Citations

Abstract Background The American Board of Anesthesiology recently introduced the BASIC Examination, a component of its new staged examinations for primary certification, typically offered to residents at the end of their first year of clinical anesthesiology training. This analysis tested the hypothesis that the introduction of the BASIC Examination was associated with an acceleration of knowledge acquisition during the residency training period, as measured by increments in annual In-Training Examination scores. Methods In-Training Examination performance was compared longitudinally among four resident cohorts (n = 6,488) before and after the introduction of the staged system using mixed-effects models that accounted for possible covariates. Results Compared with previous cohorts in the traditional examination system, the first resident cohort in the staged system had a greater improvement in In-Training Examination scores between the first and second years of clinical anesthesiology training (by an estimated 2.0 points in scaled score on a scale of 1 to 50 [95% CI, 1.7 to 2.3]). By their second year, they had achieved a score similar to that of third-year clinical anesthesiology residents in previous cohorts. The second cohort to enter the staged system had a greater improvement of the scores between the clinical base year and the first clinical anesthesiology year, compared with the previous cohorts. Conclusions These results support the hypothesis that the introduction of the BASIC Examination is associated with accelerated knowledge acquisition in residency training and provides evidence for the value of the new staged system in promoting desired educational outcomes of anesthesiology training.

Background: Studies have reported that the perioperative use of cimetidine, a histamine type 2 receptor antagonist, in addition to chemotherapy in patients with lymph node–positive colorectal cancer (CRC) improves the survival. Study Question: To determine if time to CRC recurrence could be prolonged with cimetidine. Study Design: Cimetidine was prescribed to American Joint on Cancer Committee (AJCC) stage III CRC patients perioperatively. Tumor recurrence was defined as the time (in days) between tumor resection and CRC recurrence. Medical charts of patients diagnosed with CRC between 1996 and 2006 were reviewed. Inclusion criteria were patients with (a) AJCC stage III CRC, (b) who had undergone surgical resection of the tumor, and (c) who received chemotherapy (5-fluorouracil). Measures and Outcomes: AJCC stage III CRC patients who did and did not receive cimetidine as part of the treatment regimen were compared with respect to their clinical outcomes using univariate analysis and Kaplan–Meier modeling. Results: Between 1996 and 2006, 38 patients met our inclusion criteria. Twenty-six percent (10/38) received perioperative cimetidine (mean daily dose, 750 mg; mean duration, 369 days; mean total cumulative cimetidine dose, 274,070 mg/d) in addition to chemotherapy. Time to recurrence and cancer deaths were prolonged in the chemotherapy plus cimetidine group compared with the group that received chemotherapy alone (mean ± SD: 1078 ± 290 vs. 446 ± 62; P = 0.03). In addition, we found a significant positive relationship between the duration of cimetidine therapy (days) and survival duration (correlation coefficient = 0.94, P = 0.02) and time until cancer recurrence (correlation coefficient = 0.99, P = 0.04). Moreover, there was a significant positive relationship between the total cumulative cimetidine dose and survival duration (correlation coefficient = 0.92, P = 0.03). Conclusions: Prolonged duration of cimetidine may be superior to shorter courses in prolonging recurrence of CRC and thus survival.

Brain mutations, young and old Most neurons that make up the human brain are postmitotic, living and functioning for a very long time without renewal (see the Perspective by Lee). Bae et al. examined the genomes of single neurons from the prenatal developing human brain. Both the type of mutation and the rates of accumulation changed between gastrulation and neurogenesis. These early mutations could be generating useful neuronal diversity or could predispose individuals to later dysfunction. Lodato et al. also found that neurons take on somatic mutations as they age by sequencing single neurons from subjects aged 4 months to 82 years. Somatic mutations accumulated with increasing age and accumulated faster in individuals affected by inborn errors in DNA repair. Postmitotic mutations might only affect one neuron, but the accumulated divergence of genomes across the brain could affect function. Science , this issue p. 550 , p. 555 ; see also p. 521

The mechanical response of intact blood vessels to applied loads can be delineated into passive and active components using an isometric decomposition approach. Whereas the passive response is due predominantly to the extracellular matrix (ECM) proteins and amorphous ground substance, the active response depends on the presence of smooth muscle cells (SMCs) and the contractile machinery activated within those cells. To better understand determinants of active stress generation within the vascular wall, we subjected porcine common carotid arteries (CCAs) to biaxial inflation–extension testing under maximally contracted or passive SMC conditions and semiquantitatively measured two known markers of the contractile SMC phenotype: smoothelin and smooth muscle-myosin heavy chain (SM-MHC). Using isometric decomposition and established constitutive models, an intuitive but novel correlation between the magnitude of active stress generation and the relative abundance of smoothelin and SM-MHC emerged. Our results reiterate the importance of stretch-dependent active stress generation to the total mechanical response. Overall these findings can be used to decouple the mechanical contribution of SMCs from the ECM and is therefore a powerful tool in the analysis of disease states and potential therapies where both constituent are altered.

SummaryObjectiveThymic neuroendocrine tumour (TH‐NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)‐associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice.Design and PatientsWe performed a retrospective analysis of patients treated for TH‐NET associated with MEN1 in a single institution and meta‐analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis.ResultsTH‐NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH‐NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0‐72.0 years). Forty‐three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR = 1.4, 95% CI = 1.0‐1.8, P = .03), maximum tumour diameter (HR = 1.5, 95% CI = 1.0‐2.3, P = .04) and presence of metastasis (HR = 1.6, 95% CI = 1.0‐2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports.ConclusionTH‐NET is a rare but fatal component of MEN1. Earlier detection of TH‐NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.

AbstractBackgroundFatigue is a consistently reported, severe symptom among patients with gliomas throughout the disease trajectory. Genomic pathways associated with fatigue in glioma patients have yet to be identified.MethodsClinical factors (performance status, tumor details, age, gender) were collected by chart review on glioma patients with fatigue (“I have lack of energy” on Functional Assessment of Cancer Therapy-Brain), as well as available genotyping data. Candidate genes in clock and inflammatory pathways were identified from a literature review, of which 50 single nucleotide polymorphisms (SNPs) in 7 genes were available. Clinical factors and SNPs identified by univariate analyses were included in a multivariate model for moderate-severe fatigue.ResultsThe study included 176 patients (median age = 47 years, 67% males). Moderate-severe fatigue was reported by 43%. Results from multivariate analysis revealed poor performance status and 2 SNPs were associated with fatigue severity. Moderate-severe fatigue was more common in patients with poor performance status (OR = 3.52, P < .01). For each additional copy of the minor allele in rs934945 (PER2) the odds of fatigue decreased (OR = 0.51, P < .05). For each additional copy of the minor allele in rs922270 (ARTNL2) the odds of fatigue increased (OR = 2.38, P < .01). Both of these genes are important in the circadian clock pathway, which has been implicated in diurnal preference, and duration and quality of sleep. No genes in the inflammatory pathway were associated with fatigue in the current study.ConclusionsIdentifying patients at highest risk for fatigue during treatment allows for improved clinical monitoring and enrichment of patient selection for clinical trials.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.