Postoperative Pain Management in DIEP Flap Breast Reconstruction: Identification of Patients With Poor Pain Control

Objective: Adequate control of postoperative pain directly improves patient satisfaction and outcomes, and timely identification of patients with poorly controlled pain is essential. Pain management protocols are best studied in patients recovering from the same operation. In our institution, the postoperative pain regimen for patients undergoing deep inferior epigastric perforator (DIEP) flap breast reconstruction is standardized using patient-controlled analgesia (PCA) followed by conversion to oral narcotics. From this uniform population, we were able to identify a subgroup of patients with poor pain control. Methods: Over a 44-month period, 179 consecutive patients underwent DIEP flap breast reconstruction with 242 flaps performed. A retrospective chart review recorded PCA usage, visual analog scale pain scores, and length of stay. Results: Pain management with PCA after DIEP flap breast reconstruction was uniformly controlled. Most patients (74.9%) required PCA usage in the first 2 days with conversion to oral analgesics. A subgroup of patients (25.1%) continued to require PCA usage on the third postoperative day. These “nonresponder” patients had a higher visual analog scale score on the first postoperative day, higher total intravenous morphine use, and a longer length of stay (all, P < .05). A multivariate analysis revealed more nonresponders among patients undergoing immediate breast reconstruction (P < .05); however, all other factors analyzed had no correlation. Conclusion: We report a subgroup of patients with poor pain control after DIEP flap breast reconstruction. This group of patients required a longer course of pain management and subsequently a longer hospital stay. Pain management protocols that identify these patients promptly can allow for appropriate modifications

Stretch Activates Human Myometrium via ERK, Caldesmon and Focal Adhesion Signaling

An incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV) as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility

Magnetohydrodynamic Effects in Propagating Relativistic Jets: Reverse Shock and Magnetic Acceleration

We solve the Riemann problem for the deceleration of an arbitrarily magnetized relativistic flow injected into a static unmagnetized medium in one dimension. We find that for the same initial Lorentz factor, the reverse shock becomes progressively weaker with increasing magnetization \sigma (the Poynting-to kinetic energy flux ratio), and the shock becomes a rarefaction wave when \sigma exceeds a critical value, \sigma_c, defined by the balance between the magnetic pressure in the flow and the thermal pressure in the forward shock. In the rarefaction wave regime, we find that the rarefied region is accelerated to a Lorentz factor that is significantly larger than the initial value. This acceleration mechanism is due to the strong magnetic pressure in the flow. We discuss the implications of these results for models of gamma-ray bursts and active galactic nuclei.Comment: 13 pages, 3 figures, Accepted to publication in ApJ Letter

Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-$1\alpha$, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-$1\alpha$. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM

Outcomes of surgical coronary revascularization performed pre-solid abdominal organ transplant

Background Cardiac risk stratification and coronary angiography are routinely performed as part of kidney and liver transplant candidacy evaluation. There are limited data on the outcomes of surgical coronary revascularization in this patient population. We investigated outcomes in patients with end stage renal or hepatic disease undergoing coronary artery bypass grafting (CABG) to attain kidney or liver transplant candidacy. Methods Retrospective analysis of all patients who underwent isolated CABG at our institution between 2010 and 2016. Patients were divided into two cohorts: Pre-transplant (those undergoing surgery to attain renal or hepatic transplant candidacy) and Non-transplant (all others). Baseline characteristics and postoperative outcomes were compared between groups. Results A total of 1801 patients were included: 28 in Pre-transplant (n=22 kidney, n=7 liver) and 1773 in Non-transplant. Major adverse postoperative outcomes were significantly greater in Pre-transplant compared to Non-transplant: 30-day mortality (14.3% vs. 2.8%, p=0.009), neurologic events (17.9% vs. 4.8%, p=0.011), re-intubation (21.4% vs. 5.8%, p=0.005) and total postoperative ventilation (5.2 vs. 5.0 hours, p=0.0124). One- and five-year mortality in Pre-transplant was 17.9% and 53.6%, respectively. Of the Pre-transplant cohort, three patients (10.7%) underwent organ transplantation (all kidneys) at a mean 436 days after CABG. No patients received liver transplantation. Conclusions Outcomes following CABG in the pre-kidney and pre-liver transplant population are poor. Despite surgical revascularization, the vast majority of patients do not ultimately undergo transplantation. Revascularization strategies and optimal management in this high-risk population warrants further study

Comparing nuclear power trajectories in Germany and the UK: from ‘regimes' to ‘democracies’ in sociotechnical transitions and Discontinuities

This paper focuses on arguably the single most striking contrast in contemporary major energy politics in Europe (and even the developed world as a whole): the starkly differing civil nuclear policies of Germany and the UK. Germany is seeking entirely to phase out nuclear power by 2022. Yet the UK advocates a ‘nuclear renaissance’, promoting the most ambitious new nuclear construction programme in Western Europe.Here,this paper poses a simple yet quite fundamental question: what are the particular divergent conditions most strongly implicated in the contrasting developments in these two countries. With nuclear playing such an iconic role in historical discussions over technological continuity and transformation, answering this may assist in wider understandings of sociotechnical incumbency and discontinuity in the burgeoning field of‘sustainability transitions’. To this end, an ‘abductive’ approach is taken: deploying nine potentially relevant criteria for understanding the different directions pursued in Germany and the UK. Together constituted by 30 parameters spanning literatures related to socio-technical regimes in general as well as nuclear technology in particular, the criteria are divided into those that are ‘internal’ and ‘external’ to the ‘focal regime configuration’ of nuclear power and associated ‘challenger technologies’ like renewables. It is ‘internal’ criteria that are emphasised in conventional sociotechnical regime theory, with ‘external’ criteria relatively less well explored. Asking under each criterion whether attempted discontinuation of nuclear power would be more likely in Germany or the UK, a clear picture emerges. ‘Internal’ criteria suggest attempted nuclear discontinuation should be more likely in the UK than in Germany– the reverse of what is occurring. ‘External’ criteria are more aligned with observed dynamics –especially those relating to military nuclear commitments and broader ‘qualities of democracy’. Despite many differences of framing concerning exactly what constitutes ‘democracy’, a rich political science literature on this point is unanimous in characterising Germany more positively than the UK. Although based only on a single case,a potentially important question is nonetheless raised as to whether sociotechnical regime theory might usefully give greater attention to the general importance of various aspects of democracy in constituting conditions for significant technological discontinuities and transformations. If so, the policy implications are significant. A number of important areas are identified for future research, including the roles of diverse understandings and specific aspects of democracy and the particular relevance of military nuclear commitments– whose under-discussion in civil nuclear policy literatures raises its own questions of democratic accountability

Multi-Scale Simulations Provide Supporting Evidence for the Hypothesis of Intramolecular Protein Translocation in GroEL/GroES Complexes

The biological function of chaperone complexes is to assist the folding of non-native proteins. The widely studied GroEL chaperonin is a double-barreled complex that can trap non-native proteins in one of its two barrels. The ATP-driven binding of a GroES cap then results in a major structural change of the chamber where the substrate is trapped and initiates a refolding attempt. The two barrels operate anti-synchronously. The central region between the two barrels contains a high concentration of disordered protein chains, the role of which was thus far unclear. In this work we report a combination of atomistic and coarse-grained simulations that probe the structure and dynamics of the equatorial region of the GroEL/GroES chaperonin complex. Surprisingly, our simulations show that the equatorial region provides a translocation channel that will block the passage of folded proteins but allows the passage of secondary units with the diameter of an alpha-helix. We compute the free-energy barrier that has to be overcome during translocation and find that it can easily be crossed under the influence of thermal fluctuations. Hence, strongly non-native proteins can be squeezed like toothpaste from one barrel to the next where they will refold. Proteins that are already fairly close to the native state will not translocate but can refold in the chamber where they were trapped. Several experimental results are compatible with this scenario, and in the case of the experiments of Martin and Hartl, intra chaperonin translocation could explain why under physiological crowding conditions the chaperonin does not release the substrate protein

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts