The MINERvA collaboration operated a scaled-down replica of the solid scintillator tracking and sampling calorimeter regions of the MINERvA detector in a hadron test beam at the Fermilab Test Beam ...Facility. This article reports measurements with samples of protons, pions, and electrons from 0.35 to 2.0 GeV/c momentum. The calorimetric response to protons, pions, and electrons are obtained from these data. A measurement of the parameter in Birks' law and an estimate of the tracking efficiency are extracted from the proton sample. Overall the data are well described by a Geant4-based Monte Carlo simulation of the detector and particle interactions with agreements better than 4%, though some features of the data are not precisely modeled. These measurements are used to tune the MINERvA detector simulation and evaluate systematic uncertainties in support of the MINERvA neutrino cross section measurement program.
Beams of neutrinos have been proposed as a vehicle for communications under unusual circumstances, such as direct point-to-point global communication, communication with submarines, secure ...communications and interstellar communication. We report on the performance of a low-rate communications link established using the NuMI beam line and the MINERvA detector at Fermilab. The link achieved a decoded data rate of 0.1 bits/sec with a bit error rate of 1% over a distance of 1.035 km, including 240 m of earth.
Rigorous monitoring supports progress in achieving maternal and newborn mortality and morbidity reductions. Recent work to strengthen measurement for maternal and newborn health highlights the ...existence of a large number of indicators being used for this purpose. The definitions and data sources used to produce indicator estimates vary and challenges exist with completeness, accuracy, transparency, and timeliness of data. The objective of this study is to create a conceptual overview of how indicator validity is defined and understood by those who develop and use maternal and newborn health indicators.
A conceptual framework of validity was developed using mixed methods. We were guided by principles for conceptual frameworks and by a review of the literature and key maternal and newborn health indicator guidance documents. We also conducted qualitative semi-structured interviews with 32 key informants chosen through purposive sampling.
We categorised indicator validity into three main types: criterion, convergent, and construct. Criterion or diagnostic validity, comparing a measure with a gold standard, has predominantly been used to assess indicators of care coverage and content. Studies assessing convergent validity quantify the extent to which two or more indicator measurement approaches, none of which is a gold-standard, relate. Key informants considered construct validity, or the accuracy of the operationalisation of a concept or phenomenon, a critical part of the overall assessment of indicator validity.
Given concerns about the large number of maternal and newborn health indicators currently in use, a more consistent understanding of validity can help guide prioritization of key indicators and inform development of new indicators. All three types of validity are relevant for evaluating the performance of maternal and newborn health indicators. We highlight the need to establish a common language and understanding of indicator validity among the various global and local stakeholders working within maternal and newborn health.
Abstract
Background
Chronological age (CA) is a predictor of adverse coronavirus disease 2019 (COVID-19) outcomes; however, CA alone does not capture individual responses to severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components.
Method
In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (intensive care unit admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components.
Results
We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel >0 had higher risk of death and critical illness compared to those with lower values (log-rank p < .001). Using unsupervised clustering, we identified 4 adaptive responses to SARS-CoV-2 infection: (i) inflammaging associated with CA, (ii) metabolic dysfunction associated with cardiometabolic comorbidities, (iii) unfavorable hematological response, and (iv) response associated with favorable outcomes.
Conclusions
Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.
Women acquire HIV through sexual transmission, with increasing incidence in women >50 years old. Identifying protective mechanisms in the female genital tract (FGT) is important to prevent ...HIV-acquisition in women as they age. Human genital and blood neutrophils inactivate HIV by releasing neutrophil extracellular traps (NETs), an innate protective mechanism against HIV-infection. However, how NET formation is triggered by HIV in different tissues and whether this mechanism is affected by aging remain unknown. We demonstrate that the mechanisms that trigger NET release in response to HIV are different in blood and genital tissues, and that NET release decreases with aging. In blood neutrophils, HIV stimulation independently activated calcium pathways and endosomal TLR8, but aging reduced calcium responses, resulting in delayed NET release. In contrast, calcium responses were absent in genital neutrophils and NET release was triggered preferentially through TLR8 activation, but aging impaired this pathway. HIV induced NET formation through non-lytic pathways in blood and FGT neutrophils, except for a small subset of NETs that incorporated annexin V and lactoferrin predominantly in blood, suggesting proinflammatory and lytic NET release. Our findings demonstrate that blood neutrophils cannot model genital neutrophil responses which has important implications to understanding protection against HIV acquisition.
Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition ...(EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase
and sialyltransferase
, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate.
Obesity and overweight are established risk factors for the development of breast cancer. They are also associated with poor prognosis for higher risk of disease recurrence and lower overall survival ...(OS). The aim of this study was to evaluate the influence of overweight and obesity in OS in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy. This is a retrospective analysis that included 819 patients diagnosed with LABC between January 2004 and December 2008. The patients were treated with neoadjuvant chemotherapy (NAT) based on anthracyclines, taxanes, or both, followed by surgery. For comparison, patients were divided into the normal weight (NW) group or the overweight/obesity (OW/OB) group. The prevalence of overweight/obesity was 74 %. General characteristics of the patients, including age, tumor size, clinical stage, nuclear grade, hormone receptors, and HER2 expression, were similar between both groups. At a median follow-up of 28 months, we found a statistically significant difference in OS between the two groups, achieving a 91.5 % in NW patients versus 85.9 % in the OW/OB group (
P
= 0.050). Cox multivariate analysis demonstrated that obesity was an independent factor for poor prognosis, with a hazard ratio of 1.79 (95 % CI (Confidence Interval) 1.09–2.96;
P
= 0.022). This is the first Mexican study that confirms the role of OW/OB as a risk factor for poor outcome among patients with LABC. Obesity in our country is a public health problem and requires strong preventive intervention strategies for its control, especially among patients diagnosed with breast cancer.
Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the ...biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.
Display omitted Ultra-high field diffusion MRI can detect brain structural changes in the Huntington s disease (HD), R6/1 mouse model. Diffusion tensor imaging (DTI) can capture early microstructural changes across different brain structures. dMRI parameters can be linked to cellular neuroinflammatory markers at an early stage of HD.
The guide for monitoring and treatment of congenital hepatic hemangiomas (CHH) will depend on the subtype and the postnatal clinical behavior. Our aim is to present a series of CHH and characterize ...its clinical, histologic and genetic correlation, compared to cutaneous congenital hemangiomas (CCH).
A retrospective review of CHH patients diagnosed between 1991 and 2018 was performed. Clinical, morphological and histological data were analyzed and deep high-throughput sequencing was performed.
Sixteen patients with CHH were included. Five patients were followed up with serial ultrasounds while pharmacological treatment (corticosteroids and propranolol) was decided in five. Surgical resection was performed in five owing to hemorrhage and suspicion of malignancy, and the last patient underwent embolization. Histologic analysis was available in 7 patients and confirmed CHH, showing two different histological patterns that could be associated with the presence of somatic pathogenic variants in GNAQ and/or PIK3CA detected in the genetic testing. Review of 7 samples of CCH revealed some histologic differences compared to CHH.
CHH resemble its cutaneous homonym with similar clinical behavior. Histologic analysis can differentiate two subgroups while genetic testing can confirm mutations in GNAQ and in PIK3CA in a subset of CHH.
Treatment study.
IV
•Congenital hepatic hemangiomas (CHHs) resemble cutaneous hepatic hemangiomas (CCHs) with similar clinical behavior.•Histologic evaluation finds some differences between CHH and CCH.•In our series we differentiate two patterns in histologic analysis that can be associated with the presence of somatic pathogenic variants in GNAQ and/or PIK3CA.
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