Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs

CONTEXT Enhanced Recovery after Surgery (ERAS) programs are multimodal care pathways that aim to decrease intra-operative blood loss, decrease postoperative complications, and reduce recovery times. OBJECTIVE To overview the use and key elements of ERAS pathways, and define needs for future clinical trials. EVIDENCE ACQUISITION A comprehensive systematic MEDLINE search was performed for English language reports published before May 2015 using the terms "postoperative period," "postoperative care," "enhanced recovery after surgery," "enhanced recovery," "accelerated recovery," "fast track recovery," "recovery program," "recovery pathway", "ERAS," and "urology" or "cystectomy" or "urologic surgery." EVIDENCE SYNTHESIS We identified 18 eligible articles. Patient counseling, physical conditioning, avoiding excessive alcohol and smoking, and good nutrition appeared to protect against postoperative complications. Fasting from solid food for only 6h and perioperative liquid-carbohydrate loading up to 2h prior to surgery appeared to be safe and reduced recovery times. Restricted, balanced, and goal-directed fluid replacement is effective when individualized, depending on patient morbidity and surgical procedure. Decreased intraoperative blood loss may be achieved by several measures. Deep vein thrombosis prophylaxis, antibiotic prophylaxis, and thermoregulation were found to help reduce postsurgical complications, as was a multimodal approach to postoperative nausea, vomiting, and analgesia. Chewing gum, prokinetic agents, oral laxatives, and an early resumption to normal diet appear to aid faster return to normal bowel function. Further studies should compare anesthetic protocols, refine analgesia, and evaluate the importance of robot-assisted surgery and the need/timing for drains and catheters. CONCLUSIONS ERAS regimens are multidisciplinary, multimodal pathways that optimize postoperative recovery. PATIENT SUMMARY This review provides an overview of the use and key elements of Enhanced Recovery after Surgery programs, which are multimodal, multidisciplinary care pathways that aim to optimize postoperative recovery. Additional conclusions include identifying effective procedures within Enhanced Recovery after Surgery programs and defining needs for future clinical trials.

Molecular consequences of the loss of 3'→5' exonuclease activity of DNA polymerases delta and epsilon

The DNA replication polymerases δ and ϵ have an inherent proofreading mechanism in the form of a 3'→5' exonuclease. Upon recognition of errant deoxynucleotide incorporation into DNA, the nascent primer terminus is partitioned to the exonuclease active site where the incorrectly paired nucleotide is excised before resumption of polymerization. The goal of this project was to identify the cellular and molecular consequences of an exonuclease deficiency. The proofreading capability of model system MEFs with EXOII mutations was abolished without altering polymerase function.^ It was hypothesized that 3'→5' exonucleases of polymerases δ and ϵ are critical for prevention of replication stress and important for sensitization to nucleoside analogs. To test this hypothesis, two aims were formulated: Determine the effect of the exonuclease active site mutation on replication related molecular signaling and identify the molecular consequences of an exonuclease deficiency when replication is challenged with nucleoside analogs.^ Via cell cycle studies it was determined that larger populations of exonuclease deficient cells are in the S-phase. There was an increase in levels of replication proteins, cell population growth and DNA synthesis capacity without alteration in cell cycle progression. These findings led to studies of proteins involved in checkpoint activation and DNA damage sensing. Finally, collective modifications at the level of DNA replication likely affect the strand integrity of DNA at the chromosomal level.^ Gemcitabine, a DNA directed nucleoside analog is a substrate of polymerases δ and ϵ and exploits replication to become incorporated into DNA. Though accumulation of gemcitabine triphosphate was similar in all cell types, incorporation into DNA and rates of DNA synthesis were increased in exonuclease defective cells and were not consistent with clonogenic survival. This led to molecular signaling investigations which demonstrated an increase in S-phase cells and activation of a DNA damage response upon gemcitabine treatment.^ Collectively, these data indicate that the loss of exonuclease results in a replication stress response that is likely required to employ other repair mechanisms to remove unexcised mismatches introduced into DNA during replication. When challenged with nucleoside analogs, this ongoing stress response coupled with repair serves as a resistance mechanism to cell death.^

A systematic analysis of INO80 in DNA replication

ATP-dependent chromatin remodeling has been shown to be critical for transcription and DNA repair. However, the involvement of ATP-dependent chromatin remodeling in DNA replication remains poorly defined. Interestingly, we found that the INO80 chromatin-remodeling complex is directly involved in the DNA damage tolerance pathways activated during DNA replication. DNA damage tolerance is important for genomic stability and is controlled by formation of either mono-ubiquitinated or multi-ubiquitinated PCNA, which respectively induce error prone or error-free replication bypass of the lesions. In addition, homologous recombination (HR) mediated by the Rad51 pathway is also involved in the DNA damage tolerance pathways. ^ We found that INO80 is specifically recruited to replication origins during S phase in a genome-wide fashion. In addition, DNA combing analysis shows INO80 is required for the resumption of replication at stalled forks induced by methyl methane-sulfonate (MMS). Mechanistically, we find that INO80 is required for PCNA ubiquitination as well as for Rad51 mediated processing of replication forks after MMS treatment. Furthermore, chromatin immunoprecipitation at specific ARSs indicates INO80 is necessary for Rad18 and Rad51 recruitment to replication forks after MMS treatment. Moreover, 2D gel analysis shows INO80 is necessary to process Rad51 mediated intermediates at impeded replication forks. ^ In conclusion, our findings establish a novel role of a chromatin-remodeling complex in DNA damage tolerance pathways and suggest that chromatin remodeling is fundamentally important to ensure faithful replication of DNA and genome stability in eukaryotes. ^

Age determination of sediment core SO75-26KL, Portuguese margin

A benthic isotope record has been measured for core SO75-26KL from the upper Portuguese margin (1099 m water depth) to monitor the response of thermohaline overturn in the North Atlantic during Heinrich events. Evaluating benthic delta18O in TS diagrams in conjunction with equilibrium deltac fractionation implies that advection of Mediterranean outflow water (MOW) to the upper Portuguese margin was significantly reduced during the last glacial (< 15% compared to 30% today). The benthic isotope record along core SO75-26KL therefore primarily monitors variability of glacial North Atlantic conveyor circulation. The 14C-accelerator mass spectrometry ages of 13.54±.07 and 20.46±.12 ka for two ice-rafted detritus (IRD) layers in the upper core section and an interpolated age of 36.1 ka for a third IRD layer deeper in the core are in the range of published 14C ages for Heinrich events H1, H2, and H4. Marked depletion of benthic delta13C by 0.7-1.1 per mil during the Heinrich events suggests reduced thermohaline overturn in the North Atlantic during these events. Close similarity between meltwater patterns (inferred from planktonic delta18O) at Site 609 and ventilation patterns (inferred from benthic delta13C) in core SO75-26KL implies coupling between thermohaline overturn and surface forcing, as is also suggested by ocean circulation models. Benthic delta13C starts to decrease 1.5-2.5 kyr before Heinrich events Hl and H4, fully increased values are reached 1.5-3 kyr after the events, indicating a successive slowdown of thermohaline circulation well before the events and resumption of the conveyor's full strength well after the events. Benthic delta13C changes in the course of the Heinrich events show subtle maxima and minima suggesting oscillatory behavior of thermohaline circulation, a distinct feature of thermohaline instability in numerical models. Inferrred gradual spin-up of thermohaline circulation after Hl and H4 is in contrast to abrupt wanning in the North Atlantic region that is indicated by sudden increases in Greenland ice core delta18O and in marine faunal records from the northern North Atlantic. From this we infer that thermohaline circulation can explain only in part the rapid climatic oscillations seen in glacial sections of the Greenland ice core record.

Determination of millennial-scale climate variability based on alkenones in the western Atlantic Ocean

High-resolution records of alkenone-derived sea surface temperatures and elemental Ti/Ca ratios from a sediment core retrieved off northeastern Brazil (4° S) reveal short-term climate variability throughout the past 63,000 a. Large pulses of terrigenous sediment discharge, caused by increased precipitation in the Brazilian hinterland, coincide with Heinrich events and the Younger Dryas period. Terrigenous input maxima related to Heinrich events H6-H2 are characterized by rapid cooling of surface water ranging between 0.5 and 2° C. This signature is consistent with a climate model experiment where a reduction of the Atlantic meridional overturning circulation (AMOC) and related North Atlantic cooling causes intensification of NE trade winds and a southward movement of the Intertropical Convergence Zone, resulting in enhanced precipitation off northeastern Brazil. During deglaciation the surface temperature evolution at the core site predominantly followed the Antarctic warming trend, including a cooling, prior to the Younger Dryas period. An abrupt temperature rise preceding the onset of the Bølling/Allerød transition agrees with model experiments suggesting a Southern Hemisphere origin for the abrupt resumption of the AMOC during deglaciation caused by Southern Ocean warming and associated with northward flow anomalies of the South Atlantic western boundary current.

Study on the last deglaciation section of sediment core GeoB6211-2

The North Atlantic Ocean underwent an abrupt temperature increase of 9 °C at high latitudes within a couple of decades during the transition from Heinrich event 1 (H1) to the Bølling warm event, but the mechanism responsible for this warming remains uncertain. Here we address this issue, presenting high-resolution last deglaciation planktic and benthic foraminiferal records of temperature and oxygen isotopic composition of seawater (d18OSW) for the subtropical South Atlantic. We identify a warming of ~6.5 °C and an increase in d18Osw of 1.2 per mil at the permanent thermocline during the transition, and a simultaneous warming of ~3.5 °C with no significant change in d18Osw at intermediate depths. Most of the warming can be explained by tilting the South Atlantic east-west isopycnals from a flattened toward a steepened position associated with a collapsed (H1) and strong (Bølling) Atlantic meridional overturning circulation (AMOC). However, this zonal seesaw explains an increase of just 0.3 per mil in permanent thermocline d18Osw. Considering that d18Osw at the South Atlantic permanent thermocline is strongly influenced by the inflow of salty Indian Ocean upper waters, we suggest that a strengthening in the Agulhas leakage took place at the transition from H1 to the Bølling, and was responsible for the change in d18Osw recorded in our site. Our records high-light the important role played by Indian-Atlantic interocean exchange as the trigger for the resumption of the AMOC and the Bølling warm event. of the AMOC and the Bølling warm event.

Forestry Sector Reform and Distributional Change of Natural Resource Rent in Indonesia

After the collapse of the centralized Soeharto regime, deforestation caused by over-logging accelerated. To tackle this problem, an IMF/World Bank-led forestry sector reform program adopted a market-friendly approach involving the resumption of round wood exports and raising of the resource rent fee, with the aim to stop rent accumulation by plywood companies, which had enjoyed a supply of round wood at privileged prices. The Indonesian government, for its part, decentralized the forest concession management system to provide incentives for local governments and communities to carry out sustainable forest management. However, neither policy reform worked effectively. The round wood export ban was reimposed and the forest management system centralized again with cooperation from a newly funded industry-led institution. In the midst of the confusion surrounding the policy reversal, the gap between the price of round wood in international and domestic markets failed to contract, although rent allocations to plywood industries were reduced during 1998-2003. The rents were not collected properly by the government, but accumulated unexpectedly in the hands of players in the black market for round wood.

HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4+ T cell counts ≥ 350 cells/μl and viral load below the limits of detection for ≥1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2–3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log10 copies) day−1, which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log10 copies) day−1 (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4+ T cells.

Correction of obesity and diabetes in genetically obese mice by leptin gene therapy

The ob/ob mouse is genetically deficient in leptin and exhibits both an obese and a mild non-insulin-dependent diabetic phenotype. To test the hypothesis that correction of the obese phenotype by leptin gene therapy will lead to the spontaneous correction of the diabetic phenotype, the ob/ob mouse was treated with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. The subsequent diminishment in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. These results not only demonstrated that the obese and diabetic phenotypes in the adult ob/ob mice are corrected by leptin gene treatment but also provide confirming evidence that body weight control may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients.

Participation of recombination proteins in rescue of arrested replication forks in UV-irradiated Escherichia coli need not involve recombination

Alternative reproductive cycles make use of different strategies to generate different reproductive products. In Escherichia coli, recA and several other rec genes are required for the generation of recombinant genomes during Hfr conjugation. During normal asexual reproduction, many of these same genes are needed to generate clonal products from UV-irradiated cells. However, unlike conjugation, this latter process also requires the function of the nucleotide excision repair genes. Following UV irradiation, the recovery of DNA replication requires uvrA and uvrC, as well as recA, recF, and recR. The rec genes appear to be required to protect and maintain replication forks that are arrested at DNA lesions, based on the extensive degradation of the nascent DNA that occurs in their absence. The products of the recJ and recQ genes process the blocked replication forks before the resumption of replication and may affect the fidelity of the recovery process. We discuss a model in which several rec gene products process replication forks arrested by DNA damage to facilitate the repair of the blocking DNA lesions by nucleotide excision repair, thereby allowing processive replication to resume with no need for strand exchanges or recombination. The poor survival of cellular populations that depend on recombinational pathways (compared with that in their excision repair proficient counterparts) suggests that at least some of the rec genes may be designed to function together with nucleotide excision repair in a common and predominant pathway by which cells faithfully recover replication and survive following UV-induced DNA damage.

1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease believed to be a model for the human disease multiple sclerosis (MS). Induced by immunizing B10.PL mice with myelin basic protein (MBP), EAE was completely prevented by the administration of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. 1,25-(OH)2D3 could also prevent the progression of EAE when administered at the appearance of the first disability symptoms. Withdrawal of 1,25-(OH)2D3 resulted in a resumption of the progression of EAE. Thus, the block by 1,25-(OH)2D3 is reversible. A deficiency of vitamin D resulted in an increased susceptibility to EAE. Thus, 1,25-(OH)2D3 or its analogs are potentially important for treatment of MS.

Increased accommodation of nascent RNA in a product site on RNA polymerase II during arrest.

RNA polymerases encounter specific DNA sites at which RNA chain elongation takes place in the absence of enzyme translocation in a process called discontinuous elongation. For RNA polymerase II, at least some of these sequences also provoke transcriptional arrest where renewed RNA polymerization requires elongation factor SII. Recent elongation models suggest the occupancy of a site within RNA polymerase that accommodates nascent RNA during discontinuous elongation. Here we have probed the extent of nascent RNA extruded from RNA polymerase II as it approaches, encounters, and departs an arrest site. Just upstream of an arrest site, 17-19 nucleotides of the RNA 3'-end are protected from exhaustive digestion by exogenous ribonuclease probes. As RNA is elongated to the arrest site, the enzyme does not translocate and the protected RNA becomes correspondingly larger, up to 27 nucleotides in length. After the enzyme passes the arrest site, the protected RNA is again the 18-nucleotide species typical of an elongation-competent complex. These findings identify an extended RNA product groove in arrested RNA polymerase II that is probably identical to that emptied during SII-activated RNA cleavage, a process required for the resumption of elongation. Unlike Escherichia coli RNA polymerase at a terminator, arrested RNA polymerase II does not release its RNA but can reestablish the normal elongation mode downstream of an arrest site. Discontinuous elongation probably represents a structural change that precedes, but may not be sufficient for, arrest by RNA polymerase II.

Recovery of respiration following the SOS response of Escherichia coli requires RecA-mediated induction of 2-keto-4-hydroxyglutarate aldolase.

Agents that damage DNA in Escherichia coli or interfere with its replication induce DNA repair and mutagenesis via the SOS response. This well-known activity is regulated by the RecA protein and the LexA repressor. Following repair or bypass of the DNA lesion, the cell returns to its resting state by a largely unknown process. We found that 2-keto-4-hydroxyglutarate aldolase (4-hydroxy-2-oxoglutarate aldolase; EC 4.1.3.16) is necessary for the recovery of respiration and that it is regulated by the SOS response. This protein was induced by DNA-damaging agents. Induction required RecA activation. When the LexA regulon was repressed, activation of RecA was not sufficient for induction, indicating the requirement for an additional protein under LexA control. Finally, a mutant in the corresponding hga gene was UV sensitive. 2-Keto-4-hydroxyglutarate aldolase also plays a role in respiratory metabolic pathways, which suggests a mechanism for respiration resumption during the termination of the SOS response.

Efetividade dos instrumentos de políticas públicas nos gastos privados de P&D no Brasil

Esse trabalho teve como objetivo contribuir para o debate sobre a importância das políticas de incentivo à inovação no Brasil. Os resultados esperados do uso que as empresas fizeram dos diferentes tipos de instrumentos sobre os gastos em pesquisa e desenvolvimento (P&D) foram avaliados pelo método de diferenças em diferenças. O método permitiu obter as diferenças de gastos entre empresas beneficiárias de instrumentos e as não-beneficiárias em três períodos consecutivos: 2005 em relação à 2003; 2008 em relação à 2005 e de 2011 em relação à 2008. Ao fazer isso, foi possível identificar se tais diferenças foram positivas e significativas, podendo ser atribuídas às influências dos instrumentos. Os instrumentos utilizados foram: incentivos fiscais, Lei de Informática, financiamentos em parcerias, financiamentos sem parcerias e subvenção. E a utilização dos mesmos pelas empresas teve maior relevância no âmbito de diversos programas de apoio à inovação vigentes no país a partir da retomada das políticas industriais e tecnológicas, nos anos 2000. O estudo concluiu que os efeitos positivos e significativos são limitados à determinados grupos tecnológicos e à poucos instrumentos, em geral, de caráter fiscal. Além disso, esses efeitos positivos surgem em apenas um período, sendo que para cada grupo tecnológico foram efetuadas estimativas para três períodos. Também não houve evidências de que os instrumentos financeiros exerçam efeitos significativos sobre as decisões de gastos em pesquisa e desenvolvimento, apesar da maior ênfase dada aos mesmos no período estudado. Os resultados sugerem fraca influência dos mecanismos de apoio à P&D no Brasil sobre o aumento dos gastos privados, apesar dos avanços recentes.

A Proper Yield Curve for Greece to Kick-Start Financial Intermediation. ECMI Policy Brief No. 21, 10 December 2013

At present, the market is severely mispricing Greece’s sovereign risk relative to the country’s fundamentals. As a result of the mispricing, financial intermediation in Greece has become dysfunctional and the privatisation of state-owned assets has stalled. This mispricing is partially due to an illiquid and fragmented government yield curve. A well-designed public liability management exercise can lead to a more efficient pricing of Greece’s government bonds and thereby help restore stable and affordable financing for the country’s private sector, which is imperative in order to overcome Greece’s deep recession. This paper proposes three measures to enhance the functioning of the Greek government debt market: i) Greece should issue a new five-year bond, ii) it should consolidate the 20 individual series of government bonds into four liquid securities and iii) it should offer investors a swap of these newly created bonds into dollar-denominated securities. Each of these measures would be beneficial to the Hellenic Republic, since the government would be able to reduce the face value and the net present value of its debt stock. Furthermore, this exercise would facilitate the resumption of market access, which is a necessary condition for continuous multilateral disbursements to Greece.