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Monocytes and monocyte-derived macrophages originate through a multistep differentiation process. First, hematopoietic stem cells generate lineage-restricted progenitors that eventually develop into peripheral, postmitotic monocytes. Second, blood-circulating monocytes undergo differentiation into macrophages, which are specialized phagocytic cells capable of tissue infiltration. While monocytes mediate some level of inflammation and cell toxicity, macrophages boast the widest set of defense mechanisms against pathogens and elicit robust inflammatory responses. Here, we analyze the molecular determinants of monocytic and macrophagic commitment by profiling the EGR1 transcription factor. EGR1 is essential for monopoiesis and binds enhancers that regulate monocytic developmental genes such as CSF1R. However, differentiating macrophages present a very different EGR1 binding pattern. We identify novel binding sites of EGR1 at a large set of inflammatory enhancers, even in the absence of its binding motif. We show that EGR1 repressive activity results in suppression of inflammatory genes and is mediated by the NuRD corepressor complex.…

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.…

The classic NF-B pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKβ, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in Nfkb1-deficient mice. In this study, we found that IKKβ ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKβ ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.…

Devices that electrically modulate the deep brain have enabled important breakthroughs in the management of neurological and psychiatric disorders. Such devices are typically centimeter-scale, requiring surgical implantation and wired-in powering, which increases the risk of hemorrhage, infection, and damage during daily activity. Using smaller, remotely powered materials could lead to less invasive neuromodulation. Here, we present injectable, magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field. This mechanism of modulation requires no genetic modification of neural tissue, allows animals to freely move during stimulation, and uses nonresonant carrier frequencies. Using these nanoelectrodes, we demonstrate neuronal modulation in vitro and in deep brain targets in vivo. We also show that local subthalamic modulation promotes modulation in other regions connected via basal ganglia circuitry, leading to behavioral changes in mice. Magnetoelectric materials present a versatile platform technology for less invasive, deep brain neuromodulation.…

O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is notably decreased in Alzheimer’s disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered O-GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear. Here, we found that O-GlcNAcylation plays a protective role in AD by inhibiting necroptosis. Necroptosis was increased in AD patients and AD mouse model compared with controls; however, decreased necroptosis due to O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine protein kinase 3) was observed in 5xFAD mice with insufficient O-linked β-N-acetylglucosaminase. O-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O-GlcNAcylation ameliorated AD pathology, including Aβ burden, neuronal loss, neuroinflammation, and damaged mitochondria and recovered the M2 phenotype and phagocytic activity of microglia. Thus, our data establish the influence of O-GlcNAcylation on Aβ accumulation and neurodegeneration, suggesting O-GlcNAcylation–based treatments as potential interventions for AD.…

The COVID-19 lockdowns led to major reductions in air pollutant emissions. Here, we quantitatively evaluate changes in ambient NO2, O3, and PM2.5 concentrations arising from these emission changes in 11 cities globally by applying a deweathering machine learning technique. Sudden decreases in deweathered NO2 concentrations and increases in O3 were observed in almost all cities. However, the decline in NO2 concentrations attributable to the lockdowns was not as large as expected, at reductions of 10 to 50%. Accordingly, O3 increased by 2 to 30% (except for London), the total gaseous oxidant (Ox = NO2 + O3) showed limited change, and PM2.5 concentrations decreased in most cities studied but increased in London and Paris. Our results demonstrate the need for a sophisticated analysis to quantify air quality impacts of interventions and indicate that true air quality improvements were notably more limited than some earlier reports or observational data suggested.…

The reaction-center light-harvesting complex 1 (RC-LH1) is the core photosynthetic component in purple phototrophic bacteria. We present two cryo–electron microscopy structures of RC-LH1 complexes from Rhodopseudomonas palustris. A 2.65-Å resolution structure of the RC-LH114-W complex consists of an open 14-subunit LH1 ring surrounding the RC interrupted by protein-W, whereas the complex without protein-W at 2.80-Å resolution comprises an RC completely encircled by a closed, 16-subunit LH1 ring. Comparison of these structures provides insights into quinone dynamics within RC-LH1 complexes, including a previously unidentified conformational change upon quinone binding at the RC QB site, and the locations of accessory quinone binding sites that aid their delivery to the RC. The structurally unique protein-W prevents LH1 ring closure, creating a channel for accelerated quinone/quinol exchange.…

by Fudong Zhu, Yao Chen, Yunxian Yu, Yanyi Xie, Haihua Zhu, Huiming Wang Dental caries is one of the most common infectious diseases affecting 6–8-year-old children, especially their first permanent molars (FPMs). This study explored the prevalence of dental caries on FPMs by analyzing the oral health status of 1,423,720 children aged 6–8 years in Zhejiang Province, China. The data were extracted from the dental electronic records of the schoolchildren attending the Oral Health Promotion Project (OHPP), conducted during 2013–2017 in Zhejiang Province. Multiple logistic regression models were used to determine the factors affecting dental caries. Boys and girls accounted for 53.2% and 46.8% of the subjects, respectively. From 2013 to 2017, the prevalence of dental caries on FPMs increased: 2013: 20.4%; 2014: 25.3%; 2015: 24.5%; 2016: 27.0%; and 2017: 29.0%, despite the OHPP conducted. Based on multiple logistic regression model, girls had a significantly higher risk of FPM caries compared to boys (OR = 1.38, 95% CI: 1.37–1.39, p < 0.0001); compared with the caries rates in urban areas, the caries risk was significantly higher in rural areas (OR = 1.15, 95% CI: 1.14–1.16, p < 0.0001). In terms of geographic location in Zhejiang Province, the odds ratios of the caries risk of the east, south, west, and north were 1.35 (1.33–1.36), 1.3 (1.28–1.31), 0.81 (0.8–0.83), and 0.82 (0.81–0.84), respectively (p < 0.0001), by considering the central region as a reference. The caries prevalence of FPMs was high, with an increasing tendency and gender, social, cultural, and environmental factors affecting the caries prevalence.

by Dina Zucchi, Chiara Tani, Elena Elefante, Chiara Stagnaro, Linda Carli, Viola Signorini, Francesco Ferro, Francesca Trentin, Giovanni Fulvio, Chiara Cardelli, Marco Di Battista, Gianmaria Governato, Antonio Figliomeni, Marta Mosca Introduction The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity. Materials and methods SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation. Results 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p

by John Lednicky, Marco Salemi, Kuttichantran Subramaniam, Thomas B. Waltzek, Tara Sabo-Attwood, Julia C. Loeb, Shannon Hentschel, Massimiliano S. Tagliamonte, Simone Marini, Md. Mahbubul Alam, Caroline J. Stephenson, Maha Elbadry, J. Glenn Morris Jr. In February and March, 2020, environmental surface swab samples were collected from the handle of the main entry door of a major university building in Florida, as part of a pilot surveillance project screening for influenza. Samples were taken at the end of regular classroom hours, between the dates of February 1–5 and February 19-March 4, 2020. Influenza A(H1N1)pdm09 virus was isolated from the door handle on four of the 19 days sampled. Both SARS-CoV-2 and A(H1N1)pdm09 virus were detected in a sample collected on February 21, 2020. Based on sequence analysis, the Florida SARS-CoV-2 strain (designated UF-11) was identical to strains being identified in Washington state during the same time period, while the earliest similar sequences were sampled in China/Hubei between Dec 30th 2019 and Jan 5th 2020. The first human case of COVID-19 was not officially reported in Florida until March 1st. In an analysis of sequences from COVID-19 patients in this region of Florida, there was only limited evidence of subsequent dissemination of the UF-11 strain. Identical or highly similar strains, possibly related through a common transmission chain, were detected with increasing frequency in Washington state between end of February and beginning of March. Our data provide further documentation of the rapid early spread of SARS-CoV-2 and underscore the likelihood that closely related strains were cryptically circulating in multiple U.S. communities before the first “official” cases were recognized.

by Farhaan S. Vahidy, Alan P. Pan, Hilda Ahnstedt, Yashasvee Munshi, Huimahn A. Choi, Yordanos Tiruneh, Khurram Nasir, Bita A. Kash, Julia D. Andrieni, Louise D. McCullough Introduction Sex is increasingly recognized as an important factor in the epidemiology and outcome of many diseases. This also appears to hold for coronavirus disease 2019 (COVID-19). Evidence from China and Europe has suggested that mortality from COVID-19 infection is higher in men than women, but evidence from US populations is lacking. Utilizing data from a large healthcare provider, we determined if males, as compared to females have a higher likelihood of SARS-CoV-2 susceptibility, and if among the hospitalized COVID-19 patients, male sex is independently associated with COVID-19 severity and poor in-hospital outcomes. Methods and findings Using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, we conducted a cross-sectional analysis of data from a COVID-19 Surveillance and Outcomes Registry (CURATOR). Data were extracted from Electronic Medical Records (EMR). A total of 96,473 individuals tested for SARS-CoV-2 RNA in nasopharyngeal swab specimens via Polymerized Chain Reaction (PCR) tests were included. For hospital-based analyses, all patients admitted during the same time-period were included. Of the 96,473 patients tested, 14,992 (15.6%) tested positive, of whom 4,785 (31.9%) were hospitalized and 452 (9.5%) died. Among all patients tested, men were significantly older. The overall SARS-CoV-2 positivity among all tested individuals was 15.5%, and was higher in males as compared to females 17.0% vs. 14.6% [OR 1.20]. This sex difference held after adjusting for age, race, ethnicity, marital status, insurance type, median income, BMI, smoking and 17 comorbidities included in Charlson Comorbidity Index (CCI) [aOR 1.39]. A higher proportion of males (vs. females) experienced pulmonary (ARDS, hypoxic respiratory failure) and extra-pulmonary (acute renal injury) complications during their hospital course. After adjustment, length of stay (LOS), need for mechanical ventilation, and in-hospital mortality were significantly higher in males as compared to females. Conclusions In this analysis of a large US cohort, males were more likely to test positive for COVID-19. In hospitalized patients, males were more likely to have complications, require ICU admission and mechanical ventilation, and had higher mortality than females, independent of age. Sex disparities in COVID-19 vulnerability are present, and emphasize the importance of examining sex-disaggregated data to improve our understanding of the biological processes involved to potentially tailor treatment and risk stratify patients.…

by Marcel Goic, Mirko S. Bozanic-Leal, Magdalena Badal, Leonardo J. Basso By early May 2020, the number of new COVID-19 infections started to increase rapidly in Chile, threatening the ability of health services to accommodate all incoming cases. Suddenly, ICU capacity planning became a first-order concern, and the health authorities were in urgent need of tools to estimate the demand for urgent care associated with the pandemic. In this article, we describe the approach we followed to provide such demand forecasts, and we show how the use of analytics can provide relevant support for decision making, even with incomplete data and without enough time to fully explore the numerical properties of all available forecasting methods. The solution combines autoregressive, machine learning and epidemiological models to provide a short-term forecast of ICU utilization at the regional level. These forecasts were made publicly available and were actively used to support capacity planning. Our predictions achieved average forecasting errors of 4% and 9% for one- and two-week horizons, respectively, outperforming several other competing forecasting models.

by Alhassan Abdul-Mumin, Cesia Cotache-Condor, Sheila Agyeiwaa Owusu, Haruna Mahama, Emily R. Smith Neonatal deaths now account for more than two-thirds of all deaths in the first year of life and for about half of all deaths in children under-five years. Sub-Saharan Africa accounts up to 41% of the total burden of neonatal deaths worldwide. Our study aims to describe causes of neonatal mortality and to evaluate predictors of timing of neonatal death at Tamale Teaching Hospital (TTH), Ghana. This retrospective study was conducted at TTH located in Northern Ghana. All neonates who died in the Neonatal Intensive Care Unit (NICU) from 2013 to 2017 were included and data was obtained from admission and discharge books and mortality records. Bivariate and multivariate logistic regression were used to assess predictors of timing of neonatal death. Out of the 8,377 neonates that were admitted at the NICU during the 5-year study period, 1,126 died, representing a mortality rate of 13.4%. Of those that died, 74.3% died within 6 days. There was an overall downward trend in neonatal mortality over the course of the 5-year study period (18.2% in 2013; 14.3% in 2017). Preterm birth complications (49.6%) and birth asphyxia (21.7%) were the top causes of mortality. Predictors of early death included being born within TTH, birth weight, and having a diagnosis of preterm birth complication or birth asphyxia. Our retrospective study found that almost 3/4 of neonatal deaths were within the first week and these deaths were more likely to be associated with preterm birth complications or birth asphyxia. Most of the deaths occurred in babies born within health facilities, presenting an opportunity to reduce our mortality by improving on quality of care provided during the perinatal period.

