Faculty Bibliography

BACKGROUND:Understanding the dynamics of the gut-brain axis has clinical implications for physical and mental health conditions, including obesity and anxiety. As such disorders have early life antecedents, it is of value to determine if associations between the gut microbiome and behavior are present in early life in humans. METHODS:We used next generation pyrosequencing to examine associations between the community structure of the gut microbiome and maternal ratings of child temperament in 77 children at 18-27months of age. It was hypothesized that children would differ in their gut microbial structure, as indicated by measures of alpha and beta diversity, based on their temperamental characteristics. RESULTS:Among both boys and girls, greater Surgency/Extraversion was associated greater phylogenetic diversity. In addition, among boys only, subscales loading on this composite scale were associated with differences in phylogenetic diversity, the Shannon Diversity index (SDI), beta diversity, and differences in abundances of Dialister, Rikenellaceae, Ruminococcaceae, and Parabacteroides. In girls only, higher Effortful Control was associated with a lower SDI score and differences in both beta diversity and Rikenellaceae were observed in relation to Fear. Some differences in dietary patterns were observed in relation to temperament, but these did not account for the observed differences in the microbiome. CONCLUSIONS:Differences in gut microbiome composition, including alpha diversity, beta diversity, and abundances of specific bacterial species, were observed in association with temperament in toddlers. This study was cross-sectional and observational and, therefore, does not permit determination of the causal direction of effects. However, if bidirectional brain-gut relationships are present in humans in early life, this may represent an opportunity for intervention relevant to physical as well as mental health disorders.

OBJECTIVE:To estimate the rate of inpatient stay and the factors predicting inpatient status after robotic surgery for endometrial cancer following the change in the Medicare definition of "inpatient" to include hospitalization spanning 2 midnights. DESIGN/METHODS:Retrospective chart review (Canadian Task Force classification II-1). SETTING/METHODS:Academic hospital. PATIENTS/METHODS:All patients (n = 395) with endometrial cancer who underwent robotic surgical management between 2006 and 2010. INTERVENTION/METHODS:The outpatient stay group with hospitalization spanning 1 midnight was compared with the inpatient stay group with hospitalization spanning 2 midnights or longer through estimation of the adjusted relative risk (aRR) for various characteristics of interest. RESULTS:Ninety-six of 395 patients (24.3%) stayed at least 2 midnights and thus were deemed inpatients. Clinical factors associated with inpatient stay were increasing age, history of myocardial infarction (aRR, 2.0; 95% confidence interval [CI], 1.0-3.7), surgery start time at or after 12 noon (aRR, 1.7; 95% CI, 1.2-2.4), perioperative blood transfusion (aRR, 3.2; 95% CI, 2.3-4.5), and surgery performed in the year 2010 (aRR, 0.5; 95% CI, 0.3-0.7). Age ≥ 60 years was associated with at least a 2-fold adjusted risk of prolonged hospitalization. Body mass index, other medical comorbidities, operative duration, estimated blood loss, and performance of lymphadenectomy or additional surgical procedures were not identified as significant risk factors. CONCLUSION/CONCLUSIONS:Approximately 75% of the patients undergoing robotic surgery for endometrial cancer were discharged as outpatients. Recognition of factors predicting inpatient stay can improve hospital resource allocation and throughput in women undergoing robotic surgery for endometrial cancer.

OBJECTIVE:We assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies. METHODS:A retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia. RESULTS:Four hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87-3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9-1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6-1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group. CONCLUSIONS:The incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.

OBJECTIVE:The standard weekly dose of 17-alpha hydroxyprogesterone caproate (17OHP-C; 250 mg/wk) to reduce the risk of recurrent preterm birth was adopted without regard to patient characteristics. We examined the relationship between prepregnancy body mass index (BMI) and gestational age at birth after 17OHP-C prophylaxis. We hypothesized that rates of births before 32, 35, and 37 weeks of gestation would be increased in women with a BMI of 25 kg/m(2) or greater. STUDY DESIGN/METHODS:A retrospective cohort study was conducted from a deidentified database of women treated with 17OHP-C for prior spontaneous preterm birth. The frequency of recurrent preterm delivery before 32, 35, and 37 weeks of gestation was investigated for women with a BMI less than 25 kg/m(2) compared with women with a BMI of 25 kg/m(2) or greater. The adjusted relative risk of preterm delivery was estimated through a modified Poisson regression approach. RESULTS:Of 390 women who met inclusion criteria, 60 (15.4%) delivered before 32 weeks, 89 (22.8%) before 35 weeks, and 156 (40.0%) before 37 weeks. A total of 174 women had a BMI less than 25 kg/m(2) (mean [SD], 21.2 [2.5]) and 216 had a BMI of 25 kg/m(2) or greater (mean [SD], 33.5 [6.7]). Risk of birth before 32 weeks was 1.7 times higher on average (adjusted relative risk, 1.7; 95% confidence interval, 1.05-2.77) in overweight women than in women with a BMI less than 25 kg/m(2), adjusting for age, race, smoking, and short cervix. There was no difference in the risk of preterm birth before 35 or 37 weeks. CONCLUSION/CONCLUSIONS:Among pregnant women receiving 17OHP-C prophylaxis for a prior preterm birth, recurrent preterm birth before 32 weeks was significantly more common in those women whose prepregnancy BMI was 25 kg/m(2) or greater than in women with BMI less than 25 kg/m(2). This observation is consistent with pharmacological studies suggesting that dosing regimens of 17OHP-C may affect efficacy.

The use of propensity score methods to adjust for selection bias in observational studies has become increasingly popular in public health and medical research. A substantial portion of studies using propensity score adjustment treat the propensity score as a conventional regression predictor. Through a Monte Carlo simulation study, Austin and colleagues. investigated the bias associated with treatment effect estimation when the propensity score is used as a covariate in nonlinear regression models, such as logistic regression and Cox proportional hazards models. We show that the bias exists even in a linear regression model when the estimated propensity score is used and derive the explicit form of the bias. We also conduct an extensive simulation study to compare the performance of such covariate adjustment with propensity score stratification, propensity score matching, inverse probability of treatment weighted method, and nonparametric functional estimation using splines. The simulation scenarios are designed to reflect real data analysis practice. Instead of specifying a known parametric propensity score model, we generate the data by considering various degrees of overlap of the covariate distributions between treated and control groups. Propensity score matching excels when the treated group is contained within a larger control pool, while the model-based adjustment may have an edge when treated and control groups do not have too much overlap. Overall, adjusting for the propensity score through stratification or matching followed by regression or using splines, appears to be a good practical strategy.

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

OBJECTIVES/OBJECTIVE:In addition to hysterectomy and bilateral salpingo-oophorectomy, comprehensive surgical staging for endometrial cancer includes pelvic and para-aortic lymphadenectomy. Clarifying and addressing the morbidity from these surgical procedures is imperative. The goal of this study was to assess the prevalence of lower extremity swelling after surgery for endometrial cancer. MATERIALS AND METHODS/METHODS:We performed a descriptive, cross-sectional survey study of women who underwent surgery for endometrial cancer at our institution from 2006 to 2008. Survey information included symptoms, management, and education regarding lymphedema. Demographic information such as race and education was collected in addition to clinical data such as body mass index and age. RESULTS:Of the 482 patients identified, 440 were determined eligible and 305 (69.3%) responded to the survey with information on lower limb swelling (LLS). Of the 108 (35%) responders who reported swelling, only 68 (22%) participants reported a diagnosis of lower limb lymphedema (LLL). The most commonly experienced symptoms among those who reported LLS were tightness, pain/tenderness, and heaviness. Among those with a diagnosis of LLL, most (60%) stated it affected their daily activities and noted exacerbating factors such as prolonged standing, heat, and walking. The most common therapies used to reduce symptoms included leg elevation (96%), compression stockings (65%), diuretics (46%), massage therapy (35%), and bandaging (25%). There was no association between LLS or LLL diagnosis and body mass index, age, race, and tobacco use. Only 8% of responders reported receiving preoperative education regarding risks for LLS and a desire for more comprehensive education was frequently noted. CONCLUSIONS:The patient-reported incidence of LLS occurred in approximately 35% of survey participants who underwent surgery for endometrial cancer. However, only 22% reported a diagnosis of LLL. Efforts to obtain the true incidence of LLL and to develop effective educational materials and programs to improve the management of lymphedema are warranted.

OBJECTIVE:To compare the efficacy of a regimen combining mental practice (MP) with overground training (OT) with the efficacy of a regimen consisting of OT only on gait velocity and lower extremity motor outcomes in individuals with chronic (>12mo postinjury), incomplete spinal cord injury (SCI). DESIGN/METHODS:Randomized, controlled, single-blinded study. SETTING/METHODS:Outpatient rehabilitation laboratories. PARTICIPANTS/METHODS:Subjects with chronic, incomplete SCI (N=18). INTERVENTIONS/METHODS:Subjects were randomly assigned to receive (1) OT only, occurring 3d/wk for 8 weeks; or (2) OT augmented by MP (MP + OT), during which randomly assigned subjects listened to an MP audio recording directly after OT sessions. MAIN OUTCOME MEASURES/METHODS:Subjects were administered a test of gait velocity as well as the Tinetti Performance Oriented Mobility Assessment, Spinal Cord Injury Independence Measure, and Satisfaction With Life Scale on 2 occasions before intervention, 1 week after intervention, and 12 weeks after intervention. RESULTS:A significant increase in gait velocity was exhibited across subjects at both 1 week posttherapy (P=.005) and at 12 weeks posttherapy (P=.006). However, no differences were seen in intervention response at either 1 or 12 weeks postintervention among subjects in the MP + OT group versus the OT-only group. CONCLUSIONS:OT was associated with significant gains in gait velocity, and these gains were not augmented by further addition of MP.

Cardiac surgery associated acute kidney injury (CSA-AKI) is associated with poor outcomes including increased mortality, length of hospital stay (LOS) and cost. The incidence of acute kidney injury (AKI) is reported to be between 3 and 30% depending on the definition of AKI. We designed a multicenter randomized controlled trial to test our hypothesis that a perioperative infusion of sodium bicarbonate (SB) during cardiac surgery will attenuate the post-operative rise in creatinine indicating renal injury when compared to a perioperative infusion with normal saline. An interim analysis was performed after data was available on the first 120 participants. A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received sodium chloride (SC) and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6-2.1, chi-square p-value = 0.68) for patients receiving SB compared to those who received SC. The data safety monitoring board for the trial recommended closing the study early as there was only a 12% probability that the null hypothesis would be rejected. We therefore concluded that a perioperative infusion of SB failed to attenuate the risk of CSA-AKI.