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The lymphatic system functions in fluid homeostasis, lipid absorption and the modulation of the immune response. The role of Gpnmb (osteoactivin), an established osteoinductive molecule with newly identified anti-inflammatory properties, has not been studied in lymphangiogenesis. Here, we demonstrate that Gpnmb increases lymphatic endothelial cell (LEC) migration and lymphangiogenesis marker gene expression in vitro by enhancing pro-autophagic gene expression, while no changes were observed in cell proliferation or viability. In addition, cellular spreading and cytoskeletal reorganization was not altered following Gpnmb treatment. We show that systemic Gpnmb overexpression in vivo leads to increases in lymphatic tubule number per area. Overall, data presented in this study suggest Gpnmb is a positive modulator of lymphangiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics of the long-acting mAb sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients., Methods: All participants received an intravenous infusion of sotrovimab within 1 week prior to initiating the pretransplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks posttransplant., Results: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease (GVHD) posttransplant., Conclusions: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased gastrointestinal clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations., Competing Interests: Potential conflicts of interest. Q. W., A. N., S. F., and J. H. are employees of and hold shares in GSK. A. L. G. reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic and research support from Gilead, outside of the described work. M. B. reports research support from Merck and consulting for Moderna and AstraZeneca, outside of the described work. A. W. reports research support from Ansun Biopharma, Allovir, and Pfizer and consulting for Vir Biotechnology and GlaxoSmithKline, outside of the described work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Quantitative monitoring of cytomegalovirus (CMV) DNAemia in venous blood is standard in solid organ transplant recipients (SOTr) but is limited by the need for phlebotomy facilities and personnel. The aim of the study was to evaluate the Tasso+ capillary blood (CB) self-collection device for quantitation of plasma CMV DNAemia. Thirty adult SOTr with suspected CMV DNAemia were enrolled to have a supervised Tasso+ CB sample collection within 24 h of a venous sample. CMV DNA was quantitated in paired samples by using the Abbott M2000 Real-Time qPCR instrument. The participants were provided with a study-specific survey that measured patient acceptability of the Tasso+ device compared with venipuncture. A Tasso + CB sample was successfully collected in 28/30 (93%) patients, and 44 paired samples were analyzed. Concordance for detection of CMV DNAemia above the limit of detection (LOD) was 91% (42/44), and the Tasso + CB sample was estimated to be 95% sensitive at a viral load (VL) of 308 IU/mL. Among samples with a quantifiable DNAemia result with both methods ( N = 31), there was excellent correlation between methods (Spearman R 2 = 0.99). The difference in CMV VL between venous and Tasso+ CB samples was not dependent on time ( P > 0.1). Of 12 who completed the survey, 11 (92%) expressed a preference for Tasso+ CB collection over venipuncture. Collection of CB with the Tasso+ device is feasible, patient-acceptable, and yields generally comparable CMV DNAemia load to standard venous samples, but with lower sensitivity. Future studies to optimize and evaluate this methodology for patient self-collected samples are warranted., Importance: We evaluate an FDA-cleared blood self-collection device (Tasso+) and demonstrate that it is patient-acceptable and yields a liquid blood sample with quantitative CMV DNAemia results comparable to those of standard venipuncture samples. This opens up possibilities for self-blood collection to monitor for CMV and potentially other viruses in transplant and other at-risk populations., Competing Interests: The authors declare no conflict of interest.

Letermovir is a relatively new antiviral for prophylaxis against cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT). CMV-seropositive HCT recipients who received letermovir prophylaxis from 2018 to 2020 at our center were evaluated for letermovir resistance and breakthrough CMV reactivation. Two-hundred twenty-six letermovir recipients were identified and 7/15 (47%) with CMV DNAemia ≥200 IU/mL were successfully genotyped for UL56 resistance. A single C325Y resistance mutation was identified in an umbilical cord blood recipient. Ninety-five (42%), 43 (19%), and 15 (7%) patients had breakthrough CMV at any level, ≥150 IU/mL, and ≥500 IU/mL, respectively. Risk factors for breakthrough CMV reactivation at each viral threshold were examined. Cumulative steroid exposure was the strongest risk factor for CMV at all evaluated viral thresholds. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide (aHR 2.34, 95% CI 1.28-4.28, p = 0.001) or calcineurin inhibitors plus mycophenolate (aHR 2.24, 95% CI 1.30-3.86, p = 0.004) were also associated with an increased risk of CMV reactivation at any level. De novo letermovir resistance is rare and can be successfully treated using other antivirals. Letermovir effectively prevents clinically significant CMV, however, subclinical CMV reactivation occurs frequently at our center., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Amplicon-based sequencing methods are central in characterizing the diversity, transmission, and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but need to be rigorously assessed for clinical utility. Herein, we validated the Swift Biosciences' SARS-CoV-2 Swift Normalase Amplicon Panels using remnant clinical specimens. High-quality genomes meeting our established library and sequence quality criteria were recovered from positive specimens, with 95% limit of detection of 40.08 SARS-CoV-2 copies/PCR. Breadth of genome recovery was evaluated across a range of C T values (11.3 to 36.7; median, 21.6). Of 428 positive samples, 413 (96.5%) generated genomes with <10% unknown bases, with a mean genome coverage of 13,545× ± SD 8382×. No genomes were recovered from PCR-negative specimens (n = 30) or from specimens positive for non-SARS-CoV-2 respiratory viruses (n = 20). Compared with whole-genome shotgun metagenomic sequencing (n = 14) or Sanger sequencing for the spike gene (n = 11), pairwise identity between consensus sequences was 100% in all cases, with highly concordant allele frequencies (R 2  = 0.99) between Swift and shotgun libraries. When samples from different clades were mixed at varying ratios, expected variants were detected even in 1:99 mixtures. When deployed as a clinical test, 268 tests were performed in the first 23 weeks, with a median turnaround time of 11 days, ordered primarily for outbreak investigations and infection control., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOCs) and had a median Ct of 20.2 (IQR, 17.1-23.3). When compared with 5174 contemporaneous samples sequenced in our laboratory, VOCs were significantly enriched among breakthrough infections (P < .05)., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs); however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout - Sod1 -/- ), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1 -/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors., Competing Interests: JL, MM, JC, PU, PF, KS, SP, SK, JC, WL, RH, LB, JM, KD, BL, SM, GV, JC, YJ, SB, CA No competing interests declared, (© 2021, Larouche et al.)

Quantitative DNA detection of cytomegalovirus (CMV) and BK virus (BKV) is critical in the management of transplant patients. Quantitative laboratory-developed procedures for CMV and BKV have been described in which much of the processing is automated, resulting in rapid, reproducible, and high-throughput testing of transplant patients. To increase the efficiency of such assays, the performance and stability of four commercial preassembled frozen fast qPCR master mixes (Roche FastStart Universal Probe Master Mix with Rox, Bio-Rad SsoFast Probes Supermix with Rox, Life Technologies TaqMan FastAdvanced Master Mix, and Life Technologies Fast Universal PCR Master Mix), in combination with in-house designed primers and probes, was evaluated using controls and standards from standard CMV and BK assays. A subsequent parallel evaluation using patient samples was performed comparing the performance of freshly prepared assay mixes versus aliquoted frozen master mixes made with two of the fast qPCR mixes (Life Technologies TaqMan FastAdvanced Master Mix, and Bio-Rad SsoFast Probes Supermix with Rox), chosen based on their performance and compatibility with existing PCR cycling conditions. The data demonstrate that the frozen master mixes retain excellent performance over a period of at least 10 weeks. During the parallel testing using clinical specimens, no difference in quantitative results was observed between the preassembled frozen master mixes and freshly prepared master mixes. Preassembled fast real-time qPCR frozen master mixes perform well and represent an additional strategy laboratories can implement to reduce assay preparation times, and to minimize technical errors and effort necessary to perform clinical PCR., (© 2015 Wiley Periodicals, Inc.)

Human cytomegalovirus (CMV) is a significant contributor to morbidity and mortality in immunocompromised patients, particularly in the transplant setting. The availability of anti-CMV drugs has improved treatment, but drug resistance is an emerging problem. Here, we describe an improved, rapid, sequencing-based assay for the two genes in CMV where drug resistance occurs, the UL97 and UL54 genes. This assay is performed in 96-well format with a single master mix and provides clinical results within 2 days. It sequences codons 440 to 645 in the UL97 gene and codons 255 to 1028 in the UL54 gene with a limit of detection of 240 IU/ml. With this assay, we tested 43 specimens that had previously been tested for UL97 drug resistance and identified 3 with UL54 mutations. One of these patients had no concurrent UL97 mutation, pointing toward the need for an assay that facilitates dual UL97/UL54 gene testing for complete resistance profiling.

The NA60 experiment at the CERN Super Proton Synchrotron has studied dimuon production in 158A GeV In-In collisions. The strong excess of pairs above the known sources found in the complete mass region 0.2

We present the first x-ray scattering measurements of the state of compression and heating in laser irradiated solid beryllium. The scattered spectra at two different angles show Compton and plasmon features indicating a dense Fermi-degenerate plasma state with a Fermi energy above 30 eV and with temperatures in the range of 10-15 eV. These measurements indicate compression by a factor of 3 in agreement with Hugoniot data and detailed radiation-hydrodynamic modeling.

Spectrally resolved scattering of ultrafast K-alpha x-rays has provided experimental validation of the modeling of the compression and heating of shocked matter. The elastic scattering component has characterized the evolution and coalescence of two shocks launched by a nanosecond laser pulse into lithium hydride with an unprecedented temporal resolution of 10 picoseconds. At shock coalescence, we observed rapid heating to temperatures of 25,000 kelvin when the scattering spectra show the collective plasmon oscillations that indicate the transition to the dense metallic plasma state. The plasmon frequency determines the material compression, which is found to be a factor of 3, thereby reaching conditions in the laboratory relevant for studying the physics of planetary formation.

Background: Connect to Protect (C2P): Partnerships for Youth Prevention Interventions is an initiative that alters the community's structural elements to reduce youth HIV rates., Objectives: This study details a community resource assessment and describes how resources were evaluated in the context of local needs., Methods: Fifteen sites developed a community resource list, conducted a brief survey, created a youth service directory, and mapped where disease prevalence and community resources intersected. Sites also completed a survey to review and verify local site findings., Results: On average, sites identified 267 potential community resources. Sites narrowed their resource list to conduct a brief survey with 1,162 agencies; the site average was 78. Final products of this process included maps comparing resources with risk data., Conclusions: The evaluation of local resources is an important initial step in partnership development and is essential for the success of health promotion and disease prevention interventions that target adolescents.

The NA60 experiment at the CERN SPS has studied low-mass dimuon production in 158A GeV In-In collisions. An excess of pairs above the known meson decays has been reported before. We now present precision results on the associated transverse momentum spectra. The slope parameter Teff extracted from the spectra rises with dimuon mass up to the rho, followed by a sudden decline above. While the initial rise is consistent with the expectations for radial flow of a hadronic decay source, the decline signals a transition to an emission source with much smaller flow. This may well represent the first direct evidence for thermal radiation of partonic origin in nuclear collisions.

The NA60 experiment studies muon pair production at the CERN Super Proton Synchrotron. In this Letter we report on a precision measurement of J/psi in In-In collisions. We have studied the J/psi centrality distribution, and we have compared it with the one expected if absorption in cold nuclear matter were the only active suppression mechanism. For collisions involving more than approximately 80 participant nucleons, we find that an extra suppression is present. This result is in qualitative agreement with previous Pb-Pb measurements by the NA50 experiment, but no theoretical explanation is presently able to coherently describe both results.

Ganciclovir-resistant cytomegalovirus can cause disease and death in transplant recipients. We describe here a rapid PCR- and sequencing-based assay for ganciclovir resistance that can be performed in 1 to 2 working days directly from patient specimens, without the need for amplification of the virus by cell culture. An evaluation of 120 sequential samples submitted for clinical testing revealed a variety of silent and amino acid mutations.

Purpose: This study describes the partner selection process in 15 U.S. communities developing community-researcher partnerships for the Connect to Protect (C2P): Partnerships for Youth Prevention Interventions, an initiative of the Adolescent Trials Network for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) Interventions., Methods: Each site generated an epidemiological profile of urban youth in their community, selected a focus population and geographic area of youth at risk for HIV, conducted a series of successive structured interviews, and engaged in a process of relationship-building efforts culminating in a collaborative network of community agencies., Results: Sites chose as their primary target population young women who have sex with men (n = 8 sites), young men who have sex with men (n = 6), and intravenous drug users (n = 1). Of 1162 agencies initially interviewed, 281 of 335 approached (84%) agreed to join the partnership (average 19/site). A diverse array of community agencies were represented in the final collaborative network; specific characteristics included: 93% served the sites' target population, 54% were predominantly youth oriented, 59% were located in the geographical area of focus, and 39% reported provision of HIV/STI (sexually transmitted infection) prevention services. Relationship-building activities, development of collaborative relationships, and lessons learned, including barriers and facilitators to partnership, are also described., Conclusions: Study findings address a major gap in the community partner research literature. Health researchers and policymakers need an effective partner selection framework whereby community-researcher partnerships can develop a solid foundation to address public health concerns.

We report on a precision measurement of low-mass muon pairs in 158 AGeV indium-indium collisions at the CERN SPS. A significant excess of pairs is observed above the yield expected from neutral meson decays. The unprecedented sample size of 360,000 dimuons and the good mass resolution of about 2% allow us to isolate the excess by subtraction of the decay sources. The shape of the resulting mass spectrum is consistent with a dominant contribution from pi+pi- -->rho -->mu+mu- annihilation. The associated space-time averaged spectral function shows a strong broadening, but essentially no shift in mass. This may rule out theoretical models linking hadron masses directly to the chiral condensate.

Introduction: The aim of this study is to describe implantation techniques and lead performance for biventricular pacing, dual-chamber implantable cardioverter defibrillators (ICDs)., Methods and Results: A dual-chamber ICD with biventricular pacing was implanted in 87 patients with congestive heart failure (ejection fraction: 0.21 +/- 0.09), prolonged QRS duration (161 +/- 22 msec), and an indication for ICD therapy. Left ventricular pacing was achieved with a thoracotomy approach (n = 21) or a nonthoracotomy approach (n = 66). With a thoracotomy, biventricular devices were implanted successfully in all patients. During follow-up (17 +/- 11 months), 9 patients died (43%), 2 underwent transplantation, and 2 required left ventricular lead revision. At last follow-up, biventricular sensing and capture threshold were 11 +/- 5 mV and 1.5 +/- 0.8 V, respectively. For nonthoracotomy procedures, two types of coronary sinus (CS) leads were implanted: an over-the-wire lead (n = 45) and a shaped lead (n = 21). The rate of successful implantation (overall: 89%) (over-the-wire 93% vs shaped 81%; P = 0.1) and durations for CS lead placement (66 +/- 50 vs 58 +/- 34 min, P = 0.6) and the procedure (133 +/- 58 vs 129 +/- 33 min, P = 0.8) were not different between the two CS leads. During follow-up (11 +/- 9 months), 9 patients died (14%), and the shaped CS lead dislodged in 3 patients (3 shaped vs 0 over-the-wire, P = 0.01). At last follow-up, biventricular sensing and capture threshold were 10 +/- 4 mV and 1.8 +/- 0.7 V, respectively, and there was no difference between over-the-wire and shaped leads. By multivariate analysis, mortality was associated with absence of spironolactone therapy but not procedural features., Conclusion: Nonthoracotomy CS lead implantation is feasible, with a success rate of about 90% and few adverse events. For the remaining 10%, a thoracotomy approach can be completed safely in these ill patients without increased risk for death.