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Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

ABSTRACTCongenital hearing loss is a common chronic condition affecting children in both developed and developing nations. Viruses correlated with congenital hearing loss include human cytomegalovirus (HCMV) and Zika virus (ZIKV), which causes congenital Zika syndrome. The mechanisms by which HCMV and ZIKV infections cause hearing loss are poorly understood. It is challenging to study human inner ear cells because they are encased in bone and also scarce as autopsy samples. Recent advances in culturing human stem cell-derived otic progenitor cells (OPCs) have allowed us herein to describe successful in vitro infection of OPCs with HCMV and ZIKV, and also to propose potential mechanisms by which each viral infection could affect hearing. We find that ZIKV infection rapidly and significantly induces the expression of type I interferon and interferon-stimulated genes, while OPC viability declines, at least in part, from apoptosis. In contrast, HCMV infection did not appear to upregulate interferons or cause a reduction in cell viability, and instead disrupted expression of key genes and pathways associated with inner ear development and function, including Cochlin, nerve growth factor receptor, SRY-box transcription factor 11, and transforming growth factor-beta signaling. These findings suggest that ZIKV and HCMV infections cause congenital hearing loss through distinct pathways, that is, by inducing progenitor cell death in the case of ZIKV infection, and by disruption of critical developmental pathways in the case of HCMV infection.IMPORTANCECongenital virus infections inflict substantial morbidity and devastating disease in neonates worldwide, and hearing loss is a common outcome. It has been difficult to study viral infections of the human hearing apparatus because it is embedded in the temporal bone of the skull. Recent technological advances permit the differentiation of otic progenitor cells (OPCs) from human-induced pluripotent stem cells. This paper is important for demonstrating that inner ear virus infections can be modeled in vitro using OPCs. We infected OPCs with two viruses associated with congenital hearing loss: human cytomegalovirus (HCMV), a DNA virus, or Zika virus (ZIKV), an RNA virus. An important result is that the gene expression and cytokine production profiles of HCMV/ZIKV-infected OPCs are markedly dissimilar, suggesting that mechanisms of hearing loss are also distinct. The specific molecular regulatory pathways identified in this work could suggest important targets for therapeutics.

Symbolic, spatial, and visual information, which is important for comprehending and learning physical and natural sciences, is not readily accessible to blind and low-vision (BLV) students in the undergraduate chemistry classroom, laboratory, and virtual environment via conventional means (through print and images), thus, creating a disadvantageous and inequitable situation. Appropriate instruction methods can be used to include these differently abled students in the learning process while also enhancing the learning outcomes of a diverse student population. By considering the teaching approach and universal design practices, and utilizing adapted methods, collaborative learning, and nonvisual assistive technologies and equipment, chemistry classroom/laboratory work for BLV students can be transformed from a passive experience to an active one. By creating the least restrictive learning environment, BLV students are enabled to become independent workers. Nonvisual ways (i.e., auditory, and text-to-speech applications, speech-enabled equipment, tactile graphics, and physical artifacts) by which BLV students can conduct their work are described, and practical ways for faculty to enhance teaching are presented.

ObjectivesTo compare prevalence and severity of diaper dermatitis (DD) in infants and toddlers (babies) across three countries (China, USA, and Germany), including diapered skin measures and caregiver practices.MethodsA cross-sectional study of 1791 babies (~600 from each country) was recruited at each clinical site. Based on regional toilet-training habits, exclusively diaper-wearing infants were recruited between ages 2-8 months in China and 2-18 months in the USA and Germany. DD was measured, as well as skin pH, transepidermal water loss (TEWL), and relative humidity (RH) in the diapered region. Caregiver habits were collected via a questionnaire and included information on hygienic practices.ResultsDiaper dermatitis was highest in the perianal area, followed by the intertriginous, genital, and buttock regions. In general, DD was significantly lower in babies in China, highest in Germany, and intermediate in the USA. This rank ordering of DD by geography was also observed in baby age 2-8 months. The lower DD observed in China was associated with lower skin pH and TEWL on diapered skin and decreased RH in the diaper. Chinese caregivers had the highest rate of prophylactic topical product usage, the most robust cleaning of the diapered area, lack of cleansing after urine-only diaper changes, and Chinese infants spent the least time in an overnight diaper.ConclusionsThese data suggest caregiver behaviors including prophylactic use of topical products, thorough cleaning after stooling and reduced time in an overnight diaper are associated with less DD, lower superficial skin pH, and enhanced skin barrier.

Abstract To determine the differential impact of the irreversible eye diseases on vision-related quality of life (VRQoL) in a multi-ethnic Asian population. 2652 participants from the Singapore Epidemiology of Eye Disease Study, with any of the following early and late-stage eye conditions including age-related macular degeneration (AMD, n = 158), diabetic retinopathy (DR, n = 105; non vision threatening [non-VTDR]; VTDR), glaucoma (n = 57) and myopic macular degeneration (MMD, n = 106), or none of the above (controls, 2226 [83.9%]) were included. Rasch-scaled scores of the Emotional well-being Mobility and Reading subscales of the Impact of Vision Impairment (IVI) questionnaire, collectively referred to as “VRQoL” were assessed. Multivariable linear regression analyses and pairwise comparisons adjusting for age, gender, ethnicity, socio-economic status, BMI, smoking, alcohol use, presence of systemic diseases and presenting VI were performed to assess and compare the impact of the presence and severity of each eye condition on the three IVI domains. Multivariable adjusted pairwise comparisons of VRQoL between early stages of the four eye diseases showed no significant differences (all P > 0.05). For late stage diseases, individuals with VTDR had significantly larger decrements in Emotional well-being compared to glaucoma (β − 0.81; 95% CI − 1.47 to − 0.16) and MMD (β − 1.17; 95% CI − 2.16 to − 0.18); and Reading decrements compared to glaucoma (β − 0.66; 95% CI − 1.22 to − 0.11). When compared to late glaucoma, individuals with late AMD (β − 0.76; 95% CI − 1.50 to − 0.01) had significantly larger IVI Mobility subscale decrements. VTDR and late AMD, appear to have the greatest impact on VRQoL, compared to late glaucoma and MMD, suggesting a differential impact of late-stage eye disease categorization on VRQoL.

The recent detection of ethanolamine (EtA, HOCH |$_2$| CH |$_2$| NH |$_2$|⁠), a key component of phospholipids, i.e. the building blocks of cell membranes, in the interstellar medium is in line with an exogenous origin of life-relevant molecules. However, the stability and survivability of EtA molecules under inter/circumstellar and Solar System conditions have yet to be demonstrated. Starting from the assumption that EtA mainly forms on interstellar ice grains, we have systematically exposed EtA, pure and mixed with amorphous water (H |$_2$| O) ice, to electron, ion, and thermal processing, representing 'energetic' mechanisms that are known to induce physicochemical changes within the ice material under controlled laboratory conditions. Using infrared (IR) spectroscopy, we have found that heating of pure EtA ice causes a phase change from amorphous to crystalline at 180 K, and further temperature increase of the ice results in sublimation-induced losses until full desorption occurs at about 225 K. IR and vacuum ultraviolet (VUV) spectra of EtA-containing ices deposited and irradiated at 20 K with 1 keV electrons as well as IR spectra of H |$_2$| O:EtA mixed ice obtained after 1 MeV He |$^+$| ion irradiation have been collected at different doses. The main radiolysis products, including H |$_2$| O, CO, CO |$_2$|⁠ , NH |$_3$|⁠ , and CH |$_3$| OH, have been identified and their formation pathways are discussed. The measured column density of EtA is demonstrated to undergo exponential decay upon electron and ion bombardment. The half-life doses for electron and He |$^+$| ion irradiation of pure EtA and H |$_2$| O:EtA mixed ice are derived to range between |$10.8\!-\!26.3$|  eV/16u. Extrapolating these results to space conditions, we conclude that EtA mixed in H |$_2$| O ice is more stable than in pure form and it should survive throughout the star and planet formation process. [ABSTRACT FROM AUTHOR]

Background: A systematic review of the literature uncovered little explanation as to why academics as individuals switch mobile applications or continue to use the same mobile applications. Knowing and being able to explain the personal behaviour are important and could be of value to practitioners and researchers, especially when it comes to predicting the future behaviour. Objectives: The main objective of this study was to explain and to model switching and continued use of mobile computing applications by South African academics. Method: A survey was carried out within South African academics as participants to test 14 hypotheses and explain switching and continued use of mobile computing applications. The adopted positivist study was associated with the quantitative research approach to test hypotheses so that the truth about objectives are obtainable. Results: The results of the study contributed to the body of knowledge by explaining and modelling the determinants influencing and significant to mobile computing application switching and continued use behaviour. Conclusion: The developed model may help to inform practitioners and researchers on what actually satisfies users to switch or continue to use mobile computing applications.

Background: The application of enhanced recovery after surgery (ERAS) has the potential to improve outcomes, hasten patient recovery, and reduce costs. ERAS has been applied to spine surgery for several years, but data are limited around the impact of ERAS on minimally invasive spine surgery, specifically. The authors report their experience implementing a multimodal ERAS protocol for patients receiving minimally invasive transforaminal lumbar interbody fusion. Methods: The ERAS protocol was implemented at The Valley Hospital in Ridgewood, New Jersey in January 2020. Following implementation, all patients receiving minimally invasive transforaminal lumbar interbody fusion by a single surgeon were studied. The authors analyze the impact of the protocol on length of stay (LOS), disposition post discharge, and opioid consumption postoperatively in the inpatient and outpatient settings. Results: Sixteen patients were enrolled in the protocol and compared with 17 historical controls. LOS was significantly shorter in the ERAS cohort (1.6 vs. 2.4 days, P = 0.022). There was no significant difference between the groups with respect to disposition; the majority of patients were discharged to home without need for in-home medical services. Patients in the ERAS cohort consumed significantly fewer opioid analgesics postoperatively in the inpatient setting (51 mg morphine milligram equivalents vs. 320 mg morphine milligram equivalents, P = 0.00016). On average, patients in the ERAS cohort were prescribed fewer opioids analgesics post discharge. Conclusions: ERAS application to minimally invasive transforaminal lumbar interbody fusion was safe and effective, significantly reducing LOS and inpatient opioid consumption. These data reflect the importance of uniformly applying a multimodal ERAS protocol to accelerate recovery and reduce narcotic use.

Flaviviruses are present on every continent and cause significant morbidity and mortality. In many instances, severe cases of infection with flaviviruses involve the invasion of and damage to the central nervous system (CNS). Currently, there are several mechanisms by which it has been hypothesized flaviviruses reach the brain, including the disruption of the blood–brain barrier (BBB) which acts as a first line of defense by blocking the entry of many pathogens into the brain, passing through the BBB without disruption, as well as travelling into the CNS through axonal transport from peripheral nerves. After flaviviruses have entered the CNS, they cause different neurological symptoms, leading to years of neurological sequelae or even death. Similar to neuroinvasion, there are several identified mechanisms of neuropathology, including direct cell lysis, blockage of the cell cycle, indication of apoptosis, as well as immune induced pathologies. In this review, we aim to summarize the current knowledge in the field of mechanisms of both neuroinvasion and neuropathogenesis during infection with a variety of flaviviruses and examine the potential contributions and timing of each discussed pathway.

Introduction As childhood mortality from infectious diseases falls across sub-Saharan Africa (SSA), the burden of disease attributed to surgical conditions is increasing. However, limited data exist on paediatric surgical outcomes in SSA. We compared the outcomes of five common paediatric surgical conditions in SSA with published benchmark data from high-income countries (HICs).Methods A multicentre, international, prospective cohort study was undertaken in hospitals providing paediatric surgical care across SSA. Data were collected on consecutive children (birth to 16 years), presenting with gastroschisis, anorectal malformation, intussusception, appendicitis or inguinal hernia, over a minimum of 1 month, between October 2016 and April 2017. Participating hospitals completed a survey on their resources available for paediatric surgery.The primary outcome was all-cause in-hospital mortality. Mortality in SSA was compared with published benchmark mortality in HICs using χ2 analysis. Generalised linear mixed models were used to identify patient-level and hospital-level factors affecting mortality. A p

Introduction. Social disparities in out-of-hospital cardiac arrest (OHCA) outcomes are preventable, costly, and unjust. We sought to perform the first large artificial intelligence- (AI-) guided statistical and geographic information system (GIS) analysis of a multiyear and multisite cohort for OHCA outcomes (incidence and poor neurological disposition). Method. We conducted a retrospective cohort analysis of a prospectively collected multicenter dataset of adult patients who sequentially presented to Houston metro area hospitals from 01/01/07-01/01/16. Then AI-based machine learning (backward propagation neural network) augmented multivariable regression and GIS heat mapping were performed. Results. Of 3,952 OHCA patients across 38 hospitals, African Americans were the most likely to suffer OHCA despite representing a significantly lower percentage of the population (42.6 versus 22.8%; p

Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In this review, we will summarize some current findings on how estrogens interact with and regulate inflammation and immunity. Specifically, we will focus on describing the mechanisms by which estrogens alter immune pathway activation, the impact of these changes during infection and the development of long-term immunity, and how different types of estrogens and their respective concentrations mediate these outcomes.

Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known that the accumulation of these defective particles can limit viral disease by interfering with the spread of fully infectious particles. In order to harness this phenomenon therapeutically, we defined which viral packaging signals were amenable to duplication and developed a viral genetic platform which produced replication competent IAVs that require up to two additional artificial genome segments for full infectivity. The modified and artificial genome segments propagated by this approach are capable of acting as "decoy" segments that, when packaged by coinfecting wild-type viruses, lead to the production of non-infectious viral particles. Although IAVs which require 10 genomic segments for full infectivity are able to replicate themselves and spread in vivo, their genomic modifications render them avirulent in mice. Administration of these viruses, both prophylactically and therapeutically, was able to rescue animals from a lethal influenza virus challenge. Together, our results show that replicating IAVs designed to propagate and spread defective genomic segments represent a potent anti-influenza biological therapy that can target the conserved process of particle assembly to limit viral disease.

An improved HVAC system for portable classrooms was specified to address key problems in existing units. These included low energy efficiency, poor control of and provision for adequate ventilation, and excessive acoustic noise. Working with industry, a prototype improved heat pump air conditioner was developed to meet the specification. A one-year measurement-intensive field-test of ten of these IHPAC systems was conducted in occupied classrooms in two distinct California climates. These measurements are compared to those made in parallel in side by side portable classrooms equipped with standard 10 SEER heat pump air conditioner equipment. The IHPAC units were found to work as designed, providing predicted annual energy efficiency improvements of about 36percent to 42percent across California's climate zones, relative to 10 SEER units. Classroom ventilation was vastly improved as evidenced by far lower indoor minus outdoor CO2 concentrations. The IHPAC units were found to provide ventilation that meets both California State energy and occupational codes and the ASHRAE minimum ventilation requirements; the classrooms equipped with the 10 SEER equipment universally did not meet these targets. The IHPAC system provided a major improvement in indoor acoustic conditions. HVAC system generated background noise was reduced in fan-only and fan and compressor modes, reducing the nose levels to better than the design objective of 45 dB(A), and acceptable for additional design points by the Collaborative on High Performance Schools. The IHPAC provided superior ventilation, with indoor minus outdoor CO2 concentrations that showed that the Title 24 minimum ventilation requirement of 15 CFM per occupant was nearly always being met. The opposite was found in the classrooms utilizing the 10 SEER system, where the indoor minus outdoor CO2 concentrations frequently exceeded levels that reflect inadequate ventilation. Improved ventilation conditions in the IHPAC lead to effective removal of volatile organic compounds and aldehydes, on average lowering the concentrations by 57percent relative to the levels in the 10 SEER classrooms. The average IHPAC to 10 SEER formaldehyde ratio was about 67percent, indicating only a 33percent reduction of this compound in indoor air. The IHPAC thermal control system provided less variability in occupied classroom temperature than the 10 SEER thermostats. The average room temperatures in all seasons tended to be slightly lower in the IHPAC classrooms, often below the lower limit of the ASHRAE 55 thermal comfort band. State-wide and national energy modeling provided conservative estimates of potential energy savings by use of the IHPAC system that would provide payback a the range of time far lower than the lifetime of the equipment. Assuming electricity costs of $0.15/kWh, the perclassroom range of savings is from about $85 to $195 per year in California, and about $89 to $250 per year in the U.S., depending upon the city. These models did not include the non-energy benefits to the classrooms including better air quality and acoustic conditions that could lead to improved health and learning in school. Market connection efforts that were part of the study give all indication that this has been a very successful project. The successes include the specification of the IHPAC equipment in the CHPS portable classroom standards, the release of a commercial product based on the standards that is now being installed in schools around the U.S., and the fact that a public utility company is currently considering the addition of the technology to its customer incentive program. These successes indicate that the IHPAC may reach its potential to improve ventilation and save energy in classrooms.