptying time, duodenal motility index, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with GP-like symptoms.

The Microbiome in Quiescent Crohn's Disease With Persistent Symptoms Show Disruptions in Microbial Sulfur and Tryptophan Pathways.

Background and Aims: Even in the absence of inflammation, persistent symptoms in Crohn's disease (CD) are prevalent and worsen quality of life. Amongst patients without inflammation (quiescent CD), we hypothesized that microbial community structure and function, including tryptophan metabolism, would differ between patients with persistent symptoms (qCD + S) and without persistent symptoms (qCD-S). Methods: We performed a multicenter observational study nested within the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease. Quiescent inflammation was defined by fecal calprotectin level <150 mcg/g. Persistent symptoms were defined by Crohn's Disease Patient-Reported Outcome-2. Active CD, diarrhea-predominant irritable bowel syndrome, and healthy controls were included as controls. Stool samples underwent whole-genome shotgun metagenomic sequencing. Results: Thirty-nine patients with qCD + S, 274 qCD-S, 21 active CD, 40 diarrhea-predominant irritable bowel syndrome, and 50 healthy controls were included for analysis. Patients with qCD + S had a less-diverse microbiome. Furthermore, patients with qCD + S showed significant enrichment of bacterial species that are normal inhabitants of the oral microbiome (eg Rothia dentocariosa, Fusobacterium nucleatum) and sulfidogenic microbes (eg Prevotella copri, Bilophila spp.). Depletion of important butyrate and indole producers (eg Eubacterium rectale, Faecalibacterium prausnitzii) was also noted in qCD + S. Potential metagenome-related functional changes in cysteine and methionine metabolism, ATP transport, and redox reactions were disturbed in qCD + S, also suggestive of altered sulfur metabolism. Finally, qCD + S showed significant reductions in bacterial tnaA genes, which mediate tryptophan metabolism to indole, and significant tnaA allelic variation compared with qCD-S. Conclusion: The microbiome in qCD + S showed significant differences in sulfidogenesis, butyrate producers, and typically oral microbes compared to qCD-S and active CD. These results suggest that inflammation may lead to durable microbiome alterations which may mediate persistent symptoms through testable mechanisms.

Early adaptive schemas, emotional regulation, and cognitive flexibility in eating disorders: subtype specific predictors of eating disorder symptoms using hierarchical linear regression.

PURPOSE: Understanding how early adaptive schemas, cognitive flexibility, and emotional regulation influence eating disorder (ED) symptoms, and whether this differs across diagnostic subtypes is critical to optimising treatment. The current study investigated the relationship between these variables and ED symptomology in individuals self-reporting an ED diagnosis and healthy controls. METHODS: A dataset of 1576 online survey responses yielded subsamples for anorexia nervosa (n = 155), bulimia nervosa (n = 55), binge eating disorder (n = 33), other specified feeding or eating disorder (n = 93), and healthy participants (n = 505). The hierarchical linear regression analysis included Eating Disorder Examination Questionnaire 6.0 Global Score as the dependent variable; Young Positive Schema Questionnaire, Emotional Regulation Questionnaire, and Cognitive Flexibility Inventory subscale scores as the independent variables; and demographic measures as the covariates. RESULTS: The number of significant predictors varied considerably by ED sub-group. Amongst the anorexia nervosa, bulimia nervosa, and healthy subsamples, the adaptive schema Self-Compassion and Realistic Expectations was associated with lower ED symptom severity. In comparison, age and body mass index were the strongest predictors for binge eating disorder, whilst the Expressive Suppression (a subscale of the Emotional Regulation Questionnaire) was the strongest predictor for other specified feeding or eating disorders. CONCLUSION: Early adaptive schemas, cognitive flexibility, and emotional regulation vary across ED subtype, suggesting the need for tailored treatment that disrupts the self-reinforcing cycle of ED psychopathology. Future research investigating how early adaptive schemas may predict or be associated with treatment response across diagnostic subtypes is needed. LEVEL OF EVIDENCE: Level IV, evidence obtained from multiple time-series with or without the intervention, such as case studies.

Predicting Response to Neuromodulators or Prokinetics in Patients with Suspected Gastroparesis Using Machine Learning: the "BIDnD" Model.

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis have limited efficacy and it is difficult to predict which patients will respond. In this study, we implemented a machine-learning model to predict the response to prokinetics and/or neuromodulators in patients with gastroparesis-like symptoms. METHODS: Subjects with suspected gastroparesis underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule (WMC) and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their Gastroparesis Cardinal Symptom Index (GCSI) at 6 months decreased by ≥1 from baseline. A machine-learning model was trained using lasso regression, ridge regression or random forest. Five-fold cross-validation was used to train the models and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were non-responders. A ridge regression model with the variables: BMI, Infectious prodrome, delayed GES, no diabetes (BIDnD), had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with GET, duodenal MI, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with gastroparesis-like symptoms.

Sport-specific Differences in Cartilage Treatment.

Articular cartilage defects in the knee are common in athletes who have a variety of loading demands across the knee. Athletes of different sports may have different baseline risk of injury. The most studied sports in terms of prevalence and treatment of cartilage injuries include soccer (football), American football, and basketball. At this time, the authors do not specifically treat patients by their sport; however, return to sports timing may be earlier in sports with fewer demands on the knee based on the rehabilitation protocol. If conservative management is unsuccessful, the authors typically perform a staging arthroscopy with chondroplasty, followed by osteochondral allograft transplantation with possible additional concomitant procedures, such as osteotomies or meniscal transplants. Athletes in a variety of sports and at high levels of competition can successfully return to sports with the appropriate considerations and treatment.

Formation of Linear Plasmonic Heterotrimers Using Nanoparticle Docking to DNA Origami Cages.

The fabrication of complex assemblies with interesting collective properties from plasmonic nanoparticles (NPs) is often challenging. While DNA-directed self-assembly has emerged as one of the most promising approaches to forming such complex assemblies, the resulting structures tend to have large variability in gap sizes and shapes, as the DNA strands used to organize these particles are flexible, and the polydispersity of the NPs leads to variability in these critical structural features. Here, we use a new strategy termed docking to DNA origami cages (D-DOC) to organize spherical NPs into a linear heterotrimer with a precisely defined geometrical arrangement. Instead of binding NPs to the exterior of the DNA templates, D-DOC binds the NPs to either the interior or the opening of a 3D cage, which significantly reduces the variability of critical structural features by incorporating multiple diametrically arranged capture strands to tether NPs. Additionally, such a spatial arrangement of the capture strand can work synergistically with shape complementarity to achieve tighter confinement. To assemble NPs via D-DOC, we developed a multistep assembly process that first encapsulates an NP inside a cage and then binds two other NPs to the openings. Microscopic characterization shows low variability in the bond angles and gap sizes. Both UV-vis absorption and surface-enhanced Raman scattering (SERS) measurements showed strong plasmonic coupling that aligned with predictions by electrodynamic simulations, further confirming the precision of the assembly. These results suggest D-DOC could open new opportunities in biomolecular sensing, SERS and fluorescence spectroscopies, and energy harvesting through the self-assembly of NPs into more complex 3D assemblies.

Automated quantitative assessment of bone contusions and overlying articular cartilage following anterior cruciate ligament injury.

Quantitative methods to characterize bone contusions and associated cartilage injury remain limited. We combined standardized voxelwise normalization and 3D mapping to automate bone contusion segmentation post-anterior cruciate ligament (ACL) injury and evaluate anomalies in articular cartilage overlying bone contusions. Forty-five patients (54% female, 26.4 ± 11.8 days post-injury) with an ACL tear underwent 3T magnetic resonance imaging of their involved and uninvolved knees. A novel method for voxelwise normalization and 3D anatomical mapping was used to automate segmentation, labeling, and localization of bone contusions in the involved knee. The same mapping system was used to identify the associated articular cartilage overlying bone lesions. Mean regional T1ρ was extracted from articular cartilage regions in both the involved and uninvolved knees for quantitative paired analysis against ipsilateral cartilage within the same compartment outside of the localized bone contusion. At least one bone contusion lesion was detected in the involved knee within the femur and/or tibia following ACL injury in 42 participants. Elevated T1ρ (p = 0.033) signal were documented within the articular cartilage overlying the bone contusions resulting from ACL injury. In contrast, the same cartilaginous regions deprojected onto the uninvolved knees showed no ipsilateral differences (p = 0.795). Automated bone contusion segmentation using standardized voxelwise normalization and 3D mapping deprojection identified altered cartilage overlying bone contusions in the setting of knee ACL injury.

Association between sleep microarchitecture and cognition in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) increases the risk of cognitive impairment. Measures of sleep microarchitecture from EEG may help identify patients at risk of this complication. METHODS: Participants with suspected OSA (n=1142) underwent in-laboratory polysomnography and completed sleep and medical history questionnaires, and tests of global cognition (Montreal Cognitive Assessment, MoCA), memory (Rey Auditory Verbal Learning Test, RAVLT) and information processing speed (Digit-Symbol Coding, DSC). Associations between cognitive scores and stage 2 NREM sleep spindle density, power, frequency and %-fast (12-16Hz), odds-ratio product (ORP), normalized EEG power (EEGNP) and the delta:alpha ratio were assessed using multivariable linear regression (MLR) adjusted for age, sex, education, and total sleep time. Mediation analyses were performed to determine if sleep microarchitecture indices mediate the negative effect of OSA on cognition. RESULTS: All spindle characteristics were lower in participants with moderate and severe OSA (p≤0.001, versus no/mild OSA) and positively associated with MoCA, RAVLT and DSC scores (false discovery rate corrected p-value, q≤0.026), except spindle power which was not associated with RAVLT (q=0.185). ORP during NREM sleep (ORPNREM) was highest in severe OSA participants (p≤0.001) but neither ORPNREM (q≥0.230) nor the delta:alpha ratio were associated with cognitive scores in MLR analyses (q≥0.166). In mediation analyses, spindle density and EEGNP (p≥0.048) mediated moderate-to-severe OSA's negative effect on MoCA scores while ORPNREM, spindle power and %-fast spindles mediated OSA's negative effect on DSC scores (p≤0.018). CONCLUSION: Altered spindle activity, ORP and normalized EEG power may be important contributors to cognitive deficits in patients with OSA.

Genome-wide DNA methylation and transcriptomic analysis of liver tissues subjected to early ischemia/reperfusion injury upon human liver transplantation.

INTRODUCTION AND OBJECTIVES: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. PATIENTS AND METHODS: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. RESULTS: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. CONCLUSIONS: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.

The Gut Microbiome and Joint Microbiome Show Alterations in Patients With Knee Osteoarthritis Versus Controls: A Systematic Review.

PURPOSE: To assess the current scientific literature on the microbiome's relation with knee osteoarthritis (OA), with specific focuses on the gut microbiome-joint axis and joint microbiome-joint axis. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines; the PubMed, Embase, and Cochrane databases were searched for relevant English-language clinical studies on the gut and/or joint microbiomes' association with knee OA in humans. Bias was evaluated using the Methodological Index for Non-randomized Studies score. RESULTS: Thirty-five thousand bacterial species comprise the gut microbiome; approximately 90% are members of the phyla Bacteroides and Firmicutes. Symbiosis between the gut microbiome and host under normal physiological conditions positively affects host growth, development, immunity, and longevity. Gut microbiome imbalance can negatively influence various physiological processes, including immune response, inflammation, metabolism, and joint health including the development of knee OA. In addition, next-generation gene sequencing suggests the presence of microorganisms in the synovial fluid of OA knees, and distinct microbiome profiles detected are presumed to play a role in the development of OA. Regarding the gut microbiome, consistent alterations in microbial composition between OA patients and controls are noted, in addition to several associations between certain gut bacteria and OA-related knee pain, patient-reported outcome measure performance, imaging findings, and changes in metabolic and inflammatory pathways. Regarding the joint microbiome, studies have revealed that increased levels of lipopolysaccharide and lipopolysaccharide-binding protein in synovial fluid are associated with activated macrophages-and are correlated with worsened osteophyte severity, joint space narrowing, and pain scores in knee OA patients. In addition, studies have shown various microbial composition differences in OA patients compared with controls, with certain joint microbes directly associated with OA pathogenesis, inflammation, and metabolic dysregulation. CONCLUSIONS: The gut microbiome-joint axis and joint microbiome show alterations in microbial composition between patients with OA and controls. These alterations are associated with perturbations of metabolic and inflammatory pathways, imaging findings, OA-related pain, and patient-reported outcome measure performance. LEVEL OF EVIDENCE: Level III, systematic review of Level II and III studies.

There is high variability in quantitative measurement techniques in glenohumeral capsular measurements for shoulder instability: A systematic review.

PURPOSE: Instability of the glenohumeral joint remains a complex clinical issue with high rates of surgical failure and significant morbidity. Advances in specific radiologic measurements involving the glenoid and the humerus have provided insight into glenohumeral pathology, which can be corrected surgically towards improving patient outcomes. The contributions of capsular pathology to ongoing instability remain unclear. The purpose of this study is to provide a systematic review of existing glenohumeral capsular measurement techniques published in the last 15 years. METHODS: A systematic review of multiple databases was performed following PRISMA guidelines for all primary research articles between 2008 and 2023 with quantitative measurements of the glenohumeral capsule in patients with instability, including anterior, posterior and multi-directional instability. RESULTS: There were a total of 14 articles meeting the inclusion criteria. High variability in measurement methodology across studies was observed, including variable amounts of intra-articular contrast, heterogeneity among magnetic resonance sequence acquisitions, differences in measurements performed and the specific approach taken to compute each measurement. CONCLUSION: There is a need for standardization of methods in the measurement of glenohumeral capsular pathology in the setting of glenohumeral instability to allow for cross-study analysis. LEVEL OF EVIDENCE: Level III.

