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.

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 human-shark 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 capture 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 human-shark incidents.

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

STUDY OBJECTIVES: To determine if 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 2003-2014 completed a questionnaire about their medical history and sleep habits prior to undergoing a polysomnogram (PSG). Blood samples were collected the morning after PSG and processed for biomarkers of inflammation and angiogenesis. The clinical, PSG, and biomarker data were linked to the British Columbia Cancer Registry to ascertain incident cancer diagnoses. Cox proportional hazard regression were 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 PSG. OSA severity was significantly associated with cancer risk after controlling for relevant covariates (hazard ratio (HR) = 1.08 per 10 events/h apnea-hypopnea index (AHI) increase, CI = 1.02-1.15, p=0.015). In an exploratory analysis, two biomarkers were significantly associated with an increased cancer risk after controlling for relevant covariates (HR per interquartile range (IQR) pg/mL increase of endostatin = 1.45, CI = 1.12-1.87, p=0.01 and HR for IQR pg/mL increase of VCAM-1 = 1.48, CI = 1.04-2.11, p=0.03, respectively). CONCLUSIONS: OSA severity was an independent risk factor for cancer. Furthermore, two 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 OSA patients with respect to cancer risk.

Design of the first fusion experiment to achieve target energy gain G>1.

In this work we present the design of the first controlled fusion laboratory experiment to reach target gain G>1 N221204 (5 December 2022) [Phys. Rev. Lett. 132, 065102 (2024)10.1103/PhysRevLett.132.065102], performed at the National Ignition Facility, where the fusion energy produced (3.15 MJ) exceeded the amount of laser energy required to drive the target (2.05 MJ). Following the demonstration of ignition according to the Lawson criterion N210808, experiments were impacted by nonideal experimental fielding conditions, such as increased (known) target defects that seeded hydrodynamic instabilities or unintentional low-mode asymmetries from nonuniformities in the target or laser delivery, which led to reduced fusion yields less than 1 MJ. This Letter details design changes, including using an extended higher-energy laser pulse to drive a thicker high-density carbon (also known as diamond) capsule, that led to increased fusion energy output compared to N210808 as well as improved robustness for achieving high fusion energies (greater than 1 MJ) in the presence of significant low-mode asymmetries. For this design, the burnup fraction of the deuterium and tritium (DT) fuel was increased (approximately 4% fuel burnup and a target gain of approximately 1.5 compared to approximately 2% fuel burnup and target gain approximately 0.7 for N210808) as a result of increased total (DT plus capsule) areal density at maximum compression compared to N210808. Radiation-hydrodynamic simulations of this design predicted achieving target gain greater than 1 and also the magnitude of increase in fusion energy produced compared to N210808. The plasma conditions and hotspot power balance (fusion power produced vs input power and power losses) using these simulations are presented. Since the drafting of this manuscript, the results of this paper have been replicated and exceeded (N230729) in this design, together with a higher-quality diamond capsule, setting a new record of approximately 3.88MJ of fusion energy and fusion energy target gain of approximately 1.9.

Observations and properties of the first laboratory fusion experiment to exceed a target gain of unity.

An indirect-drive inertial fusion experiment on the National Ignition Facility was driven using 2.05 MJ of laser light at a wavelength of 351 nm and produced 3.1±0.16 MJ of total fusion yield, producing a target gain G=1.5±0.1 exceeding unity for the first time in a laboratory experiment [Phys. Rev. E 109, 025204 (2024)10.1103/PhysRevE.109.025204]. Herein we describe the experimental evidence for the increased drive on the capsule using additional laser energy and control over known degradation mechanisms, which are critical to achieving high performance. Improved fuel compression relative to previous megajoule-yield experiments is observed. Novel signatures of the ignition and burn propagation to high yield can now be studied in the laboratory for the first time.

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.

Arthroscopic Debridement of Mild and Moderate Knee Osteoarthritis Results in Clinical Improvement at Short-Term Follow-Up: A Systematic Review.

PURPOSE: To report the clinical outcomes of arthroscopic debridement for the treatment of Kellgren-Lawrence (KL) grade I and II (mild) and III (moderate) knee osteoarthritis (OA) at a minimum 1-year follow-up. METHODS: A systematic review of primary literature was performed in concordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using the Medline, Embase, and Cochrane databases for studies regarding arthroscopic debridement/chondroplasty for management of knee OA at a minimum 1-year follow-up. Studies were included if they included KL grades I to III or dichotomized clinical outcomes by KL grade. The primary outcome was patient-reported outcome measures (PROMs) at the final follow-up. Bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) score. RESULTS: Eight studies including a total of 773 patients met inclusion criteria (range of patients in each study, 31-214). Mean age of patients ranged from 35.5 to 64 years, with most studies having a mean patient age of 55 to 65 years. Mean follow-up ranged from 1.5 to 10 years. Seven of the 8 (87.5%) studies reported good to excellent PROMs at a minimum 1- to 4-year follow-up after arthroscopic debridement. Improvements in PROMs were superior in patients with less severe knee OA (KL I-II) in comparison to KL III in most studies. Conversion to arthroplasty ranged from 7.6% to 50% in KL III patients compared with 0% to 4.5% in KL I-II patients after arthroscopic debridement. Two of the 3 studies with at least a 4-year clinical follow-up reported that clinical improvements diminished with time (improvements no longer significant in total Western Ontario and McMaster Universities Osteoarthritis Index score). The lone randomized controlled trial was the only investigation that did not find a benefit of arthroscopic debridement over quality nonoperative care. MINORS scores ranged from 6 to 10 (mean, 8.0) for the 5 nonrandomized studies without controls. CONCLUSIONS: Arthroscopic debridement for the management of mild to moderate knee OA is effective at short-term follow-up in patients who have exhausted conservative care. There is limited evidence demonstrating the durability of improvement following arthroscopic debridement after 2 years. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.

Achievement of Target Gain Larger than Unity in an Inertial Fusion Experiment.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Orthopaedic Musculoskeletal Biologics Research Impacts Patient Care: The Second Annual Arthroscopy Orthobiologics Virtual Special Issue.

The field of orthobiologics is rapidly evolving, offering clinicians a shift in treatment from symptom relief to the potential for disease modification and tissue repair. These agents, derived from autologous tissues, components of blood, and growth factors, are used as surgical adjuncts or as standalone treatments. Their clinical applications are expanding to encompass a variety of conditions, supported by a growing base of research efforts. Arthroscopy and its companion publications are committed to evidence-based research with a robust history of publications that enhance clinical decision-making and impact patient care. This curated collection of articles highlights the year's most compelling advancements in orthopaedic musculoskeletal biologics research.

Is the Comparator in Your Diagnostic Cost-Effectiveness Model "Standard of Care"? Recommendations from Literature Reviews and Expert Interviews on How to Identify and Operationalize It.

OBJECTIVES: This research aimed to develop best-practice recommendations for identifying the "standard of care" (SoC) and integrate it when it is the comparator in diagnostic economic models (SoC comparator). METHODS: A multi-methods approach comprising 2 pragmatic literature reviews and 9 expert interviews was used. Experts rated their agreement with draft recommendations based on the authors' analysis of the reviews. These were refined iteratively to produce final recommendations. RESULTS: Fourteen best-practice recommendations are provided. Care pathway mapping (using quantitative, qualitative, or mixed-methods approaches) should be used for identifying the SoC comparator. Guidelines analysis can be integrated with expert opinion to identify pathway variability and discrepancies from clinical practice. For integrating the SoC comparator into the model, recommendations around structure, input sourcing, data aggregation and reporting, input uncertainty, and model variability are presented. For example, modelers should consider that the reference standard is not synonymous with the SoC, and the SoC may not be the only comparator. The comparator limitations should be discussed with clinical experts, but elicitation of its diagnostic accuracy is not recommended. Probabilistic sensitivity analysis is recommended when evaluating the overall input uncertainty, and deterministic sensitivity analysis is useful when there is high model uncertainty or SoC variability. Consensus could not be reached for some topics (eg, the role of real-world data, model averaging, and alternative model structures), but the reported discussions provide points for consideration. CONCLUSIONS: To our knowledge, this is the first guidance to support modelers when identifying and operationalizing the SoC comparator in diagnostic cost-effectiveness models.

Evidence Synthesis and Linkage for Modelling the Cost-Effectiveness of Diagnostic Tests: Preliminary Good Practice Recommendations.

OBJECTIVES: To develop preliminary good practice recommendations for synthesising and linking evidence of treatment effectiveness when modelling the cost-effectiveness of diagnostic tests. METHODS: We conducted a targeted review of guidance from key Health Technology Assessment (HTA) bodies to summarise current recommendations on synthesis and linkage of treatment effectiveness evidence within economic evaluations of diagnostic tests. We then focused on a specific case study, the cost-effectiveness of troponin for the diagnosis of myocardial infarction, and reviewed the approach taken to synthesise and link treatment effectiveness evidence in different modelling studies. RESULTS: The Australian and UK HTA bodies provided advice for synthesising and linking treatment effectiveness in diagnostic models, acknowledging that linking test results to treatment options and their outcomes is common. Across all reviewed models for the case study, uniform test-directed treatment decision making was assumed, i.e., all those who tested positive were treated. Treatment outcome data from a variety of sources, including expert opinion, were utilised for linked clinical outcomes. Preliminary good practice recommendations for data identification, integration and description are proposed. CONCLUSION: Modelling the cost-effectiveness of diagnostic tests poses unique challenges in linking evidence on test accuracy to treatment effectiveness data to understand how a test impacts patient outcomes and costs. Upfront consideration of how a test and its results will likely be incorporated into patient diagnostic pathways is key to exploring the optimal design of such models. We propose some preliminary good practice recommendations to improve the quality of cost-effectiveness evaluations of diagnostics tests going forward.

Bioabsorbable Screw Fixation Provides Good Results With Low Failure Rates at Mid-term Follow-up of Stable Osteochondritis Dissecans Lesions That Do Not Improve With Initial Conservative Treatment.

Purpose: To evaluate the clinical and radiographic outcomes of patients who have undergone bioabsorbable screw fixation for intact, stable grade I and II osteochondritis dissecans (OCD) lesions for which at least 6 months of conservative management has failed. Methods: A retrospective review of prospectively collected data from a single institution was performed to identify patients who underwent internal fixation of stable grade I and II OCD lesions (according to the Guhl classification) between January 2010 and January 2020. Patients were included regardless of the presence of concomitant procedures. The inclusion criteria consisted of (1) primary surgery, (2) failure of at least 6 months of conservative management, (3) the use of a bioabsorbable screw (or screws), and (4) minimum 2-year clinical follow-up. Radiographs were obtained at a minimum of 1 year postoperatively. Patient demographic characteristics, clinical patient-reported outcomes, complications, and failure rates were noted. Results: Twenty-four knees among 23 patients (96% follow-up) were analyzed and followed up for 6.36 ± 3.42 years (range, 2.0-12.7 years). Patients showed statistically significant postoperative improvements in all patient-reported outcomes including the Lysholm score, International Knee Documentation Committee score, and Knee Injury and Osteoarthritis Outcome Score subscales (P < .05). In 3 knees (12%), a reoperation was required due to failure at an average of 3.64 years after the index procedure. No specific complications were attributed to the use of bioabsorbable screws. Patients in whom primary surgical treatment failed did not differ in demographic characteristics, arthroscopic findings, or surgical treatment from those who had successful treatment. Conclusions: Internal fixation of stable grade I and II OCD lesions with bioabsorbable screws produces reliable results with a 12% rate of failure in appropriately indicated patients in whom at least 6 months of conservative management has failed. Clinical outcomes improved significantly during the mid-term follow-up period. Level of Evidence: Level IV, therapeutic case series.

Peptide-Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics.

Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide-drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody-drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide-drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide-drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.

All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and ß-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Interruptions in HIV and Behavioral Health Care for Criminal-Legal Involved People Living with HIV Following Implementation of Decarceration and Shelter in Place in San Francisco, California.

Decarceration policies, enacted for SARS-CoV-2 mitigation in carceral settings, potentially exacerbated barriers to care for people living with HIV (PWH) with criminal legal involvement (CLI) during Shelter-in-Place (SIP) by limiting opportunities for engagement in provisions of HIV and behavioral health care. We compared health care engagement for PWH with CLI in San Francisco, California before and after decarceration and SIP using interrupted time series analyses. Administrative data identified PWH booked at the San Francisco County Jail with at least one clinic encounter from 01/01/2018-03/31/2020 within the municipal health care network. Monthly proportions of HIV, substance use, psychiatric and acute care encounters before (05/01/2019-02/29/2020) and after (03/01/2020-12/31/2020) SIP and decarceration were compared using Generalized Estimating Equation (GEE) log-binomial and logistic regression models, clustering on the patient-level. Of 436 patients, mean age was 43 years (standard-deviation 11); 88% cisgender-male; 39% white, 66% homeless; 67% had trimorbidity by Elixhauser score (medical comorbidity, psychotic disorder or depression, and substance use disorder). Clinical encounters immediately dropped following SIP for HIV (aOR = 0.77; 95% CI: 0.67, 0.90) and substance use visits (aRR = 0.83; 95% CI: 0.70, 0.99) and declined in subsequent months. Differential reductions in clinical encounters were seen among Black/African Americans (aRR = 0.93; 95% CI: 0.88, 0.99) and people experiencing homelessness (aRR = 0.92; 95% CI: 0.87, 0.98). Significant reductions in care were observed for PWH with CLI during the COVID-19 pandemic, particularly among Black/African Americans and people experiencing homelessness. Strategies to End the HIV Epidemic must improve engagement across diverse care settings to improve outcomes for this key population.

Blood-Brain Barrier Dysfunction and Exposure to Head Impacts in University Football Players.

OBJECTIVE: To investigate the link between dysfunction of the blood-brain barrier (BBB) and exposure to head impacts in concussed football athletes. DESIGN: This was a prospective, observational pilot study. SETTING: Canadian university football. PARTICIPANTS: The study population consisted of 60 university football players, aged 18 to 25. Athletes who sustained a clinically diagnosed concussion over the course of a single football season were invited to undergo an assessment of BBB leakage. INDEPENDENT VARIABLES: Head impacts detected using impact-sensing helmets were the measured variables. MAIN OUTCOME MEASURES: Clinical diagnosis of concussion and BBB leakage assessed using dynamic contrast-enhanced MRI (DCE-MRI) within 1 week of concussion were the outcome measures. RESULTS: Eight athletes were diagnosed with a concussion throughout the season. These athletes sustained a significantly higher number of head impacts than nonconcussed athletes. Athletes playing in the defensive back position were significantly more likely to sustain a concussion than remain concussion free. Five of the concussed athletes underwent an assessment of BBB leakage. Logistic regression analysis indicated that region-specific BBB leakage in these 5 athletes was best predicted by impacts sustained in all games and practices leading up to the concussion-as opposed to the last preconcussion impact or the impacts sustained during the game when concussion occurred. CONCLUSIONS: These preliminary findings raise the potential for the hypothesis that repeated exposure to head impacts may contribute to the development of BBB pathology. Further research is needed to validate this hypothesis and to test whether BBB pathology plays a role in the sequela of repeated head trauma.

Suture Augmentation of a Four-Strand Semitendinosus Graft Improves Time-Zero Biomechanical Properties.

PURPOSE: To compare the time-zero biomechanical properties of hamstring graft preparations with or without suture augmentation for anterior cruciate ligament reconstruction (ACLR) in a full-construct cadaveric model. METHODS: Hamstring grafts were harvested from 24 fresh frozen human cadavers and prepared in 1 of 3 ways: quadrupled SemiTendinosus (SemiT), and quadrupled SemiT with suture augmentation (SemiT+2.0-mm tape or SemiT+1.3-mm tape; n = 8 per group). Adjustable loop suspensory implants and cortical buttons were used for fixation on a porcine tibia and acrylic block. Testing included force-controlled cyclic loading at 250 N and 400 N followed by load to failure. RESULTS: The 2 suture augmentation groups had less total elongation and increased stiffness compared to the nonsuture-augmented group (P = .025). The SemiT+2.0-mm tape group had 36% less total elongation and 34% increased stiffness compared to SemiT+1.3mm tape (P < .001). CONCLUSIONS: Suture augmentation improves construct biomechanics at time zero following hamstring tendon ACLR. Augmentation with 2.0-mm tape suture improves construct biomechanics compared to 1.3-mm tape suture. CLINICAL RELEVANCE: Independent suture augmentation of a quadrupled SemiT graft improves ACLR construct biomechanics. Outcomes were improved with augmentation using 2.0-mm tape suture compared to 1.3-mm tape suture.

Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis.

BACKGROUND & AIMS: Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear. METHODS: One hundred and twenty-nine patients with symptoms of gastroparesis underwent wireless motility capsule gastric emptying time and gastric emptying scintigraphy. Based on test results, changes in therapy were recommended. Changes in Gastroparesis Cardinal Symptom Index (GCSI) and individual symptom scores over 6 months were related to recommendations for prokinetics, gastroparesis diet, or neuromodulators given as solo new therapies or in dual combinations. Multivariate analyses were performed to adjust for gastric emptying and other variables. RESULTS: In the whole group regardless of therapy, GCSI scores decreased by 0.53 points (interquartile range, -1.25 to 0.05; P < .0001) over 6 months. GCSI did not decrease for prokinetics as solo new therapy (P = .95). Conversely, neuromodulators as solo therapy decreased GCSI scores (P = .04) and all individual symptoms except nausea/vomiting (P = .86). Prokinetics combined with gastroparesis diets or neuromodulators improved GCSI scores (P ≤ .04) and most individual symptoms. Adjusting for gastric emptying time on multivariate analyses showed greater GCSI decreases for nondelayed emptying for neuromodulators as solo new therapy (P = .01). Gastric emptying scintigraphy, gender, diabetes, and functional dyspepsia did not influence responses to any treatment. CONCLUSIONS: Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of gastroparesis. Neuromodulators as the only new therapy decreased symptoms other than nausea and vomiting, especially with nondelayed gastric emptying. Adding gastroparesis diets or neuromodulators to prokinetics offered relief, suggesting that combination therapies may be more useful in managing these patients. (ClinicalTrials.gov NCT02022826.).

Evaluation of Rhodanine Indolinones as AANAT Inhibitors.

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X-ray crystal-based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine-indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5-carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency.