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As part of the summer 2022 NYC-METS (New York City metropolitan Measurements of Emissions and TransformationS) campaign and the ASCENT (Atmospheric Science and Chemistry mEasurement NeTwork) observational network, speciated particulate matter was measured in real time in Manhattan and Queens, NY, with additional gas-phase measurements. Largely due to observed reductions in inorganic sulfate aerosol components over the 21st century, summertime aerosol composition in NYC has become predominantly organic (80-83%). Organic aerosol source apportionment via positive matrix factorization showed that this is dominated by secondary production as oxygenated organic aerosol (OOA) source factors comprised 73-76% of OA. Primary factors, including cooking-related organic aerosol (COA) and hydrocarbon-like organic aerosol (HOA) comprised minor fractions of OA, only 13-15% and 10-11%, respectively. The two sites presented considerable spatiotemporal variations in OA source factor concentrations despite similar average PM2.5 concentrations. The less- and more-oxidized OOA factors exhibited clear temperature dependences at both sites with increased concentrations and greater degrees of oxidation at higher temperatures, including during a heatwave. With strong temperature sensitivity and minimal changes in summertime concentrations since 2001, secondary OA poses a particular challenge for air quality policy in NYC that will very likely be exacerbated by continued climate change and extreme heat events.

Abstract Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1a fr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.

Abstract Most Plasmodium vivax infections contain genetically distinct parasites, but the consequences of this polyclonality on the development of asexual parasites, their sexual differentiation, and their transmission remain unknown. We describe infections of Saimiri monkeys with two strains of P. vivax and the analyses of 80,024 parasites characterized by single cell RNA sequencing and individually genotyped. In our model, consecutive inoculations fail to establish polyclonal infections. By contrast, simultaneous inoculations of two strains lead to sustained polyclonal infections, although without detectable differences in parasite regulation or sexual commitment. Analyses of sporozoites dissected from mosquitoes fed on coinfected monkeys show that all genotypes are successfully transmitted to mosquitoes. However, after sporozoite inoculation, not all genotypes contribute to the subsequent blood infections, highlighting an important bottleneck during pre-erythrocytic development. Overall, these studies provide new insights on the mechanisms regulating the establishment of polyclonal P. vivax infections and their consequences for disease transmission.

Abstract China’s strategy to concurrently address climate change and air pollution mitigation is hindered by a lack of comprehensive information on source contributions to health damage and carbon emissions. Here we show notable discrepancies between source contributions to CO2 emissions and fine particulate matter (PM2.5)-related mortality by using adjoint emission sensitivity modeling to attribute premature mortality in 2017 to 53 sector and fuel/process combinations with high spatial resolution. Our findings reveal that monetized PM2.5 health damage exceeds climate impacts in over half of the analyzed subsectors. In addition to coal-fired energy generators and industrial boilers, the combined health and climate costs from energy-intensive processes, diesel-powered vehicles, domestic coal combustion, and agricultural activities exceed 100 billion US dollars, with health-related costs predominating. This research highlights the critical need to integrate the social costs of health damage with climate impacts to develop more balanced mitigation strategies toward these dual goals, particularly during fuel transition and industrial structure upgrading.

In adults, viral load and disease severity can differ by SARS-CoV-2 variant, patterns less understood in children. We evaluated symptomatology, cycle threshold (Ct) values, and SARS-CoV-2 variants among 2,299 pediatric SARS-CoV-2 patients (0–21 years of age) in Colorado, USA, to determine whether children infected with Delta or Omicron had different symptom severity or Ct values than during earlier variants. Children infected during the Delta and Omicron periods had lower Ct values than those infected during pre-Delta, and children