Predicting whaler shark presence and interactions with humans in southern Queensland, Australia.

The Queensland Shark Control Program (QSCP) started in 1962 to reduce the number of shark-human incidents by deploying nets and drumlines across the most popular beaches. The program targets large shark species (white, tiger and bull sharks) that are potentially hazardous to bathers. However, this strategy is lethal for other sharks and marine wildlife, including threatened and endangered species. Thus, finding non-lethal strategies is a priority. To better manage shark-human interactions, establishing a better understanding of the factors that drive shark movement is key. Here we used sea surface temperature (SST), rainfall and distance to rivers as environmental variables to predict the presence of whaler sharks in southern Queensland based on 26 years of catch data from the QSCP. We found that SST is positively corelated to sharks caught by drumlines, while rainfall was associated with the number of sharks captured in shark nets. In addition, more sharks were captured by nets and drumlines further away from rivers, and nets captured roughly 10 times more sharks than drumlines over the period of study. In contrast to tiger sharks, the catch data indicate the number of whalers has not declined over the past 26 years. Our findings suggest that environmental variables can be used to predict the movement of large sharks and by incorporating this knowledge into management plans and public education programs, may ultimately reduce shark-human incidents.

Obstructive sleep apnea severity, circulating biomarkers, and cancer risk.

STUDY OBJECTIVES: To determine whether obstructive sleep apnea (OSA) severity and/or biomarkers of inflammation/angiogenesis are associated with incident cancer in this clinical cohort. METHODS: Consenting adult patients at the University of British Columbia Hospital between 2003 and 2014 completed a questionnaire about their medical history and sleep habits prior to undergoing a polysomnogram. Blood samples were collected the morning after polysomnography and processed for biomarkers of inflammation and angiogenesis. The clinical, polysomnography, and biomarker data were linked to the British Columbia Cancer Registry to ascertain incident cancer diagnoses. Cox proportional hazard regression was used to assess the association between OSA severity and biomarker concentrations with cancer risk. RESULTS: A total of 1,990 patients were included in the analysis with a mean follow-up time of 12.8 years; 181 of them (9.1%) developed cancer after polysomnography. OSA severity was significantly associated with cancer risk after controlling for relevant covariates (hazard ratio = 1.08 per 10 events/h apnea-hypopnea index increase, confidence interval = 1.02-1.15, P = .015). In an exploratory analysis, 2 biomarkers were significantly associated with an increased cancer risk after controlling for relevant covariates (hazard ratio per interquartile range pg/mL increase of endostatin = 1.45, confidence interval = 1.12-1.87, P = .01 and hazard ratio for interquartile range pg/mL increase of vascular cell adhesion molecule-1 = 1.48, confidence interval = 1.04-2.11, P = .03, respectively). CONCLUSIONS: OSA severity was an independent risk factor for cancer. Furthermore, 2 circulating markers were significantly associated with cancer risk. If these preliminary findings can be reproduced in other cohorts, biomarkers could potentially be used to prognosticate patients with OSA with respect to cancer risk. CITATION: Hirsch Allen AJ, Kendzerska T, Bhatti P, et al. Obstructive sleep apnea severity, circulating biomarkers, and cancer risk. J Clin Sleep Med. 2024;20(9):1415-1422.

The Parental Leave Paradox in Obstetrics and Gynecology.

Medical school, residency, and fellowship occur during peak reproductive years for most trainees. This poses certain challenges for medical trainees as they approach family-building decisions. While the demands of residency have been well-elucidated, attempts at mitigating these demands alongside parenthood have long been neglected across various specialties. These challenges are perhaps most pronounced in Obstetrics and Gynecology residency programs, which are made-up of an 85% female-identifying workforce and whose training focuses on prenatal and postpartum health. Recent literature suggests an improvement in attitudes and policies towards parental leave during medical graduate education, however, there remains a lack of uniformity across specialties and programs. Through a recently developed Parental Leave Task Force made up of Obstetrics and Gynecology Trainees, we sought to conduct a review of the literature examining parental leave policies and their implications across various specialties as a call for uniform parental leave policies for all residents.