Observer agreement on interpreting colposcopic images of CIN

The purpose of this work was to study intraobserver and interobserver variation in the interpretation of colposcopic images of cervical intraepithelial neoplasia (CIN). Twenty-three experienced colposcopists were asked to assess colposcopic images presented on slides and to select the biopsy site. Eleven cases were independently interpreted twice with an interval of 2-3 months by all observers. No information about the cytological classification was available. In each case the "majority assessment" was considered as the standard, being "no CIN" in 2 cases, CIN I in 4 cases, CIN II in 3 cases, and CIN III in 2 cases. Intraobserver concordance was 66.7%, the kappa value was 0.54. Interobserver agreement was found to be 52.4 and 51.0% in the first and second sessions, respectively, while the mean kappa values were 0.41 and 0.33, respectively. In selecting the site for biopsy, 77.4% of all observers agreed while the same site was selected in 85.3% of cases by the individual colposcopist in the two sessions. Overall, CIN I and II interpretations revealed lower levels of agreement than no CIN or CIN III interpretations. It is concluded that observer variability in interpreting colposcopic images and selecting the site for biopsy is in the same range as observer variation in other subjective diagnostic tests such as cytology and histopathology. This variation should be taken into account in the colposcopical management of patients with abnormal cytology.     

Early office-based vs late hospital-based nasolacrimal duct probing. A clinical decision analysis

BACKGROUND: Controversy exists regarding the treatment of infants with symptomatic nasolacrimal duct obstruction. One philosophy advocates "early" nasolacrimal duct probing, generally in the office. An alternate strategy advocates medical management until the infant is approximately 12 months old to allow for spontaneous resolution, with those with persistent nasolacrimal duct obstruction usually treated by "late" probing in the hospital with the use of general anesthesia. METHODS: We used clinical decision analysis to compare these two opposing treatment strategies. A decision tree was constructed with the usual designations for probability nodes and decision points, comparing early probing at 6 months of age in the office and late probing at 12 months of age in the hospital. The initial decision point thus addressed treatment of children who still had symptomatic nasolacrimal duct obstruction at 6 months of age. One repeated probing under same-strategy conditions was performed for patients in whom initial office probing failed. Values for probability nodes were derived from the ophthalmic literature, including a 70% rate of spontaneous resolution of nasolacrimal duct obstruction between the ages of 6 and 12 months. RESULTS: Both the early office probing strategy and the late hospital probing strategy yielded success rates greater than 99%. Based on prevailing fees, the late hospital strategy cost $2,310,000 more than the early office strategy per 10,000 patients, even though fewer procedures were performed. CONCLUSION: Early office probing and late hospital probing have similar high success rates, albeit at a higher cost for the late hospital probing strategy.     

Noble Metal Ion-Directed Assembly of 2D Materials for Heterostructured Catalysts and Metallic Micro-Texturing

Assembling 2D-material (2DM) nanosheets into micro- and macro-architectures with augmented functionalities requires effective strategies to overcome nanosheet restacking. Conventional assembly approaches involve external binders and/or functionalization, which inevitably sacrifice 2DM's nanoscale properties. Noble metal ions (NMI) are promising ionic crosslinkers, which can simultaneously assemble 2DM nanosheets and induce synergistic properties. Herein, a collection of NMI–2DM complexes are screened and categorized into two sub-groups. Based on the zeta potentials, two assembly approaches are developed to obtain 1) NMI-crosslinked 2DM hydrogels/aerogels for heterostructured catalysts and 2) NMI–2DM inks for templated synthesis. First, tetraammineplatinum(II) nitrate (TPtN) serves as an efficient ionic crosslinker to agglomerate various 2DM dispersions. By utilizing micro-textured assembly platforms, various TPtN–2DM hydrogels are fabricated in a scalable fashion. Afterward, these hydrogels are lyophilized and thermally reduced to synthesize Pt-decorated 2DM aerogels (Pt@2DM). The Pt@2DM heterostructures demonstrate high, substrate-dependent catalytic activities and promote different reaction pathways in the hydrogenation of 3-nitrostyrene. Second, PtCl₄ can be incorporated into 2DM dispersions at high NMI molarities to prepare a series of PtCl₄–2DM inks with high colloidal stability. By adopting the PtCl₄–graphene oxide ink, various Pt micro-structures with replicated topographies are synthesized with accurate control of grain sizes and porosities.     

Can twice weekly hemodialysis expand patient access under resource constraints?

The convention of prescribing hemodialysis on a thrice weekly schedule began empirically when it seemed that this frequency was convenient and likely to treat symptoms for a majority of patients. Later, when urea was identified as the main target and marker of clearance, studies supported the prevailing notion that thrice weekly dialysis provided appropriate clearance of urea. Today, national guidelines on hemodialysis from most countries recommend patients receive at least thrice weekly therapy. However, resource constraints in low‐ and middle‐income countries (LMIC) have resulted in a substantial proportion of patients using less frequent hemodialysis in these settings. Observational studies of patients on twice weekly dialysis show that twice weekly therapy has noninferior survival rates compared with thrice weekly therapy. In fact, models of urea clearance also show that twice weekly therapy can meet urea clearance “targets” if patients have significant residual function or if they follow a protein‐restricted diet, as may be common in LMIC. Greater reliance on twice weekly therapy, at least at the start of hemodialysis, therefore has potential to reduce health care costs and increase access to renal replacement therapy in low‐resource settings; however, randomized control trials are needed to better understand long‐term outcomes of twice versus thrice weekly therapy.     

Transmembrane passage of cytokine-inducing bacterial products across new and reprocessed polysulfone dialyzers

The widespread use of bicarbonate dialysate and reprocessed high-efficiency and "high-flux" dialyzers has raised concerns about the increased risk of reverse-transfer of dialysate contaminants into the blood compartment. To evaluate this concern, the reverse-transfer of bacterial products from contaminated bicarbonate dialysate into the blood compartment was compared during in vitro dialysis with new or reprocessed high-flux polysulfone dialyzers. In vitro dialysis was carried out at 37 degrees C by use of a counter-current recirculating loop dialysis circuit with either new high-flux polysulfone dialyzers or dialyzers reprocessed once or 20 times with formaldehyde (0.75%) and bleach (< 1%) with an automated system. Heparinized whole blood from healthy volunteers was circulated through the blood compartment, and bicarbonate dialysate was circulated in the dialysate compartment. The dialysate was challenged sequentially by 1:1000 and 1:100 dilutions of a sterile Pseudomonas aeruginosa culture supernatant (bacterial challenge). Samples were drawn from the blood and dialysate compartments 1 h after each challenge. Peripheral blood mononuclear cells (PBMC) were harvested by Ficoll-Hypaque separation from whole blood in the blood compartment and a 5 x 10(6) PBMC/mL cell suspension was prepared. Likewise, dialysate samples (0.5 mL) were added to 0.5 mL suspension of 5 x 10(6) PBMC/mL drawn at baseline. All PBMC suspensions were incubated upright in a humidified atmosphere at 37 degrees C with 5% CO2 for 24 h, and total interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF alpha) cytokine production (cell-associated and secreted) was measured by radioimmunoassay. Eight experiments were performed for each arm of the study with the same donor for each arm. One hour after contaminating the dialysate with a 1:1000 dilution of the bacterial challenge, IL-1 alpha production by PBMC harvested from the blood compartment was 160 +/- 0, 171 +/- 11, and 270 +/- 35 pg, respectively, for new dialyzers, dialyzers reprocessed once, and dialyzers reprocessed 20 times (P = 0.004). One hour after challenging the dialysate with 1:100 dilution, IL-1 alpha production by PBMC harvested from the blood compartment was 188 +/- 20, 228 +/- 35, and 427 +/- 67 pg, respectively, for new dialyzers, dialyzers reprocessed once, and dialyzers reprocessed 20 times (P = 0.006). IL-1 alpha production by PBMC from dialyzers reprocessed 20 times was significantly greater than both new and dialyzers reprocessed once. However, there were no significant differences between new dialyzers and dialyzers reprocessed once. Similarly, after the 1:1000 challenge, TNF alpha production by PBMC harvested from the blood compartment was 160 +/- 0, 160 +/- 0, and 213 +/- 22 pg, respectively, for new dialyzers, dialyzers reprocessed once, and dialyzers reprocessed 20 times (P = 0.008). After the 1:100 challenge, TNF alpha production was 168 +/- 8, 188 +/- 20, and 225 +/- 32 pg, respectively, for new dialyzers, dialyzers reprocessed once, and dialyzers reprocessed 20 times (P = 0.20). These results demonstrate that reprocessing of high-flux polysulfone dialyzers with bleach increases the risk of reverse-transfer of bacterial products from contaminated dialysate, and this risk appears to increase with the number of reuses. Consequently, units that reprocess membranes with bleach and have suboptimal water quality might subject their patients to a higher risk of cytokine-related morbidity.     

2,4-Diamino-5-(2'-arylpropargyl)pyrimidine derivatives as new nonclassical antifolates for human dihydrofolate reductase inhibition

Dihydrofolate reductase (DHFR) has been a well-recognized target for the development of therapeutics for human cancers for several decades. Classical inhibitors of DHFR use an active transport mechanism to gain access to the cell; disabling this mechanism creates a pathway for resistance. In response, recent research focuses on nonclassical lipid-soluble DHFR inhibitors that are designed to passively diffuse through the membrane. Here, a new series of propargyl-linked antifolates are investigated as potential nonclassical human DHFR inhibitors. Several of these compounds exhibit potent enzyme inhibition with 50% inhibition concentration values under 500 nM. Molecular docking investigations show that the compounds maintain conserved hydrogen bonds between the pyrimidine ring and the enzyme as well as form van der Waals interactions with critical residues in the active site. Interestingly, the most potent compound, 2,4-diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (compound 35), is 3500-fold more potent than trimethoprim, a potent inhibitor of bacterial DHFR but weak inhibitor of human DHFR. The two structural differences between compound 35 and trimethoprim show that the propargyl linkage and the substitution at C6 of the pyrimidine ring are critical to the formation of contacts with Thr 56, Ser 59, Ile 60, Leu 22, Phe 31 and Phe 34 and hence, to enhancing potency. The propargyl-linked antifolates are efficient ligands with a high ratio of potency to the number of non-hydrogen atoms and represent a potentially fruitful avenue for future development of antineoplastic agents.     

Improving literacy and metacognition with electronic portfolios: Teaching and learning with ePEARL

Can an electronic portfolio that is both a multimedia container for student work and a tool to support key learning processes have a positive impact on the literacy practices and self-regulated learning skills of students? This article presents the findings of a yearlong study conducted in three Canadian provinces during the 2007–2008 school year initially involving 32 teachers and 388 students. Due to varying levels of implementation our final data set included 14 teachers and 296 students. Using a non-equivalent pre-test/post-test design, we found that grade 4–6 students who were in classrooms where the teacher provided regular and appropriate use of the electronic portfolio tool ePEARL (i.e., medium–high implementation condition, n = 7 classrooms and 121 students), compared to control students (n = 7 classrooms and 175 students) who did not use ePEARL, showed significant improvements (p < .05) in their writing skills on a standardized literacy measure (i.e., the constructed response subtest of the Canadian Achievement Test-4th ed.) and certain metacognitive skills measured via student self-report. The results of this study indicate that teaching with ePEARL has positive impacts on students’ literacy and self-regulated learning skills when the tool is used regularly and integrated into classroom instruction.