The pediatric surgeon's road to research independence: utility of mentor-based National Institutes of Health grants

Background

The current research environment for academic surgeons demands that extramural funding be obtained. Financial support from the National Institutes of Health (NIH) is historically the gold standard for funding in the biomedical research community, with the R01 funding mechanism viewed as indicator of research independence. The NIH also supports a mentor-based career development mechanism (K-series awards) in order to support early-stage investigators. The goal of this study was to investigate the grants successfully awarded to pediatric surgeon-scientists and then determine the success of the K-series award recipients at achieving research independence.

Methods

In July 2012, all current members of the American Pediatric Surgery Association (APSA) were queried in the NIH database from 1988–2012 through the NIH Research Portfolio Online Reporting Tools. The following factors were analyzed: type of grant, institution, amount of funding, and funding institute or center.

Results

Among current APSA members, there have been 83 independent investigators receiving grants, representing 13% of the current APSA membership, with 171 independent grants funded through various mechanisms. Six percent currently have active NIH funding, with $7.2 million distributed in 2012. There have been 28 K-series grants awarded. Of the recipients of expired K08 awards, 39% recipients were subsequently awarded an R01 grant. A total of 63% of these K-awarded investigators transitioned to an independent NIH award mechanism.

Conclusions

Pediatric surgeon-scientists successfully compete for NIH funding. Our data suggest that although the K-series funding mechanism is not the only path to research independence, over half of the pediatric surgeons who receive a K-award are successful in the transition to independent investigator.     

Imaging tests in the diagnosis of pulmonary embolism

Imaging modalities play an essential role in diagnosing pulmonary embolism (PE). Clinical outcome studies demonstrated that PE can be safely ruled out in patients with unlikely clinical probability in combination with a normal D-dimer test result; in all other patients additional imaging is needed. The aim is to accurately confirm or rule out the diagnosis of PE, after which, if indicated, anticoagulant treatment can be initiated. Various diagnostic tests are available, and this article reviews the different imaging techniques in patients with suspected PE. Computed tomographic pulmonary angiography (CTPA) is the imaging test of choice because of its high sensitivity and specificity. Compression ultrasonography and ventilation perfusion scintigraphy are reserved for patients with concomitant suspicion of deep vein thrombosis or contraindication for CTPA. Furthermore the diagnostic process in patients with clinically suspected recurrent PE, PE during pregnancy, and PE in the elderly and in patients with malignancy are discussed.     

Validation of a Weight History Questionnaire to Identify Adolescent Obesity

Background

Past body weight may be a more informative factor than current weight for risk of chronic disease development. Often, investigators must rely on subject recall to gauge past body weights. The Cincinnati Weight History Questionnaire (CWHQ) was developed to aid in the retrospective identification of adults who were obese during adolescence.

Methods

To assess validity, the CWHQ was administered to a subset of National Heart, Lung, and Blood Growth and Health Study (NGHS) participants, a group of young adult females for whom historical measured anthropometrics were available. One hundred ninety-eight NGHS participants were contacted, of whom 191 (97 %) responded (age 26–29). Participants were asked to recall height and weight from ages 13 and 18, which were compared to previously measured values. Multiple indices of validity (Bland–Altman plots, sensitivity, and specificity) were calculated.

Results

The CWHQ was moderately sensitive (range, 19–66 %), but highly specific (range, 89–100 %). Recalled height and weight values used to determine body mass index (BMI) underestimated BMI based on recorded height and weight at ages 13 and 18. Differences in calculated BMI based on recalled and measured height and weight were found to increase with BMI calculated using measured values.

Conclusions

The CWHQ proved to be a moderately sensitive, but highly specific instrument for detecting adolescent obesity in a cohort of young adult females. Epidemiologic research seeking to discriminate between adults with adult-onset vs. adolescent-onset obesity may find the CWHQ useful.     

Influence of Preoperative and Postoperative Pelvic Floor Muscle Training (PFMT) Compared with Postoperative PFMT on Urinary Incontinence After Radical Prostatectomy: A Randomized Controlled Trial

Background

The efficacy of preoperative pelvic floor muscle training (PFMT) for urinary incontinence (UI) after open radical prostatectomy (ORP) and robot-assisted laparoscopic radical prostatectomy (RARP) is still unclear.

Objective

To determine whether patients with additional preoperative PFMT regain urinary continence earlier than patients with only postoperative PFMT after ORP and RARP.

Design, setting, and participants

A randomized controlled trial enrolled 180 men who planned to undergo ORP/RARP.

Intervention

The experimental group (E, n = 91) started PFMT 3 wk before surgery and continued after surgery. The control group (C, n = 89) started PFMT after catheter removal.

Outcome measurements and statistical analysis

The primary end point was time to continence. Patients measured urine loss daily (24-h pad test) until total continence (three consecutive days of 0 g of urine loss) was achieved. Secondary end points were 1-h pad test, visual analog scale (VAS), International Prostate Symptom Score (IPSS), and quality of life (King's Health Questionnaire [KHQ]). Kaplan-Meier analysis and Cox regression with correction for two strata (age and type of surgery) compared time and continence. The Fisher exact test was applied for the 1-h pad test and VAS; the Mann-Whitney U test was applied for IPSS and KHQ.

Results and limitations

Patients with additional preoperative PFMT had no shorter duration of postoperative UI compared with patients with only postoperative PFMT (p = 0.878). Median time to continence was 30 and 31 d, and median amount of first-day incontinence was 108 g and 124 g for groups E and C, respectively. Cox regression did not indicate a significant difference between groups E and C (p = 0.773; hazard ratio: 1.047 [0.768–1.425]). The 1-h pad test, VAS, and IPSS were comparable between both groups. However, “incontinence impact” (KHQ) was in favor of group E at 3 mo and 6 mo after surgery.

Conclusions

Three preoperative sessions of PFMT did not improve postoperative duration of incontinence.

Trial registration

Netherlands Trial Register No. NTR 1953.     

Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo¹⁵N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.     

Characteristics of differentiated CD8+ and CD4+ T cells present in the human brain

Immune surveillance of the central nervous system (CNS) by T cells is important to keep CNS-trophic viruses in a latent state, yet our knowledge of the characteristics of CNS-populating T cells is incomplete. We performed a comprehensive, multi-color flow-cytometric analysis of isolated T cells from paired corpus callosum (CC) and peripheral blood (PB) samples of 20 brain donors. Compared to PB, CC T cells, which were mostly located in the perivascular space and sporadically in the parenchyma, were enriched for cells expressing CD8. Both CD4⁺ and CD8⁺ T cells in the CC had a late-differentiated phenotype, as indicated by lack of expression of CD27 and CD28. The CC contained high numbers of T cells expressing chemokine receptor CX3CR1 and CXCR3 that allow for homing to inflamed endothelium and tissue, but hardly cells expressing the lymph node-homing receptor CCR7. Despite the late-differentiated phenotype, CC T cells had high expression of the IL-7 receptor α-chain CD127 and did not contain the neurotoxic cytolytic enzymes perforin, granzyme A, and granzyme B. We postulate that CNS T cells make up a population of tissue-adapted differentiated cells, which use CX3CR1 and CXCR3 to home into the perivascular space, use IL-7 for maintenance, and lack immediate cytolytic activity, thereby preventing immunopathology in response to low or non-specific stimuli. The presence of these cells in this tightly regulated environment likely enables a fast response to local threats. Our results will enable future detailed exploration of T-cell subsets in the brain involved in neurological diseases.