Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections.

Congenital 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. IMPORTANCE: Congenital 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.

The Yield of Ambulatory Video-EEG: Predictors of Successful Event Capture.

Background and Objectives: The purpose of this study was to assess the likelihood of capturing a patient's typical event in question on ambulatory video-EEG monitoring (AVEM) based on certain baseline patient or event characteristics. Methods: We retrospectively reviewed 300 studies that resulted between June 2021 and August 2022 ordered by adult epileptologists. Patients were included in event analysis if the study was ordered for the purpose of capturing an event (and excluded for all other purposes). Results: A total of 149 studies were included in event analysis. Sixty-eight patients (46%) had their typical events captured on AVEM. Diagnosis was an epileptic seizure in 17 patients (25%), psychogenic nonepileptic seizure in 7 (10%), and other nonepileptic events in 44 (65%). Regarding event frequency, for patients who on average had daily events, 84% had events captured, which corresponds to a significantly increased odds ratio (OR 17.90, 95% CI 7.55-42.44, p < 0.001). For those who had events <1 per week to ≥1 per month, only 9% had events captured (OR 0.06, 95% CI 0.02-0.19, p < 0.001). No patients who had events less frequently than once per month had a diagnostic AVEM. Regarding the number of antiseizure medications (ASMs), the odds ratio was increased for those not on ASMs (OR 2.65, 95% CI 1.17 -6.03, p = 0.02) and decreased for those on 1 ASM (OR 0.28, 95% CI 0.13 -0.60, p = 0.001). There was no statistical significance based on event type (motor vs nonmotor), prior seizure diagnosis, history of psychiatric comorbidity, or presence of a focal brain lesion. Discussion: Certain baseline characteristics can increase or decrease the pretest probability of capturing a typical event on AVEM, particularly the frequency of events and number of ASMs. This can be useful information for clinicians before ordering a study so that resources can be properly allocated.

Mechanisms of Neuroinvasion and Neuropathogenesis by Pathologic Flaviviruses.

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.

Genetic Variability of Complement Factor H Has Ethnicity-Specific Associations With Choroidal Thickness.

Purpose: To identify genetic alleles associated with differences in choroidal thickness (CT) in a population-based multiethnic Asian cohort. Methods: A population-based multiethnic Asian cohort without retinal pathology was subjected to spectral-domain OCT (SD-OCT) and genotyping of risk alleles in CFH, VIPR2, ARMS2, and CETP. Subfoveal choroidal thickness (SFCT) values were assessed from SD-OCT, and associations with the risk alleles were determined for each cohort. Results: A total of 1045 healthy Asian individuals (550 Chinese, 147 Indians, 348 Malays) were prospectively enrolled in the study. Several CFH alleles (rs800292, rs1061170, and rs1329428) were associated with increased SFCT in Indians (+18.7 to +31.7 µm; P = 0.001-0.038) and marginally associated with decreased SFCT in Malays (-12.7 to -20.6 µm; P = 0.014-0.022). Haplotype analysis of CFH revealed variable associations with SFCT among races, with the H6 haplotype being associated with a 29.08-µm reduction in SFCT in the Chinese cohort (P = 0.02) but a 35.2-µm increase in SFCT in the Indian cohort (P < 0.001). Finally, subfield analysis of the Chinese cohort identified associations between the CFH risk allele rs1061170 and reduced CT in the nasal and superior sectors (-20.2 to -25.8 µm; P = 0.003-0.027). Conclusions: CFH variants are variably associated with CT among Asian ethnic groups. This has broad implications for the pathogenesis of common diseases such as age-related macular degeneration and central serous choroidopathy, the pathogenesis of which is associated with CT.

Bilateral sequential small-incision lenticule extraction and LASIK result in similar short-term quality-of-life outcomes.

PURPOSE: To compare quality of life (QoL) between patients who receive bilateral small-incision lenticule extraction (SMILE) or laser in situ keratomileusis (LASIK) vs bilateral sequential SMILE-LASIK (BSSL) surgery. SETTING: Singapore National Eye Centre, Singapore. DESIGN: Retrospective cohort study. METHODS: 2 patient cohorts were recruited (2010-2012; 2014-2016). The bilateral SMILE (BS) and bilateral LASIK (BL) groups comprised patients (mean ± SD age: 30.3 ± 6.5, 50% male) from a prospective nonrandomized study who chose SMILE and LASIK, respectively. The BSSL group comprised patients (mean ± SD age: 28.6 ± 6.2, 64.3% male) randomized to receive SMILE in 1 eye and LASIK in the other. Rasch-scaled scores of the QoL Impact of Refractive Correction questionnaire between groups postoperatively at 1 and 3 months were compared. RESULTS: At month 1, scores on 3 QoL without emotional well-being items were worse in the BSSL (n = 70) compared with the BL group (n = 25), specficially, "using sunglasses" (ß: -20.6, 95% CI, -34.3 to -6.9), "reliance on refractive correction" (-23.1, 95% CI, -40.9 to -5.4), and "medical complications from optical correction" (ß: -14.8, 95% CI, -27.9 to -1.7). Emotional well-being (overall), and items "feeling able to do things" (ß: 11.0, 95% CI, 1.6-20.4) and "feeling eager to try new things" (ß: 14.1, 95% CI, 3.6-24.6) were better in the BSSL compared with the BS group (n = 25). No substantive differences were observed at month 3. CONCLUSIONS: Refractive correction-related QoL differences at month 1 between BSSL and BS/BL patients attenuated by month 3. Bilateral sequential SMILE-LASIK surgery appeared unlikely to negatively affect QoL beyond 3 months.

An Imbalance in the Force: The Need for Standardized Benchmarks for Molecular Simulation.

Force fields (FFs) for molecular simulation have been under development for more than half a century. As with any predictive model, rigorous testing and comparisons of models critically depends on the availability of standardized data sets and benchmarks. While such benchmarks are rather common in the fields of quantum chemistry, this is not the case for empirical FFs. That is, few benchmarks are reused to evaluate FFs, and development teams rather use their own training and test sets. Here we present an overview of currently available tests and benchmarks for computational chemistry, focusing on organic compounds, including halogens and common ions, as FFs for these are the most common ones. We argue that many of the benchmark data sets from quantum chemistry can in fact be reused for evaluating FFs, but new gas phase data is still needed for compounds containing phosphorus and sulfur in different valence states. In addition, more nonequilibrium interaction energies and forces, as well as molecular properties such as electrostatic potentials around compounds, would be beneficial. For the condensed phases there is a large body of experimental data available, and tools to utilize these data in an automated fashion are under development. If FF developers, as well as researchers in artificial intelligence, would adopt a number of these data sets, it would become easier to compare the relative strengths and weaknesses of different models and to, eventually, restore the balance in the force.

Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus.

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 (ERAP1; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics.

Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication.

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.

Association Between Risk of Obstructive Sleep Apnea and Glaucoma: The Singapore Epidemiology of Eye Diseases Study.

PRCIS: In this population-based, cross-sectional study of Indian and Malay adults in Singapore aged 40 years or above, intermediate or high risk of obstructive sleep apnea (OSA) was associated with 50% higher odds of having glaucoma. BACKGROUND/AIMS: The relationship between OSA and glaucoma is unclear. We assessed the association between the risk of OSA and glaucoma in an Asian population. MATERIALS AND METHODS: In this population-based, cross-sectional study, we included Indian and Malay adults aged 40 years or above recruited between 2011 and 2015. Glaucoma was assessed by trained ophthalmologists and classified into primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG). OSA risk was assessed with the Snoring, Tiredness, Observed apnea, High blood pressure, Body mass index, Age, Neck circumference, and male Gender (STOP-Bang) questionnaire and categorized as low risk (<3) or intermediate/higher risk (≥3). We used multivariable logistic regression models to evaluate the relationship between risk of OSA and glaucoma adjusted for key variables, and further stratified for subtype and ethnicity. RESULTS: Of the 3126 participants (mean age: 63.1±9.6 y; 52.5% female), 134 (4.3%) had glaucoma, comprising 86 (2.8%) POAG, 22 (0.7%) PACG and 26 (0.8%) secondary glaucomas, and 1182 (37.8%) had an intermediate/higher risk of OSA. Compared with individuals with a low risk of OSA, individuals with intermediate/higher risk had 50% greater odds of having glaucoma (odds ratio: 1.55, 95% confidence interval: 1.03-2.33; P =0.035). We observed a nonsignificant increase in likelihood of having POAG in those with intermediate/higher risk of OSA compared with those with low risk. The OSA-glaucoma relationship was modified by ethnicity, with Malays with intermediate/higher risk of OSA having a 2-fold risk of having any glaucoma (odds ratio: 2.01, 95% confidence interval: 1.12-3.59 P =0.019); while the same elevated risk was not observed for Indians. CONCLUSIONS: Intermediate or high risk of OSA is associated with 50% higher odds of having glaucoma in our Singaporean population, with a 2-fold higher risk of glaucoma observed in Malays (but not Indians); however a conformational sleep study is needed.

Rapid tissue prototyping with micro-organospheres.

In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.

A Virion-Based Combination Vaccine Protects against Influenza and SARS-CoV-2 Disease in Mice.

Vaccines targeting SARS-CoV-2 have been shown to be highly effective; however, the breadth against emerging variants and the longevity of protection remains unclear. Postimmunization boosting has been shown to be beneficial for disease protection, and as new variants continue to emerge, periodic (and perhaps annual) vaccination will likely be recommended. New seasonal influenza virus vaccines currently need to be developed every year due to continual antigenic drift, an undertaking made possible by a robust global vaccine production and distribution infrastructure. To create a seasonal combination vaccine targeting both influenza viruses and SARS-CoV-2 that is also amenable to frequent reformulation, we have developed an influenza A virus (IAV) genetic platform that allows the incorporation of an immunogenic domain of the SARS-CoV-2 spike (S) protein onto IAV particles. Vaccination with this combination vaccine elicited neutralizing antibodies and provided protection from lethal challenge with both pathogens in mice. This approach may allow the leveraging of established influenza vaccine infrastructure to generate a cost-effective and scalable seasonal vaccine solution for both influenza and coronaviruses. IMPORTANCE The rapid emergence of SARS-CoV-2 variants since the onset of the pandemic has highlighted the need for both periodic vaccination "boosts" and a platform that can be rapidly reformulated to manufacture new vaccines. In this work, we report an approach that can utilize current influenza vaccine manufacturing infrastructure to generate combination vaccines capable of protecting from both influenza virus- and SARS-CoV-2-induced disease. The production of a combined influenza/SARS-CoV-2 vaccine may represent a practical solution to boost immunity to these important respiratory viruses without the increased cost and administration burden of multiple independent vaccines.

Different impact of early and late stages irreversible eye diseases on vision-specific quality of life domains.

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 (ß - 0.81; 95% CI - 1.47 to - 0.16) and MMD (ß - 1.17; 95% CI - 2.16 to - 0.18); and Reading decrements compared to glaucoma (ß - 0.66; 95% CI - 1.22 to - 0.11). When compared to late glaucoma, individuals with late AMD (ß - 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.

Enhanced Recovery After Surgery Protocol in Minimally Invasive Lumbar Fusion Surgery Reduces Length of Hospital Stay and Inpatient Narcotic Use.

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 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.

Association between age-related sensory impairment with sarcopenia and its related components in older adults: a systematic review.

