Robot-Assisted Laparoscopic Dismembered Pyeloplasty

OBJECTIVE: Advanced laparoscopic skills limit the implementation of laparoscopic pyeloplasty to centers with extensive experience. The introduction of robotic technology into the field of minimally invasive surgery has facilitated complex surgical dissection and genitourinary reconstruction. We report our experience with robot-assisted laparoscopic pyeloplasty using the da Vinci Robotic Surgical System at 3 New York City medical centers. METHODS: A review of all robot-assisted laparoscopic Anderson-Hynes dismembered pyeloplasty cases in 38 patients (21 females, 17 males) between April 2001 and January 2004 was performed. All patients had symptoms or radiographic evidence of ureteropelvic junction obstruction. Robotic assistance with the da Vinci Robotic Surgical System was used after preparation of the ureteropelvic junction with a standard laparoscopic approach. RESULTS: The average patient age was 39.3 years (range, 15 to 69). The mean operative time and suturing time were 225.6+/-59.3 minutes and 64.2+/-14.6 minutes. The average estimated blood loss was minimal at 77.3+/-55.3 mL. The mean length of hospitalization was 69.6 hours (range, 28 to 310). The average use of intravenous morphine was 26.5 mg (range, 0 to 162). No intraoperative complications occurred, and open conversions were not necessary. A mean follow-up of 12.2 months revealed a success rate of 94.7% with 2/38 patients requiring further treatments. CONCLUSIONS: This combined multi-institutional series reveals that robot-assisted pyeloplasty with the da Vinci Surgical System is safe and reproducible. These intermediate results appear comparable to results with open and laparoscopic pyeloplasty repairs

Publishing Makerspace: A New Approach to Scholarly Publishing

This article describes the concept of the Publishing Makerspace, which is a publishing environment that is reconfigured as a place where all the components of a scholarly project—books and e‐books, virtual and physical exhibits, visualizations, live performance and film—can be integrated using a collaborative process. This place enables the creation of a multimodal publishing environment that fully integrates digital content with manuscripts and “traditional” scholarly content. Starting with an overview of the history of the team that devised this approach and its membership, the article describes the problem that the authors have identified with current approaches to multimodal publishing and outlines a workshop model for engaging in a reconfiguration of the publishing process, including a description of a new publishing and knowledge making ecosystem that includes librarians, publishers, and other collaborators

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

Multivariate association analysis of the components of metabolic syndrome from the Framingham Heart Study

Metabolic syndrome, by definition, is the manifestation of multiple, correlated metabolic impairments. It is known to have both strong environmental and genetic contributions. However, isolating genetic variants predisposing to such a complex trait has limitations. Using pedigree data, when available, may well lead to increased ability to detect variants associated with such complex traits. The ability to incorporate multiple correlated traits into a joint analysis may also allow increased detection of associated genes. Therefore, to demonstrate the utility of both univariate and multivariate family-based association analysis and to identify possible genetic variants associated with metabolic syndrome, we performed a scan of the Affymetrix 50 k Human Gene Panel data using 1) each of the traits comprising metabolic syndrome: triglycerides, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, blood glucose, and body mass index, and 2) a composite trait including all of the above, jointly. Two single-nucleotide polymorphisms within the cholesterol ester transfer protein (CETP) gene remained significant even after correcting for multiple testing in both the univariate (p < 5 × 10-7) and multivariate (p < 5 × 10-9) association analysis. Three genes met significance for multiple traits after correction for multiple testing in the univariate analysis, while five genes remained significant in the multivariate association. We conclude that while both univariate and multivariate family-based association analysis can identify genes of interest, our multivariate approach is less affected by multiple testing correction and yields more significant results

An organizing framework for informal caregiver interventions: detailing caregiving activities and caregiver and care recipient outcomes to optimize evaluation efforts

Abstract Background Caregiver interventions may help improve the quality of informal care. Yet the lack of a systematic framework specifying the targets and outcomes of caregiver interventions hampers our ability to understand what has been studied, to evaluate existing programs, and to inform the design of future programs. Our goal was to develop an organizing framework detailing the components of the caregiving activities and the caregiver and care recipient outcomes that should be affected by an intervention. In so doing, we characterize what has been measured in the published literature to date and what should be measured in future studies to enable comparisons across interventions and across time. Methods Our data set comprises 121 reports of caregiver interventions conducted in the United States and published between 2000 and 2009. We extracted information on variables that have been examined as primary and secondary outcomes. These variables were grouped into categories, which then informed the organizing framework. We calculated the frequency with which the interventions examined each framework component to identify areas about which we have the most knowledge and under-studied areas that deserve attention in future research. Results The framework stipulates that caregiver interventions seek to change caregiving activities, which in turn affect caregiver and care recipient outcomes. The most frequently assessed variables have been caregiver psychological outcomes (especially depression and burden) and care recipient physical and health care use outcomes. Conclusions Based on the organizing framework, we make three key recommendations to guide interventions and inform research and policy. First, all intervention studies should assess quality and/or quantity of caregiving activities to help understand to what extent and how well the intervention worked. Second, intervention studies should assess a broad range of caregiver and care recipient outcomes, including considering whether expanding to economic status and health care use of the caregiver can be accommodated, to ease subsequent economic evaluations of caregiving. Third, intervention studies should measure a common set of outcomes to facilitate cross-time and cross-study comparisons of effectiveness

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in <i>RUNX1</i>, <i>GATA2</i>, and <i>DDX41</i>

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted

Identifying viable regulatory and innovation pathways for regenerative medicine:A case study of cultured red blood cells

The creation of red blood cells for the blood transfusion markets represents a highly innovative application of regenerative medicine with a medium term (5–10 year) prospect for first clinical studies. This article describes a case study analysis of a project to derive red blood cells from human embryonic stem cells, including the systemic challenges arising from (i) the selection of appropriate and viable regulatory protocols and (ii) technological constraints related to stem cell manufacture and scale up to clinical Good Manufacturing Practice (GMP) standard. The method used for case study analysis (Analysis of Life Science Innovation Systems (ALSIS)) is also innovative, demonstrating a new approach to social and natural science collaboration to foresight product development pathways. Issues arising along the development pathway include cell manufacture and scale-up challenges, affected by regulatory demands emerging from the innovation ecosystem (preclinical testing and clinical trials). Our discussion reflects on the efforts being made by regulators to adapt the current pharmaceuticals-based regulatory model to an allogeneic regenerative medicine product and the broader lessons from this case study for successful innovation and translation of regenerative medicine therapies, including the role of methodological and regulatory innovation in future development in the field

A 1.9 Earth Radius Rocky Planet and the Discovery of a Non-Transiting Planet in the Kepler-20 System*

Kepler-20 is a solar-type star (V = 12.5) hosting a compact system of five transiting planets, all packed within the orbital distance of Mercury in our own Solar System. A transition from rocky to gaseous planets with a planetary transition radius of ∼ 1.6 R⊕ has recently been proposed by several publications in the literature (Rogers 2015; Weiss& Marcy 2014). Kepler-20b (Rp ∼ 1.9 R⊕) has a size beyond this transition radius, however previous mass measurements were not sufficiently precise to allow definite conclusions to be drawn regarding its composition. We present new mass measurements of Kepler-20 three of the planets in the Kepler-20 system facilitated by 104 radial velocity measurements from the HARPS-N spectrograph and 30 archival Keck/HIRES observations, as well as an updated photometric analysis of the Kepler data and an asteroseismic analysis of the host star (M* = 0.948 ± 0.051 M☉ and R* = 0.964 ± 0.018 R☉).Kepler-20b is a 1.868+0.066 −0.034 R⊕ planet in a 3.7 day period with amass of 9.70+1.41 −1.44 M⊕ resulting in a mean density of 8.2 +1.5 −1.3 g cm−3 indicating a rocky composition with an iron to silicate ratio consistent with that of the Earth. This makes Kepler-20b the most massive planet with a rocky composition found to date. Furthermore, we report the discovery of an additional non-transiting planet with a minimum mass of 19.96+3.08 −3.61 M⊕ and an orbital period of ∼ 34 days in the gap between Kepler-20f (P ∼ 11 days) and Kepler-20d (P ∼78 days).PostprintPeer reviewe

Streptococcus iniae M-Like Protein Contributes to Virulence in Fish and Is a Target for Live Attenuated Vaccine Development

Streptococcus iniae is a significant pathogen in finfish aquaculture, though knowledge of virulence determinants is lacking. Through pyrosequencing of the S. iniae genome we have identified two gene homologues to classical surface-anchored streptococcal virulence factors: M-like protein (simA) and C5a peptidase (scpI).S. iniae possesses a Mga-like locus containing simA and a divergently transcribed putative mga-like regulatory gene, mgx. In contrast to the Mga locus of group A Streptococcus (GAS, S. pyogenes), scpI is located distally in the chromosome. Comparative sequence analysis of the Mgx locus revealed only one significant variant, a strain with an insertion frameshift mutation in simA and a deletion mutation in a region downstream of mgx, generating an ORF which may encode a second putative mga-like gene, mgx2. Allelic exchange mutagenesis of simA and scpI was employed to investigate the potential role of these genes in S. iniae virulence. Our hybrid striped bass (HSB) and zebrafish models of infection revealed that M-like protein contributes significantly to S. iniae pathogenesis whereas C5a peptidase-like protein does not. Further, in vitro cell-based analyses indicate that SiMA, like other M family proteins, contributes to cellular adherence and invasion and provides resistance to phagocytic killing. Attenuation in our virulence models was also observed in the S. iniae isolate possessing a natural simA mutation. Vaccination of HSB with the Delta simA mutant provided 100% protection against subsequent challenge with a lethal dose of wild-type (WT) S. iniae after 1,400 degree days, and shows promise as a target for live attenuated vaccine development.Analysis of M-like protein and C5a peptidase through allelic replacement revealed that M-like protein plays a significant role in S. iniae virulence, and the Mga-like locus, which may regulate expression of this gene, has an unusual arrangement. The M-like protein mutant created in this research holds promise as live-attenuated vaccine

An Accurate Mass Determination for Kepler-1655b, a Moderately Irradiated World with a Significant Volatile Envelope

Funding: A.C.C. acknowledges support from STFC consolidated grant number ST/M001296/1. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant Agreement No. 313014 (ETAEARTH).We present the confirmation of a small, moderately-irradiated (F= 155±7 F⊕) Neptune with a substantial gas envelope in a P=11.8728787±0.0000085-day orbit about a quiet, Sun-like G0V star Kepler-1655. Based on our analysis of the Kepler light curve, we determined Kepler-1655b’s radius to be 2.213±0.082 R⊕. We acquired 95 high-resolution spectra with TNG/HARPS-N, enabling us to characterize the host star and determine an accurate mass for Kepler-1655b of 5.0±^3.1_2.8 M⊕ via Gaussian-process regression. Our mass determination excludes an Earth-like composition with 98% confidence. Kepler-1655b falls on the upper edge of the evaporation valley, in the relatively sparsely occupied transition region between rocky and gas-rich planets. It is therefore part of a population of planets that we should actively seek to characterize further.PostprintPeer reviewe