Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. (“GUIDED”), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian “GAPP-MDD” RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477)

Submicron and Nanometer Structures Technology and Research

Contains reports on twenty research projects and a list of publications.Defense Advanced Research Projects Agency Contract N00019-92-K-0021Joint Services Electronics Program Contract DAAL03-92-C-0001National Science Foundation Grant ECS 90-16437U.S. Army Research Office Grant DAAL03-92-G-0291IBM CorporationU.S. Air Force - Office of Scientific Research Grant F49620-92-J-0064National Science Foundation Grant DMR 87-19217National Science Foundation Grant DMR 90-22933Defense Advanced Research Projects Agency Consortium for Superconducting ElectronicsNational Aeronautics and Space Administration Contract NAS8-36748National Aeronautics and Space Administration Grant NAGW-200

Oscillatory Dynamics of Cell Cycle Proteins in Single Yeast Cells Analyzed by Imaging Cytometry

Progression through the cell division cycle is orchestrated by a complex network of interacting genes and proteins. Some of these proteins are known to fluctuate periodically during the cell cycle, but a systematic study of the fluctuations of a broad sample of cell-cycle proteins has not been made until now. Using time-lapse fluorescence microscopy, we profiled 16 strains of budding yeast, each containing GFP fused to a single gene involved in cell cycle regulation. The dynamics of protein abundance and localization were characterized by extracting the amplitude, period, and other indicators from a series of images. Oscillations of protein abundance could clearly be identified for Cdc15, Clb2, Cln1, Cln2, Mcm1, Net1, Sic1, and Whi5. The period of oscillation of the fluorescently tagged proteins is generally in good agreement with the inter-bud time. The very strong oscillations of Net1 and Mcm1 expression are remarkable since little is known about the temporal expression of these genes. By collecting data from large samples of single cells, we quantified some aspects of cell-to-cell variability due presumably to intrinsic and extrinsic noise affecting the cell cycle

Nanostructures Technology, Research, and Applications

Contains reports on twenty research projects and a list of publications.Joint Services Electronics Program Contract DAAL03-92-C-0001Semiconductor Research Corporation Contract 94-MJ-550U.S. Army Research Office Grant DAAL03-92-G-0291Advanced Research Projects Agency/Naval Air Systems Command Contract N00019-92-K-0021National Science Foundation Grant ECS 90-16437National Science Foundation Grant ECS 90-16737IBM Corporation Contract 1622U.S. Air Force - Office of Scientific Research Grant F-49-62-92-J-0064National Science Foundation Grant DMR 87-19217National Science Foundation Grant DMR 90-22933National Aeronautics and Space Administration Contract NAS8-3674

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Endocrine surgery: where are we today? A national survey of young endocrine surgeons

In recent years, there has been a growing interest in endocrine surgery. Educational objectives have been published by the American Association of Endocrine Surgeons (AAES), but data have not been collected describing the recruitment pool, fellowship, or postfellowship experiences. A survey was distributed to endocrine surgeons in practice <7 years and endocrine surgery fellows. Demographic, training, and practice data were collected. The survey response rate was 69% (46/67); 85% were practicing endocrine surgeons and 15% were fellows. In all, 72% of respondents completed an endocrine surgery fellowship, 17% completed surgical oncology, and the remaining individuals completed no fellowship. The mean age was 38 (32-49) years; 39% were women, 67% were white, 26% were Asian, 11% were Hispanic, and 2% were black. A total of 89% completed residency at academic centers. Endocrine surgery fellows performed significantly more endocrine surgery cases in residency than the average graduating chief resident. Mentorship was a critical factor in fellows' decisions to pursue endocrine surgery. Fellows graduated with a median (range) of 150 (50-300) thyroid, 80 (35-200) parathyroid, 10 (2-50) neck dissection, 13 (0-60) laparoscopic adrenal, and 3 (0-35) endocrine-pancreas. Fellows felt the least prepared in neck dissection and pancreas. Of the respondents, 76% of endocrine surgeons in practice are at academic centers, and 75% have practices where most cases are endocrine based. Exposure to endocrine surgery and mentorship are powerful factors that influence residents to pursue careers in endocrine surgery. Significant variation is found in the case distribution of fellowships with a relative paucity in neck dissection, pancreas procedures, and research. Recruitment to endocrine surgery should begin in residency, and the standardization of training should be a goal

Sponsor-imposed publication restrictions disclosed on ClinicalTrials.gov

We investigated whether sponsor-imposed publication restrictions for ClinicalTrials.gov trials were reasonable, based on consistency with Good Publication Practice 2 (GPP2). ClinicalTrials.gov trial record data were electronically imported (October 7, 2012) and screened for eligibility (phase 2–4, interventional, recruitment closed, results available, first received for registration after November 10, 2009, any sponsor type, investigators not sponsor employees). Two authors categorized restrictions information as consistent or not consistent with GPP2, resolving discrepancies by consensus. Of the eligible trials (388/484, n = 81,768 participants), 80.7% (313/388) had restrictions disclosed, and 92.5% (311/388) were industry-sponsored. Significantly more trials had restrictions that were consistent with GPP2 than not (74.1% [232/313], n = 55,280 participants vs. 25.9% [81/313], n = 19,677 participants; P < .001). Reasons for inconsistency were insufficient, unclear, or ambiguous information (48.1%, 39/81), sponsor-required approval for publication (35.8%, 29/81), sponsor-required text changes (8.6%, 7/81), and outright bans (7.4%, 6/81). Follow-up of trials with insufficient information and a contact email (response rate, 46.9% [15/32]) revealed 2 additional bans. A total of 776 participants had consented to trials that had publication bans. Many, but not all, sponsor-imposed publication restrictions disclosed on ClinicalTrials.gov may be considered reasonable. Sponsors should ensure restrictions are appropriately disclosed. Volunteers should be alerted to any restrictions before consenting to participate in a clinical trial

CD4 \u3csup\u3e+\u3c/sup\u3efoxp3 \u3csup\u3e+\u3c/sup\u3e T-regulatory cells in noninfectious uveitis

Objective: To evaluate CD4 +Foxp3 + (forkhead box P3) T-regulatory cell populations in patients with uveitis and to determine if T-regulatory cell populations are associated with disease features. Methods: Patients with uveitis were evaluated for CD4 +Foxp3 +T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the resence of cystoid macular edema were reviewed. Percentages of CD4 +Foxp3 +lymphocytes were compared for patients with inactive vs active disease, systemic vs ocular diagnoses, and the presence or absence of cys-toid macular edema. Real-time polymerase chain reaction testing was performed on 2 patients with extremely low CD4 +oxp3 +cell populations to assess Foxp3 mRNA. Results: A total of 20 patients with intermediate uveitis, posterior uveitis, and panuveitis were evaluated. The mean age was 40.6 years and the mean visual acuity was 20/57. Percentages of CD4 +Foxp3 + cells were lower in patients with active compared with inactive uveitis (P\u3c 5). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated less than 1% CD4 +Foxp3 + lymphocytes showed extremely low or absent Foxp3 mRNA. Conclusion: T-regulatory cells are reduced in patients with active compared with inactive disease. Severe depletion of CD4 +Foxp3 + T cells and Foxp3 mRNA in 2 patients with severe uveitis suggests that loss of the T-regulatory cells of uveitis may be a salient feature in certain patients. ©2009 American Medical Association. All rights reserved

Fundus autofluorescence imaging of the white dot syndromes

Objective: To characterize the fundus autofluorescence (FAF) findings in patients with white dot syndromes (WDSs). Methods: Patients with WDSs underwent ophthalmic examination, fundus photography, fluorescein angiography, and FAF imaging. Patients were categorized as having no, minimal, or predominant foveal hypoautofluorescence. The severity of visual impairment was then correlated with the degree of foveal hypoautofluorescence. Results: Fifty-five eyes of 28 patients with WDSs were evaluated. Visual acuities ranged from 20/12.5 to hand motions. Diagnoses included serpiginous choroidopathy (5 patients), birdshot retinochoroidopathy (10), multifocal choroiditis (8), relentless placoid chorioretinitis (1), presumed tuberculosis-associated serpiginouslike choroidopathy (1), acute posterior multifocal placoid pigment epitheliopathy (1), and acute zonal occult outer retinopathy (2). In active serpiginous choroidopathy, notable hyperautofluorescence in active disease distinguished it from the variegated FAF features of tuberculosisassociated serpiginouslike choroidopathy. The percentage of patients with visual acuity impairment of less than 20/40 differed among eyes with no, minimal, and predominant foveal hypoautofluorescence (P\u3c.001). Patients with predominant foveal hypoautofluorescence demonstrated worse visual acuity than those with minimal or no foveal hypoautofluorescence (both P\u3c.001). Conclusions: Fundus autofluorescence imaging is useful in the evaluation of the WDS. Visual acuity impairment is correlated with foveal hypoautofluorescence. Further studies are needed to evaluate the precise role of FAF imaging in the WDSs. ©2010 American Medical Association. All rights reserved