Cavity-Enhanced 2D Material Quantum Emitters Deterministically Integrated with Silicon Nitride Microresonators.

Optically active defects in 2D materials, such as hexagonal boron nitride (hBN) and transition-metal dichalcogenides (TMDs), are an attractive class of single-photon emitters with high brightness, operation up to room temperature, site-specific engineering of emitter arrays with strain and irradiation techniques, and tunability with external electric fields. In this work, we demonstrate a novel approach to precisely align and embed hBN and TMDs within background-free silicon nitride microring resonators. Through the Purcell effect, high-purity hBN emitters exhibit a cavity-enhanced spectral coupling efficiency of up to 46% at room temperature, exceeding the theoretical limit (up to 40%) for cavity-free waveguide-emitter coupling and demonstrating nearly a 1 order of magnitude improvement over previous work. The devices are fabricated with a CMOS-compatible process and exhibit no degradation of the 2D material optical properties, robustness to thermal annealing, and 100 nm positioning accuracy of quantum emitters within single-mode waveguides, opening a path for scalable quantum photonic chips with on-demand single-photon sources.

Neprilysin Controls the Synaptic Activity of Neuropeptides in the Intercalated Cells of the Amygdala.

Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however, we do not know which specific peptidase(s) to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase(s) regulate enkephalin signaling in this region. Thiorphan (10 µM), captopril (1 µM), or bestatin (10 µM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme, or aminopeptidase N, respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus, and spinal cord, where multiple peptidases metabolize enkephalin. These data highlight the importance of knowing which specific peptidase(s) control opioid actions in the relevant neural circuit and how they change in disease states to allow rational choices of drugs targeting the specific peptidase of interest. SIGNIFICANCE STATEMENT: Endogenous opioids modulate many of our emotional and behavioral responses. In the amygdala, they modulate our pain, fear, and addictive behaviors. Their actions are terminated when they are catabolized into inactive fragments by at least three different peptidases. In this study, we found that neprilysin selectively controls endogenous opioid concentrations at synapses in the intercalated cells of the amygdala. This peptidase may be a target for regulation of endogenous opioid modulation of amygdala-mediated emotional and behavioral responses.

Local anaesthetic techniques for post-caesarean delivery analgesia.

In this narrative review we summarise pertinent data from published studies investigating the use of local anaesthetic techniques as adjuncts for managing post-caesarean delivery pain. Based on currently available evidence, ultrasound-guided transversus abdominis plane (TAP), quadratus lumborum (QL) and ilio-inguinal and iliohypogastric (ILIH) blocks are preferable to landmark techniques. When intrathecal morphine is used for caesarean delivery analgesia, TAP blocks do not confer any additional benefit. In the absence of intrathecal morphine, TAP blocks have been shown to reduce pain scores and opioid consumption in the first 24 h postoperatively. In the absence of intrathecal morphine, single-dose local anaesthetic wound infiltration also results in a moderate reduction in opioid consumption postoperatively. If a wound catheter is to be incorporated into a multimodal analgesic regimen, a position below the fascia and a continuous infusion of low-concentration local anaesthetic solutions should be considered. Intraperitoneal local anaesthetic instillation may be of benefit in patients who undergo peritoneal closure but larger studies are still needed. Quadratus lumborum and ILIH blocks show promising results but the data are limited, so recommendations for routine use cannot be made. In summary, evidence supports the use of local anaesthetic techniques for post-caesarean delivery pain but additional research is required to determine the optimum dosing regimens, and the potential role of liposomal local anaesthetics. Further studies are required to compare techniques and determine their role in conjunction with low-dose long-acting neuraxial opioids.

Comparison of angioplasty and bypass surgery for critical limb ischaemia in patients with infrapopliteal peripheral artery disease.

BACKGROUND: Both infrapopliteal (IP) bypass surgery and percutaneous transluminal angioplasty have been shown to be effective in patients with critical limb ischaemia (CLI). The most appropriate method of revascularization has yet to be established, as no randomized trials have been reported. The aim of this study was to compare the outcomes of patients with similar characteristics treated using either revascularization method. METHODS: Consecutive patients undergoing IP bypass and IP angioplasty for CLI (Rutherford 4-6) at a single institution were compared following propensity score matching. The study endpoints were primary, assisted primary and secondary patency, and amputation-free survival at 12 months, calculated by Kaplan-Meier analysis. RESULTS: Some 279 limbs in 243 patients were included in the study. The two groups differed significantly with respect to the incidence of diabetes (P = 0·024), estimated glomerular filtration rate (P = 0·006), total lesion length (P < 0·001) and Rutherford classification (P = 0·008). These factors were used to construct the propensity score model, which yielded a matched cohort of 125 legs in each group. Primary patency (54·4 versus 51·4 per cent; P = 0·014), assisted primary patency (77·5 versus 62·7 per cent; P = 0·003), secondary patency (84·4 versus 65·8 per cent; P < 0·001) and amputation-free survival (78·7 versus 74·1 per cent; P = 0·043) were significantly better after bypass than angioplasty. However, limb salvage was similar (90·4 versus 94·2 per cent; P = 0·161), and overall complications (36·0 versus 21·6 per cent; P = 0·041) as well as length of hospital stay (18(4-134) versus 5(0-110); P = 0·001) were worse in the surgical bypass group. CONCLUSION: There was no difference in limb salvage rates, but patency and amputation-free survival rates were better 1 year after bypass surgery.

