T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector.

We recently developed an immuno-oncotherapy against human papillomavirus (HPV)-induced tumors based on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18 genotypes, namely "Lenti-HPV-07". The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07 is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we first established that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy of a homologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of the T-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, we tracked T-cell clonotypes by deep sequencing of T-Cell Receptor (TCR) variable ß and α chain mRNA, applied to whole peripheral blood cells (PBL) and a T cell population specific of an immunodominant E7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied by increased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification of clonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstrated that the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpoint inhibitory treatments by systemic administration of anti-TIM3 or anti-NKG2A monoclonal antibodies. While Lenti-HPV-07 is about to enter a Phase I/IIa clinical trial, these results will help better elucidate its mode of action in immunotherapy against established HPV-mediated malignancies.

Perioperative Fluid Management in Colorectal Surgery: Institutional Approach to Standardized Practice.

The present review discusses restrictive perioperative fluid protocols within enhanced recovery after surgery (ERAS) pathways. Standardized definitions of a restrictive or liberal fluid regimen are lacking since they depend on conflicting evidence, institutional protocols, and personal preferences. Challenges related to restrictive fluid protocols are related to proper patient selection within standardized ERAS protocols. On the other hand, invasive goal-directed fluid therapy (GDFT) is reserved for more challenging disease presentations and polymorbid and frail patients. While the perfusion rate (mL/kg/h) appears less predictive for postoperative outcomes, the authors identified critical thresholds related to total intravenous fluids and weight gain. These thresholds are discussed within the available evidence. The authors aim to introduce their institutional approach to standardized practice.

Full eradication of pre-clinical human papilloma virus-induced tumors by a lentiviral vaccine.

Human papillomavirus (HPV) infections are the cause of all cervical and numerous oropharyngeal and anogenital cancers. The currently available HPV vaccines, which induce neutralizing antibodies, have no therapeutic effect on established tumors. Here, we developed an immuno-oncotherapy against HPV-induced tumors based on a non-integrative lentiviral vector encoding detoxified forms of the Early E6 and E7 oncoproteins of HPV16 and 18 genotypes, namely, "Lenti-HPV-07". A single intramuscular injection of Lenti-HPV-07 into mice bearing established HPV-induced tumors resulted in complete tumor eradication in 100% of the animals and was also effective against lung metastases. This effect correlated with CD8+ T-cell induction and profound remodeling of the tumor microenvironment. In the intra-tumoral infiltrates of vaccinated mice, the presence of large amounts of activated effector, resident memory, and transcription factor T cell factor-1 (TCF-1)+ "stem-like" CD8+ T cells was associated with full tumor eradication. The Lenti-HPV-07-induced immunity was long-lasting and prevented tumor growth after a late re-challenge, mimicking tumor relapse. Lenti-HPV-07 therapy synergizes with an anti-checkpoint inhibitory treatment and therefore shows promise as an immuno-oncotherapy against established HPV-mediated malignancies.

Single-cell mass cytometry on peripheral cells in Myasthenia Gravis identifies dysregulation of innate immune cells.

Myasthenia Gravis (MG) is a neurological autoimmune disease characterized by disabling muscle weaknesses due to anti-acetylcholine receptor (AChR) autoantibodies. To gain insight into immune dysregulation underlying early-onset AChR+ MG, we performed an in-depth analysis of peripheral mononuclear blood cells (PBMCs) using mass cytometry. PBMCs from 24 AChR+ MG patients without thymoma and 16 controls were stained with a panel of 37 antibodies. Using both unsupervised and supervised approaches, we observed a decrease in monocytes, for all subpopulations: classical, intermediate, and non-classical monocytes. In contrast, an increase in innate lymphoid cells 2 (ILC2s) and CD27- γδ T cells was observed. We further investigated the dysregulations affecting monocytes and γδ T cells in MG. We analyzed CD27- γδ T cells in PBMCs and thymic cells from AChR+ MG patients. We detected the increase in CD27- γδ T cells in thymic cells of MG patients suggesting that the inflammatory thymic environment might affect γδ T cell differentiation. To better understand changes that might affect monocytes, we analyzed RNA sequencing data from CD14+ PBMCs and showed a global decrease activity of monocytes in MG patients. Next, by flow cytometry, we especially confirmed the decrease affecting non-classical monocytes. In MG, as for other B-cell mediated autoimmune diseases, dysregulations are well known for adaptive immune cells, such as B and T cells. Here, using single-cell mass cytometry, we unraveled unexpected dysregulations for innate immune cells. If these cells are known to be crucial for host defense, our results demonstrated that they could also be involved in autoimmunity.

ERAS® protocol improves survival after radical cystectomy: A single-center cohort study.

INTRODUCTION: To evaluate Enhanced recovery after surgery (ERAS®) protocol on oncological outcomes for patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). METHODS: A prospectively maintained single-institutional database comprising 160 consecutive UCB patients who underwent open RC from 2012 to 2020 was analyzed. Patients receiving chemotherapy and those with a urinary diversion other than ileal conduit were excluded. Patients were divided into two groups according to the perioperative management (ERAS® and pre-ERAS®). The study aimed to evaluate the impact of the ERAS® protocol on survival at five years after surgery using a Kaplan-Meier log-rank test. A multivariable Cox proportional hazards model was used to identify prognostic factors for cancer-specific (CSS) and overall survival (OS). RESULTS: Of the 107 patients considered for the final analysis, 74 (69%) were included in the ERAS® group. Median follow-up for patients alive at last follow-up was 28 months (interquartile range [IQR] 12-48). Five-years CSS rate was 74% for ERAS® patients, compared to 48% for the control population (P = 0.02), while 5-years OS was 31% higher in the ERAS® (67% vs. 36%, P = .003). In the multivariable analysis, ERAS® protocol and tumor stage were independent factors of CSS, while ERAS®, tumor stage so as total blood loss were independent factors for OS. DISCUSSION: A dedicated ERAS® protocol for UCB patients treated with RC has a significant impact on survival. Reduction of stress after a major surgery and its potential improvement of perioperative patient's immunity may explain these data.

A lentiviral vector encoding fusion of light invariant chain and mycobacterial antigens induces protective CD4+ T cell immunity.

Lentiviral vectors (LVs) are highly efficient at inducing CD8+ T cell responses. However, LV-encoded antigens are processed inside the cytosol of antigen-presenting cells, which does not directly communicate with the endosomal major histocompatibility complex class II (MHC-II) presentation pathway. LVs are thus poor at inducing CD4+ T cell response. To overcome this limitation, we devised a strategy whereby LV-encoded antigens are extended at their N-terminal end with the MHC-II-associated light invariant chain (li), which contains an endosome-targeting signal sequence. When evaluated with an LV-encoded polyantigen composed of CD4+ T cell targets from Mycobacterium tuberculosis, intranasal vaccination in mice triggers pulmonary polyfunctional CD4+ and CD8+ T cell responses. Adjuvantation of these LVs extends the mucosal immunity to Th17 and Tc17 responses. A systemic prime and an intranasal boost with one of these LV induces protection against M. tuberculosis. This strategy improves the protective power of LVs against infections and cancers, where CD4+ T cell immunity plays an important role.

Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures.

The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen-identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients' immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38+-activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients' transcriptomic profiles, particularly with overexpression of the ectoenzyme NT5E (encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.

Immune checkpoint inhibitors increase T cell immunity during SARS-CoV-2 infection.

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.

NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a global concern because of its impact on human health. ZIKV infection during pregnancy can cause microcephaly and other severe brain defects in the developing fetus and there have been reports of the occurrence of Guillain-Barré syndrome in areas affected by ZIKV. NK cells are activated during acute viral infections and their activity contributes to a first line of defense because of their ability to rapidly recognize and kill virus-infected cells. To provide insight into NK cell function during ZIKV infection, we have profiled, using mass cytometry, the NK cell receptor-ligand repertoire in a cohort of acute ZIKV-infected female patients. Freshly isolated NK cells from these patients contained distinct, activated, and terminally differentiated, subsets expressing higher levels of CD57, NKG2C, and KIR3DL1 as compared with those from healthy donors. Moreover, KIR3DL1+ NK cells from these patients produced high levels of IFN-γ and TNF-α, in the absence of direct cytotoxicity, in response to in vitro stimulation with autologous, ZIKV-infected, monocyte-derived dendritic cells. In ZIKV-infected patients, overproduction of IFN-γ correlated with STAT-5 activation (r = 0.6643; p = 0.0085) and was mediated following the recognition of MHC class 1-related chain A and chain B molecules expressed by ZIKV-infected monocyte-derived dendritic cells, in synergy with IL-12 production by the latter cells. Together, these findings suggest that NK cells contribute to the generation of an efficacious adaptive anti-ZIKV immune response that could potentially affect the outcome of the disease and/or the development of persistent symptoms.

Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models.

To develop a vaccine candidate against coronavirus disease 2019 (COVID-19), we generated a lentiviral vector (LV) eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, confers only partial protection despite high levels of serum neutralizing activity. However, eliciting an immune response in the respiratory tract through an intranasal boost results in a >3 log10 decrease in the lung viral loads and reduces local inflammation. Moreover, both integrative and non-integrative LV platforms display strong vaccine efficacy and inhibit lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and closely mirror human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of LV-based vaccination against SARS-CoV-2 and designate intranasal immunization as a powerful approach against COVID-19.

Anaesthesia in a Toxic Environment: Pressurised Intraperitoneal Aerosol Chemotherapy: A Retrospective Analysis.

OBJECTIVE: Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is a new type of intraperitoneal chemotherapy for peritoneal carcinosis via minimally invasive surgery. This technique's specificity is the remote application of the therapy because of the potential risk of exposure to toxic products. The present paper summarises the important aspects of PIPAC and analyses the anaesthetic outcomes. METHODS: This retrospective study included all patients undergoing PIPAC treatment between January 2015 and February 2018. Data on protocol adherence and perioperative anaesthetic complications and postoperative nausea and vomiting (PONV) and pain levels (visual analogue scale 0-10) from recovery room to 72 h were analysed. RESULTS: The overall analysis included 193 PIPAC procedures on 87 patients. Protocol adherence was high as regards the use of propofol (100%), rocuronium (98%), antiemetic prophylaxis (99%) and lidocaine intravenous (i.v.) (87%). No accidental exposure to chemotherapy occurred during the study period. Of the 87 patients, 6.3% suffered delayed recovery, 58% due to hypothermia and 42% due to excessive sedation or curarisation. In the recovery room, 16% of patients suffered moderate to severe pain, requiring >8 mg of morphine i.v., with average doses of 13.7 mg. Median postoperative pain scores were 1 and 3 at 12 h and 0 and 0 at 72 h at rest and mobilisation, respectively. PONV was observed in <10% of patients during the first 12 h, but in 40% at 72 h. CONCLUSION: A dedicated anaesthetic protocol and intraoperative safety checklist facilitates safe, well-tolerated anaesthesia for PIPAC treatments.

Prospective validation of classification of intraoperative adverse events (ClassIntra): international, multicentre cohort study.

OBJECTIVE: To prospectively assess the construct and criterion validity of ClassIntra version 1.0, a newly developed classification for assessing intraoperative adverse events. DESIGN: International, multicentre cohort study. SETTING: 18 secondary and tertiary centres from 12 countries in Europe, Oceania, and North America. PARTICIPANTS: The cohort study included a representative sample of 2520 patients in hospital having any type of surgery, followed up until discharge. A follow-up to assess mortality at 30 days was performed in 2372 patients (94%). A survey was sent to a representative sample of 163 surgeons and anaesthetists from participating centres. MAIN OUTCOME MEASURES: Intraoperative complications were assessed according to ClassIntra. Postoperative complications were assessed daily until discharge from hospital with the Clavien-Dindo classification. The primary endpoint was construct validity by investigating the risk adjusted association between the most severe intraoperative and postoperative complications, measured in a multivariable hierarchical proportional odds model. For criterion validity, inter-rater reliability was evaluated in a survey of 10 fictitious case scenarios describing intraoperative complications. RESULTS: Of 2520 patients enrolled, 610 (24%) experienced at least one intraoperative adverse event and 838 (33%) at least one postoperative complication. Multivariable analysis showed a gradual increase in risk for a more severe postoperative complication with increasing grade of ClassIntra: ClassIntra grade I versus grade 0, odds ratio 0.99 (95% confidence interval 0.69 to 1.42); grade II versus grade 0, 1.39 (0.97 to 2.00); grade III versus grade 0, 2.62 (1.31 to 5.26); and grade IV versus grade 0, 3.81 (1.19 to 12.2). ClassIntra showed high criterion validity with an intraclass correlation coefficient of 0.76 (95% confidence interval 0.59 to 0.91) in the survey (response rate 83%). CONCLUSIONS: ClassIntra is the first prospectively validated classification for assessing intraoperative adverse events in a standardised way, linking them to postoperative complications with the well established Clavien-Dindo classification. ClassIntra can be incorporated into routine practice in perioperative surgical safety checklists, or used as a monitoring and outcome reporting tool for different surgical disciplines. Future studies should investigate whether the tool is useful to stratify patients to the appropriate postoperative care, to enhance the quality of surgical interventions, and to improve long term outcomes of surgical patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03009929.

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

Pain Intensity in the First 96 Hours After Abdominal Surgery: A Prospective Cohort Study.

OBJECTIVE: Multimodal pain management strategies aim to improve postoperative pain control. The purpose of this study was to analyze pain scores and risk factors for acute postoperative pain after various abdominal surgery procedures. METHODS: Data on 11 different abdominal surgery procedures were prospectively recorded. Pain intensity (rest, mobilization) and patient satisfaction at discharge were assessed using a visual analog scale (VAS; 0-10), and analgesic consumption was recorded until 96 hours postoperation. Demographic, surgery-related, and pain management-related univariate risk factors for insufficient pain control (VAS ≥ 4) were entered in a multivariate logistic regression model. RESULTS: A total of 1,278 patients were included. Overall, mean VAS scores were <3 at all time points, and scores at mobilization were consistently higher than at rest (P < 0.05). Thirty percent of patients presented a prolonged VAS score ≥4 at mobilization at 24 hours, significantly higher than at rest (14%, P < 0.05). High pain scores correlated with high opioid consumption, whereas a variability of pain scores was observed in patients with low opioid consumption. The only independent risk factor for moderate and severe pain (VAS ≥ 4) was younger age (<70 years, P = 0.001). The mean satisfaction score was 8.18 ± 1.29. CONCLUSIONS: Among 1,278 patients, pain was controlled adequately during the first four postoperative days, resulting in high levels of patient satisfaction. Pain levels were higher at mobilization. Younger age was the only independent risk factor for insufficient pain control. Preventive treatment in patients <70 years old and before mobilization could be evaluated for potential improvement.

Multiplexed Quantitation of Intraphagocyte Mycobacterium tuberculosis Secreted Protein Effectors.

The pathogenic potential of Mycobacterium tuberculosis largely depends on ESX secretion systems exporting members of the multigenic Esx, Esp, and PE/PPE protein families. To study the secretion and regulation patterns of these proteins while circumventing immune cross-reactions due to their extensive sequence homologies, we developed an approach that relies on the recognition of their MHC class II epitopes by highly discriminative T cell receptors (TCRs) of a panel of T cell hybridomas. The latter were engineered so that each expresses a unique fluorescent reporter linked to specific antigen recognition. The resulting polychromatic and multiplexed imaging assay enabled us to measure the secretion of mycobacterial effectors inside infected host cells. We applied this novel technology to a large panel of mutants, clinical isolates, and host-cell types to explore the host-mycobacteria interplay and its impact on the intracellular bacterial secretome, which also revealed the unexpected capacity of phagocytes from lung granuloma to present mycobacterial antigens via MHC class II.

Pain perception after colorectal surgery: A propensity score matched prospective cohort study.

The purpose of this prospective cohort study was to compare multimodal pain management and pain perception after open vs. laparoscopic colorectal surgery within enhanced recovery care. Pain scores at rest and at mobilization were prospectively assessed in consecutive patients using Visual Analog Scales (VAS 0-10) and consumption of different analgesics was recorded daily until 96 hours postoperatively. Uni- and multivariate risk factors for pain peaks (≥ 4/10) were identified by logistic regression and compared between two propensity score matched groups (open vs. laparoscopic). 156 open and 176 laparoscopic procedures were included. Mean VAS scores were consistently < 3 until 96 hours at rest and at mobilization. Patients operated by laparoscopy experienced more pain peaks (≥ 4) within 24 hours (p < 0.05), while patients operated by open approach experienced more pain peaks (≥ 4) during mobilization at 72 hours (p < 0.05). Independent risk factors for insufficient pain control (≥ 4) within 24 hours from surgery were duration of the procedure (OR 3.37, 95%CI 2.03-5.59), emergency surgery (OR 3.01, 95%CI 1.72-5.31), wound infiltration (OR 3.23, 95%CI 0.97-10.70), age < 70 years (OR 2.03, 95% CI 1.18-3.48) and ASA I-II score (OR 2.06, 95% CI 1.19-3.56). The perioperative adding of lidocaine ± ketamine to opioids did not improve postoperative pain perception nor decrease morphine equivalents. In conclusion, overall pain scores were low after colorectal surgery. However, pain peaks remained a concern early after minimally invasive surgery and after epidural removal for open surgery. Multimodal strategies were not superior to opioids alone.

Fibrogenic Potential of PW1/Peg3 Expressing Cardiac Stem Cells.

BACKGROUND: Pw1 gene expression is a marker of adult stem cells in a wide range of tissues. PW1-expressing cells are detected in the heart but are not well characterized. OBJECTIVES: The authors characterized cardiac PW1-expressing cells and their cell fate potentials in normal hearts and during cardiac remodeling following myocardial infarction (MI). METHODS: A human cardiac sample was obtained from a patient presenting with reduced left ventricular (LV) function following a recent MI. The authors used the PW1nLacZ+/- reporter mouse to identify, track, isolate, and characterize PW1-expressing cells in the LV myocardium in normal and ischemic conditions 7 days after complete ligature of the left anterior descending coronary artery. RESULTS: In both human and mouse ischemic hearts, PW1 expression was found in cells that were mainly located in the infarct and border zones. Isolated cardiac resident PW1+ cells form colonies and have the potential to differentiate into multiple cardiac and mesenchymal lineages, with preferential differentiation into fibroblast-like cells but not into cardiomyocytes. Lineage-tracing experiments revealed that PW1+ cells differentiated into fibroblasts post-MI. Although the expression of c-Kit and PW1 showed little overlap in normal hearts, a marked increase in cells coexpressing both markers was observed in ischemic hearts (0.1 ± 0.0% in control vs. 5.7 ± 1.2% in MI; p < 0.001). In contrast to the small proportion of c-Kit+/PW1- cells that showed cardiogenic potential, c-Kit+/PW1+ cells were fibrogenic. CONCLUSIONS: This study demonstrated the existence of a novel population of resident adult cardiac stem cells expressing PW1+ and their involvement in fibrotic remodeling after MI.

Postoperative urinary retention in colorectal surgery within an enhanced recovery pathway.

BACKGROUND: Enhanced recovery after surgery (ERAS) guidelines for colorectal surgery suggest routine transurethral bladder drainage with early removal to prevent urinary tract infection (UTI). The aim of this study was to identify risk factors for urinary retention (UR). METHODS: This retrospective analysis included all colorectal patients since ERAS implementation in May 2011-November 2014. From the prospective ERAS database, over 100 items related to demographics, surgery, compliance, and outcome were analyzed. Risk factors for UR were identified by multiple logistic regressions; then, UR was correlated to functional outcomes and UTI and acute kidney injury rates. RESULTS: The study cohort consisted of 513 consecutive patients. Of these, 73 patients (14%) presented with UR. Multivariate analysis identified male gender (odds ratio 1.4; 95% CI, 1-1.8; P = 0.045) and postoperative thoracic epidural analgesia (EDA; odds ratio 2.6; 95% CI, 1.6-4.3; P ≤ 0.001) as independent risk factors for postoperative UR. Functional recovery was impeded in patients with UR, who were less mobile (mobilization day 1 >4 h: 57% versus 70%, P = 0.024) and gained more weight (2.8 ± 2.5 kg versus 1.6 ±3 kg on day 1, P = 0.001) due to fluid overload. Furthermore, patients with urinary catheters reported more pain (visual analog scales day 3: 3.1 ± 2.5 versus 2.2 ± 2.4, P = 0.002) and depended longer on intravenous fluid administration (termination of intravenous fluids later than day 1: 53% versus 39%, P = 0.021). Ten of 73 patients (14%) developed UTI in patients with UR and 42 of 440 (10%) in patients without UR (P = 0.276). Six of 73 patients (8%) developed acute kidney injury in patients with UR and 36 of 440 (8%) in patients without UR (P = 0.991). CONCLUSIONS: Male gender and EDA were independent risk factors for postoperative UR which appeared to be a significant impediment for functional recovery.