Biomarkers of cellular senescence and risk of death in humans.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Comparing risk stratification criteria for predicting lymphatic dissemination in endometrial cancer.

OBJECTIVE: To compare two published risk stratification models (Milwaukee Model vs. Mayo Criteria) to predict lymphatic dissemination (LD) in endometrioid endometrial cancer (EC). METHODS: Patients with stage I-III EC undergoing surgery from 1/1/2004-9/30/2013 were retrospectively reviewed and classified as low-risk vs at-risk for LD using two independent risk models. LD was defined as positive nodes at surgery or lymph node recurrence within 2 years of surgery after negative lymph node dissection (LND) or when LND was not performed. False positive (FP) and false negative (FN) rates for each risk model were calculated. RESULTS: Among 1103 patients, 81 (7.3%) had LD (72 positive LN and 9 LN recurrences), and most (90.2%) had stage I EC. The Milwaukee Model yielded a low at-risk rate for LD (38.1%) but a high FN rate (13.6%, 95% CI 7.0-23.0). The traditional Mayo Criteria using a cut-off of 2 cm for tumor diameter (TD) had a higher at-risk rate for LD (69.5%) but a FN rate of 0% (95% CI, 0-4.5). Modifying the Mayo Criteria using a TD cutoff of ≤3 cm identified fewer women at-risk (56.8% vs. 69.5%) and had a lower FP rate (53.6% vs. 67.1%), but had a higher FN rate (3.7%, 95% CI, 0.8-10.4). CONCLUSIONS: The Milwaukee Model had the lowest at-risk rate of LD but an unacceptable FN rate. Modifying the Mayo Criteria by increasing the TD cutoff from the traditional ≤2 cm to ≤3 cm would spare an estimated 13.5% of patients LND, but the accompanying FN rate is unacceptably high. The traditional Mayo Criteria for low-risk EC remains the most sensitive in determining which patients LND can be omitted.

Predictors of extensive lymphatic dissemination and recurrences in node-positive endometrial cancer.

OBJECTIVE: To identify predictors of extensive lymphatic dissemination and distant recurrences in node-positive endometrial cancer (EC). METHODS: Clinicopathologic data were collected of patients who had fully staged EC with at least 1 positive lymph node. Permanent sections of metastatic lymph nodes were reviewed; metastases were characterized according to size (≤2 mm and >2 mm) and location in the lymph node (intra- vs extracapsular). Risk of occurrence of multiple pelvic and para-aortic lymph node dissemination was calculated by combining risk factors identified at multivariate analysis. RESULTS: Of 96 patients, 85 had positive pelvic nodes, of whom 71 (83.5%) had high-volume metastases. In the presence of both macrometastasis in the pelvic basin (odds ratio [OR], 13.42; [95% CI, 2.44-73.83]) and uterine serosal involvement of the tumor at final pathologic evaluation (OR, 11.84 [95% CI, 1.22-115.11]), multiple pelvic node dissemination occurred in 91.7% of cases (vs 7.7% in the absence of both). Concomitant presence of pelvic macrometastasis, lymphovascular space invasion (LVSI), and extracapsular invasion led to 85.7% occurrence of para-aortic involvement (vs 11.1% if no factors present). LVSI was independently associated with nonvaginal recurrences (hazard ratio, 2.62 [95% CI, 1.33-5.16]). CONCLUSIONS: Presence of high-volume metastases in the pelvic lymph nodes is associated with concomitant presence of multiple positive pelvic nodes, as well as para-aortic node involvement. LVSI is associated with both para-aortic node involvement and occurrence of nonvaginal relapses. In this era of sentinel lymph node mapping, these factors may help predict the extent of lymphatic dissemination in EC.

Intrapartum factors associated with neonatal hypoxic ischemic encephalopathy: a case-controlled study.

BACKGROUND: Neonatal encephalopathy (NE) affects 2-4/1000 live births with outcomes ranging from negligible neurological deficits to severe neuromuscular dysfunction, cerebral palsy and death. Hypoxic ischemic encephalopathy (HIE) is the sub cohort of NE that appears to be driven by intrapartum events. Our objective was to identify antepartum and intrapartum factors associated with the development of neonatal HIE. METHODS: Hospital databases were searched using relevant diagnosis codes to identify infants with neonatal encephalopathy. Cases were infants with encephalopathy and evidence of intrapartum hypoxia. For each hypoxic ischemic encephalopathy case, four controls were randomly selected from all deliveries that occurred within 6 months of the case. RESULTS: Twenty-six cases met criteria for hypoxic ischemic encephalopathy between 2002 and 2014. In multivariate analysis, meconium-stained amniotic fluid (aOR 12.4, 95% CI 2.1-144.8, p = 0.002), prolonged second stage of labor (aOR 9.5, 95% CI 1.0-135.3, p = 0.042), and the occurrence of a sentinel or acute event (aOR 74.9, 95% CI 11.9-infinity, p < 0.001) were significantly associated with hypoxic ischemic encephalopathy. The presence of a category 3 fetal heart rate tracing in any of the four 15-min segments during the hour prior to delivery (28.0% versus 4.0%, p = 0.002) was more common among hypoxic ischemic encephalopathy cases. CONCLUSION: Prolonged second stage of labor and the presence of meconium-stained amniotic fluid are risk factors for the development of HIE. Close scrutiny should be paid to labors that develop these features especially in the presence of an abnormal fetal heart tracing. Acute events also account for a substantial number of HIE cases and health systems should develop programs that can optimize the response to these emergencies.

Effect of chair types on work-related musculoskeletal discomfort during vaginal surgery.

BACKGROUND: Evidence supports that surgeons are at high risk for work-related musculoskeletal disorders. OBJECTIVE: The objective of the study was to compare the effect of different chairs on work-related musculoskeletal discomfort for surgeons during vaginal operations. STUDY DESIGN: This crossover study randomly assigned 4 surgeons to 4 chair types using a 4 × 4 Latin square model: a conventional round stool, a round stool with a backrest, a saddle chair with a backrest, and a Capisco chair. Subjective assessments of surgeon discomfort were performed with a validated body discomfort survey, and workload was assessed with the surgical task load index. The objective postural load was quantified with inertial measurement units of the modified rapid upper limb assessment limits. Subjective and objective assessments of chair comfort were performed with an 11 point scale and seat interface pressure-mapped distributions, respectively. The primary outcome was the difference in body discomfort scores between pre- and postsurgery measurements. Secondary outcomes were the differences in chair comfort scores, postural load, and seating interface pressure-mapped distribution. For each outcome, comparisons among the chair types were based on fitting a linear mixed model that handled the surgeon as a random effect and the chair type as a fixed effect. RESULTS: Data were collected for 48 vaginal procedures performed for pelvic organ prolapse. Mean (SD) duration of surgery was 122.3 (25.1) minutes. Surgeons reported body discomfort during 31 procedures (67.4%). Subjective increase in discomfort from the preoperative state was noted most commonly in the lower back (n = 14, 30.4%), followed by right shoulder (n = 12, 26.1%), upper back (n = 8, 17.4%), hips and buttocks (n = 7, 15.2%), left shoulder (n = 6, 13.0%), right or left thigh (n = 6, 13.0%), and neck (n = 6, 13.0%). Pre- and postsurgery body discomfort scores did not differ with respect to chair type. Chair discomfort scores for the round stool and the saddle chair were significantly higher than the round stool with backrest and the Capisco chair (P < .001). Although the average modified rapid upper limb assessment postural scores showed moderate to high musculoskeletal risk of neck and shoulder discomfort across the 4 surgeons; chair type did not affect postural scores. The saddle chair had significantly reduced dispersion of seated pressure vs the round stool with backrest (P ≤ .001), depicted by the number of cells with pressure values >5 mm Hg. An increased dispersion of pressure across the chair surface was associated with increased comfort (Spearman correlation, 0.40, P = .006). CONCLUSION: Musculoskeletal strain and associated discomfort for surgeons are very high during vaginal operations. Chair type can affect comfort, and chairs with more uniform distribution and fewer pressure points are more comfortable. However, the chair type used in surgery did not influence the musculoskeletal postural load findings.

Integrating Pharmacogenomics into Clinical Practice: Promise vs Reality.

BACKGROUND: Limited information is available regarding primary care clinicians' response to pharmacogenomic clinical decision support (PGx-CDS) alerts integrated in the electronic health record. METHODS: In February 2015, 159 clinicians in the Mayo Clinic primary care practice were sent e-mail surveys to understand their perspectives on the implementation and use of pharmacogenomic testing in their clinical practice. Surveys assessed how the clinicians felt about pharmacogenomics and whether they thought electronic PGx-CDS alerts were useful. Information was abstracted on the number of CDS alerts the clinicians received between October 2013 and the date their survey was returned. CDS alerts were grouped into 2 categories: the alert recommended caution using the prescription, or the alert recommended an alternate prescription. Finally, data were abstracted regarding whether the clinician changed their prescription in response to the alert recommendation. RESULTS: The survey response rate was 57% (n = 90). Overall, 52% of the clinicians did not expect to use or did not know whether they would use pharmacogenomic information in their future prescribing practices. Additionally, 53% of the clinicians felt that the alerts were confusing, irritating, frustrating, or that it was difficult to find additional information. Finally, only 30% of the clinicians that received a CDS alert changed their prescription to an alternative medication. CONCLUSIONS: Our results suggest a lack of clinician comfort with integration of pharmacogenomic data into primary care. Further efforts to refine PGx-CDS alerts to make them as useful and user-friendly as possible are needed to improve clinician satisfaction with these new tools.

The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts.

OBJECTIVE: To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity score (PS) matching to account for confounding factors. METHODS: We retrospectively identified consecutive patients with stage I-IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes. RESULTS: Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio [HR], 1.01; 95% CI, 0.72-1.42) and PFS (HR, 1.01; 95% CI, 0.60-1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57-1.85; PFS HR, 1.14; 95% CI, 0.49-2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30-1.23; PFS HR, 1.06; 95% CI, 0.34-3.30). CONCLUSIONS: When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients.