An Evaluation of the Online Quality of Content of United States Accredited Pain Medicine Fellowship Training Programs.

BACKGROUND: Pain medicine fellowship applicants often seek information about programs from the Internet, which is becoming even more relevant with the transition to virtual interviews as a consequence of the global pandemic. Previous literature has revealed the significance of training program websites as part of the application process in other specialties. OBJECTIVES: The objective of this cross-sectional study was to evaluate the content, design, organization, and user friendliness by using a composite score to determine the quality of the pain medicine fellowship websites (PMFW). METHODS: Accredited pain medicine fellowship programs was queried from three databases for pain medicine education: (1) Electronic Residency Application Service (ERAS); (2) the Fellowship and Residency Electronic Interactive Database (FREIDA); and (3) the National Resident Matching Program (NRMP). Programs that appeared within one and/or more databases were eligible for study inclusion. PMFW were evaluated for the accessibility of recruitment and education content items. The quality of PMFW was determined as multifactorial composed of four dimensions: content, design, organization, and user friendliness. RESULTS: For program recruitment, PMFW contained an average of 12 ± 4.0 of 32 content items (38%) for fellowship programs: (1) 83% of fellowship programs specified the number of positions available for the 2021 Match; (2) 17% indicated alumni career placement; (3) 6.8% supplied interview dates; and (4) merely 4.9% detailed the selection process. For program education, PMFW contained an average of 7 ± 3.4 of 16 content items (44%): (1) 70% of programs provided a rotation schedule; (2) 49% detailed operative experiences; and (3) just 16% included simulation training. Regarding the quality based on content, design, organization, and user friendliness, the average PMFW was not "good" with only 1% of PMFW meeting "great" standards. A kappa value of 0.92 was calculated for inter-rater reliability. CONCLUSIONS: The web presence of pain medicine fellowship programs falls short of providing essential accessibility, content, design, organization, and user friendliness to allow applicants to adequately access information about program characteristics. There are ample opportunities to increase the effectiveness of PMFW to benefit training programs and to inform prospective applicants, especially given the rise of virtual applications and interviews.

Clinical inertia during postoperative management of diabetes mellitus: relationship between hyperglycemia and insulin therapy intensification.

OBJECTIVE: Our objective was to assess the application of insulin regimens in surgical postoperative patients with diabetes. METHODS: A chart review was conducted of patients with diabetes who were hospitalized postoperatively between January 1 and April 30, 2011. Analysis was restricted to patients hospitalized for ≥3 days and excluded cases with an endocrinology consult. Insulin regimens were categorized as "basal plus short acting," "short acting only," or "none," and the pattern of use was evaluated by hyperglycemia severity according to tertiles of both mean glucose and the number of glucose measurements >180 mg/dl. RESULTS: Among cases selected for analysis (n = 119), examination of changes in insulin use based on tertiles of mean glucose showed that use of basal plus short-acting insulin increased from 10% in the lowest tertile (mean glucose, 120 mg/dl) to 18% in the highest tertile (mean glucose, 198 mg/dl; p < .01); however, 70% of patients in the highest tertile continued to receive short-acting insulin only, with 12% receiving no insulin. Intensification of insulin to a basal plus short-acting regimen was also seen when changes were evaluated by the number of measurements >180 mg/dl (p < .01), but 70% and 12% of patients in the highest tertile still remained only on short-acting insulin or received no insulin, respectively. CONCLUSIONS: Use of basal plus short-acting insulin therapy increased with worsening hyperglycemia, but many cases did not have therapy intensified to the recommended insulin regimen--evidence of clinical inertia. Strategies should be devised to overcome inpatient clinical inertia in the treatment of postoperative patients with diabetes.

Perioperative management of patients with diabetes undergoing ambulatory elective surgery.

OBJECTIVE: The objective was to assess processes of care for patients with diabetes undergoing elective surgery. METHODS: A retrospective review of medical records was conducted to determine frequency of perioperative glucose monitoring, changes in glucose control, and treatment of intraoperative hyperglycemia. RESULTS: A total of 268 patients underwent 287 elective procedures. Mean age was 67 years, 63% were men, 97% had type 2 diabetes, and most (57%) were treated with oral hypoglycemic agents. Average perioperative time was approximately 8 h. Mean preoperative hemoglobin A1c was 7.0%; however, this value was checked in only 52% of cases. A glucose measurement was obtained in 89% of cases in the preoperative area and in 87% in the postanesthesia care unit, but in only 33% of cases did a value get checked intraoperatively. Average glucose was 139 mg/dl preoperatively, increasing to 166 mg/dl postoperatively (p <.001). Glucose levels increased regardless of type of outpatient medical therapy used to treat hyperglycemia, except for those on combination oral agents plus insulin (p =.06). CONCLUSIONS: These data indicate suboptimal documentation of outpatient hemoglobin A1c. Intraoperative glucose monitoring seldom occurred, despite prolonged periods under anesthesia and perioperative deterioration of glycemic control. Standards need to be developed and interventions are needed to enhance management of diabetes patients undergoing elective procedures.

Genetic Diversity in Normal Cell Populations is the Earliest Stage of Oncogenesis Leading to Intra-Tumor Heterogeneity.

Random mutations and epigenetic alterations provide a rich substrate for microevolutionary phenomena to occur in proliferating epithelial tissues. Genetic diversity resulting from random mutations in normal cells is critically important for understanding the genetic basis of oncogenesis. However, evaluation of the cell-specific role of individual (epi-)genetic alterations in living tissues is extremely difficult from a direct experimental perspective. For this purpose, we have developed a single cell model to describe the fate of every cell in the uterine epithelium and to simulate occurrence of the first cancer cell. Computational simulations have shown that a baseline mutation rate of two mutations per cell division is sufficient to explain sporadic endometrial cancer as a rare evolutionary consequence with an incidence similar to that reported in SEER data. Simulation of the entire oncogenic process has allowed us to analyze the features of the tumor-initiating cells and their clonal expansion. Analysis of the malignant features of individual cancer cells, such as de-differentiation status, proliferation potential, and immortalization status, permits a mathematical characterization of malignancy at the single cell level and a comparison of intra-tumor heterogeneity between individual tumors. We found, under the conditions specified, that cancer stem cells account for approximately 7% of the total cancer cell population. Therefore, our mathematical modeling describes the genetic diversity and evolution in a normal cell population at the early stages of oncogenesis and characterizes intra-tumor heterogeneity. This model has explored the role of accumulation of a large number of genetic alterations in oncogenesis as an alternative to traditional biological approaches emphasizing the driving role of a small number of genetic mutations. A quantitative description of the contribution of a large set of genetic alterations will allow the investigation of the impact of environmental factors on the growth advantage of and selection pressure on individual cancer cells for tumor progression.

Quantitative interpretation of a genetic model of carcinogenesis using computer simulations.

The genetic model of tumorigenesis by Vogelstein et al. (V theory) and the molecular definition of cancer hallmarks by Hanahan and Weinberg (W theory) represent two of the most comprehensive and systemic understandings of cancer. Here, we develop a mathematical model that quantitatively interprets these seminal cancer theories, starting from a set of equations describing the short life cycle of an individual cell in uterine epithelium during tissue regeneration. The process of malignant transformation of an individual cell is followed and the tissue (or tumor) is described as a composite of individual cells in order to quantitatively account for intra-tumor heterogeneity. Our model describes normal tissue regeneration, malignant transformation, cancer incidence including dormant/transient tumors, and tumor evolution. Further, a novel mechanism for the initiation of metastasis resulting from substantial cell death is proposed. Finally, model simulations suggest two different mechanisms of metastatic inefficiency for aggressive and less aggressive cancer cells. Our work suggests that cellular de-differentiation is one major oncogenic pathway, a hypothesis based on a numerical description of a cell's differentiation status that can effectively and mathematically interpret some major concepts in V/W theories such as progressive transformation of normal cells, tumor evolution, and cancer hallmarks. Our model is a mathematical interpretation of cancer phenotypes that complements the well developed V/W theories based upon description of causal biological and molecular events. It is possible that further developments incorporating patient- and tissue-specific variables may build an even more comprehensive model to explain clinical observations and provide some novel insights for understanding cancer.

Development of a phylogenetic tree model to investigate the role of genetic mutations in endometrial tumors.

With the advancement of modern genome sequencing technology, thousands of genetic mutations have been identified in human tumors. However, analysis of the role of genetic mutations in tumor development is limited by the need for prevalence information among multiple tumors and by the lack of analytic capability to define the functional contribution of genetic mutations in patients, individually and collectively. To understand the genetic basis of human endometrial cancer, the fourth most common cancer in women, transcriptome sequencing was performed on an endometrial tumor paired with normal cervical tissue. Twenty-six non-synonymous somatic mutations were validated in the tumor genome. A phylogenetic tree illustrating the mutational time-line was developed based upon the distribution of 26 mutations in 30 randomly-selected laser-captured single cells from the tumor sections. Five ubiquitous mutations were identified that are presumed to occur in the cancer founder cell of the tumor, and may collectively play critical roles in endometrial oncogenesis. However, further testing in 10 additional endometrial tumors failed to show overlapping mutations in the cancer founder cells, indicating the lack of a single common oncogenic pathway for these endometrial tumors. The effects of individual mutations in cancer cell proliferation were calculated based on descendant cell number and time span since acquiring each mutation. We have developed a phylogenetic approach to characterize individual genetic mutations in cancer cell proliferation in a single resected patient tumor. This approach provides the capability to study the tumor-specific role of genetic mutations, without relying on prevalence information from other patients.

Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent.

Endometrial cancer (ECa) is the fourth most common malignancy in women. Currently, there is no effective therapy for advanced and recurrent cancer. Among the poor-outcome endometrial cancers, there is a high frequency of TP53 mutations. We have previously reported that amifostine has a direct anti-cancer effect and has a significant synergistic effect with paclitaxel when used in endometrial cancer cell and xenograft models. In this report, using a cell line with knock-down p53 expression through siRNA, we found that amifostine enhancement of paclitaxel's anticancer effect is p53 status-dependent. Amifostine promotes entry into the G2-M phase through regulation of cyclin-dependent kinase-1 activity in cells with dysfunctional p53, thereby enhancing cancer cell sensitivity to paclitaxel. The synergistic effect between amifostine and paclitaxel was further confirmed in vivo using xenografts created with primary patient tumor tissue. Sensitivity to the therapeutic effect of paclitaxel in combination with amifostine was dependent upon the status of p53. A tumor with a nonsense TP53 mutation showed increased therapeutic response to paclitaxel and amifostine as measured by tumor weight compared to a tumor with wild- type TP53. Our study provides a rationale for a clinical trial of combined paclitaxel and amifostine in endometrial cancer patients whose tumors harbor TP53 mutations.