Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.

A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma.

MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) and predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to MNA+ NB remains poorly understood. Here, we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently coexpressed with MYCN and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN, among which we uncover myosin 1B (MYO1B) as being highly expressed in MNA+ NB and, using a chick chorioallantoic membrane (CAM) model, as a crucial regulator of invasion and metastasis. Global secretome and proteome profiling further delineates MYO1B in regulating secretome reprogramming in MNA+ NB cells, and the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism promoting aggressive behavior in MNA+ NB and independently of MYCN.

Mental Health Care Following Firearm and Motor Vehicle-related Injuries: Differences Impacting Our Treatment Strategies.

OBJECTIVE: To compare new mental health diagnoses (NMHD) in children after a firearm injury versus following a motor vehicle collision (MVC). BACKGROUND: A knowledge gap exists regarding childhood mental health diagnoses following firearm injuries, notably in comparison to other forms of traumatic injury. METHODS: We utilized Medicaid MarketScan claims (2010-2016) to conduct a matched case-control study of children ages 3 to 17 years. Children with firearm injuries were matched with up to 3 children with MVC injuries. Severity was determined by injury severity score and emergency department disposition. We used multivariable logistic regression to measure the association of acquiring a NMHD diagnosis in the year postinjury after firearm and MVC mechanisms. RESULTS: We matched 1450 children with firearm injuries to 3691 children with MVC injuries. Compared to MVC injuries, children with firearm injuries were more likely to be black, have higher injury severity score, and receive hospital admission from the emergency department ( P <0.001). The adjusted odds ratio (aOR) of NMHD diagnosis was 1.55 [95% confidence interval (95% CI): 1.33-1.80] greater after firearm injuries compared to MVC injuries. The odds of a NMHD were higher among children admitted to the hospital compared to those discharged. The increased odds of NMHD after firearm injuries was driven by increases in substance-related and addictive disorders (aOR: 2.08; 95% CI: 1.63-2.64) and trauma and stressor-related disorders (aOR: 2.07; 95% CI: 1.55-2.76). CONCLUSIONS: Children were found to have 50% increased odds of having a NMHD in the year following a firearm injury as compared to MVC. Programmatic interventions are needed to address children's mental health following firearm injuries.

High-Powered Magnet Exposures in Children: A Multi-Center Cohort Study.

BACKGROUND AND OBJECTIVES: High-powered magnets were effectively removed from the US market by the Consumer Product Safety Commission (CPSC) in 2012 but returned in 2016 after federal court decisions. The United States Court of Appeals for the 10th Circuit cited imprecise data among other reasons as justification for overturning CPSC protections. Since then, incidence of high-powered magnet exposure has increased markedly, but outcome data are limited. In this study, we aim to describe the epidemiology and outcomes in children seeking medical care for high-powered magnets after reintroduction to market. METHODS: This is a multicenter, retrospective cohort study of patients aged 0 to 21 years with a confirmed high-powered magnet exposure (ie, ingestion or insertion) at 25 children's hospitals in the United States between 2017 and 2019. RESULTS: Of 596 patients with high-powered magnet exposures identified, 362 (60.7%) were male and 566 (95%) were <14 years of age. Nearly all sought care for magnet ingestion (n = 574, 96.3%), whereas 17 patients (2.9%) presented for management of nasal or aural magnet foreign bodies, 4 (0.7%) for magnets in their genitourinary tract, and 1 patient (0.2%) had magnets in their respiratory tract. A total of 57 children (9.6%) had a life-threatening morbidity; 276 (46.3%) required an endoscopy, surgery, or both; and 332 (55.7%) required hospitalization. There was no reported mortality. CONCLUSIONS: Despite being intended for use by those >14 years of age, high-powered magnets frequently cause morbidity and lead to high need for invasive intervention and hospitalization in children of all ages.

People aging with HIV - protecting a population vulnerable to effects of COVID-19 and its control measures.

Certain comorbidities known to increase the risk of poor outcomes in COVID-19 exist at higher rates in people with HIV; people aging with HIV (PAWH) face additional risk due to the association of advanced age with COVID-19 mortality. Cognitive and functional deficits and social barriers have been identified in cohorts of people aging with HIV. It is postulated that the COVID-19 pandemic potentially threatens PAWH disproportionately to the general population, both in mortality risk due to age and comorbidities, and in potential deleterious effects of policies that seek to drastically limit in-person interaction and access to healthcare systems. A description of and preliminary data from a demonstration project to improve geriatric assessments of people with HIV over age 50 in an urban HIV clinic are presented, in support of this theory. Advice is offered on key strategies utilized to continue to provide care to PAWH during the COVID-19 pandemic, including transition to telemedicine, vaccination, revision of staff roles, repurposing of funding, and a new reliance on available local resources.

Energy Regulation Mechanism and Therapeutic Potential of Asprosin.

Genetic studies of patients with neonatal progeroid syndrome led to the discovery of the novel fasting-induced, glucogenic, and orexigenic hormone named asprosin, the C-terminal cleavage product of profibrillin. Upon secretion, asprosin travels to the liver, where it exerts a glucogenic effect through OR4M1, an olfactory G-protein-coupled receptor. It also crosses the blood-brain barrier to stimulate appetite-modulating neurons in the arcuate nucleus of the hypothalamus, exerting an orexigenic effect via an as yet unidentified receptor. Specifically, it stimulates appetite by activating orexigenic AgRP neurons and inhibiting anorexigenic POMC neurons. Studies have also focused on the therapeutic potential of inhibiting asprosin for treatment of obesity and type 2 diabetes, both of which are characterized by high levels of circulating asprosin. It has been shown that anti-asprosin monoclonal antibodies reduce blood glucose, appetite, and body weight, validating asprosin as a therapeutic target. Current work aims to uncover key features of the asprosin biology such as the identification of its neuronal receptor, identification of the secretion mechanism from adipose tissue, and development of anti-asprosin monoclonal antibodies as diabetes and obesity therapies.

Tuberculosis and hepatic steatosis are prevalent liver pathology findings among HIV-infected patients in South Africa.

Liver disease epidemiology in sub-Saharan Africa has shifted as a result of HIV and the increased use of antiretroviral therapy leading to a need for updated data on common causes of liver disease. We retrospectively reviewed records from all hospitalized patients who had liver biopsy at a single hospital in South Africa from 2001 to 2009 and compared diagnosis by HIV status. During the period of study 262 patients had liver biopsy, 108 (41%) were HIV-infected, 25 (10%) were HIV-sero-negative, and 129 (49%) had unknown or unrecorded HIV status. Overall 81% of biopsies provided additional diagnostic data. Malignancy was the most common finding reported on 56 (21%) biopsies followed by granuloma or TB, hepatic steatosis, and fibrosis or cirrhosis. HIV-infected patients were more likely to have granulomas and steatosis. Half of patients with granulomas were already on TB treatment, suggesting paradoxical reactions or drug induced liver injury may have been important causes of liver inflammation among these patients. We note that TB, paradoxical reactions during TB treatment, possible drug induced liver injury, and hepatic steatosis are important causes of liver pathology among HIV-infected hospitalized patients with unclear etiology of liver disease after initial assessment. Among HIV sero-negative patients, malignancy was the major cause of liver disease. Our findings re-enforce the importance of TB as a diagnosis among HIV-infected individuals.

Concordant Oral-Genital HPV Infection in South Africa Couples: Evidence for Transmission.

OBJECTIVE: Cervical cancer is a leading cause of cancer mortality in South Africa. However, little is known about oral human papillomavirus (HPV) infection in high human immunodeficiency virus (HIV) seroprevalence settings. METHOD: Thirty-four adult heterosexual couples attending an HIV testing center in Soweto, South Africa were enrolled. Each participant provided an oral rinse sample and genital swab, which were tested for 37 types of HPV DNA, and completed a risk behavior survey. RESULTS: Median age was 31 years and 9% (3/34) of men and 29% (10/34) of women enrolled tested HIV-positive; median CD4 count was 437 cells/mm(3). Oral HPV prevalence was similar in women and men (12 vs. 18%, p = 0.48), and was non-significantly higher in HIV-infected vs. HIV-uninfected (23 vs. 13%, p = 0.34) subjects. Most men (82%) and women (84%) reported ever performing oral sex. Median number of lifetime sexual partners was "2-5" while median number of lifetime oral sex partners was 1. Oncogenic HPV subtypes were detected in 4% of oral, 26% of penile, and 74% of vaginal samples, including HPV16 in 1, 12, and 21% of these samples respectively. Genital HPV prevalence was significantly higher than oral HPV prevalence (75 vs. 15%, p ≤ 0.001). Thirty-five percent of couples (12/34) had at least one type-specific concordant vaginal-penile HPV infection but only one of nine couples with oral HPV had concordant oral-oral infection. However, 67% (4/6) of men and 25% (1/4) of women with oral HPV infection had partners with concordant genital HPV infection. Implications and Impact: Oral-oral HPV concordance between couples is low, but oral-genital and genital-genital HPV concordance is higher, including concordance of male oral HPV infection with their partners' vaginal HPV infection. This data is consistent with possible transmission of vaginal HPV infection to the oral cavity of sexual partners performing oral sex.

Improved survival in patients with ventricular assist device therapy: the University of Wisconsin experience.

OBJECTIVE: Ventricular assist devices (VADs) have been implanted since 1990 in our institution, becoming an increasingly common treatment for end-stage heart failure. Beginning in 1997, VAD patients were discharged home when feasible. In August 2003, a dedicated multidisciplinary VAD team (cardiac surgeons, cardiologists, VAD coordinators, nurses, rehabilitation specialists, nutrition experts, psychologists, pharmacists, social workers, and administrators) was created to optimize the management of VAD patients. The purpose of this study is to analyze the impact of these changes in care at our center over the last 17 years. METHODS: We retrospectively studied 107 consecutive VAD recipients between June 1990 and August 2006. VADs were implanted as bridge to recovery, bridge to transplant and destination therapy. The cohort was divided by care plans into early (n=37, June 1990-1996), mid (n=32, 1997-July 2003), and late groups (n=38, August 2003-August 2006). Demographic profile, survival and complications were assessed. RESULTS: Patient demographics tended to show an increased severity of illness over time. Post-VAD survival rate significantly improved in the late group (post-VAD 1- and 3-year survival rates; early: 54.1% and 40.5%; mid: 51.6% and 41.9%; late: 86.8% and 82.5%, p<0.001, respectively). The incidence of complications including re-operation, major bleeding and major infection, significantly decreased in the late group (p<0.05). CONCLUSIONS: Outcomes have improved dramatically in recent VAD patients, despite an increasingly high-risk patient population. These data suggest that advances in device technology and medical therapies, as well as a multidisciplinary approach, have improved survival on VAD therapy.

Altered gene expression: a mechanism for reproductive toxicity in zebrafish exposed to benzo[a]pyrene.

Exposure of fish to polycyclic aromatic hydrocarbons (PAHs) has consistently been shown to have a negative impact on reproduction (e.g. decreased spawning success, decreased ovarian somatic index (OSI) and lower circulating levels of 17beta-estradiol and vitellogenin). While an understanding of the mechanism behind these changes has yet to be fully elucidated, it has been proposed that PAHs can alter the expression of genes important in regulating reproduction. The objectives of this study were to: (1) determine the effect of exposure to waterborne benzo[a]pyrene (B[a]P) (0, 1.5 and 3.0 microg/L) for 56 days on egg production and OSI in female zebrafish (Danio rerio) and (2) determine the effect of B[a]P on transcription of genes involved in reproduction including gonadotropins (follicle stimulating hormone (FSH) and luteinizing hormone (LH)), steroidogenic enzymes (CYP11A1, CYP17, CYP19A1, CYP19A2 and 20beta-HSD), estrogen receptor beta (ERbeta) and vitellogenin. Cytochrome P4501A1 (CYP1A1) was also measured in the liver and heads as an indicator of exposure to B[a]P. A reduction in total egg output was observed in B[a]P exposed fish as well as a decrease in OSI in fish exposed to 3.0 microg/L B[a]P. A significant increase in CYP1A1 expression in the heads as compared to the control was observed whereas no significant difference in CYP1A1 was detected in livers. A significant increase in 20beta-HSD mRNA occurred in heads and pre-vitellogenic oocytes from fish exposed to 1.5 and 3.0 microg/L as compared to the controls. CYP19A2 and vitellogenin were significantly increased following exposure to 3.0 microg/L in the heads and liver, respectively. No effects on the expression of FSH, LH, CYP19A1 or ERbeta were observed. Results from this study demonstrate that reproduction in zebrafish is affected by waterborne exposure to B[a]P and that altered transcription of genes important in regulating reproduction (20beta-HSD, CYP19A2 and vitellogenin) may be one of the underlying mechanisms of B[a]P-induced reproductive toxicity.

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss.

Hyperglycemia-induced mitochondrial overproduction of reactive oxygen species leads to the activation of different biochemical pathways involved in endothelial damage of the diabetic retina. Tenilsetam [(+/-)-3-(2-thienyl)-2-piperazinone] is a dicarbonyl scavenger in the millimolar range and a transition metal ion chelator in the micromolar range. We tested its effect on experimental diabetic retinopathy, and on endothelial cell characteristics in vitro. Streptozotocin diabetic male Wistar rats (60 mg/kg BW) received 50 mg/kg BW tenilsetam (D-T) for 36 weeks, or no treatment (D). The impact of tenilsetam (0-30 mM) on endothelial proliferation, apoptosis, sprouting, cytokine-induced leucocyte-endothelial interaction, and VEGF expression was tested in vitro. Tenilsetam did not affect glycemic control or body weight in diabetic animals. The 3.7 fold increase in acellular capillaries in diabetic rats [p < 0.001 vs. non-diabetic controls (N)] was reduced by 70% (p < 0.001) through treatment, but pericyte loss (D vs. N -33%; p < 0.001) remained unaffected. In vitro, tenilsetam inhibited endothelial proliferation at lower doses, while inducing apoptosis at high doses. Leucocyte adhesion was only inhibited at high doses. Sprouting angiogenesis of bovine retinal endothelial cells was promoted at lower doses (< or = 10 mM). At micromolar concentrations, endothelial VEGF expression was upregulated by 100%. Long-term treatment with the AGE-inhibitor and iron-chelating compound tenilsetam inhibits the formation of acellular capillaries without correcting pericyte loss. The compound has dose-dependent effects on endothelial cell function. These data suggest that, independent of known properties, tenilsetam shows important rescue functions on endothelial cells which could be useful for the treatment of early diabetic retinopathy.