Stability Metrics for Simulation and Flight-Software Assessment and Monitoring of Adaptive Control Assist Compensators

Due to a need for improved reliability and performance in aerospace systems, there is increased interest in the use of adaptive control or other nonlinear, time-varying control designs in aerospace vehicles. While such techniques are built on Lyapunov stability theory, they lack an accompanying set of metrics for the assessment of stability margins such as the classical gain and phase margins used in linear time-invariant systems. Such metrics must both be physically meaningful and permit the user to draw conclusions in a straightforward fashion. We present in this paper a roadmap to the development of metrics appropriate to nonlinear, time-varying systems. We also present two case studies in which frozen-time gain and phase margins incorrectly predict stability or instability. We then present a multi-resolution analysis approach that permits on-line real-time stability assessment of nonlinear systems

Stability of Dihydroartemisinin-Piperaquine Tablet Halves During Prolonged Storage Under Tropical Conditions.

Dihydroartemisinin-piperaquine (DP) is recommended for the treatment of uncomplicated malaria, used in efforts to contain artemisinin resistance, and increasingly considered for mass drug administration. Because of the narrow therapeutic dose range and available tablet strengths, the manufacturers and World Health Organization recommended regimens involve breaking tablets into halves to accurately dose children according to body weight. Use of tablet fractions in programmatic settings under tropical conditions requires a highly stable product; however, the stability of DP tablet fractions is unknown. We aged full and half DP (Eurartesim®) tablets in a stability chamber at 30°C and 70% humidity level. The active pharmaceutical ingredients dihydroartemisinin and piperaquine remained at ≥ 95% over the 3 months' period of ageing in light and darkness. These findings are reassuring for DP, but highlight the need to assess drug stability under real-life settings during the drug development process, particularly for key drugs of global disease control programs

A Singular Perturbation Approach for Time-Domain Assessment of Phase Margin

This paper considers the problem of time-domain assessment of the Phase Margin (PM) of a Single Input Single Output (SISO) Linear Time-Invariant (LTI) system using a singular perturbation approach, where a SISO LTI fast loop system, whose phase lag increases monotonically with frequency, is introduced into the loop as a singular perturbation with a singular perturbation (time-scale separation) parameter Epsilon. First, a bijective relationship between the Singular Perturbation Margin (SPM) max and the PM of the nominal (slow) system is established with an approximation error on the order of Epsilon(exp 2). In proving this result, relationships between the singular perturbation parameter Epsilon, PM of the perturbed system, PM and SPM of the nominal system, and the (monotonically increasing) phase of the fast system are also revealed. These results make it possible to assess the PM of the nominal system in the time-domain for SISO LTI systems using the SPM with a standardized testing system called "PM-gauge," as demonstrated by examples. PM is a widely used stability margin for LTI control system design and certification. Unfortunately, it is not applicable to Linear Time-Varying (LTV) and Nonlinear Time-Varying (NLTV) systems. The approach developed here can be used to establish a theoretical as well as practical metric of stability margin for LTV and NLTV systems using a standardized SPM that is backward compatible with PM

Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination.

The lethality of the aggressive brain tumor glioblastoma multiforme (GBM) results in part from its strong propensity to invade surrounding normal brain tissue. Although oncogenic drivers such as epidermal growth factor receptor activation and Phosphatase and Tensin homolog inactivation are thought to promote the motility and invasiveness of GBM cells via phosphatidylinostitol 3-kinase activation, other unexplored mechanisms may also contribute to malignancy. Here we demonstrate that several components of the planar cell polarity (PCP) arm of non-canonical Wnt signaling including VANGL1, VANGL2 and FZD7 are transcriptionally upregulated in glioma and correlate with poorer patient outcome. Knockdown of the core PCP pathway component VANGL1 suppresses the motility of GBM cell lines, pointing to an important mechanistic role for this pathway in glioblastoma malignancy. We further observe that restoration of Nrdp1, a RING finger type E3 ubiquitin ligase whose suppression in GBM also correlates with poor prognosis, reduces GBM cell migration and invasiveness by suppressing PCP signaling. Our observations indicate that Nrdp1 physically interacts with the Vangl1 and Vangl2 proteins to mediate the K63-linked polyubiquitination of the Dishevelled, Egl-10 and Pleckstrin (DEP) domain of the Wnt pathway protein Dishevelled (Dvl). Ubiquitination hinders Dvl binding to phosphatidic acid, an interaction necessary for efficient Dvl recruitment to the plasma membrane upon Wnt stimulation of Fzd receptor and for the propagation of downstream signals. We conclude that the PCP pathway contributes significantly to the motility and hence the invasiveness of GBM cells, and that Nrdp1 acts as a negative regulator of PCP signaling by inhibiting Dvl through a novel polyubiquitination mechanism. We propose that the upregulation of core PCP components, together with the loss of the key negative regulator Nrdp1, act coordinately to promote GBM invasiveness and malignancy

Lipid specificity of the immune effector perforin

Perforin is a pore forming protein used by cytotoxic T lymphocytes to remove cancerous or virus-infected cells during immune response. During the response, the lymphocyte membrane becomes refractory to perforin function by accumulating densely ordered lipid rafts and externalizing negatively charged lipid species. The dense membrane packing lowers the capacity of perforin to bind, and negatively charged lipids scavenge any residual protein before pore formation. Using atomic force microscopy on model membrane systems, we here provide insight into the molecular basis of perforin lipid specificity

A Note on Monotonically Metacompact Spaces

We show that any metacompact Moore space is monotonically metacompact and use that result to characterize monotone metacompactness in certain generalized ordered (GO)spaces. We show, for example, that a generalized ordered space with a sigma-closed-discrete dense subset is metrizable if and only if it is monotonically (countably) metacompact, that a monotonically (countably) metacompact GO-space is hereditarily paracompact, and that a locally countably compact GO-space is metrizable if and only if it is monotonically (countably) metacompact. We give an example of a non-metrizable LOTS that is monotonically metacompact, thereby answering a question posed by S. G. Popvassilev. We also give consistent examples showing that if there is a Souslin line, then there is one Souslin line that is monotonically countable metacompact, and another Souslin line that is not monotonically countably metacompact

Improving polygenic prediction with genetically inferred ancestry.

Genome-wide association studies (GWASs) have demonstrated that most common diseases have a strong genetic component from many genetic variants each with a small effect size. GWAS summary statistics have allowed the construction of polygenic scores (PGSs) estimating part of the individual risk for common diseases. Here, we propose to improve PGS-based risk estimation by incorporating genetic ancestry derived from genome-wide genotyping data. Our method involves three cohorts: a base (or discovery) for association studies, a target for phenotype/risk prediction, and a map for ancestry mapping; successively, (1) it generates for each individual in the base and target cohorts a set of principal components based on the map cohort-called mapped PCs, (2) it associates in the base cohort the phenotype with the mapped-PCs, and (3) it uses the mapped PCs in the target cohort to generate a phenotypic predictor called the ancestry score. We evaluated the ancestry score by comparing a predictive model using a PGS with one combining a PGS and an ancestry score. First, we performed simulations and found that the ancestry score has a greater impact on traits that correlate with ancestry-specific variants. Second, we showed, using UK Biobank data, that the ancestry score improves genetic prediction for our nine phenotypes to very different degrees. Third, we performed simulations and found that the more heterogeneous the base and target cohorts, the more beneficial the ancestry score is. Finally, we validated our approach under realistic conditions with UK Biobank as the base cohort and Swiss individuals from the CoLaus|PsyCoLaus study as the target cohort

A systematic analysis of preprints in Trauma & Orthopaedic surgery

AIMS Preprint servers allow authors to publish full-text manuscripts or interim findings prior to undergoing peer review. Several preprint servers have extended their services to biological sciences, clinical research, and medicine. The purpose of this study was to systematically identify and analyze all articles related to Trauma & Orthopaedic (T&O) surgery published in five medical preprint servers, and to investigate the factors that influence the subsequent rate of publication in a peer-reviewed journal. METHODS All preprints covering T&O surgery were systematically searched in five medical preprint servers (medRxiv, OSF Preprints, Preprints.org, PeerJ, and Research Square) and subsequently identified after a minimum of 12 months by searching for the title, keywords, and corresponding author in Google Scholar, PubMed, Scopus, Embase, Cochrane, and the Web of Science. Subsequent publication of a work was defined as publication in a peer-reviewed indexed journal. The rate of publication and time to peer-reviewed publication were assessed. Differences in definitive publication rates of preprints according to geographical origin and level of evidence were analyzed. RESULTS The number of preprints increased from 2014 to 2020 (p < 0.001). A total of 38.6% of the identified preprints (n = 331) were published in a peer-reviewed indexed journal after a mean time of 8.7 months (SD 5.4 (1 to 27)). The highest proportion of missing subsequent publications was in the preprints originating from Africa, Asia/Middle East, and South America, or in those that covered clinical research with a lower level of evidence (p < 0.001). CONCLUSION Preprints are being published in increasing numbers in T&O surgery. Depending on the geographical origin and level of evidence, almost two-thirds of preprints are not subsequently published in a peer-reviewed indexed journal after one year. This raises major concerns regarding the dissemination and persistence of potentially wrong scientific work that bypasses peer review, and the orthopaedic community should discuss appropriate preventive measures.Cite this article: Bone Jt Open 2022;3(7):582-588

Articular degeneration after subchondral cementation for giant cell tumors at the knee

PURPOSE To quantify joint degeneration and the clinical outcome after curettage and cementation in subchondral giant cell tumors of the bone (GCTB) at the knee. METHODS We conducted a retrospective analysis of 14 consecutive patients (seven female, seven male) with a mean age of 34 years (range 19-51) who underwent curettage and subchondral cementation for a biopsy-confirmed GCTB at the distal femur or the proximal tibia between August 2001 and August 2017, with a mean follow-up period of 54.6 months (range 16.1-156 months). The Whole-Organ Magnetic Resonance Imaging Score (WORMS), Kellgren-Lawrence (KL) classification, and Musculo-Skeletal Tumor Society (MSTS) score were assessed. RESULTS Radiological degeneration progressed from preoperative to the latest follow-up, with a median WORMS from 2.0 to 4.0 (p = 0.006); meanwhile, the median KL score remained at 0 (p = 0.102). Progressive degeneration (WORMS) tended to be associated with the proximity of the tumor to the articular cartilage (mean 1.57 mm; range 0-12 mm) (p = 0.085). The most common degenerative findings were cartilage lesions (n = 11), synovitis (n = 5), and osteophytes (n = 4). Mean MSTS score increased from 23.1 (preoperatively) to 28.3 at the latest follow-up (p < 0.01). Seven patients (50%) were treated for a local recurrence, with six revision surgeries performed. Removal of the cement spacer and filling of the cavity with a cancellous autograft was performed in seven patients. Conversion to a total knee arthroplasty was performed in one patient for local tumor control. CONCLUSIONS Cementation following the curettage of GCTB around the knee is associated with slight degeneration at medium-term follow-up and leads to a significant reduction in pain. Removal of the cement and reconstruction with an autograft may be beneficial in the long term