Long-Term Followup Comparing Two Treatment Dosing Strategies of 125

Objective. To investigate the efficacy of two different dosing strategies of radioactive iodine-125 (125I) in the management of small- and medium-sized posterior uveal melanoma. Patients and Methods. The medical records of consecutive patients with choroidal melanomas between 1.5 and 5.0 mm in apical height treated initially with 125I plaque radiotherapy were reviewed. Patients were treated with one of the following two treatment dosing strategies: (1) 85 Gy to the apical height of the tumor (group 1) or (2) 85 Gy to a prescription point of 5.0 mm (group 2). Results. Of 95 patients, 55 patients were treated to the apical height of the tumor, and 40 were treated to a prescription point of 5.0 mm. Comparative analysis of the incidence rates of specific complications between the two groups demonstrates that group 2 had a significantly higher incidence of radiation retinopathy, radiation optic neuropathy, and/or visually significant cataract formation than group 1 (). Conclusion. Treatment of choroidal melanomas less than 5 mm in apical height with 125I brachytherapy to the true apical height is equally effective when compared to treatment with 85 Gy to 5.0 mm. Treatment to the apical height of the tumor may result in lower incidence of radiation-related complications

Clinical Study Long-Term Followup Comparing Two Treatment Dosing Strategies of 125 I Plaque Radiotherapy in the Management of Small/Medium Posterior Uveal Melanoma

Objective. To investigate the efficacy of two different dosing strategies of radioactive iodine-125 ( 125 I) in the management of smalland medium-sized posterior uveal melanoma. Patients and Methods. The medical records of consecutive patients with choroidal melanomas between 1.5 and 5.0 mm in apical height treated initially with 125 I plaque radiotherapy were reviewed. Patients were treated with one of the following two treatment dosing strategies: (1) 85 Gy to the apical height of the tumor (group 1) or (2) 85 Gy to a prescription point of 5.0 mm (group 2). Results. Of 95 patients, 55 patients were treated to the apical height of the tumor, and 40 were treated to a prescription point of 5.0 mm. Comparative analysis of the incidence rates of specific complications between the two groups demonstrates that group 2 had a significantly higher incidence of radiation retinopathy, radiation optic neuropathy, and/or visually significant cataract formation than group 1 ( = 0.028). Conclusion. Treatment of choroidal melanomas less than 5 mm in apical height with 125 I brachytherapy to the true apical height is equally effective when compared to treatment with 85 Gy to 5.0 mm. Treatment to the apical height of the tumor may result in lower incidence of radiation-related complications

Development of a Consensus-Based Definition of Focused Assessment with Sonography for Trauma in Children

Importance: The wide variation in the accuracy and reliability of the Focused Assessment With Sonography for Trauma (FAST) and the extended FAST (E-FAST) for children after blunt abdominal trauma reflects user expertise. FAST and E-FAST that are performed by experts tend to be more complete, better quality, and more often clinically valuable. Objective: To develop definitions of a complete, high-quality, and accurate interpretation for the FAST and E-FAST in children with injury using an expert, consensus-based modified Delphi technique. Design, Setting, and Participants: This consensus-based qualitative study was conducted between May 1 to June 30, 2021. It used a scoping review and iterative Delphi technique and involved 2 rounds of online surveys and a live webinar to achieve consensus among a 26-member panel. This panel consisted of international experts in pediatric emergency point-of-care ultrasonography. Main Outcomes and Measures: Definitions of complete, high-quality, and accurate FAST and E-FAST studies for children after injury. Results: Of the 29 invited pediatric FAST experts, 26 (15 men [58%]) agreed to participate in the panel. All 26 panelists completed the 2 rounds of surveys, and 24 (92%) participated in the live and asynchronous online discussions. Consensus was reached on FAST and E-FAST study definitions, and the panelists rated these 5 anatomic views as important and appropriate for a complete FAST: right upper-quadrant abdominal view, left upper-quadrant abdominal view, suprapubic views (transverse and sagittal), and subxiphoid cardiac view. For E-FAST, the same FAST anatomic views with the addition of the lung or pneumothorax view were deemed appropriate and important. In addition, the panelists rated a total of 32 landmarks as important for assessing completeness. Similarly, the panelists rated 14 statements on quality and 20 statements on accurate interpretation as appropriate. Conclusions and Relevance: This qualitative study generated definitions for complete FAST and E-FAST studies with high image quality and accurate interpretation in children with injury. These definitions are similar to those in adults with injury and may be used for future education, quality assurance, and research. Future research may focus on interpretation of trace volumes of abdominal free fluid and the use of serial FAST

Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites

Motivation: Histone acetylation (HAc) is associated with open chromatin, and HAc has been shown to facilitate transcription factor (TF) binding in mammalian cells. In the innate immune system context, epigenetic studies strongly implicate HAc in the transcriptional response of activated macrophages. We hypothesized that using data from large-scale sequencing of a HAc chromatin immunoprecipitation assay (ChIP-Seq) would improve the performance of computational prediction of binding locations of TFs mediating the response to a signaling event, namely, macrophage activation

Alveolar Epithelial Type II Cells Activate Alveolar Macrophages and Mitigate P. Aeruginosa Infection

Although alveolar epithelial type II cells (AECII) perform substantial roles in the maintenance of alveolar integrity, the extent of their contributions to immune defense is poorly understood. Here, we demonstrate that AECII activates alveolar macrophages (AM) functions, such as phagocytosis using a conditioned medium from AECII infected by P. aeruginosa. AECII-derived chemokine MCP-1, a monocyte chemoattractant protein, was identified as a main factor in enhancing AM function. We proposed that the enhanced immune potency of AECII may play a critical role in alleviation of bacterial propagation and pneumonia. The ability of phagocytosis and superoxide release by AM was reduced by MCP-1 neutralizing antibodies. Furthermore, MCP-1−/− mice showed an increased bacterial burden under PAO1 and PAK infection vs. wt littermates. AM from MCP-1−/− mice also demonstrated less superoxide and impaired phagocytosis over the controls. In addition, AECII conditioned medium increased the host defense of airway in MCP-1−/− mice through the activation of AM function. Mechanistically, we found that Lyn mediated NFκB activation led to increased gene expression and secretion of MCP-1. Consequently Lyn−/− mice had reduced MCP-1 secretion and resulted in a decrease in superoxide and phagocytosis by AM. Collectively, our data indicate that AECII may serve as an immune booster for fighting bacterial infections, particularly in severe immunocompromised conditions

Revisiting Gender Differences in Somatic Symptoms of Depression: Much Ado about Nothing?

Women have a higher prevalence of Major Depressive Disorder (MDD) and report more severe depressive symptoms than men. Several studies have suggested that gender differences in depression may occur because women report higher levels of somatic symptoms than men. Those studies, however, have not controlled or matched for non-somatic symptoms. The objective of this study was to examine if women report relatively more somatic symptoms than men matched on cognitive/affective symptoms.Male and female patients receiving treatment for MDD in outpatient psychiatric clinics in New Jersey and Pennsylvania, USA were matched on Beck Depression Inventory-II (BDI-II) cognitive/affective symptom scores. Male and female BDI-II somatic symptom scores were compared using independent samples 2-tailed t-tests.Of 472 male and 1,026 female patients, there were 470 male patients (mean age = 40.1 years, SD = 15.1) and 470 female patients (mean age = 43.1 years, SD = 17.2) successfully matched on BDI-II cognitive/affective symptom scores. Somatic symptoms accounted for 35% of total BDI-II scores for male patients versus 38% for matched female patients. Female patients had somatic symptom scores on average 1.3 points higher than males (p<.001), equivalent to 4% of the total BDI-II scores of female patients. Only 5% of male patients and 7% of female patients scored 2 or higher on all BDI-II somatic symptom items.Gender differences in somatic scores were very small. Thus, differences in the experience and reporting of somatic symptoms would not likely explain gender differences in depression rates and symptom severity

Transcriptional responses of Burkholderia cenocepacia to polymyxin B in isogenic strains with diverse polymyxin B resistance phenotypes

<p>Abstract</p> <p>Background</p> <p><it>Burkholderia cenocepacia </it>is a Gram-negative opportunistic pathogen displaying high resistance to antimicrobial peptides and polymyxins. We identified mechanisms of resistance by analyzing transcriptional changes to polymyxin B treatment in three isogenic <it>B. cenocepacia </it>strains with diverse polymyxin B resistance phenotypes: the polymyxin B-resistant parental strain K56-2, a polymyxin B-sensitive K56-2 mutant strain with heptoseless lipopolysaccharide (LPS) (RSF34), and a derivative of RSF34 (RSF34 4000B) isolated through multiple rounds of selection in polymyxin B that despite having a heptoseless LPS is highly polymyxin B-resistant.</p> <p>Results</p> <p>A heptoseless LPS mutant of <it>B. cenocepacia </it>was passaged through multiple rounds of selection to regain high levels of polymyxin B-resistance. This process resulted in various phenotypic changes in the isolate that could contribute to polymyxin B resistance and are consistent with LPS-independent changes in the outer membrane. The transcriptional response of three <it>B. cenocepacia </it>strains to subinhibitory concentrations of polymyxin B was analyzed using microarray analysis and validated by quantitative Real Time-PCR. There were numerous baseline changes in expression between the three strains in the absence of polymyxin B. In both K56-2 and RSF34, similar transcriptional changes upon treatment with polymyxin B were found and included upregulation of various genes that may be involved in polymyxin B resistance and downregulation of genes required for the synthesis and operation of flagella. This last result was validated phenotypically as both swimming and swarming motility were impaired in the presence of polymyxin B. RSF34 4000B had altered the expression in a larger number of genes upon treatment with polymyxin B than either K56-2 or RSF34, but the relative fold-changes in expression were lower.</p> <p>Conclusions</p> <p>It is possible to generate polymyxin B-resistant isolates from polymyxin B-sensitive mutant strains of <it>B. cenocepacia</it>, likely due to the multifactorial nature of polymyxin B resistance of this bacterium. Microarray analysis showed that <it>B. cenocepacia </it>mounts multiple transcriptional responses following exposure to polymyxin B. Polymyxin B-regulated genes identified in this study may be required for polymyxin B resistance, which must be tested experimentally. Exposure to polymyxin B also decreases expression of flagellar genes resulting in reduced swimming and swarming motility.</p

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead