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Human cytomegalovirus (CMV) is a widespread persistent herpes virus requiring lifelong immune surveillance to maintain latency. Such long-term interactions with the immune system may be associated with deleterious effects including immune exhaustion and senescence. Regarding the COVID-19 pandemic, we asked whether CMV-specific cellular and humoral activity could influence immune responses toward SARS-CoV-2 and/or disease severity. All adults with mild (n = 15) and severe (n = 14) COVID-19 were seropositive for anti-CMV IgG, but negative for IgM antibodies. Antibody titers did not correlate with COVID-19 severity. Six patients presented elevated frequencies of CMV-specific CD4 + and CD8 + T cells producing IFNγ, IL-17, and TNFα, designated as CMV high responders (hiT CMV). In comparison to low CMV responders, hiT CMV individuals exhibited higher frequencies of SARS-CoV-2-specific CD4 + IL-17 + and CD8 + IFNγ + , IL-17 + or TNFα + T cells. These results indicate that high frequencies of CMV-specific T cells may be associated with a SARS-CoV-2-reactive profile skewed toward Th17-dominated immunity.

To interpret microbially influenced paleoenvironments in the sedimentary record, it is crucial to understand what processes control the development of microbial mats in modern environments. This article reports results from a multiyear study of Little Ambergris Cay, Turks and Caicos Islands, an uninhabited island floored by broad tracts of well-developed microbial mats on the wind-dominated and wave-dominated Caicos Platform. Uncrewed aerial vehicle-based imaging, differential global positioning system topographic surveys, radiocarbon data, and in situ sedimentological and microbial ecological observations were integrated to identify and quantify the environmental factors that influence the distribution and morphologies of Little Ambergris Cay microbial mats, including their response to large storm events. Based on these data, this study proposes that Little Ambergris Cay initially developed from the accretion and rapid lithification of carbonate sediment delivered by converging wave fronts in the lee of adjacent Big Ambergris Cay. Broad tracts of microbial mats developed during late Holocene time as the interior became restricted due to beach ridge development. Minor elevation differences regulate subaerial exposure time and lead to three categories of microbial mats, differentiated by surface texture and morphology: smooth mats, polygonal mats and blister mats. The surface texture and morphology of the mats is controlled by subaerial exposure time. In addition to elevation, the spatial distribution of mats is largely controlled by hydrodynamics and sediment transport during large storm events. This detailed assessment of the controls on mat formation and preservation at Little Ambergris Cay provides a framework within which to identify and understand the interactions between microbial communities and sediment transport processes in ancient high-energy carbonate depositional systems.

Background:Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy.Objective:To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML.Methods:We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics.Results:The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75–1.32) and TIC IRR = 0.83 (95% CI, 0.49–1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar.Conclusions:In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.

Objective To evaluate the accuracy of an antibody point-of-care lateral flow immunoassay (LFI - Wondfo Biotech Co., Guangzhou, China) in a pediatric population. Methods Children and adolescents (2 months to 18 years) with signs and symptoms suggestive of acute SARS-CoV-2 infection were prospectively investigated with nasopharyngeal RT-PCR and LFI at the emergency room. RT-PCR was performed at baseline, and LFI at the same time or scheduled for those with less than 7 days of the clinical picture. Overall accuracy, sensitivity and specificity were assessed, as well as according to the onset of symptoms (7-13 or ≥14 days) at the time of LFI test. Results In 175 children included, RT-PCR and LFI were positive in 51 (29.14%) and 36 (20.57%), respectively. The overall sensitivity, specificity, positive and negative predictive value was of 70.6% (95%CI 56.2-82.5), 96.8% (95%CI 91.9-99.1), 90.0% (95%CI 77.2-96.0), and 88.9% (95%CI 83.9-92.5), respectively. At 7-13 and ≥14 days after the onset of symptoms, sensitivity was 60.0% (95%CI 26.2-87.8) and 73.2% (95%CI 57.1-85.8) and specificity was 97.9% (95%CI 88.7-99.9) and 96.1% (95%CI 89.0-99.2), respectively. Conclusion Despite its high specificity, in the present study, the sensitivity of LFI in children was lower (around 70%) than most reports in adults. In acute care settings, although a positive result is informative, a negative LFI test cannot rule out COVID-19 in children.

Supplementary Data 3

Supplemental Table 1 shows venetoclax screen data (AUC and IC50) across 791 solid tumor cell lines.

Supplementary Figure 1

Purpose:KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy.Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C–activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models.Results:Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K–AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT–mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models.Conclusions:Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.

EWS-FLI1 increases BCL-2 expression in EWFT.

Supplementary Table 1

Supplemental Figure 1. Venetoclax sensitivity and BCL-2 mRNA correlation analysis; Supplemental Figure 2. Cell viability assays of border line venetoclax-sensitive and - resistant SCLC cell lines and combination of venetoclax with chemotherapy; Supplemental Figure 3. Correlation analysis of BCL-2 family members to venetoclax sensitivity in SCLC cell lines; Supplemental Figure 4. Comparison of BCL-2 family members to venetoclax sensitivity in SCLC cell lines; Supplemental Figure 5. BCL-2 mRNA expression is increased in SCLC compared to other cancer types; Supplemental Figure 6. Cell viability of venetoclax-sensitive and -resistant SCLC cell lines; Supplemental Figure 7. Weight profiles of xenograft and PDX models treated with venetoclax; Supplemental Figure 8. The PDX models from this study express high levels of BCL-2.

Purpose:It was recently demonstrated that the EWSR1-FLI1 t(11;22)(q24;12) translocation contributes to the hypersensitivity of Ewing sarcoma to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pretreated Ewing sarcoma tumors. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in patients with Ewing sarcoma. We sought to elucidate the resistance factors to PARP inhibitor therapy in Ewing sarcoma and identify a rational drug combination capable of rescuing PARP inhibitor activity.Experimental Design:We employed a pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenograft (PDX) and cell line xenograft models.Results:We found olaparib sensitivity was diminished following chemotherapy. The matched cell line pair revealed increased expression of the antiapoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, whereas the addition of the BCL-2/XL inhibitor navitoclax led to tumor growth inhibition. In 2 PDXs, olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone by venetoclax is insufficient to sensitize Ewing sarcoma cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL in Ewing sarcoma survival.Conclusions:These data reveal BCL-2 and BCL-XL act together to drive olaparib resistance in Ewing sarcoma and reveal a novel, rational combination therapy that may be put forward for clinical trial testing.

Figure legends for Supplementary Figures S1-S8.

Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2–expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2–expressing SCLCs.Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2–expressing SCLCs. Clin Cancer Res; 24(2); 360–9. ©2017 AACR.

Legends to supplementary table, data and figures

A novel multiple mapping conditioning (MMC) mixing time scale model for turbulent premixed combustion has been developed. It combines time scales for the flamelet and distributed flame regimes with the aid of a blending function. The blending function serves two purposes. Firstly, it helps to identify zones where the premixed flame resides and where the time scale associated with the premixed flame shall be used. Secondly, it uses the Karlovitz number to identify the turbulent premixed combustion regime and to reduce the weighting of the premixed flame time scale if Karlovitz numbers are high and deviations from the flamelet regime are expected. A series of three-dimensional direct numerical simulations (DNS) of statistically one dimensional, freely propagating turbulent methane-air flames provides a wide range of turbulent combustion regimes for the mixing model validation. The new mixing time scale provides correct predictions of the flame speed of freely propagating turbulent flames which could not be matched by most recognized mixing models. The turbulent flame structure predicted by the new model is in good agreement with DNS for all combustion regimes from flamelet to the thickened reaction zone.

The COVID-19 pandemic has had a profound impact on the global economy, physical health, and mental health. This pandemic, like previous viral outbreaks, has resulted in spikes in anxiety, depression, and stress. Even though millions of individuals face the physical health consequences of infection by COVID-19, even more individuals are confronted with the mental health consequences of this pandemic. This significantly increased demand for mental health services cannot be easily met by existing mental health systems, which often rely on courses of therapy to be delivered over months. Single session interventions (SSIs) may be one important approach to meeting this increased demand, as they are treatments designed to be delivered over the course of a single meeting. SSIs have been found to be effective for a range of mental health challenges, with durable effects lasting months to years later. Here, we describe an SSI designed for the COVID-19 pandemic. This Brief Assessment-informed Skills Intervention for COVID-19 (BASIC) program draws upon therapeutic skills from existing empirically supported treatments to target common presenting complaints due to this pandemic. We discuss the process of developing and implementing this intervention, as well as explore feasibility and initial clinical insights. In short, BASIC is an easy-to-adopt intervention that is designed to be effective in a single session, making it well-suited for handling the increased demand for mental health services due to COVID-19.

Supplemental Digital Content is available in the text., Background: The viral dynamics and the role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not completely understood. Our aim was to evaluate reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) values among children with confirmed SARS-CoV-2 compared with that of adult subjects. Methods: Patients (from 2 months to ≤18 years of age and adults) with signs and symptoms of acute SARS-CoV-2 infection for less than 7 days were prospectively enrolled in the study from May to November 2020. All participants performed RT-PCR assay for SARS-CoV-2 detection; Ct values of ORF1ab, N and S gene targets and the average of all the 3 probes were used as surrogates of viral load. Results: There were 21 infants (2 months to

IntroductionThe high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures.MethodsA global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management.ResultsNinety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision.ConclusionSeven key actions for improving RSV prevention and management in LMICs are proposed.

This is the third year of the SARS-CoV-2 pandemic, and yet most children remain unvaccinated. COVID-19 in children manifests as mostly mild or asymptomatic, however high viral titers and strong cellular and humoral responses are observed upon acute infection. It is still unclear how long these responses persist, and if they can protect from re-infection and/or disease severity. Here, we analyzed immune memory responses in a cohort of children and adults with COVID-19. Important differences between children and adults are evident in kinetics and profile of memory responses. Children develop early N-specific cytotoxic T cell responses, that rapidly expand and dominate their immune memory to the virus. Children’s anti-N, but not anti-S, antibody titers increase over time. Neutralization titers correlate with N-specific antibodies and CD8+T cells. However, antibodies generated by infection do not efficiently cross-neutralize variants Gamma or Delta. Our results indicate that mechanisms that protect from disease severity are possibly different from those that protect from reinfection, bringing novel insights for pediatric vaccine design. They also underline the importance of vaccination in children, who remain at risk for COVID-19 despite having been previously infected.

Objective: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. Methods: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8–14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. Results: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p = 0.01) and with increased Tregs frequency (p = 0.01). The other variants did not present consistent associations. Conclusions: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.

Some individuals’ understanding of informed consent (IC) information may improve with electronic delivery, but others may benefit from face-to-face (F2F). This randomized, multisite study explores how individuals from diverse backgrounds understand electronic IC documents versus F2F, their confidence in understanding, and enrollment in research. A total of 501 patients at two U.S. biobanks with diverse populations participated. There were no overall differences between electronic and F2F understanding, but F2F predicted higher confidence in understanding and enrollment. Ethnicity and a higher educational level predicted higher understanding and confidence. Study findings suggest that electronic consent may lead to better understanding for non-Hispanic patients of higher socioeconomic status. F2F processes may lead to better understanding and higher enrollment of patients from Hispanic and lower socioeconomic levels. Researchers should carefully consider how they implement electronic IC processes and whether to maintain an F2F process to better address the needs and limitations of some populations.