by Suvajyoti Guha, Alexander Herman, Ian A. Carr, Daniel Porter, Rucha Natu, Shayna Berman, Matthew R. Myers Background Face coverings constitute an important strategy for containing pandemics, such as COVID-19. Infection from airborne respiratory viruses including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can occur in at least three modes; tiny and/or dried aerosols (typically < 1.0 μm) generated through multiple mechanisms including talking, breathing, singing, large droplets (> 0.5 μm) generated during coughing and sneezing, and macro drops transmitted via fomites. While there is a growing number of studies looking at the performance of household materials against some of these situations, to date, there has not been any systematic characterization of household materials against all three modes. Methods A three-step methodology was developed and used to characterize the performance of 21 different household materials with various material compositions (e.g. cotton, polyester, polypropylene, cellulose and blends) using submicron sodium chloride aerosols, water droplets, and mucous mimicking macro droplets over an aerosol-droplet size range of ~ 20 nm to 0.6 cm. Results Except for one thousand-thread-count cotton, most single-layered materials had filtration efficiencies < 20% for sub-micron solid aerosols. However, several of these materials stopped > 80% of larger droplets, even at sneeze-velocities of up to 1700 cm/s. Three or four layers of the same material, or combination materials, would be required to stop macro droplets from permeating out or into the face covering. Such materials can also be boiled for reuse. Conclusion Four layers of loosely knit or woven fabrics independent of the composition (e.g. cotton, polyester, nylon or blends) are likely to be effective source controls. One layer of tightly woven fabrics combined with multiple layers of loosely knit or woven fabrics in addition to being source controls can have sub-micron filtration efficiencies > 40% and may offer some protection to the wearer. However, the pressure drop across such fabrics can be high (> 100 Pa).…

by Francisco Arroyo-Marioli, Francisco Bullano, Simas Kucinskas, Carlos Rondón-Moreno We develop a new method for estimating the effective reproduction number of an infectious disease (R) and apply it to track the dynamics of COVID-19. The method is based on the fact that in the SIR model, R is linearly related to the growth rate of the number of infected individuals. This time-varying growth rate is estimated using the Kalman filter from data on new cases. The method is easy to implement in standard statistical software, and it performs well even when the number of infected individuals is imperfectly measured, or the infection does not follow the SIR model. Our estimates of R for COVID-19 for 124 countries across the world are provided in an interactive online dashboard, and they are used to assess the effectiveness of non-pharmaceutical interventions in a sample of 14 European countries.

by Nichola Shackleton, Eileen Li, Sheree Gibb, Amanda Kvalsvig, Michael Baker, Andrew Sporle, Rebecca Bentley, Barry J. Milne Background Very little high quality evidence exists on the causal relationship between income poverty and childhood health. We provide a comprehensive overview of the association between household income poverty and hospitalisations for children. Methods We used New Zealand’s Integrated Data Infrastructure (IDI) to link income poverty data from the Survey of Family, Income and Employment (SoFIE; n = 21,759 households) and the 2013 New Zealand Census (n = 523,302 households) to publicly funded hospital records of children aged 0–17 (SoFIE: n = 39,459; Census, n = 986,901). Poverty was defined as equivalised household income below 60% of the median income, calculated both before and after housing costs, and using both self-reported and tax-recorded income. Results Correlations for the association between income poverty and hospitalisation were small (ranging from 0.02 to 0.05) and risk ratios were less than 1.35 for all but the rarest outcome—oral health hospitalisation. Weak or absent associations were apparent across age groups, waves of data collection, cumulative effects, and for estimates generated from fixed effects models and random effect models adjusted for age and ethnicity. Alternative measures of deprivation (area-level deprivation and material deprivation) showed stronger associations with hospitalisations (risk ratios ranged from 1.27–2.55) than income-based poverty measures. Conclusion Income poverty is at best weakly associated with hospitalisation in childhood. Measures of deprivation may have a stronger association. Income measures alone may not be sufficient to capture the diversity of household economic circumstances when assessing the poverty-health relationship.…

by A. T. M. Hasibul Hasan, Subir Chandra Das, Muhammad Sougatul Islam, Mohaimen Mansur, Md. Shajedur Rahman Shawon, Rashedul Hassan, Mohammad Shah Jahirul Hoque Chowdhury, Md. Badrul Alam Mondal, Quazi Deen Mohammad Background With the proposed pathophysiologic mechanism of neurologic injury by SARS CoV-2, the frequency of stroke and henceforth the related hospital admissions were expected to rise. This paper investigated this presumption by comparing the frequency of admissions of stroke cases in Bangladesh before and during the pandemic. Methods This is a retrospective analysis of stroke admissions in a 100-bed stroke unit at the National Institute of Neurosciences and Hospital (NINS&H) which is considerably a large stroke unit. All the admitted cases from 1 January to 30 June 2020 were considered. Poisson regression models were used to determine whether statistically significant changes in admission rates can be found before and after 25 March since when there is a surge in COVID-19 infections. Results A total of 1394 stroke patients took admission in the stroke unit during the study period. Half of the patients were older than 60 years, whereas only 2.6% were 30 years old or younger. The male to female ratio is 1.06:1. From January to March 2020, the mean rate of admission was 302.3 cases per month, which dropped to 162.3 cases per month from April to June, with an overall reduction of 46.3% in acute stroke admission per month. In those two periods, reductions in average admission per month for ischemic stroke (IST), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) and venous stroke (VS) were 45.5%, 37.2%, 71.4% and 39.0%, respectively. Based on weekly data, results of Poisson regressions confirm that the average number of admissions per week dropped significantly during the last three months of the sample period. Further, in the first three months, a total of 22 cases of hyperacute stroke management were done, whereas, in the last three months, there was an 86.4% reduction in the number of hyperacute stroke patients getting reperfusion treatment. Only 38 patients (2.7%) were later found to be RT-PCR SARS Cov-2 positive based on nasal swab testing. Conclusion This study revealed a more than fifty percent reduction in acute stroke admission during the COVID-19 pandemic. Whether the reduction is related to the fear of getting infected by COVID-19 from hospitalization or the overall restriction on public movement or stay-home measures remains unknown.…

by Sylvain Coly, Myriam Garrido, David Abrial, Anne-Françoise Yao Disease mapping aims to determine the underlying disease risk from scattered epidemiological data and to represent it on a smoothed colored map. This methodology is based on Bayesian inference and is classically dedicated to non-infectious diseases whose incidence is low and whose cases distribution is spatially (and eventually temporally) structured. Over the last decades, disease mapping has received many major improvements to extend its scope of application: integrating the temporal dimension, dealing with missing data, taking into account various a prioris (environmental and population covariates, assumptions concerning the repartition and the evolution of the risk), dealing with overdispersion, etc. We aim to adapt this approach to model rare infectious diseases proposing specific and generic variants of this methodology. In the context of a contagious disease, the outcome of a primary case can in addition generate secondary occurrences of the pathology in a close spatial and temporal neighborhood; this can result in local overdispersion and in higher spatial and temporal dependencies due to direct and/or indirect transmission. In consequence, we test models including a Negative Binomial distribution (instead of the usual Poisson distribution) to deal with local overdispersion. We also use a specific spatio-temporal link in order to better model the stronger spatial and temporal dependencies due to the transmission of the disease. We have proposed and tested 60 Bayesian hierarchical models on 400 simulated datasets and bovine tuberculosis real data. This analysis shows the relevance of the CAR (Conditional AutoRegressive) processes to deal with the structure of the risk. We can also conclude that the negative binomial models outperform the Poisson models with a Gaussian noise to handle overdispersion. In addition our study provided relevant maps which are congruent with the real risk (simulated data) and with the knowledge concerning bovine tuberculosis (real data).

Nature Medicine, Published online: 13 January 2021; doi:10.1038/s41591-020-01199-0Is it time to shift to a model of ‘inclusion unless otherwise justified’ in trials of vaccines for pandemics?…