Simultaneous and divergent evolution of resistance to cephalosporin/ß-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections.

OBJECTIVES: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. METHODS: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on ß-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. RESULTS: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC ß-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. CONCLUSIONS: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new ß-lactam/ß-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.

Transmission of toxigenic Clostridiodes difficile between a pet dog with diarrhea and a 10-month-old infant.

We describe a case of interspecies transmission of toxigenic Clostridioides difficile involving a female and her dog, both with diarrhea without another diagnosis. Genomic analysis showed that isolates were grouped into MLST clade I, closely related to ribotype 020 and shared identical genotypes.

Microbiome in Immune-Mediated Uveitis.

In the last decades, personalized medicine has been increasing its presence in different fields of medicine, including ophthalmology. A new factor that can help us direct medicine towards the challenge of personalized treatments is the microbiome. The gut microbiome plays an important role in controlling immune response, and dysbiosis has been associated with immune-mediated diseases such as non-infectious uveitis (NIU). In this review, we gather the published evidence, both in the pre-clinical and clinical studies, that support the possible role of intestinal dysbiosis in the pathogenesis of NIU, as well as the modulation of the gut microbiota as a new possible therapeutic target. We describe the different mechanisms that have been proposed to involve dysbiosis in the causality of NIU, as well as the potential pharmacological tools that could be used to modify the microbiome (dietary supplementation, antibiotics, fecal microbiota transplantation, immunomodulators, or biologic drugs) and, consequently, in the control of the NIU. Furthermore, there is increasing scientific evidence suggesting that the treatment with anti-TNF not only restores the composition of the gut microbiota but also that the study of the composition of the gut microbiome will help predict the response of each patient to anti-TNF treatment.

Molecular mechanisms driving the in vivo development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR Pseudomonas aeruginosa infections.

BACKGROUND: The development of resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of Pseudomonas aeruginosa infections is concerning. OBJECTIVES: Characterization of the mechanisms leading to the development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR P. aeruginosa infections. METHODS: Four paired ceftolozane/tazobactam- and ceftazidime/avibactam-susceptible/resistant isolates were evaluated. MICs were determined by broth microdilution. STs, resistance mechanisms and genetic context of ß-lactamases were determined by genotypic methods, including WGS. The OXA-10 variants were cloned in PAO1 to assess their impact on resistance. Models for the OXA-10 derivatives were constructed to evaluate the structural impact of the amino acid changes. RESULTS: The same XDR ST253 P. aeruginosa clone was detected in all four cases evaluated. All initial isolates showed OprD deficiency, produced an OXA-10 enzyme and were susceptible to ceftazidime, ceftolozane/tazobactam, ceftazidime/avibactam and colistin. During treatment, the isolates developed resistance to all cephalosporins. Comparative genomic analysis revealed that the evolved resistant isolates had acquired mutations in the OXA-10 enzyme: OXA-14 (Gly157Asp), OXA-794 (Trp154Cys), OXA-795 (ΔPhe153-Trp154) and OXA-824 (Asn143Lys). PAO1 transformants producing the evolved OXA-10 derivatives showed enhanced ceftolozane/tazobactam and ceftazidime/avibactam resistance but decreased meropenem MICs in a PAO1 background. Imipenem/relebactam retained activity against all strains. Homology models revealed important changes in regions adjacent to the active site of the OXA-10 enzyme. The blaOXA-10 gene was plasmid borne and acquired due to transposition of Tn6746 in the pHUPM plasmid scaffold. CONCLUSIONS: Modification of OXA-10 is a mechanism involved in the in vivo acquisition of resistance to cephalosporin/ß-lactamase inhibitor combinations in P. aeruginosa.

Sterility assurance of technetium-99m radiopharmaceuticals: no specific air conditions are required for their preparation, storage and dispensation.

BACKGROUND: The aim of this study was to ascertain whether the extemporaneous technetium-99m radiopharmaceuticals - prepared by closed procedures - maintain or not sterility throughout their lifespan regardless the quality of the environmental air where they are prepared, stored and dispensed, provided that the basic aseptic rules for closed procedures are followed. METHODS: Three different types of assays were performed in this study: 1) sterility tests of each and every one of the vials with the remains of technetium-99m radiopharmaceuticals, which have been prepared in our hospital radiopharmacy during three years without any special environmental air conditions; 2) integrity tests of punctured rubber plug closures using both microbial challenge testing and dye ingress testing; and 3) simulation of the dispensing process using a liquid growth medium. RESULTS: Sterility tests of more than 6,000 vials with the remains of technetium-99m radiopharmaceuticals - prepared without any special ambient air conditions - were performed, all of them with a negative result (no growth of microorganisms occurs). The integrity of punctured rubber plugs closure was sufficiently proven under extreme conditions by two different methods. The maintenance of sterility during the dispensing process of technetium-99m radiopharmaceuticals was also proven by simulation of the dispensing process using a liquid growth medium. CONCLUSIONS: This study strongly supports that it is not necessary any special ambient air conditions to prepare, store and dispense extemporaneous technetium-99m radiopharmaceuticals in order to preserve their sterility when the basic aseptic rules for closed procedures are followed.

Impact of Green Cosolvents on the Catalytic Dehydrogenation of Formic Acid: The Case of Iridium Catalysts Bearing NHC-phosphane Ligands.

The catalysts [Ir(COD)(κ3-P,C,P'-PCNHCP)]BF4 and [Ir(COD)(κ2-P,C-PCNHCO)]BF4 proved to be active in the solventless dehydrogenation of formic acid. The impact of various cosolvents on the activity was evaluated, showing an outstanding improvement of the catalytic performance of [Ir(COD)(κ2-P,C-PCNHCO)]BF4] in "green" organic carbonates: namely, dimethyl carbonate (DMC) and propylene carbonate (PC). The TOF1h value for [Ir(COD)(κ2-P,C-PCNHCO)]BF4 increases from 61 to 988 h-1 upon changing from solventless conditions to a 1/1 (v/v) DMC/HCOOH mixture. However, in the case of [Ir(COD)(PCNHCP)]BF4, only a marginal improvement from 156 to 172 h-1 was observed under analogous conditions. Stoichiometric experiments allowed the identification of various key reaction intermediates, providing valuable information on their reactivity. Experimental data and DFT calculations point to the formation of dinuclear species as the catalyst deactivation pathway, which is prevented in the presence of DMC and PC.

Smart conversational agents for the detection of neuropsychiatric disorders: A systematic review.

OBJECTIVE: To determine whether smart conversational agents can be used for detection of neuropsychiatric disorders. Therefore, we reviewed the technologies used, targeted mental disorders and validation procedures of relevant proposals in this field. METHODS: We searched Scopus, PubMed, Pro-Quest, IEEE Xplore, Web of Science, CINAHL and the Cochrane Library using a predefined search strategy. Studies were included if they focused on neuropsychiatric disorders and involved conversational data for detection and diagnosis. They were assessed for eligibility by independent reviewers and ultimately included if a consensus was reached about their relevance. RESULTS: 2356 references were initially retrieved. Eventually, 17 articles - referring 9 smart conversational agents - met the inclusion criteria. Out of the selected studies, 7 are targeted at neurocognitive disorders, 7 at depression and 3 at other conditions. They apply diverse technological solutions and analysis techniques (82.4% use Artificial Intelligence), and they usually rely on gold standard tests for criterion validity assessment. Acceptability, reliability and other aspects of validity were rarely addressed. CONCLUSION: The use of smart conversational agents for the detection of neuropsychiatric disorders is an emerging and promising field of research, with a broad coverage of mental disorders and extended use of AI. However, the few published studies did not undergo robust psychometric validation processes. Future research in this field would benefit from more rigorous validation mechanisms and standardized software and hardware platforms.

Factors affecting diabetic patient's long-term quality of life after simultaneous pancreas-kidney transplantation: a single-center analysis.

PURPOSE: Pancreas transplantation (PT) is one of the few ways to restore euglycemia within diabetic patients; however, the high morbidity caused by surgical complications and the need for immunosuppressive therapy has raised controversy about PT improving the health-related quality-of-life (HRQoL). The aim of this study is to assess the long-term (≥ 5 years after PT) HRQoL and to identify the factors affecting it. METHODS: A single-center, cross-sectional study of 49 sequential PT was performed. All patients conducted a telephone interview to fulfill the modification of Medical Outcome Health Survey Short Form questionnaire (SF-36v2) and were compared to similar post-PT studies from the literature. RESULTS: Patients with a history of replacement renal therapy (RRT) or neuropathy undergoing a PT were associated to a worse bodily pain (P = 0.03) and physical function (P = 0.04), respectively, whereas those with retinopathy showed an improved Role Emotional (P = 0.04). Multivariate analysis revealed the presence of RRT as the only independent prognostic factor for a worse bodily pain [relative risk = 3.9; 95% confidence interval (1.1-14.6)], (P = 0.04). Furthermore, nearly all PT recipients (91.8%) claimed an overall better health than prior to PT. CONCLUSION: Our study confirms that PT recipients' HRQoL improves after PT, showing similar HRQoL scores across different populations and suggests that patients in predialysis could benefit from an improved HRQoL if transplanted on the early stages of the disease.

Molecular and biochemical insights into the in vivo evolution of AmpC-mediated resistance to ceftolozane/tazobactam during treatment of an MDR Pseudomonas aeruginosa infection.

BACKGROUND: Pseudomonas aeruginosa may develop resistance to novel cephalosporin/ß-lactamase inhibitor combinations during therapy through the acquisition of structural mutations in AmpC. OBJECTIVES: To describe the molecular and biochemical mechanisms involved in the development of resistance to ceftolozane/tazobactam in vivo through the selection and overproduction of a novel AmpC variant, designated PDC-315. METHODS: Paired susceptible/resistant isolates obtained before and during ceftolozane/tazobactam treatment were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. Characterization of the novel PDC-315 variant was performed through genotypic and biochemical studies. The effects at the molecular level of the Asp245Asn change were analysed by molecular dynamics simulations using Amber. RESULTS: WGS identified mutations leading to modification (Asp245Asn) and overproduction of AmpC. Susceptibility testing revealed that PAOΔC producing PDC-315 displayed increased MICs of ceftolozane/tazobactam, decreased MICs of piperacillin/tazobactam and imipenem and similar susceptibility to ceftazidime/avibactam compared with WT PDCs. The catalytic efficiency of PDC-315 for ceftolozane was 10-fold higher in relation to the WT PDCs, but 3.5- and 5-fold lower for piperacillin and imipenem. IC50 values indicated strong inhibition of PDC-315 by avibactam, but resistance to cloxacillin inhibition. Analysis at the atomic level explained that the particular behaviour of PDC-315 is linked to conformational changes in the H10 helix that favour the approximation of key catalytic residues to the active site. CONCLUSIONS: We deciphered the precise mechanisms that led to the in vivo emergence of resistance to ceftolozane/tazobactam in P. aeruginosa through the selection of the novel PDC-315 enzyme. The characterization of this new variant expands our knowledge about AmpC-mediated resistance to cephalosporin/ß-lactamase inhibitors in P. aeruginosa.

HIV antibodies level as a marker of HIV persistence: the role of hepatitis C virus coinfection.

Human immunodeficiency virus (HIV) antibodies have been proposed as a measure of the size of the HIV reservoir. The aim of our study is to quantify the anti-HIV antibodies level in a cohort of people living with HIV (PLWH), stratified based on the presence of continuous undetectable HIV viral load and the co-existence of hepatitis C virus infection. A sample of 229 HIV-monoinfected (n = 114) or HIV/HCV-coinfected [either with resolved HCV infection (n = 75) or active HCV coinfection (n = 40)] patients, followed up a median of 34 (IQR 20-44) months, was studied. Anti-HIV index was obtained as the 1:800 dilution of HIV antibodies. CD4+ T cell count, time with undetectable HIV viral load, annual increase of CD4+ T cell count, anti-HCV therapy, and diagnosis of cirrhosis were analyzed. Patients with a continued suppressed HIV viral load had significant lower anti-HIV index compared with those with virologic failure during the follow-up. Significant higher CD4+ T cell increase was observed in those with a lower anti-HIV index. HIV-monoinfected patients showed an anti-HIV index significantly lower than patients with HCV coinfection. Resolved HCV infection after interferon-based therapy, but not with direct acting antivirals, was associated with a lower anti-HIV index. HIV/HCV-coinfected patients showed higher HIV antibodies level when compared with HIV-monoinfected individuals. A decrease in anti-HIV index in HIV/HCV-coinfected patients was detected when a sustained virological HCV response was obtained after interferon-based therapy, in possible relation with the direct or indirect effect of interferon on PLWH CD4 T cells.

Neuropsychiatric symptoms as predictors of conversion from MCI to dementia: a machine learning approach.

OBJECTIVES: To use a Machine Learning (ML) approach to compare Neuropsychiatric Symptoms (NPS) in participants of a longitudinal study who developed dementia and those who did not. DESIGN: Mann-Whitney U and ML analysis. Nine ML algorithms were evaluated using a 10-fold stratified validation procedure. Performance metrics (accuracy, recall, F-1 score, and Cohen's kappa) were computed for each algorithm, and graphic metrics (ROC and precision-recall curves) and features analysis were computed for the best-performing algorithm. SETTING: Primary care health centers. PARTICIPANTS: 128 participants: 78 cognitively unimpaired and 50 with MCI. MEASUREMENTS: Diagnosis at baseline, months from the baseline assessment until the 3rd follow-up or development of dementia, gender, age, Charlson Comorbidity Index, Neuropsychiatric Inventory-Questionnaire (NPI-Q) individual items, NPI-Q total severity, and total stress score and Geriatric Depression Scale-15 items (GDS-15) total score. RESULTS: 30 participants developed dementia, while 98 did not. Most of the participants who developed dementia were diagnosed at baseline with amnestic multidomain MCI. The Random Forest Plot model provided the metrics that best predicted conversion to dementia (e.g. accuracy=.88, F1=.67, and Cohen's kappa=.63). The algorithm indicated the importance of the metrics, in the following (decreasing) order: months from first assessment, age, the diagnostic group at baseline, total NPI-Q severity score, total NPI-Q stress score, and GDS-15 total score. CONCLUSIONS: ML is a valuable technique for detecting the risk of conversion to dementia in MCI patients. Some NPS proxies, including NPI-Q total severity score, NPI-Q total stress score, and GDS-15 total score, were deemed as the most important variables for predicting conversion, adding further support to the hypothesis that some NPS are associated with a higher risk of dementia in MCI.

Challenging Antimicrobial Susceptibility and Evolution of Resistance (OXA-681) during Treatment of a Long-Term Nosocomial Infection Caused by a Pseudomonas aeruginosa ST175 Clone.

Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of in vivo resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Pseudomonas aeruginosa Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species may often lead to their underestimation. The underlying resistance mechanisms of two sequence type 175 (ST175) P. aeruginosa isolates showing multidrug-resistant phenotypes and recovered at early and late stages of a long-term nosocomial infection were evaluated. Whole-genome sequencing (WGS) was used to investigate resistance genomics, whereas molecular and biochemical methods were used for characterization of a novel extended-spectrum OXA-2 variant selected during therapy. The metallo-ß-lactamase blaVIM-20 and the narrow-spectrum oxacillinase blaOXA-2 were present in both isolates, although they differed by an inactivating mutation in the mexB subunit, present only in the early isolate, and in a mutation in the blaOXA-2 ß-lactamase, present only in the final isolate. The new OXA-2 variant, designated OXA-681, conferred elevated MICs of the novel cephalosporin-ß-lactamase inhibitor combinations in a PAO1 background. Compared to OXA-2, kinetic parameters of the OXA-681 enzyme revealed a substantial increase in the hydrolysis of cephalosporins, including ceftolozane. We describe the emergence of the novel variant OXA-681 during treatment of a nosocomial infection caused by a Pseudomonas aeruginosa ST175 high-risk clone. The ability of OXA-681 to confer cross-resistance to ceftolozane-tazobactam and ceftazidime-avibactam together with the complex antimicrobial resistance profiles exhibited by the clinical strains harboring this new enzyme argue for maintaining active surveillance on emerging broad-spectrum resistance in P. aeruginosa.

A prospective survey of Aspergillus spp. in respiratory tract samples: Species identification and susceptibility patterns.

We analyzed the species distribution and susceptibility patterns of 433 strains of Aspergillus spp. isolated from respiratory samples of 419 in-patients included in multicenter prospective study (FUNGAE-IFI) between July 2014 and October 2015. Identification was carried out by conventional methods at each participating center and by molecular sequencing of a portion of the ß-tubulin gene at one of the centers. In vitro susceptibility was evaluated by broth microdilution methods and using the E-test (for cryptic species). Species identified included 249 A. fumigatus sensu stricto, 60 A. terreus sensu stricto, 47 A. flavus sensu stricto, 44 A. tubingensis, 18 A. niger sensu stricto , five A. nidulans sensu stricto, three A. tamarii, two A. calidoustus, two A. carneus, one A. acuelatus, one A. carbonarius, and one A. sydowii. Cryptic species were found in 12.5% of isolates (n = 54). The frequency of non-wild-type isolates for amphotericin B was 3.4% (n = 15) of the isolates tested and for azoles 3% (n = 10). None of the Aspergillus spp. were non-wild type to echinocandins. Of the 54 cryptic species only two strains were non-wild-type strains by microdilution method (3.7%) (two A. tubingensis, one to amphotericin B and another one to voriconazole) and by E-test method five strains of A. tubingensis showed high minimal inhibitory concentration (MIC) to amphotericin B (11.4%) and five to azoles (12.1%), one A. calidoustus strain showed high MICs for three azoles (50%), A. carneus to itraconazole (100%) and A. sydowii to amphotericin B and itraconazole (100%). These results provide relevant information on susceptibility patterns, frequency, and epidemiology of species involved in respiratory tract samples and of the incidence of recently described cryptic species.

HTLV-1 infection in solid organ transplant donors and recipients in Spain.

BACKGROUND: HTLV-1 infection is a neglected disease, despite infecting 10-15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. METHODS: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. RESULTS: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. CONCLUSION: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopathy.

Effectiveness of electronic point-of-care reminders versus monthly feedback to improve adherence to 10 clinical recommendations in primary care: a cluster randomized clinical trial.

BACKGROUND: Numerous studies have analyzed the effectiveness of electronic reminder interventions to improve different clinical conditions, and most have reported a small to moderate effect. Few studies, however, have analyzed reminder systems targeting multiple conditions, and fewer still have compared electronic point-of-care reminders systems with other forms of feedback designed to improve delivery of care. METHODS: We performed an unblinded cluster randomized clinical trial to compare the effectiveness of an electronic point-of-care reminder system with that of a well-established system providing monthly feedback on adherence to clinical recommendations. The control group received monthly feedback only while the intervention group received monthly feedback in addition to on-screen point-of-care reminders for 10 clinical conditions. The study targeted all physicians and nurses at the 283 primary care centers managed by the Institut Català de la Salut (approximately 6600 professionals). RESULTS: Following exclusions and randomization, 132 primary care centers (328,728 patients with reminders) were assigned to the intervention group while 137 centers (317,117 patients with reminders) were randomized to the control group. A 20.6% improvement (OR 1.29, 95% CI: 1.25-1.34) in reminder resolution rates was observed in the intervention group. Results varied according to the clinical condition. The most effective reminder was screening for diabetic retinopathy (OR 1.51, 95% CI:1.46-1.57) while the least effective reminders were measurement of glycated hemoglobin (OR: 1.10, 95% CI: 1.07-1.13) and smoking cessation encouragement (OR 1.12, 95% CI: 1.09-1.16). CONCLUSIONS: Electronic point-of-care reminders were more effective than the existing monthly feedback system at resolving the 10 clinical situations. However, more studies are needed to investigate the variations of the effect observed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42391639, 08/10/2012. Retrospectively registered.

A leap forward in iridium-NHC catalysis: new horizons and mechanistic insights.

This review summarises the most recent advances in Ir-NHC catalysis while revisiting all the classical reactions in which this type of catalyst has proved to be active. The influence of the ligand system and, in particular, the impact of the NHC ligand on the activity and selectivity of the reaction have been analysed, accompanied by an examination of the great variety of catalytic cycles hitherto reported. The reaction mechanisms so far proposed are described and commented on for each individual process. Moreover, some general considerations that attempt to explain the influence of the NHC from a mechanistic viewpoint are presented at the end of the review. The first sections are dedicated to the most widely explored reactions that use Ir-NHCs, i.e., hydrogenation and transfer hydrogenation, for which a general overview that tries to compile all the Ir-NHC catalysts hitherto reported for these processes is provided. The next sections deal with hydrogen borrowing, hydrosilylation, water splitting, dehydrogenation (of alcohols, alkanes, aminoboranes and formic acid), hydrogen isotope exchange (HIE), signal amplification by reversible exchange and C-H bond functionalisation (silylation and borylation). The last section compiles a series of reactions somewhat less explored for Ir-NHC catalysts that include the hydroalkynylation of imines, hydroamination, diboration of olefins, hydrolysis and methanolysis of silanes, arylation of aldehydes with boronic acids, addition of aroyl chlorides to alkynes, visible light driven reactions, isomerisation of alkenes, asymmetric intramolecular allylic amination and reactions that employ heterometallic catalysts containing at least one Ir-NHC unit.

Histologic Tumor Grade and Preoperative Bilary Drainage are the Unique Independent Prognostic Factors of Survival in Pancreatic Ductal Adenocarcinoma Patients After Pancreaticoduodenectomy.

BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer; most patients die during the first 6 months after diagnosis. With a 5% 5-year survival rate, is the fourth leading cause of cancer death in developed countries. In this regard, several clinical, histopathologic and biological characteristics of the disease favoring long-term survival after pancreaticoduodenectomy have been reported to be significant prognostic factors. Despite the availability of this information, there is no consensus about the different prognostic factors reported in the literature, probably due to variations in patient selection, methods, and sample size studied. The aim of this study was to identify the clinical and pathologic features associated to prognosis of the disease after pancreaticoduodenectomy. MATERIALS AND METHODS: The clinical and pathologic data from 78 patients who underwent a potentially curative resection for PDAC at our institution between 2003 and 2014 were analyzed retrospectively. RESULTS: Overall, high-grade PDAC cases showed larger tumor size (P=0.009) and a higher frequency of deaths in association with a nonsignificantly shortened patient overall survival (median of 12.5 vs. 21.7 mo; P=0.065) as compared with low-grade PDAC patients. High histologic grade (P=0.013), preoperative drainage on the main bile duct (P=0.014) and absence of adjuvant therapy (P=0.035) were associated with a significantly poorer outcome. Overall survival multivariate analysis showed histologic grade (P=0.019) and bile duct preoperative drainage (P=0.016) as the sole independent variables predicting an adverse outcome. CONCLUSIONS: Our results indicate that histologic tumor grade and preoperative biliary drainage are the only significant independent prognostic factors in PDAC patients after pancreatectomy.

Nosocomial Candiduria in the Elderly: Microbiological Diagnosis.

Candiduria is associated with high morbidity, mortality, and long hospitalization, involving high costs for the healthcare system. The use of increasingly aggressive treatments has prolonged the lives of patients susceptible to candiduria, namely the immunosuppressed, the premature, and the elderly. Our objective was to evaluate the incidence of nosocomial candiduria and the implicated species in hospitalized patients aged over 80 years old from three Spanish centers during 2012 and 2013. Urine samples received from these patients were cultured and analyzed by flow cytometry in search of leukocyturia, hematuria, proteinuria, and microbial nitrate reductase activity. The isolated yeast species were identified microscopically, by germ tube formation in serum, colony morphology after subculture onto CHROMagar Candida (Becton-Dickinson, UK), assimilation of carbon compounds ID32C (bioMérieux, France), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF) (Bruker Daltonics, Germany) and, in case of inconsistency, by sequencing of the ITS regions of ribosomal DNA (ITS1-5, 8S-ITS2). Susceptibility tests were also performed. The incidence of candiduria in the elderly population was 10.3%. A total of 155 strains of yeasts were isolated. The predominant species was Candida albicans, followed by Candida glabrata and then Candida tropicalis. Several infrequent species were found; among them, the first isolate of candiduria-producing Candida pulcherrima described in the literature. Our finding should raise concerns about the elderly population, which is probably the most important risk group for candiduria in the present moment, and the emergence of unusual yeast species producing candiduria, which are resistant against the commonly used antifungal agents.