IsoVis - a webserver for visualization and annotation of alternative RNA isoforms.

Genes commonly express multiple RNA products (RNA isoforms), which differ in exonic content and can have different functions. Making sense of the plethora of known and novel RNA isoforms being identified by transcriptomic approaches requires a user-friendly way to visualize gene isoforms and how they differ in exonic content, expression levels and potential functions. Here we introduce IsoVis, a freely available webserver that accepts user-supplied transcriptomic data and visualizes the expressed isoforms in a clear, intuitive manner. IsoVis contains numerous features, including the ability to visualize all RNA isoforms of a gene and their expression levels; the annotation of known isoforms from external databases; mapping of protein domains and features to exons, allowing changes to protein sequence and function between isoforms to be established; and extensive species compatibility. Datasets visualised on IsoVis remain private to the user, allowing analysis of sensitive data. IsoVis visualisations can be downloaded to create publication-ready figures. The IsoVis webserver enables researchers to perform isoform analyses without requiring programming skills, is free to use, and available at https://isomix.org/isovis/.

Association between more complex special care needs and overweight status and adolescents' difficulty with dental caries.

OBJECTIVE: Little is known about dental caries experience in adolescents with overweight and complex special health care needs (SHCNs). METHODS: Adolescent data (10-17 years) from the 2016-2020 National Survey of Children's Health (n = 91,196) was analyzed. The sample was grouped into the following: more complex SHCN and overweight, more complex SHCN without overweight, less complex SHCN and overweight, less complex SHCN without overweight, no SHCN but with overweight, and neither SHCN nor overweight. A multivariable-adjusted logistic regression model was conducted. RESULTS: Adolescents with more complex SHCNs with (OR: 1.82, 95% CI: 1.44-2.30, p < 0.001) or without overweight (OR: 1.51, 95% CI: 1.30-1.76, p < 0.001) were at higher odds of experiencing dental caries compared to healthy adolescents. No significant associations were observed between adolescents with less complex or no SHCN regardless of the overweight status with healthy adolescents. CONCLUSIONS: Adolescents with more complex SHCNs, irrespective of overweight status, experienced a higher caries severity than adolescents with no SHCNs or overweight.

Stemformatics data portal enables transcriptional benchmarking of lab-derived myeloid cells.

Stemformatics.org has been serving the stem cell research community for over a decade, by making it easy for users to find and view transcriptional profiles of pluripotent and adult stem cells and their progeny, comparing data derived from multiple tissues and derivation methods. In recent years, Stemformatics has shifted its focus from curation to collation and integration of public data with shared phenotypes. It now hosts several integrated expression atlases based on human myeloid cells, which allow for easy cross-dataset comparisons and discovery of emerging cell subsets and activation properties. The atlases are designed for external users to benchmark their own data against a common reference. Here, we use case studies to illustrate how to find and explore previously published datasets of relevance and how in-vitro-derived cells can be transcriptionally matched to cells in the integrated atlas to highlight phenotypes of interest.

Effectiveness of mechanical and chemical decontamination methods for the treatment of dental implant surfaces affected by peri-implantitis: A systematic review and meta-analysis.

OBJECTIVE: To assess which decontamination method(s) used for the debridement of titanium surfaces (disks and dental implants) contaminated with bacterial, most efficiently eliminate bacterial biofilms. MATERIAL AND METHODS: A systematic search was conducted in four electronic databases between January 1, 2010 and October 31, 2022. The search strategy followed the PICOS format and included only in vitro studies completed on either dental implant or titanium disk samples. The assessed outcome variable consisted of the most effective method(s)-chemical or mechanical- removing bacterial biofilm from titanium surfaces. A meta-analysis was conducted, and data was summarized through single- and multi-level random effects model (p < .05). RESULTS: The initial search resulted in 5260 articles after the removal of duplicates. After assessment by title, abstract, and full-text review, a total of 13 articles met the inclusion criteria for this review. Different decontamination methods were assessed, including both mechanical and chemical, with the most common method across studies being chlorhexidine (CHX). Significant heterogeneity was noted across the included studies. The meta-analyses only identified a significant difference in biofilm reduction when CHX treatment was compared against PBS. The remaining comparisons did not identify significant differences between the various decontamination methods. CONCLUSIONS: The present results do not demonstrate that one method of decontamination is superior in eliminating bacterial biofilm from titanium disk and implant surfaces.

Risk Factors Associated with Postoperative CSF Leak in Extrasellar Tumors.

Objective While postoperative cerebrospinal fluid (CSF) leak rates of pituitary tumors have been frequently studied, there are fewer studies examining postoperative CSF leak rates for extrasellar tumors. The purpose of this study was to identify risk factors for the development of postoperative CSF leak in patients undergoing endoscopic surgery for extrasellar tumors. Methods A retrospective chart review was done for patients who underwent endoscopic resection for extrasellar tumors between 2008 and 2020. Age, gender, tumor type, tumor location, tumor size, reconstruction technique, medical comorbidities, and other potential risk factors were identified. Data was analyzed to identify significant risk factors for development of postoperative CSF leak. Results There were 100 patients with extrasellar tumors who developed intraoperative CSF leaks. Seventeen patients (17%) developed postoperative CSF leaks. Leaks occurred at a median of 2 days following surgery (range 0-34 days). Clival tumors had a significantly higher incidence of postoperative leak than those in other sites ( p < 0.05). There were no significant differences in other locations, body mass index, tumor size, reconstruction technique, medical comorbidities, or other factors. There were nearly twice as many intraoperative grade III leaks in those who developed postoperative CSF leak, but this was not statistically significant ( p = 0.12). Conclusion Extrasellar tumors, particularly clival tumors, have a higher rate of postoperative CSF leak than pituitary tumors. Prophylactic lumbar drains can be considered for patients at high risk for developing postoperative CSF leak.

An Overview of Current Statistical Methods for Implementing Quality Tolerance Limits.

BACKGROUND: In 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use updated its efficacy guideline for good clinical practice and introduced predefined quality tolerance limits (QTLs) as a quality control in clinical trials. QTLs are complementary to Quality by Design (QbD) principles (ICH-E8) and are one of the components of the risk-based clinical trial quality management system. METHODS: Currently the framework for QTLs process is well established, extensively describing the operational aspects of Defining, Monitoring and Reporting, but a single source of commonly used methods to establish QTLs and secondary limits is lacking. This paper will primarily focus on closing this gap and include applications of statistical process control and Bayesian methods on commonly used study level quality parameters such as premature treatment discontinuation, study discontinuation and significant protocol deviations as examples. CONCLUSIONS: Application of quality tolerance limits to parameters that correspond to critical to quality factors help identify systematic errors. Some situations pose special challenges to implementing QTLs and not all methods are optimal in every scenario. Early warning signals, in addition to QTL, are necessary to trigger actions to further minimize the possibility of an end-of-study excursion.

A national sample of developmentally disabled adolescents with obesity and their utilization of preventive dental care services.

Background: Previous literature indicates that adolescents with developmental disabilities and obesity may have more oral health complications than healthy adolescents. However, dental care utilization among adolescents with developmental disabilities (DDs) and obesity is unclear. We investigated the differences in the utilization of preventive dental services between this high-risk group of adolescents and those with no DDs or obesity. Methods: Parent-reported data of adolescents 10-17 years (n = 68,942) from the 2016 to 2019 National Survey of Children's Health was used. In addition to descriptive and bivariate statistics, we ran three multiple logistic regression models guided by Andersen's Behavioral Model of Health Services Use, predicting the use of dental cleanings, fluoride treatments, and dental sealants. Results: Among adolescents with DDs and obesity, dental cleanings, fluoride treatments, and dental sealant utilization prevalence were 76%, 48%, and 21%, respectively. In comparison, adolescents with no DDs or obesity had a prevalence of 83%, 50%, and 19%, respectively. Multiple logistic regression analysis showed that adolescents with DDs and obesity did not significantly differ in their receipt of dental cleanings (p = .07), fluoride treatments (p = .55), and dental sealants (p = .23) compared to those with neither DDs nor obesity. Adolescents with DDs but no obesity were 22% and 30% more likely to receive fluoride treatments (p < .0001) and dental sealants (p < .0001), respectively. Conclusions: Fewer than half of adolescents with DDs and obesity utilized fluoride treatments, and less than one quarter utilized dental sealants but used all three preventive services at the same rate as those with no DDs or obesity. Implications: This study identified no differences in preventive dental care services utilization in adolescents with developmental disabilities (DDs) and obesity compared to those without DDs and obesity. However, the utilization of preventive dental services in this population is influenced by the federal poverty level and family background.

The status of the human gene catalogue.

Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.

ISSCR standards for the use of human stem cells in basic research.

The laboratory culture of human stem cells seeks to capture a cellular state as an in vitro surrogate of a biological system. For the results and outputs from this research to be accurate, meaningful, and durable, standards that ensure reproducibility and reliability of the data should be applied. Although such standards have been previously proposed for repositories and distribution centers, no widely accepted best practices exist for laboratory research with human pluripotent and tissue stem cells. To fill that void, the International Society for Stem Cell Research has developed a set of recommendations, including reporting criteria, for scientists in basic research laboratories. These criteria are designed to be technically and financially feasible and, when implemented, enhance the reproducibility and rigor of stem cell research.

The status of the human gene catalogue.

Scientists have been trying to identify all of the genes in the human genome since the initial draft of the genome was published in 2001. Over the intervening years, much progress has been made in identifying protein-coding genes, and the estimated number has shrunk to fewer than 20,000, although the number of distinct protein-coding isoforms has expanded dramatically. The invention of high-throughput RNA sequencing and other technological breakthroughs have led to an explosion in the number of reported non-coding RNA genes, although most of them do not yet have any known function. A combination of recent advances offers a path forward to identifying these functions and towards eventually completing the human gene catalogue. However, much work remains to be done before we have a universal annotation standard that includes all medically significant genes, maintains their relationships with different reference genomes, and describes clinically relevant genetic variants.

Reported History of Measles and Long-term Impact on Tetanus Antibody Detected in Children 9-59 Months of Age and Receiving 3 Doses of Tetanus Vaccine in the Democratic Republic of the Congo.

BACKGROUND: Recent studies suggest measles-induced immune amnesia could have long-term immunosuppressive effects via preferential depletion of memory CD150+ lymphocytes, and associations with a 2-3 year period of increased mortality and morbidity from infectious diseases other than measles has been shown in children from wealthy and low-income countries. To further examine the associations previous measles virus infection may have on immunologic memory among children in the Democratic Republic of the Congo (DRC), we assessed tetanus antibody levels among fully vaccinated children, with and without a history of measles. METHODS: We assessed 711 children 9-59 months of age whose mothers were selected for interview in the 2013-2014 DRC Demographic and Health Survey. History of measles was obtained by maternal report and classification of children who had measles in the past was completed using maternal recall and measles IgG serostatus obtained from a multiplex chemiluminescent automated immunoassay dried blood spot analysis. Tetanus IgG antibody serostatus was similarly obtained. A logistic regression model was used to identify association of measles and other predictors with subprotective tetanus IgG antibody. RESULTS: Subprotective geometric mean concentration tetanus IgG antibody values were seen among fully vaccinated children 9-59 months of age, who had a history of measles. Controlling for potential confounding variables, children classified as measles cases were less likely to have seroprotective tetanus toxoid antibody (odds ratio: 0.21; 95% confidence interval: 0.08-0.55) compared with children who had not had measles. CONCLUSIONS: History of measles was associated with subprotective tetanus antibody among this sample of children in the DRC who were 9-59 months of age and fully vaccinated against tetanus.

Dental care utilization among developmentally disabled adolescents experiencing difficulty with decayed teeth: A population-level study.

AIMS: To determine if adolescents with developmental disabilities (DDs) who experienced difficulty with dental caries differed by dental visits in the past 12 months and receipt of preventive services (fluoride treatment and dental sealants) during those visits compared to adolescents with no DDs or difficulty with dental caries. METHODS AND RESULTS: A cross-sectional study was conducted using data of 91 196 adolescents aged 10-17 years from the 2016-2020 National Survey of Children's Health. Descriptive and bivariate statistics and multivariable regression models were conducted. We derived the odds ratio for visiting a dental office (OR: 0.76, 95% CI: 0.57-1.03, p = .07), receiving fluoride treatments (OR: 1.20, 95% CI: 1.01-1.43, p = .04), and dental sealants (OR: 1.44, 95% CI: 1.19-1.75, p < .001) for DD adolescents who experienced difficulty with dental caries compared to adolescents with no DDs or difficulty with dental caries. CONCLUSIONS: DD adolescents who experienced difficulty with dental caries were more likely to receive fluoride treatments and sealants during dental visits but were equally likely to have a dental visit in the past 12 months than adolescents with no DDs or difficulty with dental caries.

Clinical Predictors of Symptom Improvement Following Eustachian Tube Balloon Dilation.

OBJECTIVE: This study aims to identify clinical predictors of treatment response to Eustachian Tube Balloon Dilation (ETBD) as measured by changes in Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) scores. METHODS: One hundred thirteen patients who underwent ETBD at an institution from 2017 to 2021 completed ETDQ-7 pre- and post-operatively. We conducted multivariable regression analyses with ETDQ-7 normalization (<2.1 post-op), minimum clinically important difference (MCID) (>0.5 pre-op - post-op), and quantitative improvement in ETDQ-7 score as outcome variables. Pre-operative ETDQ-7 score, tympanogram type, chronic otitis media, chronic rhinosinusitis (CRS), inferior turbinate hypertrophy, deviated septum, allergic rhinitis, and rhinorrhea were included as covariates. Models controlled for age, sex, ethnicity, prior ear or sinus surgery, and follow-up duration. RESULTS: The mean age was 49 years old. 51% were females, and all patients had pre-operative ETDQ-7 above 2.1. After a mean follow-up period of 13 months, 77% achieved MCID and 37% had normalized. Higher pre-operative ETDQ-7 score was associated with greater ETDQ-7 score improvement (B = 0.60, 95% CI = [0.37, 0.83]) and greater odds of achieving MCID (aOR = 1.65; 95% CI = [1.06, 2.59]). A history of CRS improved chances of achieving MCID (aOR = 4.53; 95% CI = [1.11, 18.55]) and a history of chronic otitis media predicted increased odds of ETDQ-7 normalization (aOR = 2.88; 95% CI = [1.09, 7.58]). CONCLUSIONS: Our findings suggest that ETBD was highly effective among patients with pre-operative ETDQ-7 above 2.1. Furthermore, higher pre-operative ETDQ-7 score, CRS, and chronic otitis media predicted more favorable symptomatic benefit from ETBD. These factors may be important to consider when counseling potential candidates for this procedure.

Postoperative Gabapentin's Effect on Opioid Consumption and Pain Control Following Sinonasal Surgery.

OBJECTIVE: This study investigates the impact of postoperative gabapentin on opioid consumption and pain control following endoscopic sinus surgery (ESS) and/or septoplasty. METHODS: Patients who underwent ESS and/or septoplasty at a single institution from 2021 to 2022 were enrolled. All patients received postoperative hydrocodone-acetaminophen for pain control. Half of the patients were also prescribed gabapentin for the first postoperative day in addition to hydrocodone-acetaminophen. Subjects completed the Revised American Pain Society Patient Outcome Questionnaire 24 h and 7 days after surgery. We conducted a multivariable regression analysis to assess opioid consumption and improvement in pain scores in the first week between gabapentin and non-gabapentin groups. RESULTS: A total of 102 subjects, 51 in each arm, were enrolled. The mean age was 52 years and 53% of participants were female. Controlling for important baseline demographic, clinical, and surgically related variables, the addition of postoperative gabapentin was associated with a 44% (9.5 mg from 21.6 mg) reduction in opioids consumed in the first postoperative week (B = -9.54, 95% C.I. = [-17.84, -1.24], p = 0.025). In addition, patients in both arms exhibited similar improvement in pain severity and sleep interference in the first 7 days (B = -1.59, 95% C.I. = [-5.03, 1.84], p = 0.36). CONCLUSION: To the best of our knowledge, this is the first study to investigate the impact of postoperative gabapentin on opioid consumption and pain control following ESS and/or septoplasty. Our analysis demonstrated that postoperative gabapentin effectively reduced opioid use during the first postoperative week without compromising pain control. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1065-1072, 2023.

Predictors of Death, Survival, Need for Intubation, and Need for Oxygen Support Among Admitted COVID-19 Patients of the Veterans Affairs Greater Los Angeles Healthcare System.

INTRODUCTION: While risk factors for severe COVID-19 infections have been well explored among the public, population-specific studies for the U.S. Veteran community are limited in the literature. By performing a comprehensive analysis of the demographics, comorbidities, and symptomatology of a population of COVID-19 positive Veterans Affairs (VA) patients, we aim to uncover predictors of death, survival, need for intubation, and need for nasal cannula oxygen support among this understudied community. MATERIALS AND METHODS: A retrospective review was conducted of 124 COVID-19 Veteran patients who were admitted from March to October 2020 to the VA Greater Los Angeles Healthcare System (IRB#2020-000272). Chi-square and Fisher's exact tests were employed to assess differences in baseline demographic and clinical variables between Veterans who survived COVID-19 versus those who succumbed to COVID-19 illness. Multivariate logistic regression and Cox regression analyses were employed to assess predictors of outcome variables, including death, survival, need for intubation, and need for oxygen support (via nasal cannula). Covariates included a wide range of demographic, comorbidity-related, symptom-related, and summary index variables. RESULTS: Our study population consisted of primarily senior (average age was 73) Caucasian and African American (52.5% and 40.7%, respectively) Veterans. Bivariate analyses indicated that need for intubation was significantly associated with mortality (P = 0.002). Multivariate analyses revealed that age (P < 0.001, adjusted odds ratio (OR) = 1.16), dyspnea (P = 0.015, OR = 7.73), anorexia (P = 0.022, OR = 16.55), initial disease severity as classified by WHO (P = 0.031, OR = 4.55), and having more than one of the three most common comorbidities (hypertension, diabetes, and cardiac disease) and symptoms (cough, fever, and dyspnea) among our sample (P = 0.009; OR = 19.07) were independent predictors of death. Furthermore, age (P < 0.001, hazard ratio (HR) = 1.14), cerebrovascular disease (P = 0.022, HR = 3.76), dyspnea (P < 0.001, HR = 7.71), anorexia (P < 0.001, HR = 16.75), and initial disease severity as classified by WHO (P = 0.025, HR = 3.30) were independent predictors of poor survival. Finally, dyspnea reliably predicted need for intubation (P = 0.019; OR = 29.65). CONCLUSIONS: Several independent predictors of death, survival, and need for intubation were identified. These risk factors may provide guidelines for risk-stratifying Veterans upon admission to VA hospitals. Additional investigations of COVID-19 prognosis should be conducted on the larger U.S. Veteran population to confirm our findings and add to the current body of literature.

The Human Dendritic Cell Atlas: An Integrated Transcriptional Tool to Study Human Dendritic Cell Biology.

Dendritic cells (DCs) are functionally diverse and are present in most adult tissues, but deep understanding of human DC biology is hampered by relatively small numbers of these in circulation and their short lifespan in human tissues. We built a transcriptional atlas of human DCs by combining samples from 14 expression profiling studies derived from 10 laboratories. We identified significant gene expression variation of DC subset-defining markers across tissue type and upon viral or bacterial stimulation. We further highlight critical gaps between in vitro-derived DC subsets and their in vivo counterparts and provide evidence that monocytes or cord blood progenitor in vitro-differentiated DCs fail to capture the repertoire of primary DC subsets or behaviors. In constructing a reference DC atlas, we provide an important resource for the community wishing to identify and annotate tissue-specific DC subsets from single-cell datasets, or benchmark new in vitro models of DC biology.

Fluoride exposure and blood cell markers of inflammation in children and adolescents in the United States: NHANES, 2013-2016.

BACKGROUND: Ingestion of fluoride in drinking water has been shown to result in increased cellular markers of inflammation in rodent models. However, the approximately 5-10 × increase in water fluoride concentrations required in rat and mouse models to obtain plasma fluoride concentrations similar to those found in humans has made relevant comparisons of animal to human studies difficult to assess. As an increased white blood cell count (WBC) is a marker of inflammation in humans, we used available NHANES survey data to assess the associations between plasma fluoride levels in the U.S. and blood cell counts children and adolescents.   METHODS: Multiple linear regressions were done to determine the association of blood cell counts and plasma fluoride in publicly available NHANES survey data from the 2013-2014 and 2015-2016 cycles. Plasma fluoride concentration measurements were available only for children aged 6 to 19, inclusive, and therefore this subpopulation was used for all analyses. Covariate predictors along with plasma fluoride were age, ethnicity, gender, and Body Mass Index (BMI).  RESULTS: Plasma fluoride was significantly positively associated with water fluoride, total WBC count, segmented neutrophils, and monocytes, and negatively associated with red blood cell count when adjusted for age, gender and BMI. CONCLUSION: Our finding that neutrophils and monocytes are associated with higher plasma fluoride in U.S. children and adolescents is consistent with animal data showing fluoride related effects of increased inflammation. These findings suggest the importance of further studies to assess potential mechanisms that are involved in absorption and filtration of ingested fluoride, particularly in tissues and organs such as the small intestine, liver and kidney.

Hospital emergency department visits made by developmentally disabled adolescents with oral complications.

Purpose: We used Andersen's Behavioral Model in a cross-sectional study to determine the factors associated with utilization of the emergency department (ED), controlling for whether an adolescent has a developmental disability (DD) and one or more oral complications (toothaches, decayed teeth, bleeding gums, eating or swallowing problems). Methods: Data from the 2016-2019 National Survey of Children's Health (NSCH) was used for this secondary data analysis study. We used frequencies and percentages to describe the sample characteristics. Chi-square tests were used for bivariate analyses. Multivariable logistic regression modeling was conducted to predict ED visits by adolescents aged 10-17 controlling for predisposing, enabling, and need variables. Results: The sample consisted of 68,942 adolescents who were primarily male, non-Hispanic White, and born in the U.S. Parents reported that 69% of the adolescents had neither a DD nor an oral complication; 10% had no DD but experienced one or more oral complication; 16% had a DD but no oral complication; and 5% had both DDs and one or more oral complication. Adolescents with both a DD and an oral complication reported the highest level of ED visits at 33%, compared to 14% of adolescents with neither DD nor oral complication. Regression analysis showed that adolescents with a DD and oral complication (OR: 2.0, 95% CI: 1.64-2.54, p < 0.0001), and those with DDs but no oral complications (OR: 1.45, 95% CI: 1.25-1.68, p < 0.0001) were at higher odds of having an ED visit compared to those with neither a DD nor an oral complication. Not having a Medical Home increased the likelihood of ED visits by 14% (p = 0.02). Those with private insurance (OR: 0.63, 95% CI: 0.53-0.75, p < 0.0001) and those from a family where the highest level of education was some college and above (OR: 0.85, 95% CI: 0.73-0.98, p = 0.03) were less likely than their counterparts to have had an ED visit. Conclusion: Adolescents with DDs and oral complications utilize ED visits more frequently than those with neither DDs nor oral complications. Integrating the dental and medical health systems and incorporating concepts of a Patient-Centered Medical Home could improve overall health care and reduce ED visits for adolescents.