BACKGROUND AND OBJECTIVE: The knowledge about the impact of the nonpharmacological measures to control the COVID-19 pandemic can give insight into ways in which they can also be applied for other respiratory diseases. To assess the impact of containment measures of the COVID-19 pandemic on pneumonia hospitalizations in children from 0 to 14 years of age in Brazil. METHODS: Data from hospital admissions for pneumonia were obtained from the Department of Informatics of Brazilian Public Health System database in the period of 2015-2020 and analyzed by macroregions and age groups. To evaluate the effect of containment measures, on the incidence of pneumonia, the absolute reduction and relative reduction were calculated by analyzing the subsets 2015-2019 vs. 2020. RESULTS: Comparing the subsets of April-August 2015-2019 vs. April-August 2020 for Brazil (total), there was an significant reduction in the average incidence of hospitalizations, with numbers ranging from -82% [IRR 0.17 (0.14-0.21)] for

BackgroundDepression is a prevalent and impairing condition. Behavioral activation (BA) is a parsimonious, cost-effective, and easily disseminated psychological intervention for depression. The current meta-analysis expands on the existing literature supporting the efficacy of BA for depression by examining the effects of BA on additional relevant outcomes for patients with depression, namely the reduction in anxiety symptoms and increase in activation.MethodsRandomized controlled trials of BA for depression compared to active and inactive control were identified via a systematic review. Effect sizes using Hedges's g were calculated for each outcome compared to both active and inactive control using random effects models. Subgroup analyses were used to examine the inclusion of a discussion of values as a moderator of depression symptom outcome in BA.ResultsTwenty-eight studies were included. Meta-analyses of symptom change between groups from baseline-to-post intervention indicated that BA outperformed inactive control conditions for improvements in depression (g = 0.83), anxiety (g = 0.37), and activation (g = 0.64). The difference between BA and active control conditions was not significant for improvements in depression (g = 0.15), anxiety (g = 0.03), and activation (g = 0.04). There was no evidence for a discussion of values augmenting BA efficacy. Study quality was generally low, and there was evidence of publication bias.ConclusionsIn addition to improving depression, BA shows efficacy for reducing symptoms of anxiety and increasing activation. BA may not offer better outcomes relative to other active interventions. There is room for improvement in the quality of research in this area.

Objective: To evaluate the association between obesity and hospitalization in mild COVID-19 adult outpatients in Brazil. Subjects and methods: Adults with signs and symptoms suggestive of acute SARS-CoV-2 infection who sought treatment in two hospital (public and private) emergency departments were prospectively enrolled. Patients with confirmed COVID-19 at inclusion were followed by phone calls at days D7, D14 and D28. Multivariable logistic regression models were employed to explore the association between obesity and other potential predictors for hospitalization. Results: A total of 1,050 participants were screened, and 297 completed the 28-day follow-up and were diagnosed with COVID-19 by RT-PCR. The median age was 37.2 (IQR 29.7-44.6) years, and 179 (60.0%) were female. The duration of symptoms was 3.0 (IQR 2.0-5.0) days, and 10.0 (IQR 8.0-12.0) was the median number of symptoms at inclusion. Ninety-five (32.0%) individuals had obesity, and 233 (78.5%) had no previous medical conditions. Twenty-three participants (7.7%) required hospitalization during the follow-up period. After adjusting, obesity (BMI ≥ 30.0 kg/m2) (OR = 2.69, 95% CI 1.63-4.83, P < 0.001) and older age (OR = 1.05, 95% CI 1.01-1.09, P < 0.001) were significantly associated with higher risks of hospitalization. Conclusion: Obesity, followed by aging, was the main factor associated with hospital admission for COVID-19 in a young population in a low-middle income country. Our findings highlighted the need to promote additional protection for individuals with obesity, such as vaccination, and to encourage lifestyle changes.

OM-85 is a bacterial lysate from common respiratory tract pathogens, with an excellent safety profile, widely used to prevent recurrent respiratory tract infections. Several studies have been reporting the antiviral roles of OM-85. Here we demonstrated the effect of ex-vivo OM-85 exposure in nasopharyngeal cells collected from COVID-19 patients. OM-85 decreased the SARS-CoV-2 N1 gene expression and increased RIG-I (DDX58) gene expression in these cells. These data support the antiviral effect of OM-85 against SARS-CoV-2.