Results of a planned interim toxicity analysis with trimodality therapy, including carboplatin AUC = 4, paclitaxel, 5-fluorouracil, amifostine, and radiation for locally advanced esophageal cancer: preliminary analyses and treatment recommendations from the North Central Cancer Treatment Group

PURPOSE: An aggressive trimodality approach from the Minnie Pearl Cancer Research Network [carboplatin AUC = 6, days 1 and 22; 5-fluorouracil 225 mg/m2 continuous infusion, days 1–42, paclitaxel 200 mg/m2, days 1 and 22; 45 Gy] has resulted in remarkable pathologic response rates but notable toxicity. This trial was designed to mitigate this toxicity by starting with a lower carboplatin dose, AUC = 4, and by adding subcutaneous amifostine. METHODS: This phase II trial included patients with locally advanced, potentially resectable esophageal cancer. All were to receive the above regimen with modifications of carboplatin AUC = 4 and amifostine 500 mg subcutaneously before radiation. All were then to undergo an esophagectomy. A planned interim toxicity analysis after the first 10 patients was to determine whether the carboplatin dose should escalate to AUC = 6. RESULTS: Ten patients were enrolled, and all required dose reductions/omissions during neoadjuvant therapy. One patient died from paclitaxel anaphylaxis. Six patients manifested a complete pathologic response. CONCLUSION: With this regimen, carboplatin AUC = 4 for patients with locally advanced esophageal cancer is appropriate

An integrated approach to identify new anti-filarial leads to treat river blindness, a neglected tropical disease

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adul

Practice Characteristics and Job Satisfaction of Private Practice and Academic Surgeons

IMPORTANCE: Private practice and academic surgery careers vary significantly in their daily routine, compensation schemes, and definition of productivity. Data are needed regarding the practice characteristics and job satisfaction of these career paths for surgeons and trainees to make informed career decisions and to identify modifiable factors that may be associated with the health of the surgical workforce. OBJECTIVE: To obtain and compare the differences in practice characteristics and career satisfaction measures between academic and private practice surgeons. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional survey performed from June 4 to August 1, 2018, an online survey accommodating smartphone, tablet, and desktop formats was distributed by email to 25 748 surgeons who were actively practicing fellows of the American College of Surgeons; had completed a general surgery residency or categorical fellowship in plastic, cardiothoracic, or vascular surgery; and had an active email address on file. MAIN OUTCOMES AND MEASURES: Demographic, training, and current practice characteristics were obtained, and satisfaction measures were measured on a 5-point Likert scale and compared by surgeon type. Nonresponse weights adjusted for respondent sex, age, and presence of subspecialty training between respondents and the total surveyed American College of Surgeons population. RESULTS: There were 3807 responses (15% response rate) from surgeons: 1735 academic surgeons (1390 men [80%]; median age, 53 years [interquartile range (IQR), 44-61 years]) and 1464 private practice surgeons (1276 men [87%]; median age, 56 years [IQR, 48-62 years]); 589 surgeons who reported being neither an academic surgeon nor a private practice surgeon and 19 surgeons who did not respond to questions on their practice type were excluded. Academic surgeons reported working a median of 59 hours weekly (IQR, 38-65 hours) compared with 57 hours weekly (IQR, 45-65 hours) for private practice surgeons. Academic surgeons reported more weekly hours performing nonclinical work than did private practice surgeons (24 hours [IQR, 14-38 hours] vs 9 hours [IQR, 4-17 hours]; P < .001). Academic surgeons were more likely than private practice surgeons to be satisfied with their career as a surgeon (1448 of 1706 [85%] vs 1109 of 1420 [78%]; P < .001) and their financial compensation (997 of 1703 [59%] vs 546 of 1416 [39%]; P < .001). Academic surgeons were less likely than private practice surgeons to feel that competition with other surgeons is a threat to financial security (341 of 1705 [20%] vs 559 of 1422 [39%]; P < .001) and less likely to feel that malpractice experience has decreased job satisfaction (534 of 1703 [31%] vs 686 of 1413 [49%]; P < .001). CONCLUSIONS AND RELEVANCE: This study suggests that, although overall surgeon satisfaction was high, academic surgeons reported higher career satisfaction on several measures when compared with private practice surgeons. Advocacy for private practice surgeons is important to encourage career longevity and sustain US surgeon workforce needs

WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration

Slow Wallerian degeneration (WldS) encodes a chimeric Ube4b/nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) fusion protein that potently suppresses Wallerian degeneration, but the mechanistic action of WldS remains controversial. In this study, we characterize WldS-mediated axon protection in vivo using Drosophila melanogaster. We show that Nmnat1 can protect severed axons from autodestruction but at levels significantly lower than WldS, and enzyme-dead versions of Nmnat1 and WldS exhibit severely reduced axon-protective function. Interestingly, a 16–amino acid N-terminal domain of WldS (termed N16) accounts for the differences in axon-sparing activity between WldS and Nmnat1, and N16-dependent enhancement of Nmnat1-protective activity in WldS requires the N16-binding protein valosin-containing protein (VCP)/TER94. Thus, WldS-mediated suppression of Wallerian degeneration results from VCP–N16 interactions and Nmnat1 activity converging in vivo. Surprisingly, mouse Nmnat3, a mitochondrial Nmnat enzyme that localizes to the cytoplasm in Drosophila cells, protects severed axons at levels indistinguishable from WldS. Thus, nuclear Nmnat activity does not appear to be essential for WldS-like axon protection

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments