Citations

Introduction There is a growing interest in therapy applications of cell-free extracellular vesicles (EVs) but systemically administered EVs predominantly accumulate in the liver and thereby limit their applications in extrahepatic tissues. One way of diverting EVs to extrahepatic tissues is by tethering or expressing targeting vectors onto the surface of EVs but this requires chemical or genetic modifications with potential drawbacks. There is an unmet need to direct systemically administered EVs to a desired site without genetic or chemical modifications. Methods Herein, we employed positron emission tomography imaging of 89 Zr-labeled EVs to explore the ability of various substances to alter EV trafficking in the body. Results and discussion Subcutaneous injections of phenothiazine and poly(ethylene) glycol into the hind limb of BALB/c mice significantly increased the accumulation of intravenously administered 89 Zr-labeled EVs to the hind limb. Expanding these findings, we investigated EVs isolated from various sources, the influence of timing of the administration of phenothiazine with respect to labeled EV administration, and the relationship of the trafficking of EVs to the site of phenothiazine administration with overall change in biodistribution. The findings support further exploration of phenothiazine analogs for site specific enhancement of EV trafficking in therapeutic applications.

Introduction Female distance runners are at elevated risk for impaired bone remodeling due to high mechanical loading, potential low energy availability, and sustained inflammatory stress. Collagen peptide (CP) supplementation has been proposed as a nutritional strategy to support type I collagen synthesis and modulate osteoimmune signaling; however, evidence in premenopausal endurance athletes is limited. This pilot randomized, double-blind, placebo-controlled trial examined the effects of four weeks of high-dose CP supplementation on markers of bone metabolism and inflammatory activity in endurance-trained premenopausal women. Methods Twenty-two participants (18–35 years; ≥35 miles/week [>56km/week]) were randomized to CP (INT; 20 g/day) or isocaloric maltodextrin (CON). Pre- and post-intervention assessments, conducted in the early follicular phase, included serum procollagen type I N-terminal propeptide (P1NP), plasma C-terminal telopeptide of type I collagen (CTX-1), serum soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), the sRANKL/OPG ratio, and interleukin-6 (IL-6). Repeated-measures ANCOVAs were performed, adjusting for accumulated running distance and vitamin D status. Results A significant group × time interaction was observed for P1NP ( p = 0.04), with increases in INT and no change in CON. No significant interaction was observed for CTX-1 ( p = 0.13). Significant interactions were also observed for sRANKL ( p = 0.046) and IL-6 ( p = 0.03). No significant interaction effects were detected for sRANKL, OPG, or the sRANKL/OPG ratio. Discussion Short-term CP supplementation increased a marker of bone formation, altered osteoclast-related signaling, and reduced IL-6 in endurance-trained premenopausal women. These findings support the potential for CP-mediated modulation of bone turnover and inflammatory activity and warrant further investigation in larger, adequately powered trials incorporating structural bone outcomes.

Context Women with obesity or polycystic ovary syndrome (PCOS) often require repeated ovulation induction (OI) due to ovulatory dysfunction and infertility. However, the cumulative effects of repeated stimulation on ovarian function and embryo development remain poorly understood. Aims The present study aimed to understand the consequences of repeated OI and/or repeated superovulation (SO) on preimplantation embryonic development in obese (high-fat diet-induced) and PCOS (high-fat diet and dehydroepiandrosterone-induced) mouse models. Methods Control (without any metabolic disorder), obese, and PCOS mice were divided into three experimental groups. The mice in one round of superovulation (SO1) were injected with 5 IU intraperitoneal (i.p.) injection of pregnant mare serum gonadotropin, followed by 10 IU of human chorionic gonadotropin 48 h later. In the repeated superovulation (SO3) group, mice were subjected to three rounds of superovulation with a gap of 9 days between each superovulation. Mice in the OI3 + SO3 group were administered with three doses of CC (50 mg/kg body weight, i.p., gap of 9 days between each CC injection), followed by three rounds of superovulation. Key results Both single and three rounds of superovulation resulted in decrease in primordial follicles and a moderate increase in atretic follicles in obese and PCOS mice. Reduction in the number of ovulated oocytes, increased rate of abnormal fertilization, decrease in blastocyst rate and elevated DNA damage in blastocysts were observed in in vitro fertilization-derived embryos. Conclusions These findings demonstrate compromised embryonic development following repeated ovarian stimulation. Implications The study highlights need for mild ovarian stimulation strategies in metabolically compromised patients undergoing infertility treatments.

OBJECTIVES We aimed to characterize the frequency of major complications of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) and adolescents present at 6 months after initial presentation. METHODS The Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM) study was a prospective cohort at 20 US pediatric academic medical centers. Individuals aged younger than 21 years meeting any of the following were enrolled: SARS-CoV-2 detection within 7 days, Centers for Disease Control and Prevention (CDC) MIS-C criteria, or CDC MIS-C criteria except having involvement of 1 organ system. The study was designed to assess the proportion of children with major complications (cardiovascular, pulmonary, gastrointestinal/hepatic, renal, and/or neurologic) 6 months after presentation. RESULTS Data were analyzed on 229 hospitalized participants: 59 with COVID-19 (mean age 10.4 years; SD, 5.5) and 170 with MIS-C (mean age 10.1 years; SD, 4.8). Overall, 42.8% were female, making up 55.9% and 38.2% of the COVID-19 and MIS-C groups, respectively. Overall, the frequencies of major complications at 6 months after initial presentation were: 16/195 (8.2%) cardiovascular, 11/154 (7.1%) pulmonary, 11/154 (7.1%) gastrointestinal/hepatic, 3/152 (2.0%) renal, and 3/189 (1.6%) neurologic. Organ system complications did not differ significantly between the COVID-19 and MIS-C groups. Six of 14 (42.9%) COVID-19 and 21/26 (80.7%) MIS-C participants with at least 1 six-month complication had no underlying medical condition that may have been associated with their complication(s). CONCLUSIONS Major complications were infrequent but observed in children without underlying medical conditions, underscoring the importance of prospective follow-up to optimize management and elucidate the complications associated with severe SARS-CoV-2 infection in children.

Abstract Rationale Dyspnea is a prominent symptom of fibrotic hypersensitivity pneumonitis (fHP), limiting patients’ activity and impairing their quality of life. The University of California San Diego Shortness of Breath questionnaire (UCSD-SOBQ) is a 24-item instrument used to assess dyspnea severity in patients with various respiratory conditions. Objectives This study aimed to examine the reliability and responsiveness of the UCSD-SOBQ score, its validity as a measure of dyspnea severity, and its prognostic value in a prospective cohort with fHP. Methods We conducted psychometric analyses on UCSD-SOBQ response data and assessed the association between score changes and survival in patients with fHP who completed the UCSD-SOBQ and other HP severity metrics at baseline, 6 and 12 months. We introduce the reliable change index (RCI) and the likely change index (LCI) to assess the statistical significance of within-individual change in UCSD scores. Results At baseline, internal consistency was high (Cronbach’s alpha = 0.97). Significant moderately strong correlations were observed between UCSD-SOBQ scores and percent predicted forced vital capacity (FVC%), r = -0.46, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%), r = -0.32, and Borg dyspnea scores r = 0.56. UCSD-SOBQ scores were significantly different between the lowest and highest strata of FVC% (64.9 ± 18.9 vs. 36.2 ± 22.9), DLCO% and Borg scores. The threshold for worsening within-individual change in the UCSD-SOBQ score at 95% confidence was 12 points. A 1-point higher baseline UCSD-SOBQ score was associated with a 2% increase in the risk of death or transplant (HR 1.02, 95% CI 1.00, 1.04). Conclusions In fHP, the UCSD-SOBQ score is a reliable and valid measure of dyspnea severity, is responsive to change, discriminates patients with differing severities, and is associated with transplant free survival. Additional qualitative data and psychometric analyses could tailor the UCSD-SOBQ to fHP and may further improve its measurement properties.