Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m²/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m²/day. The dose level of 80 mg/m²/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC₅₀ values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.     

Exploring the online learning experience of first-year speech–language pathology students in a Johannesburg-based university

BackgroundUnderstanding the learning experiences of first-year speech–language pathology (SLP) students during the coronavirus disease 2019 (COVID-19) pandemic is essential to ensure that academic staff are able to support and enhance the transition from secondary to tertiary education. An understanding of the student experience could lead to improved support strategies that could be beneficial for the blended learning environment that the University of the Witwatersrand will be entering from 2022.ObjectivesThis research explored the experiences of first-year SLP students in online learning during the COVID-19 pandemic.MethodAn exploratory mixed-method concurrent triangulation design was employed. Quantitative data were collected from likert scales. Qualitative data were collected from critical incident timelines. Themes were identified from both the Likert scales as well as the critical incident timelines using bottom-up thematic analysis.ResultsThe majority of participants reflected that their online learning through the pandemic in 2021 was successful. The themes that emerged from this year pertain to 2021 and the specific participants however, it provides an important insight that the students’ needs change during a year. As a lecturer, one needs to consider these evolving needs to ensure students have the support that they require to be successful in their learning.ConclusionThis research provided insights into the evolving nature of the support first-year SLP students require in the online learning space during the COVID-19 pandemic.     

Solid cancer incidence among Chinese medical diagnostic x‐ray workers, 1950–1995: Estimation of radiation‐related risks

The objective of this study was to estimate solid cancer risk attributable to long‐term, fractionated occupational exposure to low doses of ionizing radiation. Based on cancer incidence for the period 1950–1995 in a cohort of 27,011 Chinese medical diagnostic X‐ray workers and a comparison cohort of 25,782 Chinese physicians who did not use X‐ray equipment in their work, we used Poisson regression to fit excess relative risk (ERR) and excess absolute risk (EAR) dose–response models for incidence of all solid cancers combined. Radiation dose reconstruction was based on a previously published method that relied on simulating measurements for multiple X‐ray machines, workplaces and working conditions, information about protective measures, including use of lead aprons, and work histories. The resulting model was used to estimate calendar year‐specific badge dose calibrated as personal dose equivalent (Sv). To obtain calendar year‐specific colon doses (Gy), we applied a standard organ conversion factor. A total of 1,643 cases of solid cancer were identified in 1.45 million person‐years of follow‐up. In both ERR and EAR models, a statistically significant radiation dose–response relationship was observed for solid cancers as a group. Averaged over both sexes, and using colon dose as the dose metric, the estimated ERR/Gy was 0.87 (95% CI: 0.48, 1.45), and the EAR was 22 per 10⁴PY‐Gy (95% CI: 14, 32) at age 50. We obtained estimates of the ERR and EAR of solid cancers per unit dose that are compatible with those derived from other populations chronically exposed to low dose‐rate occupational or environmental radiation.     

To the point: medical education reviews--providing feedback

Formative feedback is an essential component of effective teaching and learning. Without it, the learner flounders. Furthermore, the Liaison Committee on Medical Education requires formative feedback within the clerkship and specifies that students must have the time and ability to remediate deficiencies before completing the clerkship. Few articles in the medical literature address how to give effective feedback. However, the themes within these articles are consistent. Formative feedback should be an interactive activity between the teacher and learner. Feedback must be approached with mutual respect and should be provided in a safe environment. Quality feedback is timely, specific to the situation, constructive, based on direct observation and nonjudgmental. With effective feedback, learners (and teachers) can discover what to improve, as well as which behaviors and skills to reinforce and augment. Learners appreciate and request specific feedback. In addition, learners tend to rate teachers who provide feedback more highly than they rate teachers who do not provide feedback. This article in the "To the Point" series will focus on the components of effective feedback and provide a practical and effective approach to giving feedback.     

Myelomeningocele: a review of the epidemiology, genetics, risk factors for conception, prenatal diagnosis, and prognosis for affected individuals

Although the use of folic acid before conception decreases the chance that a fetus will have an open neural tube defect, this condition still affects 0.5-1.0/1000 pregnancies in the United States. Results of a recent survey suggest that there are gaps in obstetrician-gynecologists' knowledge of risk factors for conception, strategies for prenatal diagnosis, and prognosis for affected individuals. To address these gaps this paper reviews the epidemiology, genetics, risk factors for conception, prenatal diagnosis, and prognosis for affected individuals, presents current information, and makes suggestions for expanding obstetrician-gynecologists' knowledge of myelomeningocele. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that despite a large amount of professional and public education on the use of folic acid in prevention of open neural tube defects (ONTDs) the incidence still affects 0.5-1.0/1000 pregnancies and recall that a recent survey conducted by the ACOG shows substantial misunderstanding and misinformation on major categories of neural tube birth defects.     

When is a pathology review indicated in endometrial cancer?

OBJECTIVE: Discrepancies may exist between an original pathology report and formal pathology review, with subsequent implications for treatment. We conducted a study of pathology review in endometrial cancer from a population-based study to identify areas of discrepancy and effect on treatment. METHODS: This was a retrospective cohort study in Ontario, Canada from 1996 to 2000. We identified hysterectomy cases from patients with endometrial cancer that were subject to formal pathology review by a gynecologic pathologist at one of six tertiary care centers. Sarcomas and other rare histologic subtypes with fewer than five cases were excluded. We evaluated discrepancy between original pathology and review by demographics, stage, grade, and risk group. Four risk groups were defined: 1) low (stage I), 2) intermediate (stage I and II), 3) high-risk (stage I and II), and 4) advanced stage (all stage III and IV). Reclassification from one risk group to another upon pathology review represented a potential change in treatment. Factors associated with significant discrepancy were identified by a multivariable logistic regression model. RESULTS: Formal pathology review was available on 450 cases. There were no differences by age, year, or hospital type. The overall discrepancy rate was 42.7% (95% confidence interval 38.2-47.3%). The intermediate-risk group had the highest rate of reclassification into another group (33.1%). The most significant rates of discrepancy were associated with endometrioid grades 2 and 3 tumors and stage IIA disease (39.8%, 50.9%, and 79.6%, respectively). CONCLUSION: There was significant discrepancy between original pathology and formal review in endometrial cancer, with implications for guidelines on pathology review at a population level. LEVEL OF EVIDENCE: III