Ambient air quality across the southeastern US has improved substantially in recent decades. However, emissions from prescribed burns remain high, which may pose a substantial health threat. We employed a multistage modeling framework to estimate year-round, long-term effects of prescribed burns on air quality and premature deaths. The framework integrates a chemical transport model with a data-fusion approach to estimate 24-h average PM2.5 and maximum daily 8-h averaged O3 (MDA8-O3) concentrations attributable to prescribed burns for the period 2013–2020. The Global Exposure Mortality Model and a log-linear exposure–response function were used to estimate the premature deaths ascribed to long-term prescribed burn PM2.5 and MDA8-O3 exposure in ten southeastern states. Our results indicate that prescribed burns contributed on annual average 0.59 ± 0.20 µg/m3 of PM2.5 (∼10 % of ambient PM2.5) over the ten southeastern states during the study period. On average around 15 % of the state-level ambient PM2.5 concentrations were contributed by prescribed burns in Alabama (0.90 ± 0.15 µg/m3), Florida (0.65 ± 0.19 µg/m3), Georgia (0.91 ± 0.19 µg/m3), Mississippi (0.65 ± 0.10 µg/m3) and South Carolina (0.65 ± 0.09 µg/m3). In the extensive burning season (January–April), daily average contributions to ambient PM2.5 increased up to 22 % in those states. A large part of Alabama and Georgia experiences ≥3.5 µg/m3 prescribed burn PM2.5 over 30 days/year. Additionally, prescribed burns are responsible for an average increase of 0.32 ± 0.12 ppb of MDA8-O3 (0.8 % of ambient MDA8-O3) over the ten southeastern states. The combined effect of prescribed burn PM2.5 exposure, population growth, and increase of baseline mortality over time resulted in a total of 20,416 (95 % confidence interval (CI): 16,562–24,174) excess non-accidental premature deaths in the ten southeastern states, with 25 % of these deaths in Georgia. Prescribed burn MDA8-O3 was responsible for an additional 1,332 (95 % CI: 858–1,803) premature deaths in the ten southeastern states. These findings indicate significant impacts from prescribed burns, suggesting potential benefits of enhanced forest management strategies.

BACKGROUND: Bacterial and viral infections can occur with SARS-CoV-2 infection, but prevalence, risk factors, and associated clinical outcomes are not fully understood. METHODS: We used the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET), a population-based surveillance system, to investigate the occurrence of bacterial and viral infections among hospitalized adults with laboratory-confirmed SARS-CoV-2 infection between March 2020 and April 2022. Clinician-driven testing for bacterial pathogens from sputum, deep respiratory, and sterile sites were included. The demographic and clinical features of those with and without bacterial infections were compared. We also describe the prevalence of viral pathogens including respiratory syncytial virus, rhinovirus/enterovirus, influenza, adenovirus, human metapneumovirus, parainfluenza viruses, and non-SARS-CoV-2 endemic coronaviruses. RESULTS: Among 36 490 hospitalized adults with COVID-19, 53.3% had bacterial cultures taken within 7 days of admission and 6.0% of these had a clinically relevant bacterial pathogen. After adjustment for demographic factors and co-morbidities, bacterial infections in patients with COVID-19 within 7 days of admission were associated with an adjusted relative risk of death 2.3 times that of patients with negative bacterial testing. Staphylococcus aureus and Gram-negative rods were the most frequently isolated bacterial pathogens. Among hospitalized adults with COVID-19, 2766 (7.6%) were tested for seven virus groups. A non-SARS-CoV-2 virus was identified in 0.9% of tested patients. CONCLUSIONS: Among patients with clinician-driven testing, 6.0% of adults hospitalized with COVID-19 were identified to have bacterial coinfections and 0.9% were identified to have viral coinfections; identification of a bacterial coinfection within 7 days of admission was associated with increased mortality.

Abstract Background Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. Methods The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. Results Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and − 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and − 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. Conclusion Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. Trial Registration ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1 .