Sensory impairments and sarcopenia are both highly prevalent age-related conditions, with the former having been postulated to contribute to the pathogenesis of the latter condition. Confirming this hypothesis may therefore help to better inform strategies for early treatment and intervention of sarcopenia. We performed a systematic review of the current literature examining the relationships between four major sensory impairments [vision (VI), hearing (HI), smell (SI), and taste (TI)] with (i) sarcopenia; and (ii) its associated components (low handgrip strength, slow gait speed, and low muscle mass). PubMed, EMBASE, CINAHL, and Cochrane Library databases were searched for observational studies investigating the relationship of VI, HI, SI, and TI with sarcopenia, low handgrip strength, slow gait speed, and low muscle mass, in adults aged 50 years or older, from inception until 24 May 2021. The risk of bias of the included studies was assessed using the Newcastle-Ottawa Scale. This study was registered with PROSPERO, reference CRD42021247967. Ten cross-sectional and three longitudinal population-based studies of community-dwelling adults (N = 68 235) were included, with five studies investigating more than one sensory impairment. In total, 8, 6, 3, and 1 studies investigated the relationship between VI, HI, SI, and TI and sarcopenia and its related components, respectively. Follow-up duration for the longitudinal studies ranged from 4 to 11 years. All studies had a low or moderate risk of bias. We found that the presence of VI and SI, but not TI, independently increased the odds of sarcopenia. In addition, VI and SI were each independently associated with low muscle mass; and VI, HI, and SI were each independently associated with slow gait speed. However, we found inconclusive evidence for the associations between VI, HI and SI, and low handgrip strength. Our systematic review suggests a potential association between the presence of single or multiple sensory impairments and a greater likelihood of sarcopenia and/or deficits in its associated components, especially for VI, HI, and SI. Prospective studies are needed to untangle the relationship between sensory impairment and sarcopenia to better inform clinical guidelines for disease prevention and management.

The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection.

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.

Racial and Socioeconomic Disparities in Out-Of-Hospital Cardiac Arrest Outcomes: Artificial Intelligence-Augmented Propensity Score and Geospatial Cohort Analysis of 3,952 Patients.

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 < 0.001). Compared to Caucasians, they were significantly more likely to have poor neurological disposition (OR 2.21, 95%CI 1.25-3.92; p=0.006) and be discharged to a facility instead of home (OR 1.39, 95%CI 1.05-1.85; p=0.023). Compared to the safety net hospital system primarily serving poorer African Americans, the university hospital serving primarily higher income commercially and Medicare insured patients had the lowest odds of death (OR 0.45, p < 0.001). Each additional $10,000 above median household income was associated with a decrease in the total number of cardiac arrests per zip code by 2.86 (95%CI -4.26- -1.46; p < 0.001); zip codes with a median income above $54,600 versus the federal poverty level had 14.62 fewer arrests (p < 0.001). GIS maps showed convergence of the greater density of poor neurologic outcome cases and greater density of poorer African American residences. CONCLUSION: This large, longitudinal AI-guided analysis statistically and geographically identifies racial and socioeconomic disparities in OHCA outcomes in a way that may allow targeted medical and public health coordinated efforts to improve clinical, cost, and social equity outcomes.

Value of smartphone videos for diagnosis of seizures: Everyone owns half an epilepsy monitoring unit.

The diagnosis of epilepsy is primarily based on the history and the verbal description of the events in question. Smartphone videos are increasingly used to assist in the diagnosis. The purpose of this study is to evaluate their value for the diagnosis of seizures. We prospectively collected smartphone videos from patients who presented to our epilepsy center over two years. The video-based diagnosis was then compared to the eventual diagnosis based on video-electroencephalographic (EEG) monitoring with recorded episodes. Video-EEG studies and smartphone videos were reviewed by two separate physicians, each blinded to the other's interpretation. Fifty-four patients were included in the final analysis (mean age = 34.7 years, SD = 17 years). Data (either smartphone video or video-EEG monitoring) were inconclusive in 18 patients. Of the 36 patients with conclusive data, 34 (94%) were in agreement. Smartphone video interpretation can be a useful adjunctive tool in the diagnosis of seizure-like events.

ETV7 limits antiviral gene expression and control of influenza viruses.

The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict viral spread, whereas excessive ISG activation can result in IFN-related pathologies. Although both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that several ISGs regulate aspects of the IFN response themselves. In this study, we performed a CRISPR activation screen to identify previously unknown regulators of the type I IFN response. We identified the strongly induced ISG encoding ETS variant transcription factor 7 (ETV7) as a negative regulator of the type I IFN response. However, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of antiviral ISGs that were particularly important for IFN-mediated control of influenza viruses. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a potential therapeutic target to increase innate antiviral responses and enhance IFN-based antiviral therapies.

Development and Validation of a Preference-Based Glaucoma Utility Instrument Using Discrete Choice Experiment.

IMPORTANCE: A glaucoma-specific instrument for estimating utilities across the spectrum of glaucoma severity is currently lacking, hindering the assessment of the cost-effectiveness of glaucoma treatments. OBJECTIVE: To develop and validate the preference-based Glaucoma Utility Instrument (Glau-U) and to ascertain the association between Glau-U utilities and severity of glaucoma and vision impairment. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted in 2 stages at the Singapore National Eye Centre glaucoma clinics. Stage 1 focused on the identification and pretesting of the Glau-U attributes and was carried out between June 2009 and May 2016. Stage 2 involved the development and administration of the discrete choice experiment (DCE) survey and tasks and was conducted between May 7, 2018, and December 11, 2019. Stage 2 participants were English- or Mandarin-speaking Singaporean citizens or permanent residents of Chinese, Malay, or Indian ethnicity who were 40 years or older and had a clinical diagnosis of glaucoma in at least 1 eye. EXPOSURES: Glau-U comprised 6 quality-of-life attributes: activities of daily living, lighting and glare, movement, eye discomfort, other effects of glaucoma, and social and emotional effects. The descriptions or response options for these attributes were no difficulty or never, some difficulty or sometimes, or severe difficulty or often. MAIN OUTCOMES AND MEASURES: Utility weights for Glau-U were developed using a DCE questionnaire, which was interviewer administered to participants. Mixed logit regression determined utility weights for each health state. Glau-U utility weights across better- or worse-eye glaucoma and vision impairment severity were calculated using 1-way analysis of variance. Correlations between Glau-U utilities and better- or worse-eye visual fields and EuroQol 5-Dimension utilities were ascertained to assess convergent and divergent validity. RESULTS: Of the 304 participants (mean [SD] age, 68.3 [8.7] years; 182 men [59.9%]), 281 (92.4%) had no vision impairment in the better eye, 13 (4.3%) had mild impairment, and 10 (3.3%) had moderate to severe vision impairment. Mean (SD) Glau-U utilities decreased as better-eye glaucoma severity increased (none: 0.73 [0.21]; mild: 0.66 [0.21]; moderate: 0.66 [0.20]; severe: 0.60 [0.28]; and advanced or end-stage: 0.22 [0.38]; P < .001), representing reductions of 20.7% to 76.1% in quality-adjusted life-years compared with a health state that included preperimetric glaucoma. Mean (SD) Glau-U utilities also decreased as better-eye vision impairment worsened from 0.67 (0.23) for none to 0.58 (0.32) for mild to 0.46 (0.29) for moderate to severe vision impairment. Glau-U utilities demonstrated moderate correlations with better-eye (r = 0.34; P < .001) and worse-eye (r = 0.33; P < .001) mean deviation scores and low correlations with EuroQol 5-Dimension utilities (r = 0.22; P < .001), supporting convergent and divergent validity. CONCLUSIONS AND RELEVANCE: Use of Glau-U revealed large decrements in utility that were associated with late-stage glaucoma, suggesting that this new instrument may be useful for cost-effectiveness analyses of interventions and informing resource allocation policies for glaucoma and vision loss.

Influenza viral particles harboring the SARS-CoV-2 spike RBD as a combination respiratory disease vaccine

Vaccines targeting SARS-CoV-2 have gained emergency FDA approval, however the breadth against emerging variants and the longevity of protection remains unknown. Post-immunization boosting may be required, perhaps on an annual basis if the virus becomes an endemic pathogen. Seasonal influenza virus vaccines are already developed every year, an undertaking made possible by a robust global vaccine production and distribution infrastructure. To create a seasonal combination vaccine targeting influenza viruses and SARS-CoV-2 that is also amenable to frequent reformulation, we have developed a recombinant influenza A virus (IAV) genetic platform that "reprograms" the virus to package an immunogenic domain of the SARS-CoV-2 spike (S) protein onto IAV particles. Vaccination with this combination vaccine elicits neutralizing antibodies and provides protection from lethal challenge with both pathogens. This technology may allow for leveraging of established influenza vaccine infrastructure to generate a cost-effective and scalable seasonal vaccine solution for both influenza and coronaviruses.