Extending Modelling Activity Diagrams as a tool to characterise mathematical modelling processes

In this paper, we present a qualitative study in which we analyse the videorecordings of four groups of students solving Fermi Problems. Previous studies show that Secondary School students solve this type of problems using complex problem solving processes and developing mathematical models. In order to analyse the students' problem solving processes, so-called Modelling Activity Diagrams were used. The results of the present study demonstrate that solving Fermi problems is a complex matter, and that some of the theoretical tools used in the field of Mathematical Education fail to adequately reflect this level of complexity. In addition, Modelling Activity Diagrams are presented as a more detailed analysis tool to characterise student choices and actions, as well as to make the structure of the Fermi problem addressed more visible

Multiple Measures Placement Using Data Analytics: An Implementation and Early Impacts Report

Many incoming college students are referred to remedial programs in math or English based on scores they earn on standardized placement tests. Yet research shows that these tests do not always assess student skills accurately, and colleges that rely on them often assign students to remedial courses who could succeed in college-level courses. Seven community colleges in the State University of New York (SUNY) system are participating in a random assignment study of a multiple measures placement system based on data analytics to determine whether it yields placement determinations that lead to better student outcomes than a system based on test scores alone. This interim report from the Center for the Analysis of Postsecondary Readiness (CAPR) examines the implementation of the alternative placement system at the colleges and presents results on first-term impacts for a subset of the students in the study. The early findings show that: - Many program group students were placed differently than they would have been under the status quo placement system. In math, 14 percent of program group students placed higher than they would have under a test-only system (i.e., in college-level), while 7 percent placed lower (i.e., in remedial). In English, 41.5 percent placed higher, while 6.5 percent placed lower. - Program group students were 3.1 and 12.5 percentage points more likely than control group students to both enroll in and complete (with a grade of C or higher) a college-level math or English course in the first term. - Implementation of the alternative system added roughly $110 per student to status quo fall-term costs for testing and placing students at the colleges; ongoing costs in the subsequent fall term were roughly$40 per student above status quo costs. The final report, to be released in 2019, will examine a range of student outcomes for three cohorts, including completion of introductory college-level courses, persistence, and the accumulation of college credits over the long term

A scalable adenovirus production process, from cell culture to purified bulk

Adenovirus (AdV) vectors are commonly used in cancer gene therapy trials, evaluated in gene therapy and used as vaccines for various diseases. AdV vectors are well studied and are suitable as vaccine vectors due to their ability to infect different cell types, remain episomal and produce stable high titer material. Manufacturing of safe and efficacious clinical-grade virus relies on a scalable and cost-effective production process. In this study, we have combined experimental work and process economy calculations, from AdV production in cell culture to purified bulk product up to 10L scale. An efficient and scalable process for AdV production was developed by evaluation of each process step. The most studied vector is serotype 5, making this a suitable system for process development of AdV vectors. Human AdV5 expressing the green fluorescent protein (GFP) was used for process development. First, suspension HEK 293 cells adapted to serum-free cell culture medium were optimized for AdV production and evaluated in different single use bioreactor systems. Tween 20 was used for cell lysis as a replacement for the traditionally used Triton X-100 (now on the Authorization list (Annex XIV) of REACH, the regulation on Registration, Evaluation, Authorization and restriction of Chemicals). A residual Tween 20 assay with low detection limit was set-up. Filters and conditions for clarification, concentration and buffer exchange by tangential flow filtration were optimized. Anion exchange based capture step alternatives were compared, including different chromatography resins and membrane formats. Finally, core bead technology was evaluated as an alternative to size exclusion chromatography for the polishing step before the final formulation. Analytical methods for virus titer are challenging and depend on purity and quality of the sample. For total virus titer, qPCR and HPLC methods were used. Furthermore, a method based on surface plasmon resonance (Biacore) was developed for analysis of adenovirus titer. For infectious virus titer, we have used a cell based assay with automatic image analysis. Based on analytical data different downstream process alternatives were compared regarding load capacity, recovery and purity and we propose a robust and scalable process with a favorable process economy. Please click Additional Files below to see the full abstract

Evaluation of Dosing Guidelines for Gentamicin in Neonates and Children

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children’s Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8–12 mg/L for neonates and 15–20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment

Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation +/- endoscopic resection:results from the national Dutch database in a 10-year period

OBJECTIVE: Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. DESIGN: Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. RESULTS: After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. CONCLUSION: In a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. NETHERLANDS TRIAL REGISTER NUMBER: NL7039

Incidence and outcomes of poor healing and poor squamous regeneration after radiofrequency ablation therapy for early Barrett's neoplasia

BACKGROUND: Although endoscopic eradication therapy with radiofrequency ablation (RFA) is effective in most Barrett's Esophagus (BE) patients, some might experience poor healing (PH) and/or poor squamous regeneration (PSR). We aimed to evaluate PH/PSR incidence and treatment outcomes. METHODS: We included all patients treated with RFA for early BE neoplasia, from a nationwide Dutch registry based on a joint treatment protocol. PH was defined as active inflammatory changes or visible ulcerations ≥3 months post-RFA, PSR as <50% squamous regeneration, and treatment success as complete eradication of BE (CE-BE). Results 1,386 patients (median BE C2M5) underwent RFA with baseline low-grade dysplasia (27%), high-grade dysplasia (30%), or early cancer (43%). In all 134 patients with PH (10%), additional time and acid suppression resulted in complete esophageal healing. 67/134 (50%) had normal regeneration with 97% CE-BE. In total, 74 patients had PSR (5%). As compared to patients with normal squamous regeneration, PSR patients had a higher risk for treatment failure (64% versus 2%, RR 27 [95% CI 18-40]) and progression to advanced disease (15% versus <1%, RR 30 [95% CI 12-81]). Higher BMI, longer BE, reflux esophagitis, and <50% squamous regeneration after baseline endoscopic resection were independently associated with PSR in multivariable logistic regression. Conclusions In half of the patients with PH, additional time and acid suppression may lead to normal squamous regeneration and excellent treatment outcomes. However, if patients experience PSR, the risk for treatment failure and progression to advanced disease is significantly increased with a relative risk of 27 and 30, respectively

Extending treatment criteria for Barrett's neoplasia:results of a nationwide cohort of 138 ESDs

BACKGROUND:  The use of endoscopic submucosal dissection (ESD) is gradually expanding for treatment of neoplasia in Barrett's esophagus (BE). We aimed to report outcomes of all ESDs for BE neoplasia performed in the Netherlands. METHODS:  Retrospective assessment of outcomes, using treatment and follow-up data from a joint database. RESULTS:  130/138 patients had complete ESDs, with 126/130 (97 %) en bloc resections. Median (interquartile range (IQR)) procedure time was 121 minutes (90-180). Pathology findings were high grade dysplasia (HGD) (5 %) or esophageal adenocarcinoma (EAC) T1a (43 %) or T1b (52 %; 19 % sm1, 33 % ≥ sm2). Among resections of HGD or T1a EAC lesions, 87 % (95 %CI 75 %-92 %) were both en bloc and R0; the corresponding value for T1b EAC lesions was 49 % (36 %-60 %). Among R1 resections, 10/34 (29 %) showed residual cancer, all detected at first endoscopic follow-up. The remaining 24 patients (71 %) showed no residual neoplasia. Six of these patients underwent surgery with no residual tumor; the remaining 18 underwent endoscopic follow-up during median 31 months with 1 local recurrence (annual recurrence rate 2 %). Among R0 resections, annual local recurrence rate during median 27 months was 0.5 %. CONCLUSION:  In expert hands, ESD allows safe removal of bulky intraluminal neoplasia and submucosal cancer. ESD of the latter showed R1 resection margins in 50 %, yet only one third had persisting neoplasia at follow-up. To better stratify R1 patients with an indication for additional surgery, repeat endoscopy after healing of the ESD might be a helpful possible prognostic factor for residual cancer

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.