Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurological conditions.

ObjectiveTo determine the transfer of rituximab, an anti-CD20 monoclonal antibody widely used for neurologic conditions, into mature breast milk.MethodsBreast milk samples were collected from 9 women with MS who received rituximab 500 or 1,000 mg intravenous once or twice while breastfeeding from November 2017 to April 2019. Serial breast milk samples were collected before infusion and at 8 hours, 24 hours, 7 days, and 18-21 days after rituximab infusion in 4 patients. Five additional patients provided 1-2 samples at various times after rituximab infusion.ResultsThe median average rituximab concentration in mature breast milk was low at 0.063 μg/mL (range 0.046-0.097) in the 4 patients with serial breast milk collection, with an estimated median absolute infant dose of 0.0094 mg/kg/d and a relative infant dose (RID) of 0.08% (range 0.06%-0.10%). Most patients had a maximum concentration at 1-7 days after infusion. The maximum concentration occurred in a woman with a single breast milk sample and was 0.29 μg/mL at 11 days postinfusion, which corresponds with an estimated RID of 0.33%. Rituximab concentration in milk was virtually undetectable by 90 days postinfusion.ConclusionsWe determined minimal transfer of rituximab into mature breast milk. The RID for rituximab was less than 0.4% and well below theoretically acceptable levels of less than 10%. Low oral bioavailability would probably also limit the absorption of rituximab by the newborn. In women with serious autoimmune neurologic conditions, monoclonal antibody therapy may afford an acceptable benefit to risk ratio, supporting both maternal treatment and breastfeeding

Variation in growth rates of branching corals along Australia's Great Barrier Reef

Coral growth is an important component of reef health and resilience. However, few studies have investigated temporal and/or spatial variation in growth of branching corals, which are important contributors to the structure and function of reef habitats. This study assessed growth (linear extension, density, and calcification) of three branching coral species (Acropora muricata, Pocillopora damicornis and Isopora palifera) at three distinct locations (Lizard Island, Davies/Trunk Reef, and Heron Island) along Australia’s Great Barrier Reef (GBR). Annual growth rates of all species were highest at Lizard Island and declined with increasing latitude, corresponding with differences in temperature. Within locations, however, seasonal variation in growth did not directly correlate with temperature. Between October 2012 and October 2014, the highest growth of A. muricata was in the 2013–14 summer at Lizard Island, which was unusually cool and ~0.5 °C less than the long-term summer average temperature. At locations where temperatures reached or exceeded the long-term summer maxima, coral growth during summer periods was equal to, if not lower than, winter periods. This study shows that temperature has a significant influence on spatiotemporal patterns of branching coral growth, and high summer temperatures in the northern GBR may already be constraining coral growth and reef resilience

The effect of adding comorbidities to current centers for disease control and prevention central-line–associated bloodstream infection risk-adjustment methodology

BACKGROUNDRisk adjustment is needed to fairly compare central-line–associated bloodstream infection (CLABSI) rates between hospitals. Until 2017, the Centers for Disease Control and Prevention (CDC) methodology adjusted CLABSI rates only by type of intensive care unit (ICU). The 2017 CDC models also adjust for hospital size and medical school affiliation. We hypothesized that risk adjustment would be improved by including patient demographics and comorbidities from electronically available hospital discharge codes.METHODSUsing a cohort design across 22 hospitals, we analyzed data from ICU patients admitted between January 2012 and December 2013. Demographics and International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) discharge codes were obtained for each patient, and CLABSIs were identified by trained infection preventionists. Models adjusting only for ICU type and for ICU type plus patient case mix were built and compared using discrimination and standardized infection ratio (SIR). Hospitals were ranked by SIR for each model to examine and compare the changes in rank.RESULTSOverall, 85,849 ICU patients were analyzed and 162 (0.2%) developed CLABSI. The significant variables added to the ICU model were coagulopathy, paralysis, renal failure, malnutrition, and age. The C statistics were 0.55 (95% CI, 0.51–0.59) for the ICU-type model and 0.64 (95% CI, 0.60–0.69) for the ICU-type plus patient case-mix model. When the hospitals were ranked by adjusted SIRs, 10 hospitals (45%) changed rank when comorbidity was added to the ICU-type model.CONCLUSIONSOur risk-adjustment model for CLABSI using electronically available comorbidities demonstrated better discrimination than did the CDC model. The CDC should strongly consider comorbidity-based risk adjustment to more accurately compare CLABSI rates across hospitals.Infect Control Hosp Epidemiol 2017;38:1019–1024</jats:sec

