Probabilistic Sensitivity Analysis for Launch Vehicles with Varying Payloads and Adapters for Structural Dynamics and Loads

This paper examines Probabilistic Sensitivity Analysis (PSA) methods and tools in an effort to understand their utility in vehicle loads and dynamic analysis. Specifically, this study addresses how these methods may be used to establish limits on payload mass and cg location and requirements on adaptor stiffnesses while maintaining vehicle loads and frequencies within established bounds. To this end, PSA methods and tools are applied to a realistic, but manageable, integrated launch vehicle analysis where payload and payload adaptor parameters are modeled as random variables. This analysis is used to study both Regional Response PSA (RRPSA) and Global Response PSA (GRPSA) methods, with a primary focus on sampling based techniques. For contrast, some MPP based approaches are also examined

Systematic review and meta-analysis of prevalence, trajectories, and clinical outcomes for frailty in COPD

This systematic review synthesised measurement and prevalence of frailty in COPD and associations between frailty and adverse health outcomes. We searched Medline, Embase and Web of Science (1 January 2001–8 September 2021) for observational studies in adults with COPD assessing frailty prevalence, trajectories, or association with health-related outcomes. We performed narrative synthesis and random-effects meta-analyses. We found 53 eligible studies using 11 different frailty measures. Most common were frailty phenotype (n = 32), frailty index (n = 5) and Kihon checklist (n = 4). Prevalence estimates varied by frailty definitions, setting, and age (2.6–80.9%). Frailty was associated with mortality (5/7 studies), COPD exacerbation (7/11), hospitalisation (3/4), airflow obstruction (11/14), dyspnoea (15/16), COPD severity (10/12), poorer quality of life (3/4) and disability (1/1). In conclusion, frailty is a common among people with COPD and associated with increased risk of adverse outcomes. Proactive identification of frailty may aid risk stratification and identify candidates for targeted intervention

A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Evidence-based decision support for pediatric rheumatology reduces diagnostic errors.

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ( unaided ), versus after use of the DDSS ( aided ). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p \u3c 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an open book approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists\u27 ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086

Analysis of Prostate Cancer Tumor Microenvironment Identifies Reduced Stromal CD4 Effector T-cell Infiltration in Tumors with Pelvic Nodal Metastasis.

BACKGROUND: Pelvic nodal metastasis in prostate cancer impacts patient outcome negatively. OBJECTIVE: To explore tumor-infiltrating immune cells as a potential predictive tool for regional lymph node (LN) metastasis. DESIGN SETTING AND PARTICIPANTS: We applied multiplex immunofluorescence and targeted transcriptomic analysis on 94 radical prostatectomy specimens in patients with (LN+) or without (LN-) pelvic nodal metastases. Both intraepithelial and stromal infiltrations of immune cells and differentially expressed genes (mRNA and protein levels) were correlated with the nodal status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The identified CD4 effector cell signature of nodal metastasis was validated in a comparable independent patient cohort of 184 informative cases. Patient outcome analysis and decision curve analysis were performed with the CD4 effector cell density-based signature. RESULTS AND LIMITATIONS: In the discovery cohort, both tumor epithelium and stroma from patients with nodal metastasis had significantly lower infiltration of multiple immune cell types, with stromal CD4 effector cells highlighted as the top candidate marker. Targeted gene expression analysis and confirmatory protein analysis revealed key alteration of extracellular matrix components in tumors with nodal metastasis. Of note, stromal CD4 immune cell density was a significant independent predictor of LN metastasis (odds ratio [OR] = 0.15, p = 0.004), and was further validated as a significant predictor of nodal metastasis in the validation cohort (OR = 0.26, p < 0.001). CONCLUSIONS: Decreased T-cell infiltrates in the primary tumor (particularly CD4 effector cells) are associated with a higher risk of LN metastasis. Future evaluation of CD4-based assays on prostate cancer diagnostic biopsy materials may improve selection of at-risk patients for the treatment of LN metastasis. PATIENT SUMMARY: In this report, we found that cancer showing evidence of cancer metastasis to the lymph nodes tends to have less immune cells present within the tumor. We conclude that the extent of immune cells present within a prostate tumor can help doctors determine the most appropriate treatment plan for individual patients

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions

PurposeCorneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DesignCase series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.ParticipantsFour ERED families, including 28 affected and 17 unaffected individuals.MethodsHumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle–niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.Main Outcome MeasuresLinkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.ResultsLinkage microarray analysis identified a candidate region on chromosome chr10:12,576,562–112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ–TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.ConclusionsThe COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium

An Integrated Strategy to Study Muscle Development and Myofilament Structure in Caenorhabditis elegans

A crucial step in the development of muscle cells in all metazoan animals is the assembly and anchorage of the sarcomere, the essential repeat unit responsible for muscle contraction. In Caenorhabditis elegans, many of the critical proteins involved in this process have been uncovered through mutational screens focusing on uncoordinated movement and embryonic arrest phenotypes. We propose that additional sarcomeric proteins exist for which there is a less severe, or entirely different, mutant phenotype produced in their absence. We have used Serial Analysis of Gene Expression (SAGE) to generate a comprehensive profile of late embryonic muscle gene expression. We generated two replicate long SAGE libraries for sorted embryonic muscle cells, identifying 7,974 protein-coding genes. A refined list of 3,577 genes expressed in muscle cells was compiled from the overlap between our SAGE data and available microarray data. Using the genes in our refined list, we have performed two separate RNA interference (RNAi) screens to identify novel genes that play a role in sarcomere assembly and/or maintenance in either embryonic or adult muscle. To identify muscle defects in embryos, we screened specifically for the Pat embryonic arrest phenotype. To visualize muscle defects in adult animals, we fed dsRNA to worms producing a GFP-tagged myosin protein, thus allowing us to analyze their myofilament organization under gene knockdown conditions using fluorescence microscopy. By eliminating or severely reducing the expression of 3,300 genes using RNAi, we identified 122 genes necessary for proper myofilament organization, 108 of which are genes without a previously characterized role in muscle. Many of the genes affecting sarcomere integrity have human homologs for which little or nothing is known

Was Wright Right? The Canonical Genetic Code is an Empirical Example of an Adaptive Peak in Nature; Deviant Genetic Codes Evolved Using Adaptive Bridges

The canonical genetic code is on a sub-optimal adaptive peak with respect to its ability to minimize errors, and is close to, but not quite, optimal. This is demonstrated by the near-total adjacency of synonymous codons, the similarity of adjacent codons, and comparisons of frequency of amino acid usage with number of codons in the code for each amino acid. As a rare empirical example of an adaptive peak in nature, it shows adaptive peaks are real, not merely theoretical. The evolution of deviant genetic codes illustrates how populations move from a lower to a higher adaptive peak. This is done by the use of “adaptive bridges,” neutral pathways that cross over maladaptive valleys by virtue of masking of the phenotypic expression of some maladaptive aspects in the genotype. This appears to be the general mechanism by which populations travel from one adaptive peak to another. There are multiple routes a population can follow to cross from one adaptive peak to another. These routes vary in the probability that they will be used, and this probability is determined by the number and nature of the mutations that happen along each of the routes. A modification of the depiction of adaptive landscapes showing genetic distances and probabilities of travel along their multiple possible routes would throw light on this important concept