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In the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, epithelial populations in the distal lung expressing Angiotensin-converting enzyme 2 (ACE2) are infrequent, and therefore, the model of viral expansion and immune cell engagement remains incompletely understood. Using human lungs to investigate early host-viral pathogenesis, we found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations. Human alveolar macrophages (AMs) reliably expressed ACE2 allowing both spike-ACE2-dependent viral entry and infection. In contrast to Influenza A virus, SARS-CoV-2 infection of AMs was productive, amplifying viral titers. While AMs generated new viruses, the interferon responses to SARS-CoV-2 were muted, hiding the viral dissemination from specific antiviral immune responses. The reliable and veiled viral depot in myeloid cells in the very early phases of SARS-CoV-2 infection of human lungs enables viral expansion in the distal lung and potentially licenses subsequent immune pathologies.

Objectives: We provide a novel application of psycholinguistic theories and methods to the field of auditory training to provide preliminary data regarding which minimal pair contrasts are more difficult for listeners with typical hearing to distinguish in real-time. Design: Using eye-tracking, participants heard a word and selected the corresponding image from a display of four: the target word, two unrelated words, and a word from one of four contrast categories (i.e., voiced-initial [e.g., "peach-beach"], voiced-final [e.g., "back-bag"], manner-initial [e.g., "talk-sock"], and manner-final [e.g., "bat-bass"]). Results: Fixations were monitored to measure how strongly words compete for recognition depending on the contrast type (voicing, manner) and location (word-initial or final). Manner contrasts competed more for recognition than did voicing contrasts, and contrasts that occurred in word-final position were harder to distinguish than word-initial position. Conclusion: These results are an important initial step toward creating an evidence-based hierarchy for auditory training for individuals who use cochlear implants.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p

PURPOSE: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS: Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION: Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value

Students teaching students is widely accepted to be one of the most effective teaching methods with benefits for both the students teaching and those that are learning (Sorcinelli, 1991; Stigmar, 2016). Previous studies have found that students acting as instructors experience improved content knowledge and develop skills and confidence in communication of complex subject matter (Swim, 1999). Students learning from other students experience increased enjoyment and enthusiasm in learning science (Hinck, 2013; Rao et al., 2007). We created a cross-age scientific curricular experience program model that utilized hands-on activities with instruction by trained high school students. This study aims to understand how these curricular experiences impact the self-efficacy of student instructors as well as student learner engagement. We found that student instructors commonly have positive teaching experiences and feel more confident about teaching after each curricular experience. Student engagement during all curricular experiences was high and reflections from instructors, students, and classroom-teachers highlighted the benefits of students teaching students. Overall, this study shows support for cross-age instruction and the importance of hands-on activities in scientific education. We hope educators increase cross-age instruction and hands-on activities throughout their science classes.

In 2019, the United States consumed over 57 million metric tons (MMT) of plastic with less than 7% recovered for reuse. This study provides an updated material flow analysis at national and regional scales for all durable and single-use plastics in the United States. From this material flow analysis, we develop a series of alternative future national plastic flow scenarios that envision a scale-up of recycling technologies, incorporating technical limitations and sorting infrastructure constraints. The results suggest that a maximum of 68% (24 MMT) of plastic waste could be diverted from landfills by scaling up existing commercial recycling technologies. Based on the current technological landscape, reaching near-zero waste is only possible if processes that are operating at pilot and laboratory scales can be effectively scaled and coupled with improved sorting infrastructure. Through these scenarios with increased recycling, the availability of postconsumer resin stocks could increase by 22–43 MMT.

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Effective use of classroom management practices is critical to creating positive classroom climates supporting students' academic and behavioral outcomes, and teachers in rural areas have a strong need for training in classroom management. One classroom management practice with significant support is behavior-specific praise (BSP). Research shows teachers need training to use BSP at high frequencies. Multicomponent training packages with sustained coaching have demonstrated increases in teacher use of BSP, but more flexible training approaches are needed to meet the needs of rural teachers. We used a multiple baseline design to first evaluate the effects of an online module on rural teachers' use of BSP. Then, we evaluated the additive effects of asynchronous, virtual peer coaching on BSP. Results tentatively suggest the presence of a functional relation between virtual peer coaching and BSP following the online module and suggest the absence of a functional relation between the online module alone and BSP.

PURPOSE: To characterize developing retinal blood vessels with vascular markers and to relate the histochemical profile of maturing vessels to morphologic stages in retinal vascular development. METHODS: Vessels were examined in frozen and paraffin-embedded retinas and in wholemounts of Macaca monkeys ranging in age from fetal day 75 (F75) to adulthood. Endothelial cells were visualized immunohistochemically using antisera to von Willebrand's factor and CD31 with lectins Ulex europaeus, Bandeiraea simplicifolia, peanut agglutinin, Ricinis communis, and wheat germ agglutinin, and by ATPase and ADPase enzymatic histochemistry. Antibodies to vascular basement membrane and matrix markers laminin, fibronectin, and collagen types I and VIII, and antisera recognizing cell cycle-specific nuclear proteins (cyclin, Ki-67, Mib-1) also were used. RESULTS: Newly formed and mature vessels were reactive with reagents specific for CD31, von Willebrand's factor, types I and VIII collagens, laminin, fibronectin, U. europaeus, R. communis, and peanut agglutinin. Wheat germ agglutinin labeled vessels only after pretreatment with neuraminidase. All vascular markers appeared simultaneously, but some were distributed differentially between capillaries and larger vessels, along the central-peripheral extent of a vascular plexus, and among different vascular laminae. Markers of vessels failed to label spindle-shaped presumed vascular precursor cells lying peripheral to the advancing vessels during development. Spindle cells exhibited cyclin, Ki-67, and Mib-1 immunoreactivity. CONCLUSIONS: Immature and mature vitread and sclerad vessels displayed histochemical profiles that were qualitatively similar but that had subtle quantitative differences. Results do not support identification of spindle-shaped cells as vascular precursors in the developing monkey retina and are discussed in relation to mechanisms of retinal vascularization.

PURPOSE: The temporal and spatial sequence of development of laminar vascular plexuses was determined qualitatively and quantitatively in monkey and human retina. METHODS: Histologic and cytochemical methods were used to study Macaca monkey eyes from fetal day 55 (F55d; birth = F168d) to 17 years, and human retina from fetal 21 weeks to adult. RESULTS: In monkey retina, spindle-shaped, presumed vascular precursor, cells appear at F55d in the nerve fiber layer (NFL) adjacent to the optic nerve. The vascular plexuses in the NFL-ganglion cell layer appear first and form in the presence of spindle cells. Nerve fiber layer vessels extended radially to reach the temporal ora at F95d and nasal ora at F110d. The capillary plexus at the inner border of the inner nuclear layer (INL) appears at F120d near the optic disc, whereas the plexus at the outer INL border appears at F130d. Both reach their final position before birth. The INL plexuses form by endothelial budding from more vitread vessels in the absence of spindle cells. In the NFL, vessel growth to match retinal growth at the ora also involves endothelial budding. The growth rate of all plexuses was approximately 225 microns/day. The central fovea and the most peripheral retina adjacent to the ora serrata remained avascular throughout development. Differences between humans and monkeys include: Human vessels complete maturation after birth; human vessels reach the nasal ora earlier than the temporal ora; and spindle cells are more abundant and dispersed over a greater area within human NFL. Growth rates of human plexuses were comparable to those in monkeys. CONCLUSION: In both primates, deeper capillary plexuses form only by extension from existing vessels (angiogenesis). In the NFL, early vessel formation involves spindle precursor cells (vasculogenesis). The main difference between monkey and human in these processes is that the mature monkey vascular pattern is established well before birth.

Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

Abstract Two-dimensional (2D) semiconductors are promising candidates for optoelectronic application and quantum information processes due to their inherent out-of-plane 2D confinement. In addition, they offer the possibility of achieving low-dimensional in-plane exciton confinement, similar to zero-dimensional quantum dots, with intriguing optical and electronic properties via strain or composition engineering. However, realizing such laterally confined 2D monolayers and systematically controlling size-dependent optical properties remain significant challenges. Here, we report the observation of lateral confinement of excitons in epitaxially grown in-plane MoSe2 quantum dots (~15-60 nm wide) inside a continuous matrix of WSe2 monolayer film via a sequential epitaxial growth process. Various optical spectroscopy techniques reveal the size-dependent exciton confinement in the MoSe2 monolayer quantum dots with exciton blue shift (12-40 meV) at a low temperature as compared to continuous monolayer MoSe2. Finally, single-photon emission (g2(0) ~ 0.4) was also observed from the smallest dots at 1.6 K. Our study opens the door to compositionally engineered, tunable, in-plane quantum light sources in 2D semiconductors.

Abstract Background The WHO 2016 antenatal care (ANC) policy recommends at least eight antenatal contacts during pregnancy. This study assessed ANC8 uptake following policy implementation and explored the relationship between ANC attendance and intermittent preventive treatment in pregnancy (IPTp) coverage in sub-Saharan Africa following the rollout of the World Health Organization (WHO) 2016 ANC policy, specifically, to assess differences in IPTp uptake between women attending eight versus four ANC contacts. Methods A secondary analysis of data from 20 sub-Saharan African countries with available Demographic Health and Malaria Indicator surveys from 2018 to 2023 was performed. The key variables were the number of ANC contacts and IPTp doses received during a participant's last completed pregnancy in the past two years. Pooled crude and multivariable logistic regression models were used to explore factors associated with attendance of at least four or eight ANC contacts as well as receipt of at least three doses of IPTp during pregnancy. Results Overall, only a small proportion of women (median = 3.9%) completed eight or more ANC contacts (ANC8 +). Factors significantly associated with increased odds of ANC8 + included early ANC attendance (AOR: 4.61: 95% CI 4.30—4.95), literacy (AOR: 1.20; 95% CI 1.11—1.29), and higher wealth quintile (AOR: 3.03; 95% CI 2.67—3.44). The pooled estimate across all countries showed a very slight increase in the odds of IPTp3 + among women with eight (AOR: 1.06; 95% CI 1.00—1.12) compared to those with four contacts. In all but two countries, having eight instead of four ANC contacts did not confer significantly greater odds of receiving three or more doses of IPTp (IPTp3 +), except in Ghana (AOR: 1.67; 95% CI 1.38—2.04) and Liberia (AOR: 1.43; 95% CI 1.18—1.72). Conclusion Eight years after the WHO ANC policy recommendation, all countries still had sub-optimal ANC8 + coverage rates. This paper is a call to action to actualize the vision of the WHO and the global malaria community of a malaria free world. Policies to improve ANC and IPTp coverage should be operationalized with clear actionable guidance and local ownership. Study findings can be used to inform multi-level policy, programmatic, and research recommendations to optimize ANC attendance and malaria in pregnancy prevention, thus improving maternal and child health outcomes, including the reduction of malaria in pregnancy.

BACKGROUND: Anemia in very low birth weight (VLBW) infants is common and frequently managed with red blood cell (RBC) transfusions. We utilized a linked vein-to-vein database to assess the role of blood donors and component factors on measures of RBC transfusion effectiveness in VLBW infants. STUDY DESIGN AND METHODS: We linked blood donor and component manufacturing data with VLBW infants transfused RBCs between January 1, 2013 and December 31, 2016 in the Recipient Epidemiology Donor Evaluation Study-III (REDS III) database. Using multivariable regression, hemoglobin increments and subsequent transfusion events following single-unit RBC transfusion episodes were examined with consideration of donor, component, and recipient factors. RESULTS: Data on VLBW infants (n = 254) who received one or more single-unit RBC transfusions (n = 567 units) were linked to donor demographic and component manufacturing characteristics for analysis. Reduced post-transfusion hemoglobin increments were associated with RBC units donated by female donors (-0.24 g/dL [95% confidence interval (CI) -0.57, -0.02]; p = .04) and donors

BackgroundComprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors.MethodsThe CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12-21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori "Go/No Go Criteria" guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants.DiscussionThis clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change.Trial registrationClinicalTrials.gov NCT04578912 . Registered on October 8, 2020.