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PURPOSE To compare the clinical and radiological outcomes in patients undergoing anterior cruciate ligament reconstruction (ACLR) with, or without, LARS augmentation. METHODS One-hundred and thirty-six patients that underwent double-bundle ACLR with (DB Hams/LARS, n = 67), or without (DB Hams, n = 69), LARS augmentation, were assessed clinically and with Magnetic Resonance Imaging (MRI) at a minimum of 7-years post-surgery. Patients were assessed via patient-reported outcome measures (PROMs), KT-1000 (laxity), isokinetic knee extensor and flexor strength and a 4-hop test battery. Limb symmetry indices (LSIs) were calculated. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) evaluated knee status via MRI. Sport participation, secondary operations, ACL re-tears and contralateral ACL tears were reported. RESULTS No differences (n.s.) were observed in demographics, PROMs, KT-1000 scores or strength and hop LSIs. Normal (

OBJECTIVE The aim of this study is to analyze the association between coronary artery vitamin D receptor (VDR) expression and systemic coronary artery atherosclerosis (CAA) risk factors. METHODS Female cynomolgus monkeys (n = 39) consumed atherogenic diets containing the women's equivalent of 1000 IU/day of vitamin D3. After 32 months consuming the diets, each monkey underwent surgical menopause. After 32 postmenopausal months, CAA and VDR expression were quantified in the left anterior descending coronary artery. Plasma 25OHD3, lipid profiles and serum monocyte chemotactic protein-1 (MCP-1) were measured. RESULTS In postmenopausal monkeys receiving atherogenic diets, serum MCP-1 was significantly elevated compared with baseline (482.2 ± 174.2 pg/ml vs. 349.1 ± 163.2 pg/ml, respectively; p

We report a 30-year-old right-handed man with a history of drug-resistant, non-lesional, childhood-onset focal epilepsy featuring (i) focal unaware seizures with left upper extremity automatisms and tonic posturing preceded by an aura of a ringing/beeping noise, and (ii) nocturnal hyperkinetic seizures. Non-invasive video-EEG, MEG, and PET were unable to delineate the epileptogenic zone (EZ) warranting an invasive investigation with bilateral depth electrodes (SEEG). SEEG data localized the EZ to the right superior temporal sulcus (STS) and right superior temporal gyrus (STG), wherein the auditory cortex lies, with subsequent ictal spread to anterior topography including the operculo-insular region. This hypothesis explained the patient's semiology consisting of focal aware seizures featuring auditory phenomena and nocturnal hyperkinetic seizures. Our multi-disciplinary team elected to proceed with a resection of the posterior right STG guided by electrocorticography (ECoG). Prior to resection, ECoG identified seizures arising from the peri-sylvian region, seemingly discordant to previous SEEG data. Following resection of the posterior right STG, ECoG continued to show seizures from contacts overlying the parietal operculum. It was not until the cortex was resected, at the depth of the right STS, that ECoG no longer showed epileptiform abnormalities. Pathology revealed focal cortical dysplasia type 1A.

This review summarizes the pathogenic mechanisms that underpin the monogenic epilepsies and discusses the potential of novel precision therapeutics to treat these disorders. Pathogenic mechanisms of epilepsy include recessive (null alleles), haploinsufficiency, imprinting, gain-of-function, and dominant negative effects. Understanding which pathogenic mechanism(s) that underlie each genetic epilepsy is pivotal to design precision therapies that are most likely to be beneficial for the patient. Novel therapeutics discussed include gene therapy, gene editing, antisense oligonucleotides, and protein replacement. Discussions are illustrated and reinforced with examples from the literature. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01137-z.

Background Opioids are commonly prescribed for postoperative pain following total joint arthroplasty. Despite widespread use, few studies have examined the dose-dependent effect of perioperative opioid use on postoperative complications following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Therefore, we examined the dose-dependent relationship between opioid use and postoperative complications following primary THA and TKA. Methods We queried the Premier Healthcare Database to identify adult patients who underwent primary elective THA or TKA from 2004 to 2014, and quantified opioid consumption within the first 3 postoperative days. Opioid consumption was standardized to morphine milligram equivalents (MMEs). Patients were divided into quintiles on the basis of MME exposure: 172 MMEs. Primary outcomes included postoperative periprosthetic joint infection, pulmonary embolism, deep venous thrombosis, and pulmonary complications. Secondary outcomes included wound infection, wound dehiscence, and readmission within 30 and 90 days postoperatively. Univariate and multivariate analyses were performed to compare differences between groups and to account for confounders. Results A total of 1,525,985 patients were identified. The mean age was 65.7 ± 10.8 years, 598,320 patients (39.2%) were male, and 1,174,314 patients (77.0%) were Caucasian. On multiple logistic regression analysis, increasing MME exposure was associated with a dose-dependent increased risk of postoperative complications. Compared with patients receiving 172 MMEs was associated with greater odds of periprosthetic joint infection (adjusted odds ratio [aOR], 1.37; 95% confidence interval [CI], 1.33 to 1.42), deep venous thromboembolism (aOR, 1.34; 95% CI, 1.30 to 1.38), pulmonary embolism (aOR, 1.29; 95% CI, 1.25 to 1.34), and pulmonary complications (aOR, 1.06; 95% CI, 1.05 to 1.08). Exposure to >172 MMEs was associated with increased risk of wound infection (aOR, 1.37; 95% CI, 1.33 to 1.41), wound dehiscence (aOR, 1.24; 95% CI, 1.19 to 1.31), and readmission within 30 (aOR, 1.21; 95% CI, 1.20 to 1.22) and 90 days (aOR, 1.20; 95% CI, 1.19 to 1.21). Conclusions Increasing opioid use within the early postoperative period following THA or TKA was associated with a dose-dependent increased risk of periprosthetic joint infection and venous thromboembolic events. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Advanced hip imaging and surgical findings have demonstrated that a common cause of greater trochanteric pain syndrome (GTPS) is hip abductor tendon (HAT) tears. Traditionally, these patients have been managed non-operatively, often with temporary pain relief. More recently, there has been an increase in published work presenting the results of surgical intervention. A variety of open and endoscopic transtendinous, transosseous and/or bone anchored suture surgical techniques have been reported, with and without the use of tendon augmentation for repair reinforcement. While patient outcomes have demonstrated improvements in pain, symptoms and function, post-operative rehabilitation guidelines are often vague and underreported, providing no guidance to therapists. A systematic search of the literature was initially undertaken to identify published clinical studies on patients undergoing HAT repair, over a 3-year period up until May 2020. Following the application of strict inclusion and exclusion criteria, studies were identified and the detail relevant to rehabilitation was synthesized and presented. Published detail was combined with the authors clinical experience, with a detailed overview of rehabilitation proposed for this patient cohort. A total of 17 studies were included, reporting varied detail on components of rehabilitation including post-operative weight bearing (WB) restrictions, the initiation of passive/active hip range of motion (ROM) and resistance exercises. A detailed rehabilitation guide is proposed. In combining the current published literature on rehabilitation after HAT repair and our own clinical experience in the surgical management and post-operative rehabilitation of these patients, we present an evidence-based, structured rehabilitation protocol to better assist surgeons and therapists in treating these patients. This rehabilitation protocol has been implemented for several years through our institutions with encouraging published clinical outcomes.

To report 10-year outcomes and survivorship in patients undergoing bicompartmental knee arthroplasty (BCKA) using the Journey-Deuce prosthesis in a consecutive prospective case series. Between November 2006 and November 2009, 41 patients with a mean age of 69.6 years (range 51–86) underwent 51 bicompartmental knee arthroplasties with the Journey-Deuce knee prosthesis. All patients presented with symptomatic medial and patellofemoral compartment osteoarthritis, with intact cruciate ligaments and a preserved lateral compartment on plain radiographs and Magnetic Resonance Imaging. Clinical assessment was undertaken pre-surgery and at 1, 2, 5 and 10 years post-surgery using the Oxford Knee Score (OKS), EuroQol Group 5-Dimension self-reported questionnaire (EQ-5D) and maximal active range of motion (ROM). 30 patients (37 knees) were followed-up at a mean time of 11.4 years (SD 1.1; range 10.5–14.0). Eight patients (ten knees) were deceased and three could not be contacted at final review. No major component revision was performed. Pre-operative OKS 25.4 (SD 5.2; range 15–40), knee flexion 116.4° (SD 10.3°; range 100°–140°) and EQ-5D 70.5 (SD 19.9; range 25–95). 10-year OKS 43.5 (SD 4.1; range 32–48), knee flexion 127.3° (SD 11.1°; range 105°–144°) and EQ-5D 77.4 (SD 9.3; range 60–100). The OKS (p

Patients may present to the emergency department with breast complaints due to traumatic or nontraumatic changes in the breast. Benign and malignant breast pathologies may mimic each other both in clinical presentation and imaging appearance. A complex cystic and solid mass seen on ultrasound in a patient with a palpable mass can represent breast cancer, abscess, or hematoma. A unilateral swollen breast may result from inflammatory breast cancer, mastitis, or other benign etiologies; correlation with clinical history, physical exam, and close follow-up are required to ensure complete resolution of symptoms. Uncommon breast entities such as granulomatous mastitis and breast implant–associated anaplastic large-cell lymphoma may cause changes in the appearance of the breast that prompt a patient to seek initial evaluation in the emergency department. Imaging evaluation of the breast in the emergency department is limited, and it is important that patients with a breast complaint be referred to a dedicated breast center for complete evaluation at an appropriate time interval after their discharge from the emergency department.

Spironolactone reduces morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction (EF) and decreases hospitalizations in HF with preserved EF. To minimize the risk of hyperkalemia, patients must have an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 and potassium 40% and 47.9% (n = 58) had an EF ≤ 40% with 69.4% (n = 84) CKD stage 3, 24.8% (n = 30) stage 4, and 5.8% (n = 7) stage 5. Spironolactone was initiated prior to admission (PTA) for 54.5% (n = 66) of patients, while 45.5% (n = 55) of orders were initiated during hospitalization. Eight patients (6.6%) experienced inpatient hyperkalemia—all with PTA spironolactone. Patients who experienced inpatient hyperkalemia had a numerically lower eGFR that was not statistically significant (35.40 vs. 38.22 mL/min/1.73 m2; p = 0.730). Patients with CKD stage 3 (n = 4) had numerically higher rates of inpatient hyperkalemia than stages 4 (n = 1) or 5 (n = 3) (50%, 12.5%, and 37.5% respectively; p

Background Studies have reported beneficial effects of exercise training on autoimmunity, and specifically on multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, it is unknown whether different training paradigms affect disease course via shared or separate mechanisms. Objective To compare the effects and mechanism of immune modulation of high intensity continuous training (HICT) versus high intensity interval training (HIIT) on systemic autoimmunity in EAE. Methods We used the proteolipid protein (PLP)-induced transfer EAE model to examine training effects on the systemic autoimmune response. Healthy mice performed HICT or HIIT by running on a treadmill. Lymph-node (LN)-T cells from PLP-immunized trained- versus sedentary donor mice were transferred to naive recipients and EAE clinical and pathological severity were assessed. LN cells derived from donor trained and sedentary PLP-immunized mice were analyzed in vitro for T-cell activation and proliferation, immune cell profiling, and cytokine mRNA levels and cytokine secretion measurements. Results Both HICT and HIIT attenuated the encephalitogenicity of PLP-reactive T cells, as indicated by reduced EAE clinical severity and inflammation and tissue pathology in the central nervous system, following their transfer into recipient mice. HICT caused a marked inhibition of PLP-induced T-cell proliferation without affecting the T-cell profile. In contrast, HIIT did not alter T-cell proliferation, but rather inhibited polarization of T cells into T-helper 1 and T-helper 17 autoreactive populations. Interpretation HICT and HIIT attenuate systemic autoimmunity and T cell encephalitogenicity by distinct immunomodulatory mechanisms.

Background Biomarkers that can advance precision neurorehabilitation of the traumatic brain injury (TBI) are needed. MicroRNAs (miRNAs) have biological properties that could make them well suited for playing key roles in differential diagnoses and prognoses and informing likelihood of responsiveness to specific treatments. Objective To review the evidence of miRNA alterations after TBI and evaluate the state of science relative to potential neurorehabilitation applications of TBI-specific miRNAs. Methods This scoping review includes 57 animal and human studies evaluating miRNAs after TBI. PubMed, Scopus, and Google Scholar search engines were used. Results Gold standard analytic steps for miRNA biomarker assessment are presented. Published studies evaluating the evidence for miRNAs as potential biomarkers for TBI diagnosis, severity, natural recovery, and treatment-induced outcomes were reviewed including statistical evaluation. Growing evidence for specific miRNAs, including miR21, as TBI biomarkers is presented. Conclusions There is evidence of differential miRNA expression in TBI in both human and animal models; however, gaps need to be filled in terms of replication using rigorous, standardized methods to isolate a consistent set of miRNA changes. Longitudinal studies in TBI are needed to understand how miRNAs could be implemented as biomarkers in clinical practice.

Epileptic encephalopathies such as Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) present unique challenges in the transition of care not only for the providers but also for the patients and families. Some of these challenges include the complexity of disease process, differences in medication management between children and adults, high incidence of comorbidities such as psychosocial issues, a lack of structured transition process from pediatric to adult care, and the lack of parental knowledge and reluctance to transition to an adult provider. Improving transition readiness and transfer of care are essential to long-term management and continuity of care. Studies show that patients/families who possess transition readiness skills have better health outcomes. Furthermore, participation in a structured transition intervention has been shown to improve transition readiness and utilization of ambulatory care in the adult setting. Reported benefits of implementation of transition planning include increased self-esteem, improved health literacy, fewer emergency room visits, decreased hospitalizations and comorbidities, and fewer school absences. Nevertheless, there is a lack of evidenced-based, family/patient-centered transition model of care. This review's primary goal is to provide an overview of challenges in the transition of care and recommendations for an ideal transition for patients with DS and LGS.

Purpose The clinical significance of magnetoencephalography (MEG) dipole clusters in the insular region in patients with focal epilepsy, when present in conjunction with MEG dipole clusters in other regions of the brain is not known. Methods All patients (adult and pediatric) with MEG dipole clusters involving the insula were retrospectively evaluated. Patients who underwent any form of surgical intervention were included in the study. Data obtained included age, sex, seizure characteristics, MRI brain, EEG, MEG, intracranial EEG, type of intervention, and seizure outcomes. Results Twenty-four patients (12 adults and 12 pediatric) were included. Eight patients had one staged intervention and 16 had intracranial evaluation. Ten of 11 patients (91%) with insular coverage by stereotactic EEG had interictal insular spikes, and 5 of 11 patients (45%) had ictal onset from the insula. Combined Engel (I & II) outcomes were seen in five patients with resections/ablations involving the insula MEG dipole clusters as compared with eight patients where the insular MEG dipole clusters were not resected/ablated. Conclusions Insular MEG dipole clusters identified on surface MEG correlated with interictal spikes in intracranial stereotactic electrode contacts in the insula. The presence of insular MEG dipole clusters, however, does not definitively imply a primary insular onset epilepsy.

The objective of this article is to outline opportunities for breast imaging radiologists to advocate for screening mammography. Despite breast cancer being the second most common cancer in women and screening mammography’s ability to reduce mortality from this disease, there remains suboptimal utilization in the community. The different guidelines for screening presented by respected organizations has created confusion for patients and referring clinicians and the eventual underutilization of screening mammography. As experts in the value of early detection, breast radiologists are well suited to take on the role of screening advocates. Using specific action steps and examples, we create a template for a radiologist to utilize in the promotion of screening among the breast imaging team, clinicians, administrators, and the community at large. By deliberately filling the role of screening mammography advocate, one can satisfy the mandate for radiologists to bring increased value to the health care team while contributing to community health and patient satisfaction.

Objective In the midst of the severe acute respiratory syndrome coronavirus 2 pandemic, which causes coronavirus disease 2019, there is a recognized need to expand critical care services and beds beyond the traditional boundaries. There is considerable concern that widespread infection will result in a surge of critically ill patients that will overwhelm our present adult ICU capacity. In this setting, one proposal to add "surge capacity" has been the use of PICU beds and physicians to care for these critically ill adults. Design Narrative review/perspective. Setting Not applicable. Patients Not applicable. Interventions None. Measurements and main results The virus's high infectivity and prolonged asymptomatic shedding have resulted in an exponential growth in the number of cases in the United States within the past weeks with many (up to 6%) developing acute respiratory distress syndrome mandating critical care services. Coronavirus disease 2019 critical illness appears to be primarily occurring in adults. Although pediatric intensivists are well versed in the care of acute respiratory distress syndrome from viral pneumonia, the care of differing aged adult populations presents some unique challenges. In this statement, a team of adult and pediatric-trained critical care physicians provides guidance on common "adult" issues that may be encountered in the care of these patients and how they can best be managed in a PICU. Conclusions This concise scientific statement includes references to the most recent and relevant guidelines and clinical trials that shape management decisions. The intention is to assist PICUs and intensivists in rapidly preparing for care of adult coronavirus disease 2019 patients should the need arise.

Background Patient-reported outcome measures (PROMs) are increasingly used as quality benchmarks in total joint arthroplasty. The objective of this study is to investigate whether PROMs correlate with patient satisfaction, which is arguably the most important and desired outcome. Methods Our institutional joint database was queried for patients who underwent primary, elective, unilateral total joint arthroplasty. Eligible patients were asked to complete a satisfaction survey at final follow-up. Correlation coefficients (R) were calculated to quantify the relationship between patient satisfaction and prospectively collected PROMs. We explored a wide range of PROMs including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short Form-12, Oxford Hip Score, Knee Society Clinical Rating Score (KSCRS), Single Assessment Numerical Evaluation, and University of California Los Angeles activity level rating. Results In general, there was only weak to moderate correlation between patient satisfaction and PROMs. Querying the absolute postoperative scores had higher correlation with patient satisfaction compared to either preoperative scores or net changes in scores. The correlation was higher with disease-specific PROMs (WOMAC, Oxford Hip Score, KSCRS) compared to general health (Short Form-12), activity level (University of California Los Angeles activity level rating), or perception of normalcy (Single Assessment Numerical Evaluation). Within disease-specific PROMs, the pain domain consistently carried the highest correlation with patient satisfaction (WOMAC pain subscale, R = 0.45, P Conclusion There is only weak to moderate correlation between PROMs and patient satisfaction. PROMs alone are not the optimal way to evaluate patient satisfaction. We recommend directly querying patients about satisfaction and using shorter PROMs, particularly disease-specific PROMs that assess pain perception to better gauge patient satisfaction.

Background Returning to a satisfactory activity level is expected by patients after cartilage repair, and may define overall surgical success. Purpose To investigate: 1) the level and improvement in activity in patients at two years after matrix-induced autologous chondrocyte implantation (MACI), 2) what factors are associated with post-operative (and improvement in) activity level, and 3) whether patients are satisfied with their ability to participate in recreational and/or sporting activities. Study Design Prospective cohort. Methods One hundred and fifty patients that underwent MACI were included in this analysis (83 tibiofemoral and 67 patellofemoral). All patients completed the Tegner Activity Scale (TAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) pre-surgery and at two years (range: 24-26 months) post-surgery, as well as a questionnaire evaluating satisfaction with their ability to return to recreational and sporting activities. Results The TAS significantly improved (p

PURPOSE To report a case of acute posterior multifocal placoid pigment epitheliopathy occurring in temporal association with multiple immunizations in a previously healthy 25-year-old woman. METHODS Acute posterior multifocal placoid pigment epitheliopathy was diagnosed based on ophthalmological findings of bilateral placoid subretinal lesions complicated by a serous retinal detachment in the left eye. RESULTS Through HLA typing, the patient was found to possess the HLA-B*40 and HLA-DB1*15 alleles. She was treated with topical prednisolone acetate 1% and monitored for several months. The serous retinal detachment resolved, and visual acuity returned to normal. CONCLUSION This case report adds to the body of knowledge regarding possible atypical interplay between vaccines and specific T-cell receptors of the host immune system and adds Polio and Tetanus to the growing list of vaccines potentially triggering acute posterior multifocal placoid pigment epitheliopathy. Increased awareness of the presentation of acute posterior multifocal placoid pigment epitheliopathy and that it may arise after immunization may also improve evaluation of acute changes in visual acuity.

Screening mammography’s efficacy in reducing breast cancer deaths depends on patient compliance with screening recommendations and the radiologist’s interpretative skills. Reasons for suboptimal screening compliance may be multifactorial, including possible limitations in access. Additionally, while studies show experienced breast radiologists are more accurate in their mammographic interpretation, only a minority of the nation’s mammograms are interpreted by breast imaging specialists. To simultaneously optimize the benefit of early breast cancer detection while minimizing the harms associated with a false positive interpretation, delivery models that help improve access to breast expertise should be considered. Telemammography is one such delivery model that may be underutilized in current practice. While radiologists and other stakeholders of healthcare have accepted teleradiology interpretation of non-mammography studies as routine, telemammography use and acceptance is less well known. In this article, we review the operational components of a telemammography practice in today’s information- and technology-dependent society. Current use of telemammography and remaining potential challenges are discussed. Telemammography can improve healthcare delivery and access by bringing together patients and breast expertise. If accepted, use of telemammography can help meet Centers for Disease Control’s Healthy People 2020 goals related to breast cancer.

Background: We examined clinical outcomes among combat casualties with genitourinary injuries after blast trauma. Methods: Characteristics, clinical care, urologic complications, and infections for subjects enrolled in the Trauma Infectious Disease Outcomes Study (TIDOS) were collected from Department of Defense (DOD) and Department of Veterans Affairs (VA) sources. Logistic regression identified predictors for urinary tract infections (UTIs) after genitourinary trauma. Results: Among 530 TIDOS enrollees who entered VA care, 89 (17%) sustained genitourinary trauma. The majority of subjects (93%) were injured via a blast and 27% had a dismounted complex blast injury (DCBI). Sexual dysfunction was reported with 36% of subjects, whereas 14% had urinary retention/incontinence and 8% had urethral stricture. Urologic complications were comparable between patients with and without DCBIs. Nineteen (21%) subjects had one or more UTI with a total of 40 unique UTI events (25% during initial hospitalization and 75% during subsequent DOD or VA care). The UTI incidence rate was 0.89 per patient-year during initial hospitalization, 0.05 per patient-year during DOD follow-up, and 0.07 per patient-year during VA healthcare. Subjects with UTIs had a higher proportion of bladder injury (53% vs. 13%; p

Regional gene therapy using a lentiviral vector containing the BMP-2 complementary DNA (cDNA) has been shown to heal critical-sized bone defects in rodent models. An appropriate “cellular dose” needs to be defined for eventual translation into human trials. The purpose of this study was to evaluate bone defect healing potential and quality using three different doses of transduced human bone marrow cells (HBMCs). HBMCs were transduced with a lentiviral vector containing either BMP-2 or green fluorescent protein (GFP). All cells were loaded onto compression-resistant matrices and implanted in the bone defect of athymic rats. Treatment groups included femoral defects that were treated with a low-dose (1 × 10(6) cells), standard-dose (5 × 10(6) cells), and high-dose (1.5 × 10(7) cells) HBMCs transduced with lentiviral vector containing BMP-2 cDNA. The three control groups were bone defects treated with HBMCs that were either nontransduced or transduced with vector containing GFP. All animals were sacrificed at 12 weeks. The bone formed in each defect was evaluated with plain radiographs, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. Bone defects treated with higher doses of BMP-2-producing cells were more likely to have healed (6/14 of the low-dose group; 12/14 of the standard-dose group; 14/14 of the high-dose group; χ(2)(2) = 15.501, p

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Viremia in the vertebrate host is a major determinant of arboviral reservoir competency, transmission efficiency, and disease severity. However, immune mechanisms that control arboviral viremia are poorly defined. Here, we identify critical roles for the scavenger receptor MARCO in controlling viremia during arthritogenic alphavirus infections in mice. Following subcutaneous inoculation, arthritogenic alphavirus particles drain via the lymph and are rapidly captured by MARCO+ lymphatic endothelial cells (LECs) in the draining lymph node (dLN), limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared from the circulation by MARCO-expressing Kupffer cells in the liver, limiting viremia and further viral dissemination. MARCO-mediated accumulation of alphavirus particles in the draining lymph node and liver is an important host defense mechanism as viremia and viral tissue burdens are elevated in MARCO-/- mice and disease is more severe. In contrast to prior studies implicating a key role for lymph node macrophages in limiting viral dissemination, these findings exemplify a previously unrecognized arbovirus-scavenging role for lymphatic endothelial cells and improve our mechanistic understanding of viremia control during arthritogenic alphavirus infection.

Introduction: Diseases such as celiac disease, environmental enteric dysfunction, infectious gastroenteritis, type II diabetes and inflammatory bowel disease are associated with increased gut permeability. Dual sugar absorption tests, such as the lactulose to rhamnose ratio (L:R) test, are the current standard for measuring gut permeability. Although easy to administer in adults, the L:R test has a number of drawbacks. These include an inability to assess for spatial heterogeneity in gut permeability that may distinguish different disease severity or pathology, additional sample collection for immunoassays, and challenges in carrying out the test in certain populations such as infants and small children. Here, we demonstrate a minimally invasive probe for real-time localized gut permeability evaluation through gut potential difference (GPD) measurement.Materials and Methods: The probe has an outer diameter of 1.2 mm diameter and can be deployed in the gut of unsedated subjects via a transnasal introduction tube (TNIT) that is akin to an intestinal feeding tube. The GPD probe consists of an Ag/AgCl electrode, an optical probe and a perfusion channel all housed within a transparent sheath. Lactated Ringer’s (LR) solution is pumped through the perfusion channel to provide ionic contact between the electrodes and the gut lining. The optical probe captures non-scanning (M-mode) OCT images to confirm electrode contact with the gut lining. A separate skin patch probe is placed over an abraded skin area to provide reference for the GPD measurements. Swine studies were conducted to validate the GPD probe. GPD in the duodenum was modulated by perfusing 45 ml of 45 mM glucose.Results: GPD values of −13.1 ± 2.8 mV were measured in the duodenum across four swine studies. The change in GPD in the duodenum with the addition of glucose was −10.5 ± 2.4 mV (p < 0.001). M-mode OCT images provided electrode-tissue contact information, which was vital in ascertaining the probe’s proximity to the gut mucosa.Conclusion: We developed and demonstrated a minimally invasive method for investigating gastrointestinal permeability consisting of an image guided GPD probe that can be used in unsedated subjects.

PURPOSE: The COVID-19 pandemic impacted clinical practice, education, and research in Neurophysiology/Epilepsy. Although there is published literature on clinical impact, its educational impact is not well described. A national survey of Clinical Neurophysiology (CNP) and Epilepsy fellowship programs was conducted to assess the impact of COVID-19 on fellowship education. METHODS: A list of accredited Clinical Neurophysiology and Epilepsy fellowship programs was obtained from the Accreditation Council for Graduate Medical Education. Program directors at individual locations were contacted to complete a brief survey about the program and impact of COVID-19. Fellows from responding programs were subsequently invited to share their perceptions about the impact of the pandemic on their training. RESULTS: From 176 programs, 40 PDs responded (22.7%). From these 40 programs, fellows from 26 completed surveys (65.0% response). There was a reduction in EEG and epilepsy monitoring unit volumes post-COVID-19, with a trend of change for EMG, whereas continuous EEG volumes were mostly unchanged. The impact of the pandemic on training was rated as moderate to severe (≥50%) by 30.0% of PDs and 49.0% of trainees. In remarkable agreement, 20.0% of PDs and 20.4% of fellows believed that additional fellowship training was needed before graduation. Lack of fellow satisfaction was correlated with the perceived impact of the pandemic on education (p = 0.008). CONCLUSIONS: This survey revealed a considerable impact on EEG/EMG clinical volume because of COVID-19, although continuous EEG was not as impacted. More fellows than PDs believed that training was considerably impacted by COVID-19, but a similar number thought that additional training was needed. It was unclear from this study whether the fellows' perception of educational impact was solely because of the pandemic or in addition to preexisting training deficiencies in the training programs.

Background We established an IV outpatient diuresis (IVOiD) clinic and conducted a quality improvement project to evaluate safety, effectiveness and costs associated with outpatient versus inpatient diuresis for patients presenting with acute decompensated heart failure (ADHF) to the emergency department (ED). Methods Patients who were clinically diagnosed with ADHF in the ED, but did not have high-risk features, were either diuresed in the hospital or in the outpatient IVOiD clinic. The dose of IV diuretic was based on their home maintenance diuretic dose. The outcomes measured were the effects of diuresis (urine output, weight, hemodynamic and laboratory abnormalities), 30–90 day readmissions, 30–90 day death and costs. Results In total, 36 patients (22 inpatients and 14 outpatients) were studied. There were no significant differences in the baseline demographics between groups. The average inpatient stay was six days and the average IVOiD clinic days were 1.2. There was no significant difference in diuresis per day of treatment (1159 vs. 944 ml, p = 0.46). There was no significant difference in adverse outcomes, 30–90 day readmissions or 30–90 day deaths. There was a significantly lower cost in the IVOiD group compared to the inpatient group ($839.4 vs. $9895.7, p= Conclusions Outpatient IVOiD clinic diuresis may be a viable alternative to accepted clinical practice of inpatient diuresis for ADHF. Further studies are needed to validate this in a larger cohort and in different sites.

Importance Myocarditis has been reported with COVID-19 but is not clearly recognized as a possible adverse event following COVID-19 vaccination. Objective To describe myocarditis presenting after COVID-19 vaccination within the Military Health System. Design, Setting, and Participants This retrospective case series studied patients within the US Military Health System who experienced myocarditis after COVID-19 vaccination between January and April 2021. Patients who sought care for chest pain following COVID-19 vaccination and were subsequently diagnosed with clinical myocarditis were included. Exposure Receipt of a messenger RNA (mRNA) COVID-19 vaccine between January 1 and April 30, 2021. Main Outcomes and Measures Clinical diagnosis of myocarditis after COVID-19 vaccination in the absence of other identified causes. Results A total of 23 male patients (22 currently serving in the military and 1 retiree; median [range] age, 25 [20-51] years) presented with acute onset of marked chest pain within 4 days after receipt of an mRNA COVID-19 vaccine. All military members were previously healthy with a high level of fitness. Seven received the BNT162b2-mRNA vaccine and 16 received the mRNA-1273 vaccine. A total of 20 patients had symptom onset following the second dose of an appropriately spaced 2-dose series. All patients had significantly elevated cardiac troponin levels. Among 8 patients who underwent cardiac magnetic resonance imaging within the acute phase of illness, all had findings consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, including acute COVID-19 and other infections, ischemic injury, or underlying autoimmune conditions. All patients received brief supportive care and were recovered or recovering at the time of this report. The military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period. While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose. Conclusions and Relevance In this case series, myocarditis occurred in previously healthy military patients with similar clinical presentations following receipt of an mRNA COVID-19 vaccine. Further surveillance and evaluation of this adverse event following immunization is warranted. Potential for rare vaccine-related adverse events must be considered in the context of the well-established risk of morbidity, including cardiac injury, following COVID-19 infection.

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy, but can also serve as a substrate for genotoxic reactive oxygen species generation. As a labile substance upon which aerobic life depends, the mechanisms for handling cellular oxygen have been fine-tuned and orchestrated in evolution. Protection from atmospheric oxygen toxicity as originally posited by the Endosymbiotic Theory of the Mitochondrion is likely to be one basic principle underlying oxygen homeostasis. We briefly review the literature on oxygen homeostasis both in vitro and in vivo with a focus on the role of the mitochondrion where the majority of cellular oxygen is consumed. The insights gleaned from these basic mechanisms are likely to be important for understanding disease pathogenesis and developing strategies for maintaining health.

While viremia in the vertebrate host is a major determinant of arboviral reservoir competency, transmission efficiency, and disease severity, immune mechanisms that control arboviral viremia are poorly defined. Here, we identify critical roles for the scavenger receptor MARCO in controlling viremia during arthritogenic alphavirus infections in mice. Following subcutaneous inoculation, alphavirus particles drain via the lymph and are rapidly captured by MARCO+ lymphatic endothelial cells (LECs) in the draining lymph node (dLN), limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared from the circulation by MARCO-expressing Kupffer cells in the liver, limiting viremia and further viral dissemination. MARCO-mediated accumulation of alphavirus particles in the dLN and liver is an important host defense mechanism as viremia and viral tissue burdens are elevated in MARCO-/- mice and disease is more severe. These findings uncover a previously unrecognized arbovirus scavenging role for LECs and improve our mechanistic understanding of viremia control during arboviral infections.

Background: Knee injection using either bone marrow aspirate concentrate (BMAC) or stromal vascular fraction (SVF) from adipose tissue has been shown to result in symptomatic improvement in patients with knee osteoarthritis (OA). It is still unclear whether one of these therapies is superior over the other. Purpose: To systematically report the clinical studies evaluating BMAC and SVF in the treatment of knee OA and to compare the clinical efficacy of these 2 injection therapies. Study Design: Meta-analysis; Level of evidence, 4. Methods: This meta-analysis was performed per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Studies were included if they reported the clinical outcomes after a single BMAC or SVF injection in the knee joint of patients with OA. Studies evaluating preparations of culture-expanded stem cells were excluded. A random effects model was used; the clinical efficacy of BMAC or SVF injection was assessed using the standardized mean difference (SMD) and compared. Visual analog scale (VAS) scores for pain and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) knee index were the primary outcomes. The level of statistical significance was set at P < .05. Results: Ten studies and 472 patients with knee OA who received either BMAC (233 patients) or SVF (239 patients) were included. Patients who received an injection had improved VAS outcomes (mean ± SD): from 5.8 ± 1.3 to 2.6 ± 17 for BMAC and from 6.4 ± 1.4 to 3.4 ± 0.5 for SVF. They also experienced significantly reduced pain (SMD [VAS], 2.6 for BMAC and 3.4 for SVF) and improved function (SMD [WOMAC], 1.4 for BMAC and 1.2 for SVF). However, the SVF injection had a significantly greater effect on pain reduction than did the BMAC injection ( P < .0001). Based on WOMAC, the clinical effect of BMAC versus SVF knee injection in patients with knee OA was equivalent ( P = .626). Results were limited by the presence of publication bias as well as variability in the preparation methods utilized in the BMAC and SVF injection protocols. Complications were reported in 50% of the BMAC studies (knee stiffness, persistent knee swelling) and 67% of the SVF studies (knee swelling, knee pain, positive SVF cultures without symptoms of infection, and bleeding at the abdominal harvest site). Conclusion: A single BMAC or SVF injection into the knee joint of patients with OA resulted in symptomatic improvement at short-term follow-up. However, SVF seemed to be more effective than did BMAC in the reduction of knee pain. There was significant variation in the BMAC and SVF injection preparation techniques used across the studies and a lack of stratification of outcomes based on the radiologic classification of OA. Therefore, these results should be taken with caution.

Background Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. We aimed to determine the influence of neoplastic and immune cell diversity on MB biology in patient samples and animal models. Methods To better characterize cellular heterogeneity in MB we used single-cell RNA sequencing, immunohistochemistry, and deconvolution of transcriptomic data to profile neoplastic and immune populations in patient samples and animal models across childhood MB subgroups. Results Neoplastic cells cluster primarily according to individual sample of origin which is influenced by chromosomal copy number variance. Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes, including photoreceptor and glutamatergic neuron-like cells in molecular subgroups GP3 and GP4, and a specific nodule-associated neuronally differentiated subpopulation in the sonic hedgehog subgroup. We definitively chart the spectrum of MB immune cell infiltrates, which include subpopulations that recapitulate developmentally related neuron-pruning and antigen-presenting myeloid cells. MB cellular diversity matching human samples is mirrored in subgroup-specific mouse models of MB. Conclusions These findings provide a clearer understanding of the diverse neoplastic and immune cell subpopulations that constitute the MB microenvironment.

A human single nucleotide polymorphism (SNP) in the matrix-binding domain of extracellular superoxide dismutase (EC-SOD), with arginine to glycine substitution at position 213 (R213G), redistributes EC-SOD from the matrix into extracellular fluids. We reported that, following bleomycin (bleo), knockin mice harboring the human R213G SNP (R213G mice) exhibit enhanced resolution of inflammation and protection against fibrosis, compared with wild-type (WT) littermates. In this study, we tested the hypothesis that the EC-SOD R213G SNP promotes resolution via accelerated apoptosis of recruited alveolar macrophage (AM). RNA sequencing and Ingenuity Pathway Analysis 7 d postbleo in recruited AM implicated increased apoptosis and blunted inflammatory responses in the R213G strain exhibiting accelerated resolution. We validated that the percentage of apoptosis was significantly elevated in R213G recruited AM vs. WT at 3 and 7 d postbleo in vivo. Recruited AM numbers were also significantly decreased in R213G mice vs. WT at 3 and 7 d postbleo. ChaC glutathione-specific γ-glutamylcyclotransferase 1 (Chac1), a proapoptotic γ-glutamyl cyclotransferase that depletes glutathione, was increased in the R213G recruited AM. Overexpression of Chac1 in vitro induced apoptosis of macrophages and was blocked by administration of cell-permeable glutathione. In summary, we provide new evidence that redistributed EC-SOD accelerates the resolution of inflammation through redox-regulated mechanisms that increase recruited AM apoptosis.-Allawzi, A., McDermott, I., Delaney, C., Nguyen, K., Banimostafa, L., Trumpie, A., Hernandez-Lagunas, L., Riemondy, K., Gillen, A., Hesselberth, J., El Kasmi, K., Sucharov, C. C., Janssen, W. J., Stenmark, K., Bowler, R., Nozik-Grayck, E. Redistribution of EC-SOD resolves bleomycin-induced inflammation via increased apoptosis of recruited alveolar macrophages.

Hypospadias is the abnormal opening of the urethra on the underside of the penis and occurs in approximately 1/125 live male births worldwide. The incidence rate of hypospadias has dramatically increased over the past few decades. This is now attributed, at least in part, to our exposure to endocrine-disrupting chemicals (EDCs) which alter the hormonal signals required for development of the penis. In humans androgens are the main drivers of fusion of the urethral folds to form the urethra within the shaft of the penis, a process required for termination of the urethra in its normal location at the tip of the penis. However, recent research has suggested that estrogen also plays a role in this process. To better understand how EDCs impact urethral development it is essential that we understand the normal function of hormones during development of the penis. To define the role of estrogen in urethral development we examined development of the penis in the aromatase (Cyp19a1) Knockout (ArKO) mouse strain in which endogenous estrogen production is completely ablated. We found that the ArKO penis had a mild hypospadias phenotype. The developing ArKO postnatal penis displayed an early disruption in preputial development, which likely causes the mild hypospadias observed in adults. Using qPCR, we found altered expression of keratin genes and key urethral patterning genes in response to the disrupted estrogen signaling. The hypospadias phenotype was almost identical to that reported for the estrogen receptor α (ERα) knockout confirming that ERα is the predominant receptor for mediating estrogen action during development of the mouse penis. Our results show that estrogen is required for normal prepucial development and placement of the mature urethral opening at the distal aspect of the penis. We also identified several genes which are potential downstream targets of estrogen during normal urethral closure. With this knowledge, we can now better understand how anti-estrogenic as well as estrogenic EDCs disrupt urethral closure to cause mild hypospadias in both mice and humans.

Hypospadias, a developmental defect of the penis, is one of the most common congenital malformations in humans. Its incidence has rapidly increased over recent decades, and this has been largely attributed to our increased exposure to endocrine-disrupting chemicals. Penis development is primarily an androgen-driven process; however, estrogen and xenoestrogens are known to affect penis development in both humans and mice. Here, we investigated the role of estrogen in the developing penis. Using a novel penis culture system, we showed that exogenous estrogen directly targets the developing penis in utero to cause hypospadias. In addition, we also uncovered an unexpected endogenous role for estrogen in normal postnatal penis development and showed that a loss of estrogen signaling results in a mild hypospadias phenotype, the most common manifestation of this disease in humans. Our findings demonstrated that both androgen and estrogen signaling are intrinsically required for normal urethral closure. These findings confirmed that penis development is not an entirely androgen-driven process but one in which endogenous estrogen signaling also plays a critical role.—Govers, L. C., Phillips, T. R., Mattiske, D. M., Rashoo, N., Black, J. R., Sinclair, A., Baskin, L. S., Risbridger, G. P., Pask, A. J. A critical role for estrogen signaling in penis development.

Patient-reported outcomes (PROs) are gaining an important role in the assessment of quality of care. There are currently limited data on the effect of payer type on PROs in total joint arthroplasty (TJA). This study compared both disease-specific and general health PROs among patients stratified according to their payer type.Our institutional joint registry was queried for patients who underwent primary, elective, and unilateral hip and knee arthroplasty. Patients were divided according to their insurance type at the time of surgery into 3 groups: Medicaid, Medicare, or commercial. The outcomes assessed were the net changes in PROs as well as absolute scores at 6 months and 1 year. Six of the most commonly used PROs were assessed: Short Form-12 physical and mental components, Western Ontario and McMaster Universities Osteoarthritis Index, Single Assessment Numerical Evaluation, University of Californian Los Angeles activity level rating, and Oxford Hip Score. Analysis of variance and covariance were used.We evaluated 756 procedures (273 Medicaid, 270 Medicare, and 213 commercial insurance). Medicaid patients had significantly lower mean baseline scores across all PROs compared to either Medicare or commercial insurance patients. Medicaid patients were also more likely to be smokers, live alone, have lower educational level, African-American, and have nonprimary osteoarthritis as the indication for TJA. At 1-year follow-up, the net mean outcome gains were comparable among the 3 payer types (P.05), but Medicaid patients continued to score lower while Medicare and commercial insurance patients continued to score higher (P.01). When adjusting for all baseline differences among Medicaid patients, the negative effects of payer type resolved except for Oxford Hip Score which remained lower in the Medicaid group (P = .006).When using PROs to assess the value of care, the preoperative to postoperative changes are a better indicator of surgical success than comparing absolute values, especially in Medicaid patients. While TJA imparts similar net improvements to patients of all payer types, Medicaid coverage is a predictor of lower absolute outcome scores at any given time as result of increased baseline health burden (eg, depression, tobacco smoking, and poor overall well-being). Arthroplasty surgeons should be aware of these factors when counseling patients and seek optimization when necessary. The findings should be taken into account by stakeholders when constructing value-based payment models. Further research is needed to better understand the barriers leading to higher prevalence of increased health disparities among Medicaid beneficiaries and how to effectively address them.

Challenges currently facing breast radiologists, including controversial screening mammography guidelines, radiologist burnout, and the perceived threat posed by artificial intelligence could deter potential candidates from pursuing a career in radiology. However, breast radiologists play a fulfilling role by decreasing the effect of breast cancer through both early detection and direct interaction with patients and interdisciplinary clinical colleagues. While perception is that artificial intelligence will threaten the need for radiologists, it is more likely that it will improve image interpretation and efficiency in workflow, thereby further improving patient care. Trainees can be engaged in breast imaging through interactive teaching methods and by role modeling clinical and image interpretation skills.

Electroencephalogram (EEG) recordings in Fragile X syndrome (FXS) patients have revealed enhanced sensory responses, enhanced resting “gamma frequency” (30–100 Hz) activity, and a decreased ability for sensory stimuli to modulate cortical activity at gamma frequencies. Similar changes are observed in the FXS model mouse – the Fmr1 knockout. These alterations may become effective biomarkers for diagnosis and treatment of FXS. Therefore, it is critical to better understand what circuit properties underlie these changes. We employed Channelrhodopsin2 to optically activate local circuits in the auditory cortical region in brain slices to examine how changes in local circuit function may be related to EEG changes. We focused on layers 2/3 and 5 (L2/3 and L5). In Fmr1 knockout mice, light-driven excitation of L2/3 revealed hyperexcitability and increased gamma frequency power in both local L2/3 and L5 circuits. Moreover, there is increased synchrony in the gamma frequency band between L2/3 and L5. Hyperexcitability and increased gamma power were not observed in L5 with L5 light-driven excitation, indicating that these changes were layer-specific. A component of L2/3 network hyperexcitability is independent of ionotropic receptor mediated synaptic transmission and may be mediated by increased intrinsic excitability of L2/3 neurons. Finally, lovastatin, a candidate therapeutic compound for FXS that targets ERK signaling did not normalize changes in gamma activity. In conclusion, hyperactivity and increased gamma activity in local neocortical circuits, together with increased gamma synchrony between circuits, provide a putative substrate for EEG alterations observed in both FXS patients and the FXS mouse model.

Osteogenesis imperfecta [1] is a rare disorder of connective tissue caused by abnormalities in the synthesis or processing of type I collagen. Type I collagen is the most abundant type of collagen and is expressed in almost all connective tissues. Given that type I collagen interacts with other collagens based in the extracellular matrix (ECM), we hypothesized changes in type I collagen in OI would result in perturbations in the homeostasis of other collagen types. We measured serum biomarkers of several non-type I collagens in patients with mild (type I) and moderate-to-severe (type III/IV) OI. Compared to controls, those with moderate-to severe OI had a higher mean level of the synthesis markers of collagen III (ProC3) (P = 0.02), and levels of collagen V (ProC5) (P = 0.07) were slightly, but not significantly, higher. Degradation markers of collage type IV (C4M2) (P = 0.04) and type VI (C6M) (P = 0.003) were also higher. In each case, a test for trend suggested levels were higher in moderate-to-severe OI, intermediate in mild OI, and lowest in controls (P = 0.06–0.002). These changes supports the hypothesis that mutations in type I collagen induce a widespread alteration in the ECM, and that the diverse clinical manifestations of OI reflect an extensive disruption in ECM biology.

The poly(ADP-ribose) polymerases (PARP) play important roles in repairing damaged DNA during intrinsic cell death. We recently linked PARP-1 to death receptor (DR)-activated extrinsic apoptosis, the present studies sought to elucidate the function of cytoplasmic PARP-1 in pancreatic cancer tumorigenesis and therapy. Using human normal and pancreatic cancer tissues, we analyzed the prevalence of cytoplasmic PARP-1 expression. In normal human pancreatic tissues, PARP-1 expression was present in the nucleus; however, cytoplasmic PARP-1 expression was identified in pancreatic cancers. Therefore, cytoplasmic PARP-1 mutants were generated by site-direct mutagenesis, to determine a causative effect of cytoplasmic PARP-1 on pancreatic cancer tumorigenesis and sensitivity to therapy with TRA-8, a humanized DR5 antibody. PARP-1 cytoplasmic mutants rendered TRA-8 sensitive pancreatic cancer cells, BxPc-3 and MiaPaCa-2, more resistant to TRA-8-induced apoptosis; whereas wild-type PARP-1, localizing mainly in the nucleus, had no effects. Additionally, cytoplasmic PARP-1, but not wild-type PARP-1, increased resistance of BxPc-3 cells to TRA-8 therapy in a mouse xenograft model in vivo. Inhibition of PARP enzymatic activity attenuated cytoplasmic PARP-1-mediated TRA-8 resistance. Furthermore, increased cytoplasmic PARP-1, but not wild-type PARP-1, was recruited into the TRA-8-activated death-inducing signaling complex and associated with increased and sustained activation of Src-mediated survival signals. In contrast, PARP-1 knockdown inhibited Src activation. Taken together, we have identified a novel function and mechanism underlying cytoplasmic PARP-1, distinct from nuclear PARP-1, in regulating DR5-activated apoptosis. Our studies support an innovative application of available PARP inhibitors or new cytoplasmic PARP-1 antagonists to enhance TRAIL therapy for TRAIL-resistant pancreatic cancers.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. FXS is caused by functional loss of the Fragile X Protein (FXP), also known as Fragile X Mental Retardation Protein (FMRP). In humans and animal models, loss of FXP leads to sensory hypersensitivity, increased susceptibility to seizures and cortical hyperactivity. Several components of the GABAergic system, the major inhibitory system in the brain, are dysregulated in FXS, and thus modulation of GABAergic transmission was suggested and tested as a treatment strategy. However, so far, clinical trials using broad spectrum GABAA or GABAB receptor-specific agonists have not yielded broad improvement of FXS phenotypes in humans. Here, we tested a more selective strategy in Fmr1 knockout (KO) mice using the experimental drug BAER-101, which is a selective GABAA α2/α3 agonist. Our results suggest that BAER-101 reduces hyperexcitability of cortical circuits, partially corrects increased frequency-specific baseline cortical EEG power, reduces susceptibility to audiogenic seizures and improves novel object memory. Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABAA-receptor subunit-selective agonists for the treatment of FXS.

Cholinergic urticaria is a common disorder that has been associated with anaphylaxis. We report the events, workup, and eventual second dose vaccination of a patient at the Walter Reed National Military Medical Center, who had immediate anaphylaxis after administration of the first Pfizer-BioNTech Covid-19 (BNT162b2) vaccine dose. During the initial evaluation after anaphylaxis, the patient described a history of symptoms suspicious for cholinergic urticaria but had never had this condition confirmed with standardized testing. After the episode of anaphylaxis, we performed several studies including immediate hypersensitivity skin testing, which did not demonstrate vaccine or component sensitization. We then performed an exercise provocation challenge and confirmed the diagnosis of cholinergic urticaria. These results, combined with the patient history, suggested that the episode of anaphylaxis was most likely driven by a severe flare of cholinergic urticaria. After obtaining the patient’s consent, she received and tolerated her second dose without any objective findings of anaphylaxis. We conclude that patients with mast cell disorders or anaphylaxis after their first Covid-19 immunization will benefit from referral to an allergist since receipt of their second Covid-19 immunization may be possible.

BACKGROUND: Chronic hepatitis B (HBV) is the predominant cause of hepatocellular carcinoma (HCC) worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multi-cohort study of HIV/HBV-coinfected individuals. METHODS & RESULTS: We included HIV/HBV-coinfected persons within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995–2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted hazard (aHRs [95% confidence intervals]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, hepatitis C), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 HIV/HBV-coinfected individuals (median age, 43 years; 93% male; 52.4% non-white), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5–2.1] events/1,000 person-years). Risk factors for HCC included age 40–49 years (aHR, 1.97 [1.22–3.17]), age ≥50 years (aHR, 2.55 [1.49–4.35]), hepatitis C coinfection (aHR, 1.61 [1.07–2.40]), and heavy alcohol use (aHR, 1.52 [1.04–2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56–1.43]) and time-updated CD4+ percentage 200 IU/mL (aHR, 2.22 [1.42–3.47]) and was higher with each 1.0 log(10) IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05–1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24–0.73]). CONCLUSION: HIV/HBV-coinfected individuals on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

Objective Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), which has one of the lowest 5-year survival rates in oncology. The reasons for poor survival are twofold: the large majority of diagnoses are in advanced stages (~80%) and limited treatment options, with a deficit of biology-guided therapies. As a rapidly growing public health concern with poor prognosis, research into the molecular progression for BE and novel therapeutics for EAC currently has high clinical utility. Review of the literature reveals that innovative analysis of metaplastic progression from BE to EAC at a molecular level can shed light on the underlying transformative probabilities of BE into malignant pathologies and may impact current of future therapeutic modalities for management of these diseases. Background EAC is the fastest increasing cancer in the United States with a 600% increase over the past 25 years. This cancer arises from dysplastic tissue of BE, a complication of gastroesophageal reflux disease (GERD). Chronic acid and bile reflux in the distal esophagus initiates a metaplastic conversion of normal squamous epithelium to premalignant intestinalized columnar epithelium. Patients with BE have a 125-fold higher risk of cancer compared to the general population. Methods We critically reviewed the current status of BE monitoring, and subsequent therapeutic strategies being used in patients who have progressed to cancer. Also, new diagnostic tools and therapeutic candidates for BE-related EAC are discussed. Highly-targeted searches of databases containing recent original peer-reviewed papers were utilized for this review. Conclusions Novel and well-described biomarkers analyzed in the patient's diseased tissue will provide for more powerful diagnostics, but also possess the potential to develop strategies for personalized management and identify targets for intervention to either cease disease progression or treat BE and/or EAC. Since millions of Americans develop BE without progressing to cancer, there is a critical need to identify the small percentage of Barrett's patients who possess hallmarks of disease progression or carcinogenesis with novel screening techniques. Incorporation of such tools into standard screening protocols for BE surveillance and/or therapy would be critical to detect malignant transformations before clinically obvious cancer ever develops.

Background Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016–2020. Methods A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. Results Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016–2017 – approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). Conclusions Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism.

Vascular function is further attenuated in patients with chronic heart failure implanted with a continuous-flow left ventricular assist device (LVAD), likely due to decreased arterial pulsatility, and this may contribute to LVAD-associated cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown. Therefore, 15 LVAD recipients and 15 well-matched controls underwent a 45-min, unilateral, arm pulsatility treatment, evoked by intermittent cuff inflation/deflation (2-s duty cycle), distal to the elbow. Vascular function was assessed by percent brachial artery flow-mediated dilation (%FMD) and reactive hyperemia (RH) (Doppler ultrasound). Pretreatment, %FMD (LVAD: 4.0 ± 1.7; controls: 4.2 ± 1.4%) and RH (LVAD: 340 ± 101; controls: 308 ± 94 mL) were not different between LVAD recipients and controls; however, %FMD/shear rate was attenuated (LVAD: 0.10 ± 0.04; controls: 0.17 ± 0.06%/s−1, P < 0.05). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared with controls prior to treatment (LVAD: 2 ± 2; controls: 15 ± 7 AU, P < 0.05); however, during the treatment, PI was no longer different (LVAD: 37 ± 38; controls: 36 ± 14 AU). Although time to peak dilation and RH were not altered by the pulsatility treatment, %FMD (LVAD: 7.0 ± 1.8; controls: 7.4 ± 2.6%) and %FMD/shear rate (LVAD: 0.19 ± 0.07; controls: 0.33 ± 0.15%/s−1) increased significantly in both groups, with, importantly, %FMD/shear rate in the LVAD recipients being restored to that of the controls pretreatment. This study documents that a localized pulsatility treatment in LVAD recipients and controls can recover local vascular function, an important precursor to the development of approaches to increase systemic pulsatility and reduce systemic vascular complications in LVAD recipients.

To assess the baseline EEG knowledge among adult neurology residents at our institution and their perspectives on EEG learning experience during residency. We evaluated baseline EEG knowledge and resident perception of EEG education utilizing an EEG quiz and an online EEG survey, respectively. The EEG quiz was divided in two parts, composed of normal (n=27) and abnormal (n=10) EEG examples. The EEG survey focused on the importance of EEG, EEG milestones and EEG education. Twenty-one residents completed the EEG quiz; all 21 completed the normal EEG part whereas 19 of these 21 completed the abnormal EEG part. The overall score (mean±SEM) was 42±4.5% for the normal EEG part and 44±5.5% for the abnormal EEG part. The EEG survey was completed by 28 residents. Forty-three percent of the respondents reported not being able to read EEGs even with supervision. The most commonly reported education barriers were insufficient exposure, insufficient responsibility to read EEGs, and inability to link EEG learning to direct patient care. On average, adult neurology residents were able to correctly identify less than half of normal and abnormal EEG findings. Almost half of residents reported not being able to read EEGs even with supervision.

Publisher Summary Osteoporosis is being recognized with increasing frequency in young adult women and men. The clinician is faced with a differential diagnosis that may range from an inherited disorder such as mild osteogenesis imperfecta, to acquired endocrine, gastrointestinal, and renal disorders. Representative of these are hyperparathyroidism, occult malabsorption, and idiopathic hypercalcuria. Osteoporosis associated with malignancy in a young adult is also a factor in differential diagnosis. However, a difficult diagnostic and therapeutic situation confronts the clinician attending a young male or premenopausal female when these disorders are eliminated and the diagnosis is primary idiopathic osteoporosis. A consideration of the etiology of osteoporosis in young adults between the ages of puberty and age 50 years invokes two concerns: the genetic background of the individual and the role of a heritable defect in connective tissue synthesis leading to diminished bone mass. Both factors may underlie the failure to achieve peak young adult bone mass, now recognized as leading to osteoporosis in later life. New developments in the molecular biology of connective tissues, particularly the definition of mutations affecting the synthesis of types I, II, and III collagens, have focused research perspectives on the possibility of mutations affecting other skeletal matrix components besides the collagens. Thus, osteoporosis related to a heritable disorder may present itself at any age.