On Natural Variation in Grades in Higher Education, and Its Implications for Assessing Effectiveness of Educational Innovations

To investigate the effect of innovations in the teaching?learning environment, researchers often compare study results from different cohorts across years. However, variance in scores can be attributed to both random fluctuation and systematic changes due to the innovation, complicating cohort comparisons. In the present study, we illustrate how using information about the variation in course grades over time can help researchers and practitioners better compare the grades and pass rates of different cohorts of students. To this end, all 375,093 grades from all 40,087 first-year students at a Dutch university during a period of six consecutive years were examined. Overall, about 17% of the variation in grades could be attributed to random variation between years and courses. With respect to passing courses, this percentage was almost 40%. Nonsignificant improvements in grades could be flagged as highly significant when this is ignored, thus leading to an overrepresentation of significant effects in educational literature. As a consequence, too many educational innovations are claimed to be effective

Absence of a Transcellular Oxalate Transport Mechanism in LLC-PK1 and MDCK Cells Cultured on Porous Supports

Transepithelial oxalate transport across polarized monolayers of LLC-PK1 cells, grown on collagen-coated microporous membranes in Transwell culture chambers, was studied in double-label experiments using [14C]-oxalate together with [3H]-D-mannitol as an extracellular marker. The [14C]-labeled glucose analog α-methyl-glucoside (α-MG) was used as functional marker for active proximal tubular sugar transport. Cellular uptake of oxalate and α-MG at both the apical and basolateral plasma membrane was determined. When added to the upper compartment, α-MG was actively taken up at the apical membrane, directed through the cells to the basolateral membrane and transported to the lower compartment, indicating functional epithelial sugar transport by LLC-PK1 cells. In LLC-PK1 cells, the uptake of α-MG at the apical membrane was approximately 50 times higher than that at the basolateral membrane. In contrast to this active transport of sugar, LLC-PK1 cells did not demonstrate oxalate uptake either at the apical or basolateral plasma membrane. The apical-to-basolateral (A- \u3e B) flux of oxalate in LLC-PK1 cells was identical to the basolateral-to-apical (B- \u3e A) oxalate flux in these cells. Moreover these flux characteristics were similar to those found for D-mannitol, indicating paracellular movement for both compounds. From these data, it is concluded that, under the experimental conditions used, LLC-PK1 cells do not exhibit a specific transcellular transport system for oxalate

Etiology of Experimental Calcium Oxalate Monohydrate Nephrolithiasis in Rats

In a rat-model system, tubular crystal retention as a possible mechanism for the etiology of nephrolithiasis in man, was studied by conventional transmission electron microscopy. The animals were supplied for nine days with a crystal-inducing diet, with ethylene glycol plus NH4Cl in their drinking-water. After this induction period, a two day regime with fresh drinking-water was included, to allow crystals to be removed by spontaneous crystalluria. After aldehyde fixation of the rat kidneys, large crystals were seen inside the tubular lumen. The crystals were attached to cell surfaces and covered by neighboring epithelial cells. Some crystals were overgrown by several epithelial cells and underwent a process of so-called exotubulosis, resulting in free or cell-surrounded crystals in the interstitium, and possibly in crystals in Giant cells. To investigate the fate of the retained crystals, some animals were additionally exposed to a low-oxalate challenge from drinking water containing 0.1 volume per cent of ethylene glycol for 12 or 30 days, respectively. It was assumed that this would interfere with the retained intratubular or interstitial crystals, and allow the crystals to grow into mini-stones. This was not observed. After the oxalate challenge, no crystals were found to be retained in the tubules (free or covered by cells). Interstitial crystals were observed, but it remains to be demonstrated whether such crystals actually grow into mini-stones or that they are removed by the sterile inflammation process observed

Etiology of Calcium Oxalate Nephrolithiasis in Rats. I. Can This Be a Model for Human Stone Formation?

Crystal retention is studied in a rat-model system as a possible mechanism for the etiology of human nephrolithiasis. A crystal-inducing diet (CID) of ethylene glycol plus NH4Cl in their drinking-water is offered to healthy rats to generate intratubular crystals. Subsequently, the fate of retained crystals is investigated by allowing the rats a tissue recovery/crystalluria phase for three, five and ten days, respectively, on normal drinking water. The process of exotubulosis is observed in cortex and medulla of aldehyde-fixed kidneys after three days recovery. After five days, crystals are predominantly seen there in the interstitium. After ten days, cortex and medulla are virtually free of crystals. However, in the papillary regions after five and ten days recovery, three types of calcium oxalate monohydrate (COM) crystals are present: (1) free in the calycine space, (2) sub-epithelially located surrounded by interstitial cells within, and (3) covered by macrophage-like cells, outside the original papillary surface. After a CID plus three days recovery, a further thirty-seven days extra oxalate challenge with solely 0.3 vol% ethylene glycol induced intratubular and interstitial oxalate crystals. In the papillary region, large sub-epithelial crystals are seen. However, no crystals are seen in kidneys from rats given solely (0.5 or 0.8 vol.%) ethylene glycol for thirty days. An oxalate re-challenge retards crystal removal

Etiology of Calcium Oxalate Nephrolithiasis in Rats. II. The Role of the Papilla in Stone Formation

In kidneys of healthy rats submitted to a crystal-inducing diet (CID) with ethylene glycol (EG) and NH4Cl, the fate of retained crystals in the papillar region is studied during a recovery period of one, five or ten days, as model system for human nephrolithiasis. Scanning electron microscopy (SEM) shows, at papillary tips bulging into the calycine space, crystal masses covered either by the epithelium or a thin fibrous veil, or by unidentified mobile cuboidal cells. After CID plus one or five days recovery, small sub-epithelial swellings are seen of large sub-epithelial crystals at or around the papillary tip. After CID plus ten days, massive sub-surface crystal-containing micrometer-sized stones are seen in which the presence of calcium is confirmed by X-ray microanalysis. The papillary tip of rats after a re-challenge with an oxalate load from 0.1 vol% EG for twelve or forty-two days shows minor lesions. But a re-challenge with 0.3 vol% EG for thirty-seven days induces large sub-epithelial papillary millimeter-sized stones. The Von Kossa section staining converts the crystals into a black precipitate, but large peri-tubular or peri-vascular calcium deposits are absent. A new hypothesis about the etiology of an inductive calcium oxalate monohydrate nephrolithiasis is formulated which differs from the one proposed by Randall based on his deductive human kidney studies

T1 Substaging of Nonmuscle Invasive Bladder Cancer is Associated with bacillus Calmette-Guérin Failure and Improves Patient Stratification at Diagnosis

Purpose: Currently, markers are lacking that can identify patients with high risk nonmuscle invasive bladder cancer who will fail bacillus Calmette-Guérin treatment. Therefore, we evaluated the prognostic value of T1 substaging in patients with primary high risk nonmuscle invasive bladder cancer. Materials and Methods: Patients with primary high risk nonmuscle invasive bladder cancer who received ≥5 bacillus Calmette-Guérin induction instillations were included. All tumors were centrally reviewed, which included T1 substaging (microinvasion vs extensive invasion of the lamina propria). T1 patients were stratified into high risk or highest risk subgroups according to major urology guidelines. Primary end point was bacillus Calmette-Guérin failure, defined as development of a high grade recurrence. Secondary end points were high grade recurrence-free survival, defined as time from primary diagnosis to biopsy-proven high grade recurrence and progression-free survival. Time-to-event analyses were used to predict survival. Results: A total of 264 patients with high risk nonmuscle invasive bladder cancer had tumor invasion of the lamina propria, of which 73% were classified as extensive invasion and 27% as microinvasion. Median followup was 68 months (IQR 43–98) and bacillus Calmette-Guérin failure was more common among patients with extensive vs microinvasive tumors (41% vs 21%, p=0.002). The 3-year high grade recurrence-free survival (defined as bacillus Calmette-Guerin failure) for patients with extensive vs microinvasive tumors was 64% vs 83% (p=0.004). In multivariate analysis, T1 substaging was an independent predictor of high grade recurrence-free survival (HR 3.2, p=0.005) and progression-free survival (HR 3.0, p=0.009). Patients with highest risk/microinvasive disease have an improved progression-free survival as compared to highest risk/T1e disease (p.adj=0.038). Conclusions: T1 substaging provides important prognostic information on patients with primary high risk nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin. The risk of bacillus Calmette-Guérin failure is higher in extensive vs microinvasive tumors. Substaging of T1 high risk nonmuscle invasive bladder cancer has the potential to guide treatment decisions on bacillus Calmette-Guérin vs alternative strategies at diagnosis.publishedVersio

Penetration of topically administered dexamethasone disodium phosphate and prednisolone acetate into the normal equine ocular fluids

Background: Topical dexamethasone and prednisolone are currently the mainstay treatment for equine ophthalmic inflammatory diseases, such as equine recurrent uveitis. Comparative pharmacokinetic studies in horses are lacking and current guidelines are mainly based on empirical data and extrapolation from other species. Objectives: To investigate the penetration and local concentrations of topically applied dexamethasone and prednisolone in normal equine ocular fluids and serum. Study design: Prospective randomised experimental pharmacokinetic study. Methods: Twenty-one Shetland ponies without ophthalmic disease were treated bilaterally topically every 2 hours during 24 hours to obtain steady state drug concentrations. One eye was treated with 0.15 mg of dexamethasone disodium phosphate (0.1%), and the other eye was simultaneously treated with 1.5 mg of prednisolone acetate (1%). Serum samples were taken prior to the induction of general anaesthesia. Aqueous and vitreous humour samples were taken during euthanasia at time points after administration of the last dose (t = 5 min, t = 15 min, t = 30 min, t = 60 min, t = 90 min, t = 120 min, t = 180 min). Each pony was randomly assigned to one time point, and three ponies were sampled per time point. Dexamethasone and prednisolone concentrations were measured by liquid chromatography-mass spectrometry. Results: The mean dexamethasone concentration in aqueous humour was 32.4 ng/mL (standard deviation [SD] 10.9) and the mean prednisolone concentration was 321.6 ng/mL (SD 96.0). In the vitreous and in serum samples concentrations of both corticosteroids were below the limit of detection (LOD 2.5 ng/mL). Main limitations: The study group was limited to subjects without evidence of current ophthalmic disease. A limited number of time points were measured. Conclusions: Potentially effective dexamethasone and prednisolone concentrations were measured in the anterior chamber, but vitreal concentrations were negligible. Systemic uptake was low. Therefore, treatment with only topically administered corticosteroids is deemed insufficient in horses in cases of posterior uveitis. Further studies evaluating other routes of administration are warranted

Step-wise evolution of complex chemical defenses in millipedes: a phylogenomic approach

With fossil representatives from the Silurian capable of respiring atmospheric oxygen, millipedes are among the oldest terrestrial animals, and likely the first to acquire diverse and complex chemical defenses against predators. Exploring the origin of complex adaptive traits is critical for understanding the evolution of Earth’s biological complexity, and chemical defense evolution serves as an ideal study system. The classic explanation for the evolution of complexity is by gradual increase from simple to complex, passing through intermediate “stepping stone� states. Here we present the first phylogenetic-based study of the evolution of complex chemical defenses in millipedes by generating the largest genomic-based phylogenetic dataset ever assembled for the group. Our phylogenomic results demonstrate that chemical complexity shows a clear pattern of escalation through time. New pathways are added in a stepwise pattern, leading to greater chemical complexity, independently in a number of derived lineages. This complexity gradually increased through time, leading to the advent of three distantly related chemically complex evolutionary lineages, each uniquely characteristic of each of the respective millipede groups

Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis.

BACKGROUND: Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). OBJECTIVE: To systematically review trials of prostate radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Using a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators. INTERVENTION: We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis. RESULTS AND LIMITATIONS: We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81-1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67-0.82, p=0.94×10-8) and FFS (HR=0.76, 95% CI 0.69-0.84, p=0.64×10-7), equivalent to ?10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ?5; interaction HR=1.47, 95% CI 1.11-1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases. CONCLUSIONS: Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden. PATIENT SUMMARY: Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.This article is freely available via Open Access