Particle Backtracking Improves Breeding Subpopulation Discrimination and Natal-Source Identification in Mixed Populations

We provide a novel method to improve the use of natural tagging approaches for subpopulation discrimination and source-origin identification in aquatic and terrestrial animals with a passive dispersive phase. Our method integrates observed site-referenced biological information on individuals in mixed populations with a particle-tracking model to retrace likely dispersal histories prior to capture (i.e., particle backtracking). To illustrate and test our approach, we focus on western Lake Erie\u27s yellow perch (Perca flavescens) population during 2006-2007, using microsatellite DNA and otolith microchemistry from larvae and juveniles as natural tags. Particle backtracking showed that not all larvae collected near a presumed hatching location may have originated there, owing to passive drift during the larval stage that was influenced by strong river-and wind-driven water circulation. Re-assigning larvae to their most probable hatching site (based on probabilistic dispersal trajectories from the particle backtracking model) improved the use of genetics and otolith microchemistry to discriminate among local breeding subpopulations. This enhancement, in turn, altered (and likely improved) the estimated contributions of each breeding subpopulation to the mixed population of juvenile recruits. Our findings indicate that particle backtracking can complement existing tools used to identify the origin of individuals in mixed populations, especially in flow-dominated systems

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

Mutation mapping and identification by whole-genome sequencing

Genetic mapping of mutations in model systems has facilitated the identification of genes contributing to fundamental biological processes including human diseases. However, this approach has historically required the prior characterization of informative markers. Here we report a fast and cost-effective method for genetic mapping using next-generation sequencing that combines single nucleotide polymorphism discovery, mutation localization, and potential identification of causal sequence variants. In contrast to prior approaches, we have developed a hidden Markov model to narrowly define the mutation area by inferring recombination breakpoints of chromosomes in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis of sequencing data and demonstrate its utility in the zebrafish and mouse models. Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems.Harvard Stem Cell Institute (Junior Faculty Grant)National Institutes of Health (U.S.) (Grant 1R01DK090311)National Institutes of Health (U.S.) (Grant 5R01MH084676

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

The JWST Resolved Stellar Populations Early Release Science Program I.: NIRCam Flux Calibration

We use globular cluster data from the Resolved Stellar Populations Early Release Science (ERS) program to validate the flux calibration for the Near Infrared Camera (NIRCam) on the James Webb Space Telescope (JWST). We find a significant flux offset between the eight short wavelength detectors, ranging from 1-23% (about 0.01-0.2 mag) that affects all NIRCam imaging observations. We deliver improved zeropoints for the ERS filters and show that alternate zeropoints derived by the community also improve the calibration significantly. We also find that the detector offsets appear to be time variable by up to at least 0.1 mag.Comment: Accepted for publication in RNAA

Prevalence of Respiratory Polyomaviruses Among Pediatric Patients With Respiratory Symptoms in Singapore

Background: Although WU polyomavirus (WU) and KI polyomavirus (KI) have been demonstrated to infect the human respiratory tract, it remains unclear if WU or KI cause human disease. We sought to further investigate the relationship between WU and KI infection and respiratory disease in a pediatric population with respiratory symptoms in Singapore.Methods: We conducted a cross-sectional study of pediatric patients with respiratory symptoms in a Singaporean pediatrics hospital. Upon consent, residual respiratory samples from pediatric inpatients, previously screened for common respiratory viruses, were collected and further screened for WU and KI using qPCR. The amplicons of positive samples were sequenced for confirmation. The severity of a patient's illness was assessed by chart review post-discharge looking for clinical markers of respiratory status such as presenting symptoms, diagnoses, and interventions.Results: From December 2016 to April 2017, 201 patients with residual respiratory samples were enrolled in the study. The average age of all participants recruited was 45 months. WU and KI were detected in 13% (26/201) and 3% (6/201) of patients, respectively. Conducting bivariate and multivariate modeling, patients with WU or KI positivity were not at increased risk of SARI, need for additional oxygen, intravenous fluids, and did not receive additional oral antibiotics or bronchodilators during admission. In contrast, patients with RSV detections were at increased risk of requiring supplemental oxygen during hospital admission.Conclusion: While limited in sample size, our pilot study data do not support the hypothesis that molecular evidence of WU or KI was associated with increased morbidity among a sample of general, pediatric patients with respiratory illness in Singapore