Immunocompromised persons are at increased risk for severe COVID-19-related outcomes, including intensive care unit (ICU) admission and death (1). Data on adults aged ≥18 years hospitalized with laboratory-confirmed COVID-19 from 10 U.S. states in the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to assess associations between immunocompromise and ICU admission and in-hospital death during March 1, 2020-February 28, 2022. Associations of COVID-19 vaccination status with ICU admission and in-hospital death were also examined during March 1, 2021-February 28, 2022. During March 1, 2020-February 28, 2022, among a sample of 22,345 adults hospitalized for COVID-19, 12.2% were immunocompromised. Among unvaccinated patients, those with immunocompromise had higher odds of ICU admission (adjusted odds ratio [aOR] = 1.26; 95% CI = 1.08-1.49) and in-hospital death (aOR = 1.34; 95% CI = 1.05-1.70) than did nonimmunocompromised patients. Among vaccinated patients,* those with immunocompromise had higher odds of ICU admission (aOR = 1.40; 95% CI = 1.01-1.92) and in-hospital death (aOR = 1.87; 95% CI = 1.28-2.75) than did nonimmunocompromised patients. During March 1, 2021-February 28, 2022, among nonimmunocompromised patients, patients who were vaccinated had lower odds of death (aOR = 0.58; 95% CI = 0.39-0.86) than did unvaccinated patients; among immunocompromised patients, odds of death between vaccinated and unvaccinated patients did not differ. Immunocompromised persons need additional protection from COVID-19 and using multiple known COVID-19 prevention strategies,† including nonpharmaceutical interventions, up-to-date vaccination of immunocompromised persons and their close contacts,§ early testing, and COVID-19 prophylactic (Evusheld) and early antiviral treatment,¶ can help prevent hospitalization and subsequent severe COVID-19 outcomes among immunocompromised persons.

Beginning the week of March 20–26, 2022, the Omicron BA.2 variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating variant in the United States, accounting for >50% of sequenced isolates.* Data from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to describe recent COVID-19–associated hospitalization rates among adults aged ≥18 years during the period coinciding with BA.2 predominance (BA.2 period [Omicron BA.2 and BA.2.12.1; March 20–May 31, 2022]). Weekly hospitalization rates (hospitalizations per 100,000 population) among adults aged ≥65 years increased threefold, from 6.9 (week ending April 2, 2022) to 27.6 (week ending May 28, 2022); hospitalization rates in adults aged 18–49 and 50–64 years both increased 1.7-fold during the same time interval. Hospitalization rates among unvaccinated adults were 3.4 times as high as those among vaccinated adults. Among hospitalized nonpregnant patients in this same period, 39.1% had received a primary vaccination series and 1 booster or additional dose; 5.0% had received a primary series and ≥2 boosters or additional doses. All adults should stay up to date† with COVID-19 vaccination, and multiple nonpharmaceutical and medical prevention measures should be used to protect those at high risk for severe COVID-19 illness, irrespective of vaccination status§ (1).Beginning the week of March 20–26, 2022, the Omicron BA.2 variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating variant in the United States, accounting for >50% of sequenced isolates.* Data from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to describe recent COVID-19–associated hospitalization rates among adults aged ≥18 years during the period coinciding with BA.2 predominance (BA.2 period [Omicron BA.2 and BA.2.12.1; March 20–May 31, 2022]). Weekly hospitalization rates (hospitalizations per 100,000 population) among adults aged ≥65 years increased threefold, from 6.9 (week ending April 2, 2022) to 27.6 (week ending May 28, 2022); hospitalization rates in adults aged 18–49 and 50–64 years both increased 1.7-fold during the same time interval. Hospitalization rates among unvaccinated adults were 3.4 times as high as those among vaccinated adults. Among hospitalized nonpregnant patients in this same period, 39.1% had received a primary vaccination series and 1 booster or additional dose; 5.0% had received a primary series and ≥2 boosters or additional doses. All adults should stay up to date† with COVID-19 vaccination, and multiple nonpharmaceutical and medical prevention measures should be used to protect those at high risk for severe COVID-19 illness, irrespective of vaccination status§ (1).

Abstract From August 2020 to June 2021, we assessed the efficacy of SumiShield 50WG (clothianidin), Fludora Fusion 56.25WP-SB (mixture of clothianidin and deltamethrin) and Actellic 300CS (pirimiphos-methyl) in experimental huts when partially sprayed against wild, free-flying populations of Anopheles gambiae s.l. in Tiassalé, Côte d'Ivoire. A one-month baseline period of mosquito collections was conducted to determine mosquito density and resting behavior in unsprayed huts, after which two treatments of partial indoor residual spraying (IRS) were tested: spraying only the top half of walls + ceilings or only the bottom half of walls + ceilings. These were compared to fully sprayed applications using the three IRS insecticide formulations, during twenty nights per month of collection for nine consecutive months. Mortality was assessed at the time of collection, and after a 24 h holding period (Actellic) or up to 120 h (SumiShield and Fludora Fusion). Unsprayed huts were used as a negative control. The efficacy of each partially sprayed treatment of each insecticide was compared monthly to the fully sprayed huts over the study period with a non-inferiority margin set at 10%. The residual efficacy of each insecticide sprayed was also monitored. A total of 2197 Anopheles gambiae s.l. were collected during the baseline and 17,835 during the 9-month period after spraying. During baseline, 42.6% were collected on the bottom half versus 24.3% collected on the top half of the walls, and 33.1% on the ceilings. Over the nine-month post treatment period, 73.5% were collected on the bottom half of the wall, 11.6% collected on the top half and 14.8% on the ceilings. For Actellic, the mean mortality over the nine-month period was 88.5% [87.7, 89.3] for fully sprayed huts, 88.3% [85.1, 91.4] for bottom half + ceiling sprayed walls and 80.8% [74.5, 87.1] for the top half + ceiling sprayed huts. For Fludora Fusion an overall mean mortality of 85.6% [81.5, 89.7] was recorded for fully sprayed huts, 83.7% [82.9, 84.5] for bottom half + ceiling sprayed huts and 81.3% [79.6, 83.0] for the top half + ceiling sprayed huts. For SumiShield, the overall mean mortality was 86.7% [85.3, 88.1] for fully sprayed huts, 85.6% [85.4, 85.8] for the bottom half + ceiling sprayed huts and 76.9% [76.6, 77.3] for the top half + ceiling sprayed huts. For Fludora Fusion, both iterations of partial IRS were non-inferior to full spraying. However, for SumiShield and Actellic, this was true only for the huts with the bottom half + ceiling, reflecting the resting site preference of the local vectors. The results of this study suggest that partial spraying may be a way to reduce the cost of IRS without substantially compromising IRS efficacy.

Abstract Background Vector bionomics are important aspects of vector-borne disease control programs. Mosquito-biting risks are affected by environmental, mosquito behavior and human factors, which are important for assessing exposure risk and intervention impacts. This study estimated malaria transmission risk based on vector–human interactions in northern Ghana, where indoor residual spraying (IRS) and insecticide-treated nets (ITNs) have been deployed. Methods Indoor and outdoor human biting rates (HBRs) were measured using monthly human landing catches (HLCs) from June 2017 to April 2019. Mosquitoes collected were identified to species level, and Anopheles gambiae sensu lato (An. gambiae s.l.) samples were examined for parity and infectivity. The HBRs were adjusted using mosquito parity and human behavioral observations. Results Anopheles gambiae was the main vector species in the IRS (81%) and control (83%) communities. Indoor and outdoor HBRs were similar in both the IRS intervention (10.6 vs. 11.3 bites per person per night [b/p/n]; z = −0.33, P = 0.745) and control communities (18.8 vs. 16.4 b/p/n; z = 1.57, P = 0.115). The mean proportion of parous An. gambiae s.l. was lower in IRS communities (44.6%) than in control communities (71.7%). After adjusting for human behavior observations and parity, the combined effect of IRS and ITN utilization (IRS: 37.8%; control: 57.3%) on reducing malaria transmission risk was 58% in IRS + ITN communities and 27% in control communities with ITNs alone (z = −4.07, P

BackgroundPreterm birth is a leading cause of neonatal mortality, which is often complicated by intrauterine infection and inflammation. We have established a nonhuman primate model of Group B Streptococcus (GBS, Streptococcus agalactiae) infection-associated preterm birth. Immune checkpoints are modulators of the immune response by activating or suppressing leukocyte function and are understudied in preterm birth. The objective of this study was to spatially profile changes in immune protein expression at the maternal-fetal interface during a GBS infection with a focus on immune checkpoints.MethodsTwelve nonhuman primates (pigtail macaques, Macaca nemestrina) received a choriodecidual inoculation of either: 1) 1-5 X 108 colony forming units (CFU) of hyperhemolytic/hypervirulent GBS (GBSΔcovR, N=4); 2) an isogenic/nonpigmented strain (GBS ΔcovRΔcylE, N=4); or, 3) saline (N=4). A Cesarean section was performed at preterm labor or 3 days after GBS infection or 7 days after saline inoculation. Nanostring GeoMx® Digital Spatial Profiling technology was used to segment protein expression within the amnion, chorion, and maternal decidua at the inoculation site using an immuno-oncology panel targeting 56 immunoproteins enriched in stimulatory and inhibitory immune checkpoint proteins or their protein ligands. Statistical analysis included R studio, Kruskal-Wallis, Pearson and Spearman tests.ResultsBoth inhibitory and stimulatory immune checkpoint proteins were significantly upregulated within the chorioamniotic membranes and decidua (VISTA, LAG3, PD-1, CD40, GITR), as well as their ligands (PD-L1, PD-L2, CD40L; all p

Studies in mice and older, subfertile women have found that air pollution exposure may compromise female reproduction. Our objective was to evaluate the effects of air pollution on ovarian reserve and outcomes of ovarian stimulation among young, healthy females. We included 472 oocyte donors who underwent 781 ovarian stimulation cycles at a fertility clinic in Atlanta, Georgia, USA (2008–2019). Antral follicle count (AFC) was assessed with transvaginal ultrasonography and total and mature oocyte count was assessed following oocyte retrieval. Ovarian sensitivity index (OSI) was calculated as the total number of oocytes divided by total gonadotrophin dose × 1000. Daily ambient exposure to nitric oxide (NOx), carbon monoxide (CO), and particulate matter ≤ 2.5 (PM2.5) was estimated using a fused regional + line-source model for near-surface releases at a 250 m resolution based on residential address. Generalized estimating equations were used to evaluate the associations of an interquartile range (IQR) increase in pollutant exposure with outcomes adjusted for donor characteristics, census-level poverty, and meteorological factors. The median (IQR) age among oocyte donors was 25.0 (5.0) years, and 31% of the donors were racial/ethnic minorities. The median (IQR) exposure to NOx, CO, and PM2.5 in the 3 months prior to stimulation was 37.7 (32.0) ppb, 612 (317) ppb, and 9.8 (2.9) µg/m3, respectively. Ambient air pollution exposure in the 3 months before AFC was not associated with AFC. An IQR increase in PM2.5 in the 3 months before AFC and during stimulation was associated with −7.5% (95% CI −14.1, −0.4) and −6.4% (95% CI −11.0, −1.6) fewer mature oocytes, and a −1.9 (95% CI −3.2, −0.5) and −1.0 (95% CI −1.8, −0.2) lower OSI, respectively. Our results suggest that lowering the current 24-h PM2.5 standard in the US to 25 µg/m3 may still not adequately protect against the reprotoxic effects of short-term PM2.5 exposure.

Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic "distance" between HLA-matched donors and recipients is relatively constrained. From these 2 observations, it is possible that the HLA type for a donor-recipient pair (DRP) would provide a surrogate measurement of the number of predicted mHAs, which could be related to GVHD risk. Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide-binding efficiency can be calculated for individual DRP based on the pair's HLA type. The purpose of this study was to test whether cumulative peptide-binding efficiency is associated with the risk of acute GVHD (aGVHD) or relapse. In this retrospective Center for International Blood and Marrow Transplant Research study, a total of 3242 HLA-matched DRPs were analyzed for predicted cumulative peptide-binding efficiency using their HLA types and were divided into tertiles based on their scores. Univariable and multivariable analyses was performed to test for associations between cumulative peptide-binding efficiency for DRPs, divided into the HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival, disease-free survival, and transplantation-related mortality. Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide-binding frequencies ranging from 0.1% to 3.8% of the full peptidome, and HLA class II molecules had peptide-binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41%, and 45% for HLA class I (P = .336) and 44%, 41%, and 42% for HLA class II (P = .452). The cumulative incidences of relapse at 3 years for MUD transplant recipients were 36%, 38%, and 38% for HLA class I (P = .533) and 37%, 37%, and 38% for HLA class II (P = .896). The findings were similar for MRD transplant recipients. Multivariable analysis did not identify any impact of peptide-binding efficiency on aGVHD or relapse in MUD or MRD transplant recipients. Whereas GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide-binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker, or it is possible that GVHD is driven by a subset of immunogenic mHAs. Further research should be directed at direct mHA epitope and immunogenicity prediction.

BackgroundCurrently, the United States has the largest number of reported coronavirus disease 2019 (COVID-19) cases and deaths globally. Using a geographically diverse surveillance network, we describe risk factors for severe outcomes among adults hospitalized with COVID-19.MethodsWe analyzed data from 2491 adults hospitalized with laboratory-confirmed COVID-19 between 1 March-2 May 2020, as identified through the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network, which comprises 154 acute-care hospitals in 74 counties in 13 states. We used multivariable analyses to assess associations between age, sex, race and ethnicity, and underlying conditions with intensive care unit (ICU) admission and in-hospital mortality.ResultsThe data show that 92% of patients had ≥1 underlying condition; 32% required ICU admission; 19% required invasive mechanical ventilation; and 17% died. Independent factors associated with ICU admission included ages 50-64, 65-74, 75-84, and ≥85 years versus 18-39 years (adjusted risk ratios [aRRs], 1.53, 1.65, 1.84, and 1.43, respectively); male sex (aRR, 1.34); obesity (aRR, 1.31); immunosuppression (aRR, 1.29); and diabetes (aRR, 1.13). Independent factors associated with in-hospital mortality included ages 50-64, 65-74, 75-84, and ≥ 85 years versus 18-39 years (aRRs, 3.11, 5.77, 7.67, and 10.98, respectively); male sex (aRR, 1.30); immunosuppression (aRR, 1.39); renal disease (aRR, 1.33); chronic lung disease (aRR 1.31); cardiovascular disease (aRR, 1.28); neurologic disorders (aRR, 1.25); and diabetes (aRR, 1.19).ConclusionsIn-hospital mortality increased markedly with increasing age. Aggressive implementation of prevention strategies, including social distancing and rigorous hand hygiene, may benefit the population as a whole, as well as those at highest risk for COVID-19-related complications.

Although COVID-19-associated hospitalizations and deaths have occurred more frequently in adults,† COVID-19 can also lead to severe outcomes in children and adolescents (1,2). Schools are opening for in-person learning, and many prekindergarten children are returning to early care and education programs during a time when the number of COVID-19 cases caused by the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, is increasing.§ Therefore, it is important to monitor indicators of severe COVID-19 among children and adolescents. This analysis uses Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET)¶ data to describe COVID-19-associated hospitalizations among U.S. children and adolescents aged 0-17 years. During March 1, 2020-August 14, 2021, the cumulative incidence of COVID-19-associated hospitalizations was 49.7 per 100,000 children and adolescents. The weekly COVID-19-associated hospitalization rate per 100,000 children and adolescents during the week ending August 14, 2021 (1.4) was nearly five times the rate during the week ending June 26, 2021 (0.3); among children aged 0-4 years, the weekly hospitalization rate during the week ending August 14, 2021, was nearly 10 times that during the week ending June 26, 2021.** During June 20-July 31, 2021, the hospitalization rate among unvaccinated adolescents (aged 12-17 years) was 10.1 times higher than that among fully vaccinated adolescents. Among all hospitalized children and adolescents with COVID-19, the proportions with indicators of severe disease (such as intensive care unit [ICU] admission) after the Delta variant became predominant (June 20-July 31, 2021) were similar to those earlier in the pandemic (March 1, 2020-June 19, 2021). Implementation of preventive measures to reduce transmission and severe outcomes in children is critical, including vaccination of eligible persons, universal mask wearing in schools, recommended mask wearing by persons aged ≥2 years in other indoor public spaces and child care centers,†† and quarantining as recommended after exposure to persons with COVID-19.§§.

The purpose of this paper was to argue that 21st-century realities require a fresh look at leadership and conceptualizing a new approach that reflects the new realities. Rooted in Maslow's hierarchy of needs, a new model is proposed for leading innovation that considers the multi-generational nature of the workforce, emotional intelligence of organizations, and the rapid technological changes that demand continuous innovation for organizations to stay competitive. Grounded in theory from psychology, sociology, anthropology and management disciplines, this emergent model can provide a new framework for building and leading healthy innovative organizations.

ABSTRACT Bacterial infections remain a significant cause of adverse pregnancy outcomes. Ascending infection of group B streptococcus (GBS) or Streptococcus agalactiae from the lower genital tract to the amniotic cavity leads to fetal injury, preterm births, or stillbirths. Factors increasing the invasive potential of bacteria at the maternal-fetal interface are poorly understood. Previous studies have indicated that the GBS hyaluronidase (HylB) can enhance systemic infection by breaking down host hyaluronan into disaccharides that dampen protective TLR2 and TLR4 signaling. Here, we examined the importance of hyaluronan receptors such as TLR2, TLR4, and CD44 in defense against GBS infections during pregnancy. While HylB promoted ascending GBS infection in wild-type (WT) and CD44-deficient mice, surprisingly, mice lacking both TLR2 and TLR4 (TLR2/4) were able to curtail these infections. Interleukin-10 (IL-10) and IL-10-expressing macrophages were significantly increased in the uterine tissues of WT mice during infection with HylB-proficient GBS compared with those of TLR2/4-deficient mice, and this likely promotes immune suppression and GBS dissemination. Consistent with these observations, pregnant IL-10-deficient mice exhibited diminished GBS ascension and dissemination. Similarly, the administration of a blocking antibody against the IL-10 receptor (IL-10R) in WT mice diminished ascending GBS infection. Collectively, these observations indicate that HylB promotes immune suppression in a TLR2/4- and IL-10-dependent manner to enhance the invasive potential of GBS during pregnancy-associated infections. IMPORTANCE Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial factors during infections in the placenta is not fully understood. GBS secretes a hyaluronidase enzyme that is thought to digest host hyaluronan into immunosuppressive disaccharides that dampen TLR2/4 signaling, leading to increased bacterial dissemination and adverse outcomes. In this study, we show that GBS HylB mediates immune suppression and promotes bacterial infection during pregnancy that requires TLR2, TLR4, and IL-10. Understanding the interaction between host and bacterial factors can inform future therapeutic strategies to mitigate GBS infections.

Most reported cases of coronavirus disease 2019 (COVID-19) in children aged

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

Maternal illness is a stressor that can disrupt family processes and contribute to negative child outcomes, and researchers have considered family variables that mediate or moderate the maternal illness-child outcome relationship. Through reliance on a diverse sample (ethnically and racially, as well as geographically), the current study expands prior literature with a focus on parent-child conflict. Specifically, associations between aspects of HIV positive mothers' illness and mother-child conflict were explored. One goal of the study was to determine if there were direct or indirect associations with aspects of mothers' HIV and mother-child conflict. HIV-positive mothers (N = 136) provided CD4 count and completed measures assessing their perceived level of physical functioning, depressive symptoms, HIV health-related anxiety, and mother-child conflict with their healthy school-age children. Path analysis considered the pattern of relationships across variables. Results showed maternal vitality and depressive symptoms were directly associated with mother-child conflict. CD4 cell count and health-related anxiety operated indirectly through maternal depressive symptoms. Mediation analyses further assessed the influence of maternal CD4 cell count on mother-child conflict behavior; results indicated an indirect effect was mediated by vitality. HIV health-related anxiety and vitality separately showed indirect effects on mother-child conflict, mediated by maternal depressive symptoms. These findings are the first to focus on mother-child conflict among children affected by maternal HIV and highlight the need for screening and intervention to address depressive symptoms among HIV-positive mothers.

Abstract Background SWI/SNF (BAF) chromatin remodeling complexes regulate lineage-specific enhancer activity by promoting accessibility for diverse DNA-binding factors and chromatin regulators. Additionally, they are known to modulate the function of the epigenome through regulation of histone post-translational modifications and nucleosome composition, although the way SWI/SNF complexes govern the epigenome remains poorly understood. Here, we investigate the function of ARID1A, a subunit of certain mammalian SWI/SNF chromatin remodeling complexes associated with malignancies and benign diseases originating from the uterine endometrium. Results Through genome-wide analysis of human endometriotic epithelial cells, we show that more than half of ARID1A binding sites are marked by the variant histone H3.3, including active regulatory elements such as super-enhancers. ARID1A knockdown leads to H3.3 depletion and gain of canonical H3.1/3.2 at ARID1A-bound active regulatory elements, and a concomitant redistribution of H3.3 toward genic elements. ARID1A interactions with the repressive chromatin remodeler CHD4 (NuRD) are associated with H3.3, and ARID1A is required for CHD4 recruitment to H3.3. ZMYND8 interacts with CHD4 to suppress a subset of ARID1A, CHD4, and ZMYND8 co-bound, H3.3+ H4K16ac+ super-enhancers near genes governing extracellular matrix, motility, adhesion, and epithelial-to-mesenchymal transition. Moreover, these gene expression alterations are observed in human endometriomas. Conclusions These studies demonstrate that ARID1A-containing BAF complexes are required for maintenance of the histone variant H3.3 at active regulatory elements, such as super-enhancers, and this function is required for the physiologically relevant activities of alternative chromatin remodelers.

Aberrantly up-regulated activity of the type II transmembrane protease Matriptase-1 has been associated with the development and progression of a range of epithelial-derived carcinomas, and a variety of signaling pathways can mediate Matriptase-dependent tumorigenic events. During mammalian carcinogenesis, gain of Matriptase activity often results from imbalanced ratios between Matriptase and its cognate transmembrane inhibitor Hai1. Similarly, in zebrafish, unrestrained Matriptase activity due to loss of hai1a results in epidermal pre-neoplasms already during embryogenesis. Here, based on our former findings of a similar tumor-suppressive role for the Na+/K+-pump beta subunit ATP1b1a, we identify epithelial polarity defects and systemic hypotonic stress as another mode of aberrant Matriptase activation in the embryonic zebrafish epidermis in vivo. In this case, however, a different oncogenic pathway is activated which contains PI3K, AKT and NFkB, rather than EGFR and PLD (as in hai1a mutants). Strikingly, epidermal pre-neoplasm is only induced when epithelial polarity defects in keratinocytes (leading to disturbed Matriptase subcellular localization) occur in combination with systemic hypotonic stress (leading to increased proteolytic activity of Matriptase). A similar combinatorial effect of hypotonicity and loss of epithelial polarity was also obtained for the activity levels of Matriptase-1 in human MCF-10A epithelial breast cells. Together, this is in line with the multi-factor concept of carcinogenesis, with the notion that such factors can even branch off from one and the same initiator (here ATP1a1b) and can converge again at the level of one and the same mediator (here Matriptase). In sum, our data point to tonicity and epithelial cell polarity as evolutionarily conserved regulators of Matriptase activity that upon de-regulation can constitute an alternative mode of Matriptase-dependent carcinogenesis in vivo.

Background: Various clinical pharmacy services exist to improve the health outcomes of patients. However, there are numerous barriers to their implementation and execution, especially in outpatient settings. As pharmacists design and implement clinical pharmacy services in outpatient settings, they often do not consider the needs of providers until after service development. Objectives: The purpose of this study was to assess primary care providers' (PCPs') perceptions of clinical pharmacy services and their clinical pharmacy support needs. Methods: A web-based survey was distributed via email to PCPs across North Carolina (NC). Survey dissemination was completed in two phases. Data analysis consisted of mixed methods – quantitative and qualitative. Descriptive statistics were used to analyze demographic differences within each phase as well as the ranking of medication classes/disease states by providers. Qualitative data analysis through inductive coding was done to assess provider perceptions of clinical pharmacy services. Results: The response rate of the survey was 19.7%. Providers with previous experience with a clinical pharmacist rated overall services as positive. 62.9% of PCPs (N = 80) provided their perception of the positive attributes (pros) of clinical pharmacy services. 53.5% of PCPs (N = 68) provided their perception of the negative attributes (cons) of clinical pharmacy services. The top three medication classes/disease states that providers indicated they would value clinical pharmacy services for were: comprehensive medication management (CMM), diabetes medication management, and anticoagulation medication management. Of the remaining areas assessed, statin and steroid management ranked the lowest. Conclusions: The results from this study demonstrated that clinical pharmacy services are valued by PCPs. They also highlighted how pharmacists can best contribute to collaborative care in outpatient settings. As pharmacists, we should aim to implement the clinical pharmacy services that PCPs would value most.

Summary: Background: The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. Methods: We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations