Showing papers by "University of Arkansas for Medical Sciences published in 2022"

The osteocyte as a signaling cell.

Abstract: Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells c...

Protein–protein and protein–lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation

Abstract: Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions. The BCL-2 family proteins function in protein-protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein-protein and protein-lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular α-helical proteins that participate in protein-protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein-protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein-protein interaction complexes of BCL-2 family proteins.

Telehealth Utilization During COVID-19 Among People with Diagnosed Mental Health Conditions

Abstract: Background:Despite the potential benefits and the demonstrated uptake throughout the coronavirus disease 2019 (COVID-19) pandemic, studies have found that telemental health is still underused. The objective of the study was to explore the associations between mental health diagnoses and telehealth utilization during the pandemic. Methods:The study utilized a cross-sectional survey among adult Arkansans (n = 754). Logistic regression was used to determine the association between a diagnosis of anxiety and/or depression and telehealth utilization. Results:Forty-two percent of respondents reported utilizing telehealth during the pandemic. Respondents with a diagnosis of anxiety and/or depression had three times greater odds of utilizing telehealth (odds ratio = 2.97) than those with no diagnoses. Discussion:Utilization of telehealth care during the COVID-19 pandemic was lower in our sample compared with other nationally representative surveys; however, utilization was higher among people with a diagnosis of anxiety and/or depression. Conclusions:The results indicate the need for outreach to increase telehealth utilization.

IgM+ and IgM– memory B cells represent heterogeneous populations capable of producing class-switched antibodies and germinal center B cells upon rechallenge with <i>P. yoelii</i>

Abstract: Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, aided by antigen-specific B-cell tetramers, MBC populations were evaluated to discern their phenotype and function in response to infection with a nonlethal strain of P. yoelii. Infection of mice with P. yoelii 17X resulted in 2 predominant MBC populations: somatically hypermutated isotype-switched (IgM- ) and IgM+ MBCs that coexpressed CD73 and CD80 that produced antigen-specific antibodies in response to secondary infection. Rechallenge experiments indicated that IgG-producing cells dominated the recall response over the induction of IgM-secreting cells, with both populations expanding with similar timing during the secondary response. Furthermore, using ZsGreen1 expression as a surrogate for activation-induced cytidine deaminase expression alongside CD73 and CD80 coexpression, ZsGreen1+ CD73+ CD80+ IgM+ , and IgM- MBCs gave rise to plasmablasts that secreted Ag-specific Abs after adoptive transfer and infection with P. yoelii. Moreover, ZsGreen1+ CD73+ CD80+ IgM+ and IgM- MBCs could differentiate into B cells with a germinal center phenotype after adoptive transfer. A third population of B cells (ZsGreen1- CD73- CD80- IgM- ) that is apparent after infection responded poorly to reactivation in vitro and in vivo, indicating that these cells do not represent a canonical population of MBCs. Together these data indicated that MBC function is not defined by immunoglobulin isotype, nor does coexpression of key surface markers limit the potential fate of MBCs after recall.

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8

Abstract: Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.

ED 90 of Intrathecal Chloroprocaine With Fentanyl for Prophylactic Cervical Cerclage: A Sequential Allocation Biased-Coin Design

Abstract: Chloroprocaine is a short-acting local anesthetic that has been used for spinal anesthesia in outpatient surgery. There is limited experience with spinal chloroprocaine for prophylactic cervical cerclage placement. We sought to determine the effective dose of intrathecal chloroprocaine for 90% of patients (ED90) undergoing prophylactic cervical cerclage placement. We hypothesized that the ED90 of intrathecal chloroprocaine when combined with 10-ug fentanyl would be between 33 and 54 mg.In this prospective 2-center double-blinded study, we enrolled women undergoing prophylactic cervical cerclage placement under combined spinal-epidural anesthesia. A predetermined dose of intrathecal 3% chloroprocaine with fentanyl 10 ug was administered. The initial dose was 45-mg intrathecal chloroprocaine. Subsequent dose adjustments were determined based on the response of the previous subject using an up-down sequential allocation with a biased-coin design. A dose was considered effective if at least a T12 block was achieved, and there was no requirement for epidural activation or intraoperative analgesic supplementation during the procedure. The primary outcome was the ED90 of intrathecal chloroprocaine with fentanyl 10 ug. Secondary outcomes included duration of surgery, anesthetic side effects, time to resolution of motor and sensory block, time to achieve recovery room discharge criteria, and patient satisfaction with anesthetic care. Isotonic regression was used to estimate the ED90.Forty-seven patients were enrolled into the study. Two patients were excluded (1 protocol violation and 1 failed block). In total, 45 patients completed the study. The estimated ED90 (95% confidence interval) for intrathecal chloroprocaine combined with fentanyl 10 ug was 49.5 mg (45.0-50.1 mg). The median (interquartile range [IQR]) duration of surgery was 15 (10-24) minutes. Resolution of the motor (Bromage 0) and sensory block took a median time of 60 (45-90) minutes and 90 (75-105) minutes, respectively. The median time to achieve recovery room discharge criteria was 150 (139-186) minutes. Satisfaction with anesthetic management was high in all patients. There were no reports of postdural puncture headache or transient neurological symptoms postoperatively.The ED90 of intrathecal chloroprocaine combined with fentanyl 10 ug was 49.5 mg. Intrathecal chloroprocaine was associated with rapid block recovery and high patient satisfaction, which makes it well suited for outpatient obstetric procedures.

IFN-γ Contributes to the Immune Mechanisms of Hypertension

Abstract: Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For over half a century, researchers have demonstrated that the immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that pro-inflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFNγ), in particular, as an important cytokine that modulates immune responses, has been recently identified as an critical regulator of blood pressure by several groups including us. In this review, we focus on exploring the role of IFNγ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFNγ in hypertension through global knockout studies and related downstream signaling pathways that IFNγ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.

Factors associated with telehealth use among adults in the United States: Findings from the 2020 National Health Interview Survey

Abstract: During the COVID-19 pandemic, health care shifted to virtual interactions with health professionals. The aim of this study was to examine the determinants of telehealth use in a nationally representative sample of the United States adult population.The study used data from the 2020 National Health Interview Survey of 17,582 respondents aged ≥18. Andersen's model of health services utilization was employed to examine predisposing, enabling, and needs factors associated with past-year telehealth use. Multivariable logistic regression was conducted to examine statistical associations.32.5% of adults (n = 6402; mean age 51.6, SE = 0.4) reported telehealth use. Predisposing factors: Women and married/partnered adults and those with higher levels of education had greater odds of using telehealth. Adults living in Midwest and South and adults living in medium-small and non-metropolitan areas had decreased odds of using telehealth. Enabling factors: Income and having a usual source of care were positively associated with telehealth use. A negative association was found for those with no insurance and telehealth use, whereas a positive association was found for military insurance. Needs factors: Odds of using telehealth were increased for adults who had well-visits and ER visits in the past 12 months. Mental health services quadrupled the odds of telehealth use. Odds of using telehealth increased with each additional chronic disease, including COVID-19.There are disparities in telehealth use according to sex, education, rurality, access to care, and health needs. Tackling these disparities is pivotal to ensure barriers to telehealth use are not exacerbated post-pandemic.

Endocannabinoid system and cannabis hyperemesis syndrome: a narrative update.

Abstract: Cannabis use has been increasing in the United States and throughout the world. It is derived from one of the earliest plants cultivated by humans - Cannabis sativa. Cannabis (also called marijuana) is the most commonly used psychoactive substance worldwide. The cannabis plant has more than 400 chemicals, of which more than 100 cannabinoids (such as cannabigerol, cannabidiol, and cannabinol) have been identified. The endocannabinoid system (ECS) plays an essential role in the effects of cannabis on end organs. Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed as cannabis hyperemesis syndrome (CHS), were noted recently. The legal status of cannabis in the United States has been rapidly changing from state to state. The incidence of CHS is expected to rise with rising access to cannabis in the United States. Furthermore, CHS is frequently underdiagnosed due to a lack of uniform criteria, subjective nature of symptoms, and overlap with cyclical vomiting syndrome (CVS). Understanding the ECS and its role in biphasic response (proemetic and antiemetic) of CHS is critical to explain its pathophysiology. As the use of cannabis increases globally, awareness of CHS is warranted for early recognition and prompt treatment to avoid complications. We describe the putative mechanism of CHS with an overview of the clinical features in these patients. Furthermore, we highlight the differences between CHS and CVS with important differentials to consider. We provide a narrative update on the current evidence on CHS pathophysiology, diagnosis, treatment, and identifying research gaps.

Current and Future Methodology for Quantitation and Site-Specific Mapping the Location of DNA Adducts

Abstract: Formation of DNA adducts is a key event for a genotoxic mode of action, and their presence is often used as a surrogate for mutation and increased cancer risk. Interest in DNA adducts are twofold: first, to demonstrate exposure, and second, to link DNA adduct location to subsequent mutations or altered gene regulation. Methods have been established to quantitate DNA adducts with high chemical specificity and to visualize the location of DNA adducts, and elegant bio-analytical methods have been devised utilizing enzymes, various chemistries, and molecular biology methods. Traditionally, these highly specific methods cannot be combined, and the results are incomparable. Initially developed for single-molecule DNA sequencing, nanopore-type technologies are expected to enable simultaneous quantitation and location of DNA adducts across the genome. Herein, we briefly summarize the current methodologies for state-of-the-art quantitation of DNA adduct levels and mapping of DNA adducts and describe novel single-molecule DNA sequencing technologies to achieve both measures. Emerging technologies are expected to soon provide a comprehensive picture of the exposome and identify gene regions susceptible to DNA adduct formation.

Do racial and ethnic disparities lead to the undertreatment of pain? Are there solutions?

Abstract: Purpose of review The current review aims to empower anesthesiologists, specifically pain medicine specialists, to become leaders in ensuring equitable care. Recent findings Disparities in both acute and chronic pain medicine lead to increased morbidity for patients of color. Gaps in care include misdiagnosis or under diagnosis of chronic pain disease states, undertreatment of sickle cell disease and other conditions that are common in minorities, under prescription of opioids, and lack of access to novel opioid sparing treatments. While the causes of these disparities are multifactorial, care team implicit bias and lack of representation are two of the major factors. Solutions are challenging, but the authors suggest an inside out solution. We believe that this practice will have far-reaching downstream effects, including improving diversity in our field and quality of care for our patients. Summary The current article reviews disparities in both acute and chronic pain treatment for underrepresented racial and ethnic minorities in the United States. The authors examine whether implicit bias and lack of representation are a contributing factor for these disparities. Lastly, we will discuss potential solutions.

Myoglobin Interaction with Lactate Rapidly Releases Oxygen: Studies on Binding Thermodynamics, Spectroscopy, and Oxygen Kinetics

Abstract: Myoglobin (Mb)-mediated oxygen (O2) delivery and dissolved O2 in the cytosol are two major sources that support oxidative phosphorylation. During intense exercise, lactate (LAC) production is elevated in skeletal muscles as a consequence of insufficient intracellular O2 supply. The latter results in diminished mitochondrial oxidative metabolism and an increased reliance on nonoxidative pathways to generate ATP. Whether or not metabolites from these pathways impact Mb-O2 associations remains to be established. In the present study, we employed isothermal titration calorimetry, O2 kinetic studies, and UV-Vis spectroscopy to evaluate the LAC affinity toward Mb (oxy- and deoxy-Mb) and the effect of LAC on O2 release from oxy-Mb in varying pH conditions (pH 6.0–7.0). Our results show that LAC avidly binds to both oxy- and deoxy-Mb (only at acidic pH for the latter). Similarly, in the presence of LAC, increased release of O2 from oxy-Mb was detected. This suggests that with LAC binding to Mb, the structural conformation of the protein (near the heme center) might be altered, which concomitantly triggers the release of O2. Taken together, these novel findings support a mechanism where LAC acts as a regulator of O2 management in Mb-rich tissues and/or influences the putative signaling roles for oxy- and deoxy-Mb, especially under conditions of LAC accumulation and lactic acidosis.

CReSIL: accurate identification of extrachromosomal circular DNA from long-read sequences

Abstract: Abstract Extrachromosomal circular DNA (eccDNA) of chromosomal origin is found in many eukaryotic species and cell types, including cancer, where eccDNAs with oncogenes drive tumorigenesis. Most studies of eccDNA employ short-read sequencing for their identification. However, short-read sequencing cannot resolve the complexity of genomic repeats, which can lead to missing eccDNA products. Long-read sequencing technologies provide an alternative to constructing complete eccDNA maps. We present a software suite, Construction-based Rolling-circle-amplification for eccDNA Sequence Identification and Location (CReSIL), to identify and characterize eccDNA from long-read sequences. CReSIL’s performance in identifying eccDNA, with a minimum F1 score of 0.98, is superior to the other bioinformatic tools based on simulated data. CReSIL provides many useful features for genomic annotation, which can be used to infer eccDNA function and Circos visualization for eccDNA architecture investigation. We demonstrated CReSIL’s capability in several long-read sequencing datasets, including datasets enriched for eccDNA and whole genome datasets from cells containing large eccDNA products. In conclusion, the CReSIL suite software is a versatile tool for investigating complex and simple eccDNA in eukaryotic cells.

Readability, quality, and timeliness of patient online health resources for urticaria

Abstract: To the Editor: Urticaria is a common dermatosis that can negatively impact a patient's psychological and physical health, with an increased economic burden.1O'Donnell B.F. Urticaria: impact on quality of life and economic cost.Immunol Allergy Clin North Am. 2014; 34: 89-104Google Scholar As patients increasingly use the internet to obtain health information, dermatologists should be aware of the quality and readability of urticaria-related online content.2Tan S.S. Goonawardene N. Internet health information seeking and the patient-physician relationship: a systematic review.J Med Internet Res. 2017; 19: e9Google Scholar Herein, we evaluate the readability, quality, and timeliness of online educational content on urticaria.A Google search was conducted on January 6, 2021, using the terms “urticaria,” “hives,” “wheals,” and “welts,” and the first 30 terms were evaluated. Duplicate results, advertisements, scientific articles, and resources intended for professionals, and noncomprehensive websites were excluded (Fig 1). The text from each website was run through 6 well-established and validated readability scales (Flesch reading ease, Flesch-Kincaid grade level, Gunning-Fog index, SMOG index, Coleman-Liau index, and automated readability index). The quality was assessed using the Journal of American Medical Association benchmark criteria and Discern instrument. As a marker for timeliness, the websites were analyzed for the mention of omalizumab, which was approved by the United States Food and Drug Administration for the treatment of chronic idiopathic urticaria in 2014 (Fig 1).3U.S. Food and Drug AdministrationXolair.https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pdfDate accessed: February 21, 2021Google ScholarA total of 120 websites were reviewed, and 35 met the inclusion criteria. The readability analysis showed that 1 website (Seattle Children's) met the American Medical Association's recommended sixth-grade reading level at 6.2.4Weiss B. Health Literacy and Patient Safety: Help Patients Understand.2nd ed. American Medical Association Foundation and American Medical Association, 2007Google Scholar The average readability across the websites was at the 11th-grade level (10.9, range 6.2-16.2). Medscape (14.2) and National Health Service Inform (16.2) required a university-level (≥13) reading comprehension ability. The average Discern score was 40, which is characterized as fair, with a wide range from 18.5 to 57.5. The websites with the highest quality based on the Discern instrument were Medscape (57.5), UpToDate (54), and DermNet New Zealand (54). Over half (22/35, 63%) of the websites were classified as poor or very poor quality. The average Journal of American Medical Association benchmark criteria met was 1.6 out of 4, with only 2 websites, Kids Health for Nemours and Medscape, achieving the full 4 points. Authorship was disclosed on only a third (13/35, 37%) of the websites. The date of publication or revision was unspecified on 10/35 (29%) websites. There were 11/25 (44%) websites written/modified in 2020 or later. Omalizumab was mentioned in 13/35 (37%) of the articles (Table I).Table IMost searched urticaria educational website characteristics (n = 35)Website NameAverage Readability Grade LevelSeattle Children's6.2healthychildren.org7.5Nationwide Children's8.6AAD8.7Royal Children's Hospital9.2Mount Sinai9.5Cleveland Clinic9.7Healthline9.8Air Care9.9Asthma and Allergy Foundation of America10.0Medline Plus10.1AOCD10.2Kids Health for Nemours10.2Columbia Doctors10.3Penn Medicine10.6NEDA10.8Healthline10.8Mayo Clinic10.9DermNet New Zealand11.0WebMD11.0Medline Plus11.3New York University Langone11.4ACAAI11.5MeMD11.6Johns Hopkins Medicine11.6ACAAI11.7Riley Children's Health11.8Wikipedia12.2Skin sight12.2UpToDate12.4AAAAI12.4Medical News Today12.5Very Well Health12.7Medscape14.2NHS Inform16.2Website characteristicsNo. (%)Author name provided13 (37%)Author degree (n = 13): MD or PhD equivalent13 (100%) or 1 (8%)Author is a dermatologist8 (62%)Omalizumab mentioned13 (37%)Year written/modified was mentioned25 (71%)Written/modified in 2020 or later (n = 25)11 (44%)Overall website readability∗Measures variables, such as syllables, per word and sentence length.Mean ± SD (range)Flesch-Kincaid reading ease†The Flesch-Kincaid reading ease is scored between 0 and 100 for a given passage, with a higher score indicating that the article is easier to read. The other readability scales calculate the educational grade level, likely required to comprehend the text passage.50.1 ± 12.8 (21.4 to 78.7)Flesch-Kincaid grade level9.7 ± 3.7 (−8.1 to 16.5)Gunning-Fog score12.7 ± 2.7 (7.3 to 23.6)SMOG index9.6 ± 2.0 (6 to 17.8)Coleman-Liau index11.9 ± 1.9 (8 to 17)Automated readability index10.4 ± 2.7 (4.5 to 20.6)Average readability grade level‡The average readability grade level was calculated by averaging the Flesch-Kincaid grade level, Gunning-Fog score, SMOG index, Coleman-Liau index, and automated readability index scores.10.9 ± 1.8 (6.2 to 16.2)Overall website quality scoreMean ± SD (range)JAMA benchmark§Uses 4 criteria to evaluate website quality: authorship, attribution (eg, references), disclosure (eg, mention of potential conflicts of interest), and currency (eg, whether website is dated).1.6 ± 1.21 (0 to 4)Discern instrument‖Analyzes the reliability and overall quality of written health information through 15 objective measures; 16th question was omitted because of its subjective nature. Two reviewers independently reviewed the websites for the Discern scores; discrepancies within 2 points were averaged, and those >2 points were discussed and decided based on a consensus.38.3 ± 11.7 (19.5 to 61.5)Number of websites:Excellent (63-75)0Good (51-62)5Fair (39-50)8Poor (27-38)16Very poor (15-26)6AAD, American Academy of Dermatology; AOCD, American Osteopathic College of Dermatology; ACAAI, American College of Allergy, Asthma, Immunology; AAAAI, American Academy of Allergy, Asthma, Immunology; JAMA, Journal of American Medical Association; MD, Doctor of Medicine; NEDA, Northeast Dermatology Associates; NHS, National Health Service; PhD, Doctor of Philosophy; SMOG, Simple Measure of Gobbledygook; SD, standard deviation.∗ Measures variables, such as syllables, per word and sentence length.† The Flesch-Kincaid reading ease is scored between 0 and 100 for a given passage, with a higher score indicating that the article is easier to read. The other readability scales calculate the educational grade level, likely required to comprehend the text passage.‡ The average readability grade level was calculated by averaging the Flesch-Kincaid grade level, Gunning-Fog score, SMOG index, Coleman-Liau index, and automated readability index scores.§ Uses 4 criteria to evaluate website quality: authorship, attribution (eg, references), disclosure (eg, mention of potential conflicts of interest), and currency (eg, whether website is dated).‖ Analyzes the reliability and overall quality of written health information through 15 objective measures; 16th question was omitted because of its subjective nature. Two reviewers independently reviewed the websites for the Discern scores; discrepancies within 2 points were averaged, and those >2 points were discussed and decided based on a consensus. Open table in a new tab Our results highlight the overall need to increase the readability, quality, and timeliness of online information on urticaria. Only 1 website met the recommended sixth-grade reading level. Over half of the websites met the criteria for poor and very poor quality. Although websites such as Medscape demonstrate a high quality, they require a university-level comprehension, which is not suitable for all patients. Several readability studies investigating other dermatoses have demonstrated similar deficits and underscored the need for the global improvement of online health material.5Yee D. Modiri O. Shi V.Y. Hsiao J.L. Readability, quality, and timeliness of online health resources for rosacea.Int J Dermatol. 2021; 60: e90-e92Google Scholar With pipeline immunomodulators emerging, it is increasingly important for online health information to reflect new therapeutic options. Additionally, online resources are becoming a standard in patient care and are imperative for facilitating successful shared decision making between patients and physicians.2Tan S.S. Goonawardene N. Internet health information seeking and the patient-physician relationship: a systematic review.J Med Internet Res. 2017; 19: e9Google Scholar One limitation of the study was that the websites were not evaluated for content accuracy.An improvement in online urticaria resources is urgently needed. Dermatologists should take action to vet these websites to ensure that patients receive reliable health information. To the Editor: Urticaria is a common dermatosis that can negatively impact a patient's psychological and physical health, with an increased economic burden.1O'Donnell B.F. Urticaria: impact on quality of life and economic cost.Immunol Allergy Clin North Am. 2014; 34: 89-104Google Scholar As patients increasingly use the internet to obtain health information, dermatologists should be aware of the quality and readability of urticaria-related online content.2Tan S.S. Goonawardene N. Internet health information seeking and the patient-physician relationship: a systematic review.J Med Internet Res. 2017; 19: e9Google Scholar Herein, we evaluate the readability, quality, and timeliness of online educational content on urticaria. A Google search was conducted on January 6, 2021, using the terms “urticaria,” “hives,” “wheals,” and “welts,” and the first 30 terms were evaluated. Duplicate results, advertisements, scientific articles, and resources intended for professionals, and noncomprehensive websites were excluded (Fig 1). The text from each website was run through 6 well-established and validated readability scales (Flesch reading ease, Flesch-Kincaid grade level, Gunning-Fog index, SMOG index, Coleman-Liau index, and automated readability index). The quality was assessed using the Journal of American Medical Association benchmark criteria and Discern instrument. As a marker for timeliness, the websites were analyzed for the mention of omalizumab, which was approved by the United States Food and Drug Administration for the treatment of chronic idiopathic urticaria in 2014 (Fig 1).3U.S. Food and Drug AdministrationXolair.https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pdfDate accessed: February 21, 2021Google Scholar A total of 120 websites were reviewed, and 35 met the inclusion criteria. The readability analysis showed that 1 website (Seattle Children's) met the American Medical Association's recommended sixth-grade reading level at 6.2.4Weiss B. Health Literacy and Patient Safety: Help Patients Understand.2nd ed. American Medical Association Foundation and American Medical Association, 2007Google Scholar The average readability across the websites was at the 11th-grade level (10.9, range 6.2-16.2). Medscape (14.2) and National Health Service Inform (16.2) required a university-level (≥13) reading comprehension ability. The average Discern score was 40, which is characterized as fair, with a wide range from 18.5 to 57.5. The websites with the highest quality based on the Discern instrument were Medscape (57.5), UpToDate (54), and DermNet New Zealand (54). Over half (22/35, 63%) of the websites were classified as poor or very poor quality. The average Journal of American Medical Association benchmark criteria met was 1.6 out of 4, with only 2 websites, Kids Health for Nemours and Medscape, achieving the full 4 points. Authorship was disclosed on only a third (13/35, 37%) of the websites. The date of publication or revision was unspecified on 10/35 (29%) websites. There were 11/25 (44%) websites written/modified in 2020 or later. Omalizumab was mentioned in 13/35 (37%) of the articles (Table I). AAD, American Academy of Dermatology; AOCD, American Osteopathic College of Dermatology; ACAAI, American College of Allergy, Asthma, Immunology; AAAAI, American Academy of Allergy, Asthma, Immunology; JAMA, Journal of American Medical Association; MD, Doctor of Medicine; NEDA, Northeast Dermatology Associates; NHS, National Health Service; PhD, Doctor of Philosophy; SMOG, Simple Measure of Gobbledygook; SD, standard deviation. Our results highlight the overall need to increase the readability, quality, and timeliness of online information on urticaria. Only 1 website met the recommended sixth-grade reading level. Over half of the websites met the criteria for poor and very poor quality. Although websites such as Medscape demonstrate a high quality, they require a university-level comprehension, which is not suitable for all patients. Several readability studies investigating other dermatoses have demonstrated similar deficits and underscored the need for the global improvement of online health material.5Yee D. Modiri O. Shi V.Y. Hsiao J.L. Readability, quality, and timeliness of online health resources for rosacea.Int J Dermatol. 2021; 60: e90-e92Google Scholar With pipeline immunomodulators emerging, it is increasingly important for online health information to reflect new therapeutic options. Additionally, online resources are becoming a standard in patient care and are imperative for facilitating successful shared decision making between patients and physicians.2Tan S.S. Goonawardene N. Internet health information seeking and the patient-physician relationship: a systematic review.J Med Internet Res. 2017; 19: e9Google Scholar One limitation of the study was that the websites were not evaluated for content accuracy. An improvement in online urticaria resources is urgently needed. Dermatologists should take action to vet these websites to ensure that patients receive reliable health information. Dr. Shi is on the board of directors for the Hidradenitis Suppurativa Foundation (HSF), is a stock shareholder of Learn Health, and has served as an advisor, investigator, and/or speaker for Sanofi Genzyme, Regeneron, AbbVie, Burt's Bees, Dermira, Eli Lilly, Novartis, Pfizer, Galderma, Leo Pharma, SUN Pharma, Menlo Therapeutics, TARGET-DERM, Kiniksa, GpSkin, and Skin Actives Scientific. Dr. Hsiao has served as an advisor for Novartis. Dr. Yee and authors De and Seivright have no conflicts of interest to declare.

CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation

Abstract: Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.

Distinct type I collagen alterations cause intrinsic lung and respiratory defects of variable severity in mouse models of osteogenesis imperfecta

Abstract: Type I collagen alterations cause osteogenesis imperfecta (OI), a connective tissue disorder characterized by severe bone fragility. Patients with OI can suffer from significant pulmonary manifestations including severe respiratory distress in the neonatal period and a progressive decline in respiratory function in adulthood. We and others have shown intrinsic lung defects in some mouse models of OI. In this large study, we performed histological, histomorphometric, microcomputed tomography and invasive studies on oim/+, Col1a2+/G610C , CrtapKO and oim/oim mice, mimicking mild to moderate to severe OI, with the overall goal of determining the extent of their pulmonary and respiratory mechanics defects and whether these defects correlate with the skeletal disease severity and affect each sex equally. Although with variable severity, OI lung histology consistently showed alveolar simplification with enlarged acinar airspace and reduced alveolar surface. Numerous respiratory mechanics parameters, including respiratory system resistance and elastance, tissue damping, inspiratory capacity, total lung capacity, and others, were significantly and similarly impacted in CrtapKO and oim/oim but not in oim/+ or Col1a2+/G610C compared to control mice. Our data indicate that the impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Moreover, the respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI. KEY POINTS: Different type I collagen alterations in mouse models of osteogenesis imperfecta (OI) cause similar abnormal lung histology, with alveolar simplification and reduced alveolar surface, reminiscent of emphysema. Several respiratory mechanics parameters are altered in mouse models of OI. The impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI.

Pretreatment With Fluticasone Propionate Increases Antibiotic Efficacy During Treatment of Late-Stage Primary Pneumonic Plague

Abstract: Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death.