Positive Autism Screening Rates in Toddlers Born During the COVID-19 Pandemic.

Importance: Stress and viral illness during pregnancy are associated with neurodevelopmental conditions in offspring. Autism screening positivity for children born during the pandemic remains unknown. Objective: To examine associations between prenatal exposure to the pandemic milieu and maternal SARS-CoV-2 infection with rates of positive Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) screenings. Design, Setting, and Participants: Data for this cohort study were drawn from the COVID-19 Mother Baby Outcomes (COMBO) Initiative. M-CHAT-R scores obtained from children aged 16 to 30 months during routine clinical care at Columbia University Irving Medical Center in New York City were abstracted from electronic health records (EHRs) for children born between January 2018 and September 2021 (COMBO-EHR cohort). Separately, the M-CHAT-R was administered at 18 months for children born between February 2020 and September 2021 through a prospective longitudinal study (COMBO-RSCH cohort). Prenatal pandemic exposure (birth after March 1, 2020) and maternal SARS-CoV-2 status during pregnancy was determined through EHRs. Data were analyzed from March 2022 to June 2024. Exposures: Prenatal exposures to the pandemic milieu and maternal SARS-CoV-2 infection. Main Outcomes and Measures: The primary outcome was rate of positive M-CHAT-R screenings. For all primary analyses, unadjusted χ2 tests and adjusted logistic regression models were performed. Results: The COMBO-EHR cohort included 1664 children (442 born before the pandemic and 1222 born during the pandemic; 997 SARS-CoV-2 unexposed, 130 SARS-CoV-2 exposed, and 95 with unknown SARS-CoV-2 exposure status), of whom 266 (16.0%) were Black, 991 (59.6%) were Hispanic, 400 (24.0%) were White, 1245 (74.8%) were insured through Medicaid, 880 (52.9%) were male, and 204 (12.3%) were born prematurely. The COMBO-RSCH cohort included 385 children (74 born before the pandemic and 311 born during the pandemic; 201 SARS-CoV-2 unexposed, 101 SARS-CoV-2 exposed, and 9 with unknown SARS-CoV-2 exposure status), of whom 39 (10.1%) were Black, 168 (43.6%) were Hispanic, 157 (40.8%) were White, 161 (41.8%) were insured through Medicaid, 222 (57.7%) were male, and 38 (9.9%) were born prematurely. Prenatal pandemic exposure was not associated with a higher positive M-CHAT-R screening rate in either the COMBO-EHR or COMBO-RSCH cohort. Prenatal exposure to maternal SARS-CoV-2 infection was associated with a lower rate of M-CHAT-R positivity in the COMBO-EHR cohort (12.3% [16 children] vs 24.0% [239 children]; adjusted odds ratio, 0.40; 95% CI, 0.22-0.68; P = .001), but no association was found in the COMBO-RSCH cohort (12.9% [13 children] vs 19.9% [40 children]; adjusted odds ratio, 0.51; 95% CI, 0.24-1.04; P = .07). Conclusions and Relevance: In this cohort study of 2 groups of children with prenatal pandemic exposure and/or exposure to maternal SARS-CoV-2 infection, neither exposure was associated with greater M-CHAT-R positivity.

Ultrasound Induces Similar Temporal Endothelial Expression Patterns of eNOS and KLF2 as Normal Flow.

OBJECTIVE: To determine the sensitivity of vascular endothelial cells to long durations of low-intensity pulsed ultrasound (LIPUS) compared to normal flow and identify the duration that maximizes expression of two mechanosensitive genes related to healthy endothelial function, endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 2 (KLF2). METHODS: Custom ultrasound exposure tanks were developed and the acoustic field was characterized. Human umbilical vein endothelial cells were seeded into culture plates and exposed to LIPUS at a frequency of 1 MHz and acoustic pressure of 217 kPa for 20 min, 1 h, 6 h, 9 h, or 24 h. As a comparator, other cells were exposed to normal flow. RT-qPCR was used to assess mRNA expression of eNOS and KLF2. RESULTS: Maximum eNOS and KLF2 expression occurred at 6 h and was localized to the beam path. Both genes exhibited qualitatively similar patterns of expression under LIPUS compared to normal flow. LIPUS induced a more rapid beneficial response compared to normal flow, but flow induced higher expression of both genes. eNOS expression after 6 h of LIPUS was dependent on RNA yield and culture duration prior to experiments. CONCLUSION: Endothelial cells exposed to longer durations of LIPUS than typically employed exhibited greater expression of beneficial genes. The temporal gene expression patterns resulting from LIPUS and normal flow suggest activation of similar signaling pathways. However, LIPUS also caused increased RNA yield that may be linked to proliferation, which would suggest more of a wound healing than atheroprotective phenotype.

Concurrent Varicella-Zoster Virus Reactivation and Recurrent Herpes Simplex Virus Infection in the C2 Dermatome With Varicella-Zoster Virus Encephalitis: A Case Report and Review of the Literature.

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are common viruses that are present in the general population. However, it is uncommon for both viruses to coincide at the same time and location. These viruses infect the nervous system to establish latency and have been associated with neurological disorders. We discuss a case of co-occurring VZV reactivation and recurrent HSV infection with subsequent VZV encephalitis following an insult to the neurologic system.

Feedstock variability impacts the bioconversion of sugar and lignin streams derived from corn stover by Clostridium tyrobutyricum and engineered Pseudomonas putida.

Feedstock variability represents a challenge in lignocellulosic biorefineries, as it can influence both lignocellulose deconstruction and microbial conversion processes for biofuels and biochemicals production. The impact of feedstock variability on microbial performance remains underexplored, and predictive tools for microbial behaviour are needed to mitigate risks in biorefinery scale-up. Here, twelve batches of corn stover were deconstructed via deacetylation, mechanical refining, and enzymatic hydrolysis to generate lignin-rich and sugar streams. These batches and their derived streams were characterised to identify their chemical components, and the streams were used as substrates for producing muconate and butyrate by engineered Pseudomonas putida and wildtype Clostridium tyrobutyricum, respectively. Bacterial performance (growth, product titers, yields, and productivities) differed among the batches, but no strong correlations were identified between feedstock composition and performance. To provide metabolic insights into the origin of these differences, we evaluated the effect of twenty-three isolated chemical components on these microbes, including three components in relevant bioprocess settings in bioreactors, and we found that growth-inhibitory concentrations were outside the ranges observed in the streams. Overall, this study generates a foundational dataset on P. putida and C. tyrobutyricum performance to enable future predictive models and underscores their resilience in effectively converting fluctuating lignocellulose-derived streams into bioproducts.

A descriptive review on the real-world impact of Moderna, inc. COVID-19 vaccines.

INTRODUCTION: Since the original COVID-19 vaccines were developed, abundant clinical trial and real-world evidence evaluating the efficacy, effectiveness, and safety of COVID-19 vaccines has been collected. Knowledge of the relative benefits and risks of COVID-19 vaccines is essential for building trust within target populations, ensuring they remain effectively and safely protected against an enduring infectious threat. AREAS COVERED: This descriptive review discusses the benefits and risks associated with marketed Moderna, Inc. mRNA-based COVID-19 vaccines, focusing on their real-world effectiveness and safety profiles in various age groups. Adverse events of interest and potential benefits of vaccination are reviewed, including reduced risk for severe COVID-19 and long-term health outcomes, reduced economic and societal costs, and reduced risk for SARS-CoV-2 transmission. EXPERT OPINION: Post-marketing safety and real-world data for Moderna, Inc. COVID-19 mRNA vaccines strongly support a positive benefit - risk profile favoring vaccination across all age groups. Although COVID-19 is no longer considered a global health pandemic, health risks associated with SARS-CoV-2 infection remain high. Concerted efforts are required to engage communities and maintain protection through vaccination. Continued surveillance of emerging variants and monitoring of vaccine safety and effectiveness are crucial for ensuring sustained protection against SARS-CoV-2.

Staphylococcus aureus lipid factors modulate melanoma cell clustering and invasion.

The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.

ICU outcomes following a Central Line Associated Blood Stream Infections (CLABSI) reduction quality improvement project.

BACKGROUND: Central Line Associated Blood Stream Infections (CLABSI) are significant complications for hospitalized patients. Several different approaches have been used to reduce CLABSI. OBJECTIVE: This study aimed to (1) describe a systematic approach used to analyze and reduce CLABSI rates in a surgical ICU (SICU) at a quaternary care medical facility (CLABSI reduction bundle) and (2) examine the association of the bundle on CLABSI rates in the SICU, compared to six unexposed health system ICUs. METHODS: Retrospective analysis of 14,022 adult patients with > 0 central line days within a single health system in the southeastern United States. The CLABSI intervention bundle was created and implemented in July 2021. Single and multiple interrupted time series analyses were performed to assess the impact of the CLABSI bundle on CLABSI rate in SICU (compared to control ICUs) pre- and post-intervention. Secondary analyses examined the association of the bundle with ICU mortality and length of stay. RESULTS: The CLABSI bundle was associated with a significant immediate effect in reducing the CLABSI rate in the SICU compared with control ICUs. There was no significant change in the slope of CLABSI rate post-intervention, compared to control ICUs. There was no significant association of the CLABSI reduction bundle on ICU length of stay or mortality in the SICU. CONCLUSION: The CLABSI bundle was associated with an immediate reduction in CLABSI incidence in the SICU compared to unexposed ICUs. A simple, bundled intervention can be effective in reducing CLABSI incidence in a surgical ICU population.

When in the intensive care unit (ICU), many patients have different lines, drains, catheters, and other devices inserted into the body to help care for them. Each device has a risk of getting infected and can make a patient's hospital stay more complicated, longer, and require more intense treatments. One ICU at our health system performed a long-term quality improvement intervention to reduce and prevent these kinds of infections. Over the course of 4­6 months, multiple changes to daily patient care related to central lines were implemented. Our study examined the effects of this QI intervention. Using data from our ICU database, we determined that these changes decreased the number infections immediately after implementing them, but not over the long term. They also did not impact how long patients stayed in the hospital nor their risk of dying (mortality). These new protocols offer a way to reduce infections, and more work needs to be done to continue reducing them for patients in the ICU.

Association of chronic opioid therapy and opioid use disorder with COVID-19-related hospitalization and mortality: Evidence from three health systems in the United States.

Objective: Chronic opioid use can lead to detrimental effects on the immune and various organ systems that put individuals prescribed chronic opioid therapy (COT) for pain and those with an opioid use disorder (OUD) at risk for severe COVID-19 disease. We assessed the association of COT and OUD with COVID-19-related hospitalization and death to inform targeted interventions to improve clinical outcomes in COVID-19 patients who use opioids. Methods: We conducted a retrospective cohort study of adults ages ≥ 18 with laboratory-confirmed SARS-CoV-2 infection in 2020 and 2021 from three US health systems. We used Cox proportional hazards regression to estimate the 30-day risk of COVID-19-related hospitalization and death associated with two opioid exposures (COT and OUD) following an infection. Results: The study cohort included 53,123 patients with SARS-CoV-2 infection and a mean (SD) age of 45.1 (16.5), of whom 1,059 (2.0 %) were exposed to COT and 269 (0.5 %) had an OUD diagnosis in the year prior to infection. There were 2,270 observed COVID-19-related hospitalizations or deaths (1.6 per 1,000 person-days, 95 % CI 1.5-1.7). In the fully adjusted model, COT was not associated with increased risk (HR 1.19; 95 % CI, 0.98-1.43), while past-year OUD was independently associated with severe COVID-19 disease (HR 1.82; 95 % CI, 1.18-2.80). Past-year OUD remained associated with increased risk in post-hoc analysis with COVID-19-related hospitalization alone as the outcome (HR 2.00; 95 % CI, 1.30-3.08). Conclusions: Past-year OUD is a potential independent risk factor for severe COVID-19 disease that warrants monitoring to improve the prognosis of patients with COVID-19.

Structural and Functional Characterization of a Novel Class A Flavin Monooxygenase from Bacillus niacini.

A gene cluster responsible for the degradation of nicotinic acid (NA) in Bacillus niacini has recently been identified, and the structures and functions of the resulting enzymes are currently being evaluated to establish pathway intermediates. One of the genes within this cluster encodes a flavin monooxygenase (BnFMO) that is hypothesized to catalyze a hydroxylation reaction. Kinetic analyses of the recombinantly purified BnFMO suggest that this enzyme catalyzes the hydroxylation of 2,6-dihydroxynicotinic acid (2,6-DHNA) or 2,6-dihydroxypyridine (2,6-DHP), which is formed spontaneously by the decarboxylation of 2,6-DHNA. To understand the details of this hydroxylation reaction, we determined the structure of BnFMO using a multimodel approach combining protein X-ray crystallography and cryo-electron microscopy (cryo-EM). A liganded BnFMO cryo-EM structure was obtained in the presence of 2,6-DHP, allowing us to make predictions about potential catalytic residues. The structural data demonstrate that BnFMO is trimeric, which is unusual for Class A flavin monooxygenases. In both the electron density and coulomb potential maps, a region at the trimeric interface was observed that was consistent with and modeled as lipid molecules. High-resolution mass spectral analysis suggests that there is a mixture of phosphatidylethanolamine and phosphatidylglycerol lipids present. Together, these data provide insights into the molecular details of the central hydroxylation reaction unique to the aerobic degradation of NA in Bacillus niacini.

Variants in the Late Cornified Envelope Gene Locus Are Associated With Elevated T-helper 17 Responses in Patients With Postinfectious Lyme Arthritis.

BACKGROUND: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome. METHODS: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA. RESULTS: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints. CONCLUSIONS: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.

Associations of Infant Sleep Characteristics with Childhood Cognitive Outcomes.

OBJECTIVE: The objective of this study was to quantify associations of infant 24-hour sleep duration and nighttime sleep consolidation with later child cognition. METHODS: This study included children from Project Viva, a prospective cohort in Massachusetts with (1) sleep measures in infancy (median age 6.4 months) and (2) child cognition in early childhood (median age 3.2 years) or mid-childhood (median age 7.7 years). Main exposures were parental reports of infant 24-hour sleep duration and nighttime sleep consolidation (% of total daily sleep occurring at nighttime). Cognitive outcomes were (1) early childhood vocabulary and visual-motor abilities and (2) mid-childhood verbal and nonverbal intelligence quotient (IQ), memory, and visual-motor abilities. We examined associations of infant sleep with childhood cognition using linear regression models adjusted for child sex, age, and race or ethnicity; maternal age, education, and parity; and household income. RESULTS: Early and mid-childhood analyses included 1102 and 969 children, respectively. Most mothers reported infant race or ethnicity as White (69%) and were college graduates (71%). The mean infant 24-hour sleep duration was 12.2 ± 2.0 hours, and the mean nighttime sleep consolidation was 76.8% ± 8.8%. Infant 24-hour sleep duration was not associated with any early or mid-childhood outcomes. Higher infant nighttime sleep consolidation was associated with higher mid-childhood verbal intelligence (ß: 0.12 points per % nighttime sleep; 95% CI, 0.01-0.22), but not with any early childhood cognitive measures. CONCLUSION: In this cohort, higher infant nighttime sleep consolidation was associated with higher verbal IQ in mid-childhood. Future studies should investigate causal relationships of infant sleep consolidation with child cognition among diverse populations.

Linear Hypopigmentation Following Subcutaneous Steroid Injection.

A 78-year-old woman presented to the dermatologist with linear hypopigmentation four weeks after a local corticosteroid injection. Corticosteroid injections are commonly used for various musculoskeletal conditions refractory to other conventional treatments. We discuss a case report of a patient with linear hypopigmentation in the perilymphatic distribution due to local corticosteroid injection for the treatment of carpal tunnel syndrome (CTS). Providers who routinely inject corticosteroids should discuss this rare complication prior to injections.

Osteochondroma-like parosteal osteosarcoma: A case highlighting diagnostic challenge and surgical advances.

Parosteal osteosarcomas are uncommon malignant bone tumors that arise from the bone surface. Their heterogenous components can present challenges in diagnosis. We present a case of a rare variant of this tumor known as an osteochondroma-like parosteal osteosarcoma, which was initially misdiagnosed as a cartilaginous tumor on core needle biopsy. Surgical resection of the tumor ultimately allowed for definitive diagnosis. Our case demonstrates the limitations of needle biopsy in diagnosing variants of parosteal osteosarcoma and the vital role of multidisciplinary discussions in guiding diagnosis and treatment. Furthermore, our case utilizes 3-dimensional printing technology in the surgical treatment, and illustrates the recent advances in patient-specific surgical techniques.

A clinical comparison of glycol and water-based heater-cooler systems for cardiopulmonary bypass.

INTRODUCTION: While newer heater-cooler technologies using ethylene glycol-based (GB) solutions during cardiothoracic surgery have become commercially available, there is a paucity of clinical data describing their effectiveness during cardiopulmonary bypass (CPB) support. This analysis aimed to compare clinical characteristics and procedural outcomes using water-based (WB) and GB heater-cooler systems. METHODS: A retrospective analysis was performed on consecutive adult patients undergoing CPB from June to October 2022 comparing WB or GB groups. The primary outcome was a composite of operative death or major morbidity. Secondary endpoints included transfusion requirements on CPB, patient cooling and warming rates, and vasoactive-inotropic scores (VIS) at case completion. P-control charts were used to monitor the weekly incidence of the composite outcome. A sub-analysis was performed to evaluate the primary outcome for cardiac surgery cases indexed by the Society of Thoracic Surgeons (STS). RESULTS: There were 167 patients included for analysis; 87 (52.1%) underwent CPB with a WB system and 80 (47.9%) with a GB system. GB procedure subjects were younger (p = .01), experienced longer CPB times (p = .034), and were more likely to receive thoracic transplant or aortic surgery (p = 0.015). The composite outcome of operative mortality or major morbidity occurred in 29.9% and 24% of the WB and GB groups, respectively (p = .372). P-control charts indicated a weekly mean incidence of 30% during WB practice, which decreased to 24% with GB practice. Among 106 STS-indexed cardiac surgery cases, mean composite outcome incidence decreased from 19% to 6% following our GB transition. Additionally, cooling, and warming rates indexed to patient BSA and VIS at case completion were not significantly different. CONCLUSION: Our analysis demonstrated a safe transition from WB to GB heater-cooler technologies in our practice. This early analysis suggests that GB heater coolers may be safely adopted to mitigate the risks of nontuberculous mycobacterium infections for cardiac surgical patients.

Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.

Neutrophils, the most abundant leukocytes in human peripheral circulation, are crucial for the innate immune response. They are typically quiescent but rapidly activate in response to infection and inflammation, performing diverse functions such as oxidative burst, phagocytosis, and NETosis, which require significant metabolic adaptation. Deeper insights into such metabolic changes will help identify regulation of neutrophil functions in health and diseases. Due to their short lifespan and associated technical challenges, the metabolic processes of neutrophils are not completely understood. This study uses optical metabolic imaging (OMI), which entails optical redox ratio and fluorescence lifetime imaging microscopy of intrinsic metabolic coenzymes NAD(P)H and FAD to assess the metabolic state of single neutrophils. Primary human neutrophils were imaged in vitro under a variety of activation conditions and metabolic pathway inhibitors, while metabolic and functional changes were confirmed with mass spectrometry, oxidative burst, and NETosis measurements. Our findings show that neutrophils undergo rapid metabolic remodeling to a reduced redox state, followed by a shift to an oxidized redox state during activation. Additionally, single cell analysis reveals a heterogeneous metabolic response across neutrophils and donors to live pathogen infection ( Pseudomonas aeruginosa and Toxoplasma gondii ). Finally, consistent metabolic changes were validated with neutrophils in vivo using zebrafish larvae. This study demonstrates the potential of OMI as a versatile tool for studying neutrophil metabolism and underscores its use across different biological systems, offering insights into neutrophil metabolic activity and function at a single cell level.

Visual imagery vividness correlates with afterimage conscious perception.

Afterimages are illusory, visual conscious perceptions. A widely accepted theory is that afterimages are caused by retinal signaling that continues after the physical disappearance of a light stimulus. However, afterimages have been reported without preceding visual, sensory stimulation (e.g. conditioned afterimages and afterimages induced by illusory vision). These observations suggest the role of top-down brain mechanisms in afterimage conscious perception. Therefore, some afterimages may share perceptual features with sensory-independent conscious perceptions (e.g. imagery, hallucinations, and dreams) that occur without bottom-up sensory input. In the current investigation, we tested for a link between the vividness of visual imagery and afterimage conscious perception. Participants reported their vividness of visual imagery and perceived sharpness, contrast, and duration of negative afterimages. The afterimage perceptual features were acquired using perception matching paradigms that were validated on image stimuli. Relating these perceptual reports revealed that the vividness of visual imagery positively correlated with afterimage contrast and sharpness. These behavioral results support shared neural mechanisms between visual imagery and afterimages. However, we cannot exclude alternative explanations, including demand characteristics and afterimage perception reporting inaccuracy. This study encourages future research combining neurophysiology recording methods and afterimage paradigms to directly examine the neural mechanisms of afterimage conscious perception.

Cross-validation of insurer and hospital price transparency data.

Given recent congressional interest in codifying price transparency regulations, it is important to understand the extent to which newly available price transparency data capture true underlying procedure-level prices. To that end, we compared the prices for maternity services negotiated between a large payer and 26 hospitals in Mississippi across 2 separate price transparency data sources: payer and hospital. The degree of file overlap is low, with only 16.3% of hospital-billing code observations appearing in both data sources. However, for the observations that overlap, pricing concordance is high: Corresponding prices have a correlation coefficient of 0.975, 77.4% match to the penny, and 84.4% are within 10%. Exact price matching rates are greater than 90% for 3 of the 4 service lines included in this study. Taken together, these results suggest that although administrative misalignment exists between payers and hospitals, there is a measure of signal amid the price transparency noise.

A Review of Linear Lichen Planus Case Reports.

ABSTRACT: Lichen linear planus is a rare variant of lichen planus that appears as pruritic, polygonal, purple papules in a blaschkoid distribution. This review critically assesses all reported cases of linear lichen planus (LLP) for proposed etiology, clinical and histologic traits, treatment options, and recurrence. A PubMed search from inception through March 2023, followed by article screening and full-text review, identified 51 unique cases of LLP. Data from each case including the sex of the patient, anatomic distribution of lesions, biopsy results, proposed etiology, treatment, and recurrence were recorded. LLP did not show a significant gender or age predilection, most frequently presented unilaterally with pruritus, and involved numerous anatomic regions. Various triggers including metal implants, vaccinations, infections, malignancy, and pregnancy were identified. The most common histopathologic descriptions included band-like lymphocytic or lichenoid infiltrate, basal liquefactive, vacuolar degeneration, hypergranulosis, hyperkeratosis, civatte or colloid bodies, melanin incontinence, and orthokeratosis. Treatment options, duration of treatment, and recurrence rate of LLP lesions were variable. Although LLP is rare, dermatologists should be aware of this presentation and appropriate diagnostic and treatment options because swift diagnosis can reduce patient morbidity.

Activation of ATF3 via the integrated stress response pathway regulates innate immune response to restrict Zika virus.

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated, and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using CRISPR-Cas9 system to delete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. We also determined that ATF3 enhances the expression of antiviral genes such as STAT1 and other components in the innate immunity pathway to induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between the integrated stress response and innate immune response pathways and highlights an important role for ATF3 in establishing an antiviral effect during ZIKV infection. IMPORTANCE: Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that co-opts cellular mechanisms to support viral processes that can reprogram the host transcriptional profile. Such viral-directed transcriptional changes and the pro- or anti-viral outcomes remain understudied. We previously showed that ATF3, a stress-induced transcription factor, is significantly upregulated in ZIKV-infected mammalian cells, along with other cellular and immune response genes. We now define the intracellular pathway responsible for ATF3 activation and elucidate the impact of ATF3 expression on ZIKV infection. We show that during ZIKV infection, the integrated stress response pathway stimulates ATF3 which enhances the innate immune response to antagonize ZIKV infection. This study establishes a link between viral-induced stress response and transcriptional regulation of host defense pathways and thus expands our knowledge of virus-mediated transcriptional mechanisms and transcriptional control of interferon-stimulated genes during ZIKV infection.

Hypertension increases sympathetic neuron activity by enhancing intraganglionic cholinergic collateral connections.

Autonomic dysregulation, including sympathetic hyperactivity, is a common feature of hypertension (HT) and other cardiovascular diseases. The CNS plays a role in driving chronic sympathetic activation in disease, but several lines of evidence suggest that neuroplasticity in the periphery may also contribute. The potential contribution of postganglionic sympathetic neurons to sustained sympathetic hyperactivity is not well understood. We recently discovered that noradrenergic sympathetic neurons in the stellate ganglion (SG) have excitatory cholinergic collateral connections to other neurons within the ganglion. We hypothesize that remodelling of these neurons and increased cholinergic collateral transmission contributes to sustained sympathetic hyperactivity in cardiovascular diseases, including HT. To test that hypothesis, we examined the activity of sympathetic neurons in isolated SG under control conditions and after 1 week of HT induced by peripheral angiotensin II infusion, using whole-cell patch clamp recordings. Despite the absence of central inputs, we observed elevated spontaneous activity and synaptic transmission in sympathetic SG neurons from hypertensive mice that required generation of action potentials. Genetically disrupting cholinergic transmission in noradrenergic neurons decreased basal neuronal activity and prevented angiotensin II-mediated enhancement of activity. Similar changes in activity, driven by increased collateral transmission, were identified in cardiac projecting neurons and neurons projecting to brown adipose tissue. These changes were not driven by altered A-type K+ currents. This suggests that HT stimulates increased activity throughout the intraganglionic network of collateral connections, contributing to the sustained sympathetic hyperactivity characteristic in cardiovascular disease. KEY POINTS: Sympathetic neurons in ganglia isolated from angiotensin II-treated hypertensive mice are more active than neurons from control mice despite the absence of central activation. The enhanced activity is the result of a ganglionic network of cholinergic collaterals, rather than altered intrinsic excitability. Increased neuronal activity was observed in both cardiac neurons and brown adipose tissue-projecting neurons, which are not involved in cardiovascular homeostasis.