Atherosclerotic Plaque Analysis: A Pilot Study to Assess a Novel Tool to Predict Outcome Following Lower Limb Endovascular Intervention.

INTRODUCTION: Atherosclerotic plaque analysis using computed tomography angiography (CTA) has been found to be accurate and reproducible in the coronary and carotid arteries. The aim of our study was to assess the utility of this technique in predicting outcome following lower limb endovascular interventions. METHODS: Pre-procedural CTA was retrospectively analysed in 50 patients who had undergone femoropopliteal (F-P) angioplasty (and/or stenting). Plaque analysis was performed using TeraRecon workstation by two observers blinded to the long-term outcome. Using the Hounsfield units (HU) scale atherosclerotic plaque composition was subdivided into volumes of soft (-100-100 HU) fibrocalcific (101-300 HU) or calcified (300-1000 HU) components. The relationship between plaque composition, clinical and procedural variables, and the study end points (vessel patency, binary restenosis rate, and Amputation-Free Survival [AFS]) were assessed using multivariate analysis. RESULTS: The technical success rate of the endovascular procedure was 98%, with 48% of patients receiving F-P stents. The AFS was 90%, primary patency 84%, assisted primary patency 88%, and binary restenosis 44% all at 1 year. A significantly greater total volume of calcified plaque (1.1 [.01-3.2] cm(3) vs. .11 [0-1.86] cm(3), p < .001) was found in patients developing restenosis (>50%) compared with those who did not. Patients with a calcified plaque volume greater than 1.1 cm(3) had a significantly worse AFS than those with a volume less than 1.1 cm(3) (p = .0038). Multivariate analysis showed that the percentage calcified plaque (p = .003, HR 11.4, 95% CI 1.45-37.29) was an independent predictor of binary restenosis at 12 months, and that absolute volume of calcified plaque (p = .001, HR 3.56, 95% CI 1.64-7.7) was independently associated with AFS. CONCLUSIONS: The burden of calcified plaque, but not soft or fibrocalcific plaque is related to restenosis, reintervention, and AFS. Computed tomography plaque analysis may form an important non-invasive tool for risk stratification in patients undergoing F-P endovascular procedures.

Hybrid revascularization of complex multilevel disease: a paradigm shift in critical limb ischemia treatment.

Critical limb ischemia frequently occurs on a background of extensive co-morbidities and carries a poor prognosis which requires urgent management. Disease severity and patient comorbidity influence the initial choice of management which according to traditional paradigms, is a choice between open or endovascular repair. Over the last decade hybrid intervention, which is the planned combined use of both open and endovascular techniques, has increasingly been used to tackle multilevel disease. In this review we look at the techniques and results of hybrid surgery. This technique is ideal for multilevel lesions, as it is minimally invasive, allows prompt limb revascularization as opposed to the delays inherent in staged procedures and it appears to be more convenient to patients. It also leads to reduced length of hospital stay and reduces overall cost. Most importantly it offers an alternative to open revascularization in medically high risk patients. The success and popularity of hybrid interventions has been underpinned by advances in stent and balloon technology and the advent of the hybrid operating theatre which has allowed multiple techniques to be used simultaneously. Iliac angioplasty and stenting is now the first line of treatment for TASC C/D iliac lesions with good technical success and long-term patency. In patients who also have common femoral disease, endarterectomy can be combined with iliac stenting and this has now almost replaced open bypass. Most series for a variety of hybrid procedures report good limb salvage rates, with morbidity and mortality data considered equal to or better than open bypass procedures. Careful patient selection and detailed preoperative planning are essential to achieve these excellent results. Studies have reported on prospective series or retrospective analysis for various hybrid techniques, including non randomized trials comparing hybrid and open surgical treatment. Ideally, a randomized controlled trial comparing open and hybrid treatment is needed to minimize confounding variables.

Thyroid surgery as a 23-hour stay procedure.

INTRODUCTION: The main barriers to short stay thyroidectomy are haemorrhage, bilateral recurrent laryngeal nerve palsy causing respiratory compromise and hypocalcaemia. This study assessed the safety and effectiveness of thyroidectomy as a 23-hour stay procedure. METHODS: All patients undergoing total or completion thyroidectomy were prescribed calcium and vitamin D3 supplements following surgery. Retrospective analysis identified patients admitted for longer than 23 hours and any readmissions. RESULTS: A total of 164 patients were admitted for 23-hour stay thyroid surgery over a 25-month period between 2008 and 2010. Four patients (2%) required admission for longer than 23 hours. No patients required emergency intervention for postoperative haemorrhage or airway compromise. Biochemical hypocalcaemia (despite calcium supplements) was detected in one patient when measured at the outpatient clinic two weeks following surgery. Twelve patients (7.3%) attended the accident and emergency department following discharge; four required admission for intravenous antibiotics for wound infection and one for biochemical hypocalcaemia. CONCLUSIONS: This single centre UK experience demonstrates that thyroidectomy can be carried out both safely and effectively as a 23-hour stay procedure. Prophylactic prescription of calcium and vitamin D3 reduces hypocalcaemia, and thereby also prolonged admission and readmission due to hypocalcaemia. Supplements are an acceptable, cost effective method of reducing hypocalcaemia and shortening postoperative length of stay.

Editor's choice - A shaggy aorta is associated with mesenteric embolisation in patients undergoing fenestrated endografts to treat paravisceral aortic aneurysms.

OBJECTIVES: Bowel ischaemia is a life-threatening complication of endovascular aneurysm repair. This study aims to evaluate the factors associated with mesenteric ischaemia in patients undergoing fenestrated aortic endografts to treat paravisceral aneurysms. METHODS: Consecutive patients undergoing double or triple fenestrated stent graft insertion were retrospectively analysed. No patients were declined surgery based on anatomic complexity. Preoperative demographics, procedure-related variables, and anatomical factors were examined. Using 3D software, the aortic thrombus volume from the coeliac axis to the lowest renal, aortoiliac tortuosity, and aortic irregularity index (as graded by 3 independent assessors, graded 0-3 based on severity) were compared. Univariate analysis was performed to identify risk factors for the development of bowel ischaemia. RESULTS: Ninety-nine patients underwent elective aneurysm repair (64 triple fenestrations and 35 double fenestrations), 5% of which developed bowel ischaemia, and of these 80% (4/5) died. Mesenteric ischaemia was significantly associated with increased aortic irregularity (median [range], 2 [1-3] vs. 1 [0-2], p = .005, ischaemia vs. no ischaemia) and increased thrombus volume (37 ± 8 vs. 21 ± 12, p = .007) but not aortoiliac tortuosity (1.4 [1.2-1.5] vs. 1.30 [1.2-1.7], p = .3), inferior mesenteric or internal iliac artery patency. Mesenteric ischaemia was also associated with a significantly higher preoperative creatinine (mean ± SD: 183 ± 74 vs. 111 ± 43, p = .007). CONCLUSIONS: The presence of aortic irregularity and increased thrombus volume in the paravisceral segment predicts the occurrence of mesenteric and renal ischaemia in patients treated with fenestrated endografts. This is likely to be related to graft manipulation and catheterisation of visceral vessels.

Pharmacokinetics of gatifloxacin in broiler chickens following intravenous and oral administration.

1. The pharmacokinetics of gatifloxacin were investigated following intravenous and oral administration of a single dose at a rate of 10 mg/kg body weight in broiler chicks. 2. Drug concentration in plasma was determined using High Performance Liquid Chromatography with ultraviolet detection on samples collected at frequent intervals after drug administration. 3. Following intravenous administration, the drug was rapidly distributed (t(1/2α): 0·33 ± 0·008 h) and eliminated (t(1/2ß): 3·62 ± 0·03 h; Cl(B): 0·48 ± 0·002 l/h/kg) from the body. 4. After oral administration, the drug was rapidly absorbed (C (max): 1·74 ± 0·024 µg/mL; T (max): 2 h) and slowly eliminated (t(1/2ß): 3·81 ± 0·07 h) from the body. The apparent volume of distribution (V(d(area))), total body clearance (Cl(B)) and mean residence time (MRT) were 3·61 ± 0·04 l/kg, 0·66 ± 0·01 l/h/kg and 7·16 ± 0·08 h, respectively. The oral bioavailability of gatifloxacin was 72·96 ± 1·10 %. 5. Oral administration of gatifloxacin at 10 mg/kg is likely to be highly efficacious against susceptible bacteria in broiler chickens.

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.

Case report. A novel approach to the management of a ruptured Type II endoleak following endovascular repair of an internal iliac artery aneurysm.

Endovascular repair of isolated iliac artery aneurysms is an established safe and effective management option. Type II endoleak is a potential complication, but rarely results in significant morbidity or mortality. We report a case of a patient who presented with a ruptured internal iliac artery aneurysm secondary to a Type II endoleak. To our knowledge this and the following method of managing this have not been previously reported. Established methods of managing endoleaks, such as intravascular transfemoral embolisation and open or laparoscopic ligation, were not possible. Therefore, we resorted to a novel approach to this type of aneurysm and successfully performed a transcutaneous direct puncture and embolisation of the superior gluteal artery.

Identification of blood biomarkers for psychosis using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

Convergent functional genomic studies of ω-3 fatty acids in stress reactivity, bipolar disorder and alcoholism.

Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond.

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms.

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.

Coming to grips with complex disorders: genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics.

We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.

The role of endothelial cells and their progenitors in intimal hyperplasia.

Intimal hyperplasia leading to restenosis is the major process that limits the success of cardiovascular intervention. The emergence of vascular progenitor cells and, in particular, endothelial progenitor cells has led to great interest in their potential therapeutic value in preventing intimal hyperplasia. We review the mechanism of intimal hyperplasia and highlight the important attenuating role played by a functional endothelium. The role of endothelial progenitor cells in maintaining endothelial function is reviewed and we describe how reduced progenitor cell number and function and reduced endothelial function lead to an increased risk of intimal hyperplasia. We review other potential sources of endothelial cells, including monocytes, mesenchymal stem cells and tissue resident stem cells. Endothelial progenitor cells have been used in clinical trials to reduce the risk of restenosis with varied success. Progenitor cells have huge therapeutic potential to prevent intimal hyperplasia but a more detailed understanding of vascular progenitor cell biology is necessary before further clinical trials are commenced.

Robotic surgery in gynecology.

Advanced laparoscopic procedures for gynecologic surgery have not been widely adopted in clinical practice despite nearly 20 years of improvements in laparoscopic technology. The da Vinci robotic surgical system was cleared for use in gynecologic surgery in the U.S in 2005. Many surgeons have embraced da Vinci technology over conventional laparoscopy because of its technologic advantages of wristed instrumentation, high definition 3-D optics, ergonomics, and autonomy of camera control. Furthermore, many surgeons with limited advanced laparoscopic skills have successfully converted their practice from primarily laparotomy to minimally invasive surgery using the da Vinci System. The purpose of this article is to review the development of robotic procedures in gynecology through the current literature. This article reviews recent peer-reviewed literature concerning robotic-assisted laparoscopic procedures including hysterectomy, myomectomy, radical hysterectomy, pelvic and aortic lymphadenectomy, trachelectomy, parametrectomy, tubal anastamosis, sacrocolpopexy, and others. The majority of this literature consists of descriptive retrospective case series from the investigator's early experience; in fact these early reports represent innovation of a new operative technique. Some reports compare outcomes to open and standard laparoscopic procedures. Future prospective studies comparing complications, pain, return to routine activity, and long-term clinical outcomes with open and laparoscopic procedures will be necessary to completely appreciate the impact of robotic technology.

Identifying blood biomarkers for mood disorders using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for mood disorders. The current reliance on patient self-report of symptom severity and on the clinicians' impression is a rate-limiting step in effective treatment and new drug development. We propose, and provide proof of principle for, an approach to help identify blood biomarkers for mood state. We measured whole-genome gene expression differences in blood samples from subjects with bipolar disorder that had low mood vs those that had high mood at the time of the blood draw, and separately, changes in gene expression in brain and blood of a mouse pharmacogenomic model. We then integrated our human blood gene expression data with animal model gene expression data, human genetic linkage/association data and human postmortem brain data, an approach called convergent functional genomics, as a Bayesian strategy for cross-validating and prioritizing findings. Topping our list of candidate blood biomarker genes we have five genes involved in myelination (Mbp, Edg2, Mag, Pmp22 and Ugt8), and six genes involved in growth factor signaling (Fgfr1, Fzd3, Erbb3, Igfbp4, Igfbp6 and Ptprm). All of these genes have prior evidence of differential expression in human postmortem brains from mood disorder subjects. A predictive score developed based on a panel of 10 top candidate biomarkers (five for high mood and five for low mood) shows sensitivity and specificity for high mood and low mood states, in two independent cohorts. Our studies suggest that blood biomarkers may offer an unexpectedly informative window into brain functioning and disease state.

Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms.

Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the first-generation Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in methodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood biomarkers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches.