Miracle-dz/UniFAR-FTUs huggingface dataset:
On problems in homogenization and two-scale convergence

This thesis addresses two problems from the theory of periodic homogenization and the related notion of two-scale convergence. Its main focus rests on the derivation of equivalent transmission conditions for the interaction of two adjacent bodies which are connected by a thin layer of interface material being perforated by identically shaped voids. Herein, the voids recur periodically in interface direction and shall in size be of the same order as the interface thickness. Moreover, the constitutive properties of the material occupying the bodies adjacent to the interface are assumed to be described by some convex energy densities of quadratic growth. In contrast, the interface material is supposed to show "extremal" constitutive behavior. More precisely, it is assumed that the constitutive relations of the interface material are once more characterized by a convex energy density of quadratic growth which, however, scales with the inverse thickness of the interface layer. In accordance to recent works on homogeneous interfaces in an analogous constitutive setting, it is found that in the limit of vanishing interface thickness and void size the interaction of the bodies adjacent to the interface can asymptotically be described by equivalent transmission conditions on the flattened interface. These transmission conditions are such that they penalize in-plane gradients in the interface. Cell formulas defining the homogenized transmission conditions on the flattened interface are derived, using a combination of Gamma-convergence methods and suitable adaptions of the periodic unfolding method in rescaled (perforated) thin domains. Depending on whether the voids touch the periodicity cells' faces, different periodic unfolding operators can be applied. The thesis' final chapter contains the results of a recent collaboration with Stefan Neukamm on the effects on two-scale convergence caused by a translation of the coordinate frame. It is observed that given a vanishing sequence of microscale parameters, a once two-scale convergent sequence is in general no longer two-scale convergent when described in a translated coordinate frame, even though it remains two-scale convergent along suitable subsequences. Yet, all two-scale cluster points of the translated sequence are indeed revealed as translates of the original two-scale limit. In fact, these two-scale cluster points are not only translated in the macroscopic variable, but also in the microscopic variable by microtranslations which belong to a set that is determined solely by the translation of the coordinate frame and the vanishing sequence of microscale parameters. This result is then applied to a novel homogenization problem that involves two different coordinate frames and yields a limiting behavior governed by emerging microscopic translations. Finally, in addition to these results the thesis also indicates a possible extension of the periodic unfolding method to so-called non-translatory periodic microstructures.
Convergence of flow cytometry and bacteriology. Current and future applications: a focus on food and clinical microbiology

Abstract Since its development in the 1960s, flow cytometry (FCM) was quickly revealed a powerful tool to analyse cell populations in medical studies, yet, for many years, was almost exclusively used to analyse eukaryotic cells. Instrument and methodological limitations to distinguish genuine bacterial signals from the background, among other limitations, have hampered FCM applications in bacteriology. In recent years, thanks to the continuous development of FCM instruments and methods with a higher discriminatory capacity to detect low-size particles, FCM has emerged as an appealing technique to advance the study of microbes, with important applications in research, clinical and industrial settings. The capacity to rapidly enumerate and classify individual bacterial cells based on viability facilitates the monitoring of bacterial presence in foodstuffs or clinical samples, reducing the time needed to detect contamination or infectious processes. Besides, FCM has stood out as a valuable tool to advance the study of complex microbial communities, or microbiomes, that are very relevant in the context of human health, as well as to understand the interaction of bacterial and host cells. This review highlights current developments in, and future applications of, FCM in bacteriology, with a focus on those related to food and clinical microbiology.
Radiomics for identifying lung adenocarcinomas with predominant lepidic growth manifesting as large pure ground-glass nodules on CT images

Purpose To explore the value of radiomics in the identification of lung adenocarcinomas with predominant lepidic growth in pure ground-glass nodules (pGGNs) larger than 10 mm. Methods We retrospectively analyzed CT images of 204 patients with large pGGNs (≥ 10 mm) pathologically diagnosed as minimally invasive adenocarcinomas (MIAs), lepidic predominant adenocarcinomas (LPAs), and non-lepidic predominant adenocarcinomas (NLPAs). All pGGNs in the two groups (MIA/LPA and NLPA) were randomly divided into training and test cohorts. Forty-seven patients from another center formed the external validation cohort. Baseline features, including clinical data and CT morphological and quantitative parameters, were collected to establish a baseline model. The radiomics model was built with the optimal radiomics features. The combined model was developed using the rad_score and independent baseline predictors. The performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) and compared using the DeLong test. The differential diagnosis performance of the models was compared with three radiologists (with 20+, 10+, and 3 years of experience) in the test cohort. Results The radiomics (training AUC: 0.833; test AUC: 0.804; and external validation AUC: 0.792) and combined (AUC: 0.849, 0.820, and 0.775, respectively) models performed better for discriminating than the baseline model (AUC: 0.756, 0.762, and 0.725, respectively) developed by tumor location and mean CT value of the whole nodule. The DeLong test showed that the AUCs of the combined and radiomics models were significantly increased in the training cohort. The highest AUC value of the radiologists was 0.600. Conclusion The application of CT radiomics improved the identification performance of lung adenocarcinomas with predominant lepidic growth appearing as pGGNs larger than 10 mm.
Novel Complement C5 Small-interfering RNA Lipid Nanoparticle Prolongs Graft Survival in a Hypersensitized Rat Kidney Transplant Model

Background. Prophylaxis of antibody-mediated rejection (AMR) caused by donor-specific antibodies remains challenging. Given the critical roles of complement activity in antibody-mediated graft injury, we developed a lipid nanoparticle (LNP) formulation of small-interfering RNA against complement C5 (C5 siRNA-LNP) and investigated whether C5 siRNA-LNP could downregulate the complement activity and act as an effective treatment for AMR. Methods. Lewis recipient rats were sensitized by skin grafting from Brown Norway donor rats. Kidney transplantation was performed at 4 wk post–skin grafting. C5 siRNA- or control siRNA-LNP was administered intravenously, and the weekly injections were continued until the study’s conclusion. Cyclosporin (CsA) and/or deoxyspergualin (DSG) were used as adjunctive immunosuppressants. Complement activity was evaluated using hemolysis assays. The deposition of C5b9 in the grafts was evaluated using immunohistochemical analysis on day 7 posttransplantation. Results. C5 siRNA-LNP completely suppressed C5 expression and complement activity (hemolytic activity ≤ 20%) 7 d postadministration. C5 siRNA-LNP in combination with CsA and DSG (median survival time: 56.0 d) prolonged graft survival compared with control siRNA-LNP in combination with CsA and DSG (median survival time: 21.0 d; P = 0.0012; log-rank test). Immunohistochemical analysis of the grafts revealed that downregulation of C5 expression was associated with a reduction in C5b9-positive area (P = 0.0141, Steel-Dwass test). Conclusions. C5 siRNA-LNP combined with immunosuppressants CsA and DSG downregulated C5 activity and significantly prolonged graft survival compared with control siRNA-LNP with CsA and DSG. Downregulation of C5 expression using C5 siRNA-LNP may be an effective therapeutic approach for AMR.
Non-COVID outcomes associated with the coronavirus disease-2019 (COVID-19) pandemic effects study (COPES): A systematic review and meta-analysis

Background As the Coronavirus Disease-2019 (COVID-19) pandemic continues, healthcare providers struggle to manage both COVID-19 and non-COVID patients while still providing high-quality care. We conducted a systematic review/meta-analysis to describe the effects of the COVID-19 pandemic on patients with non-COVID illness and on healthcare systems compared to non-pandemic epochs. Methods We searched Ovid MEDLINE/EMBASE/Cochrane Database of Systematic Reviews/CENTRAL/CINAHL (inception to December 31, 2020). All study types with COVID-pandemic time period (after December 31, 2019) with comparative non-pandemic time periods (prior to December 31, 2019). Data regarding study characteristics/case-mix/interventions/comparators/ outcomes (primary: mortality; secondary: morbidity/hospitalizations/disruptions-to-care. Paired reviewers conducted screening and abstraction, with conflicts resolved by discussion. Effect sizes for specific therapies were pooled using random-effects models. Risk of bias was assessed by Newcastle-Ottawa Scale, with evidence rating using GRADE methodology. Results Of 11,581 citations, 167 studies met eligibility. Our meta-analysis showed an increased mortality of 16% during the COVID pandemic for non-COVID illness compared with 11% mortality during the pre-pandemic period (RR 1.38, 95% CI: 1.28–1.50; absolute risk difference: 5% [95% CI: 4–6%], p<0.00001, very low certainty evidence). Twenty-eight studies (17%) reported significant changes in morbidity (where 93% reported increases), while 30 studies (18%) reported no significant change (very low certainty). Thirty-nine studies (23%) reported significant changes in hospitalizations (97% reporting decreases), while 111 studies (66%) reported no significant change (very low certainty). Sixty-two studies (37%) reported significant disruptions in standards-to-care (73% reporting increases), while 62 studies (37%) reported no significant change (very low certainty). Conclusions There was a significant increase in mortality during the COVID pandemic compared to pre-pandemic times for non-COVID illnesses. When significant changes were reported, there was increased morbidity, decreased hospitalizations and increased disruptions in standards-of-care. Systematic review registration PROSPERO CRD42020201256 (Sept 2, 2020).
Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome

Abstract The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.
Brain Co‐Delivery of Temozolomide and Cisplatin for Combinatorial Glioblastoma Chemotherapy

Glioblastoma (GBM) is an intractable malignancy with high recurrence and mortality. Combinatorial therapy based on temozolomide (TMZ) and cisplatin (CDDP) shows promising potential for GBM therapy in clinical trials. However, significant challenges include limited blood–brain‐barrier (BBB) penetration, poor targeting of GBM tissue/cells, and systemic side effects, which hinder its efficacy in GBM therapy. To surmount these challenges, new GBM‐cell membrane camouflaged and pH‐sensitive biomimetic nanoparticles (MNPs) inspired by the fact that cancer cells readily pass the BBB and localize with homologous cells, are developed. This study's results show that MNPs can efficiently co‐load TMZ and CDDP, transport these across the BBB to specifically target GBM. Incorporation of pH‐sensitive polymer then allows for controlled release of drug cargos at GBM sites for combination drug therapy. Mice bearing orthotopic U87MG or drug‐resistant U251R GBM tumor and treated with MNPs@TMZ+CDDP show a potent anti‐GBM effect, greatly extending the survival time relative to mice receiving single‐drug loaded nanoparticles. No obvious side effects are apparent in histological analyses or blood routine studies. Considering these results, the study's new nanoparticle formulation overcomes multiple challenges currently limiting the efficacy of combined TMZ and CDDP GBM drug therapy and appears to be a promising strategy for future GBM combinatorial chemotherapy.
How do different interventions impact stair climbing? A systematic review and meta-analysis

Objectives: This study aimed to analyze the effect of interventions to increase stair use. Study Design: Systematic review and meta-analysis. Methods: An online search was conducted in January 2021 in five databases (Web of Science, SPORTDiscus, MedLine/PubMed, PsycINFO, and CINAHL). Experimental studies (randomized and non-randomized) conducted in adults, which provided stair use measures with pre- and post-intervention periods were included. A random-effect meta-analysis, as well as subgroup analyses were conducted to evaluate the quantitative effect of interventions on stair use. Results: Overall, 34 studies were included in qualitative analyses, and 15 in the meta-analysis. Most of the studies were conducted in Europe and private settings (e.g., office buildings). Overall, interventions increased stair use in adults (odds ratio (OR) 1.48; 95% confidence intervals (CI) 1.38–1.58; I2 = 99.6%). Subgroup analyses showed that interventions increased stair use regardless of the continent and observer type (manual or electronic). However, different settings (shopping malls and office buildings), as well as studies (time of intervention) and intervention characteristics (sign size and location, message characters) were associated with increased stair use. Conclusions: Different interventions can increase stair use in several continents and settings. Sign and message characteristics should be considered when designing interventions or policies to promote physical activity by increasing stair use.
CAVES: A Novel Tool for Comparative Analysis of Variant Epitope Sequences

In silico methods for immune epitope prediction have become essential for vaccine and therapeutic design, but manual intra-species comparison of putative epitopes remains challenging and subject to human error. Created initially for analyzing SARS-CoV-2 variants of concern, comparative analysis of variant epitope sequences (CAVES) is a novel tool designed to carry out rapid comparative analyses of epitopes amongst closely related pathogens, substantially reducing the required time and user workload. CAVES applies a two-level analysis approach. The Level-one (L1) analysis compares two epitope prediction files, and the Level-two (L2) analysis incorporates search results from the IEDB database of experimentally confirmed epitopes. Both L1 and L2 analyses sort epitopes into categories of exact matches, partial matches, or novel epitopes based on the degree to which they match with peptides from the compared file. Furthermore, CAVES uses positional sequence data to improve its accuracy and speed, taking only a fraction of the time required by manual analyses and minimizing human error. CAVES is widely applicable for evolutionary analyses and antigenic comparisons of any closely related pathogen species. CAVES is open-source software that runs through a graphical user interface on Windows operating systems, making it widely accessible regardless of coding expertise. The CAVES source code and test dataset presented here are publicly available on the CAVES GitHub page.
Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma

Background Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. Methods From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. Results A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium. The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001). Conclusions Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.
Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top‐down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom‐up). This was done through meta‐analyses and meta‐regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case‐by‐case basis.
Cost-effectiveness of testing for CYP2C19 loss-of-function carriers following transient ischemic attack/minor stroke: A Canadian perspective

Background: The CHANCE-2 study compared 3 weeks of aspirin–ticagrelor to aspirin–clopidogrel in CYP2C19 loss-of-function (LOF) allele carriers following a transient ischemic attack (TIA)/minor stroke and demonstrated a modestly lower risk of stroke recurrence with aspirin–ticagrelor. This stroke protection was largely for minor stroke and came at an increased risk of bleeding. The cost-effectiveness of implementing testing for LOF allele status to personalize antiplatelet regimen for secondary stroke prevention after a TIA/minor stroke in the Canadian health care context is unknown. Methods: Cost-effectiveness analysis using a decision-analytic Markov cohort model with a lifetime horizon was performed to determine the costs and health benefits of testing for LOF allele status compared with no testing (current standard of care). The population of interest was patients living in Canada who suffered a TIA/minor stroke. Outcomes of interest were life-years gained (LYG), quality-adjusted life years (QALY) gained, costs (reported in 2022 Canadian dollars), and the incremental cost-effectiveness ratio (ICER). We adopted the perspective of the Federal, Provincial, and Territorial Ministries of Health and used a 1.5% annual discount rate. Sensitivity analyses were performed to assess uncertainty. Results: Compared to standard of care, LOF allele testing leads to 0.14 LYG (undiscounted), 0.12 QALYs gained (undiscounted), and additional lifetime costs of CAD$432 (discounted) per patient. The ICER of the LOF allele testing strategy is CAD$4310 per QALY gained compared with standard of care. The probabilistic sensitivity analyses demonstrated that LOF allele testing was cost-effective in more than 99.99% of simulations using a willingness-to-pay threshold of CAD$50,000 per QALY. Conclusion: Based on available evidence, testing for LOF allele followed by short duration 3 weeks of aspirin–ticagrelor compared to standard-of-care aspirin–clopidogrel can lead to prolonged life and improved quality of life and can be considered very cost-effective when compared with other well-accepted technologies in health and medicine.