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Background: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB., Methods: We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes., Results: Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C., Conclusions: We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB., Competing Interests: Potential conflicts of interest . C. T. reports speaker fees from Gedeon Richter. V. G. F. reports grants/research support from Astra Zeneca, MedImmune, Merck, ContraFect, Karius, Genentech, Regeneron, and Basilea; serving as a paid consultant for Astra Zeneca, GSK, Armata, Debiopharm, Genentech, Basilea Affinergy, Janssen, ContraFect, and Destiny; and royalties from UpToDate. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Although a significant number of cases of Staphylococcus aureus bacteraemia (SAB) are managed at non-referral community hospitals, the impact of a bundle-of-care intervention in this setting has not yet been explored., Methods: We performed a quasi-experimental before-after study with the implementation of a bundle of care for the management of SAB at five non-referral community hospitals and a tertiary care university hospital. Structured recommendations for the five indicators selected to assess quality of care were provided to investigators before the implementation of the bundle and monthly thereafter. Primary endpoints were adherence to the bundle intervention and treatment failure, defined as death or relapse at 90 days of follow-up., Results: One hundred and seventy patients were included in the pre-intervention period and 103 in the intervention period. Patient characteristics were similar in both periods. Multivariate analysis controlling for potential confounders showed that performance of echocardiography was the only factor associated with improved adherence to the bundle in the intervention period (adjusted OR 2.13; 95% CI 1.13-4.02). Adherence to the bundle, performance of follow-up blood cultures, and adequate duration of antibiotic therapy for complicated SAB presented non-significant improvements. The intervention was not associated with a lower rate of 90 day treatment failure (OR 1.11; 95% CI 0.70-1.77)., Conclusions: A bundle-of-care intervention for the management of SAB at non-referral community hospitals increased adherence to quality indicators, but did not significantly reduce rates of 90 day mortality or relapse., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: There is controversy regarding the maximum number of elements that can be included in a surgical site infection prevention bundle. In addition, it is unclear whether a bundle of this type can be implemented at a multicentre level., Methods: A pragmatic, multicentre cohort study was designed to analyse surgical site infection rates in elective colorectal surgery after the sequential implementation of two preventive bundle protocols. Secondary outcomes were to determine compliance with individual measures and to establish their effectiveness, duration of stay, microbiology and 30-day mortality rate., Results: A total of 32 205 patients were included. A 50% reduction in surgical site infection was achieved after the implementation of two sequential sets of bundles: from 18.16% in the Baseline group to 10.03% with Bundle-1 and 8.19% with Bundle-2. Bundle-2 reduced superficial-surgical site infection (OR 0.74 (95% c.i. 0.58 to 0.95); P = 0.018) and deep-surgical site infection (OR 0.66 (95% c.i. 0.46 to 0.93); P = 0.018) but not organ/space-surgical site infection (OR 0.88 (95% c.i. 0.74 to 1.06); P = 0.172). Compliance increased after the addition of four measures to Bundle-2. In the multivariable analysis, for organ/space-surgical site infection, laparoscopy, oral antibiotic prophylaxis and mechanical bowel preparation were protective factors in colonic procedures, while no protective factors were found in rectal surgery. Duration of stay fell significantly over time, from 7 in the Baseline group to 6 and 5 days for Bundle-1 and Bundle-2 respectively (P < 0.001). The mortality rate fell from 1.4% in the Baseline group to 0.59% and 0.6% for Bundle-1 and Bundle-2 respectively (P < 0.001). There was an increase in Gram-positive bacteria and yeast isolation, and reduction in Gram-negative bacteria and anaerobes in organ/space-surgical site infection., Conclusions: The addition of measures to create a final 10-measure protocol had a cumulative protective effect on reducing surgical site infection. However, organ/space-surgical site infection did not benefit from the addition. No protective measures were found for organ/space-surgical site infection in rectal surgery. Compliance with preventive measures increased from Bundle-1 to Bundle-2., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

The importance of melon aroma in determining fruit quality has been highlighted in recent years. The fruit volatile profile is influenced by the type of fruit ripening. Non-climacteric fruits contain predominantly aldehydes, while climacteric fruits mainly produce esters. Several genes have been described to participate in volatile organic compounds (VOCs) biosynthesis pathways, but knowledge in this area is still incomplete. In this work we analysed the volatile profile of two reciprocal Introgression Line (IL) collections generated from a cross between 'Piel de Sapo' (PS) and 'Védrantais' (VED) melons, differing in their aroma profile and ripening behaviour. SPME GC-MS was performed to identify genes responsible for VOCs formation. More than 1000 QTLs for many volatiles were detected taken together both populations. Introgressions on chromosomes 3, 5, 6, 7 and 8 modified ester-aldehyde balance and were correlated to ripening changes in both genetic backgrounds. Some previously identified QTLs for fruit ripening might be involved in these phenotypes, such as ETHQV8.1 on chromosome 8 and ETHQV6.3 on chromosome 6. PS alleles on chromosomes 2, 6, 10 and 11 were found to increase ester content when introgressed in VED melons. Terpenes showed to be affected by several genomic regions not related to ripening. In addition, several candidate genes have been hypothesized to be responsible for some of the QTLs detected. The analysis of volatile compounds in two reciprocal IL collections has increased our understanding of the relationship between ripening and aroma and offers valuable plant material to improve food quality in melon breeding programs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Fruit ripening is a complex and highly regulated process where tomato and strawberry have been the model species classically used for studying climacteric and non-climacteric fleshy fruit ripening types, respectively. Melon has emerged as an alternative ripening model because climacteric and non-climacteric cultivars exist, which makes it possible to dissect the regulation of ripening using a genetic approach. Several quantitative trait loci that regulate climacteric fruit ripening have been identified to date, and their combination in both climacteric and non-climacteric genetic backgrounds resulted in lines with different ripening behaviors, demonstrating that the climacteric intensity can be genetically modulated. This review discusses our current knowledge of the physiological changes observed during melon climacteric fruit ripening such as ethylene production, fruit abscission, chlorophyll degradation, firmness, and aroma, as well as their complex genetic control. From pioneer experiments in which ethylene biosynthesis was silenced, to the recent genetic edition of ripening regulators, current data suggest that the climacteric response is determined by the interaction of several loci under quantitative inheritance. The exploitation of the rich genetic diversity of melon will enable the discovery of additional genes involved in the regulation of the climacteric response, ultimately leading to breeding aromatic melon fruits with extended shelf life., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Colorectal cancer management may require an ostomy formation; however, a stoma may negatively impact health-related quality of life (HRQoL). This study aimed to compare generic and stoma-specific HRQoL in patients with a permanent colostomy after rectal cancer across different countries., Method: A cross-sectional cohorts of patients with a colostomy after rectal cancer in Denmark, Sweden, Spain, the Netherlands, China, Portugal, Australia, Lithuania, Egypt, and Israel were invited to complete questionnaires regarding demographic and socioeconomic factors along with the Colostomy Impact (CI) score, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and five anchor questions assessing colostomy impact on HRQoL. The background characteristics of the cohorts from each country were compared and generic HRQoL was measured with the EORTC QLQ-C30 presented for the total cohort. Results were compared with normative data of reference European populations. The predictors of reduced HRQoL were investigated by multivariable logistic regression, including demographic and socioeconomic factors and stoma-related problems., Results: A total of 2557 patients were included. Response rates varied between 51-93 per cent. Mean time from stoma creation was 2.5-6.2 (range 1.1-39.2) years. A total of 25.8 per cent of patients reported that their colostomy impairs their HRQoL 'some'/'a lot'. This group had significantly unfavourable scores across all EORTC subscales compared with patients reporting 'no'/'a little' impaired HRQoL. Generic HRQoL differed significantly between countries, but resembled the HRQoL of reference populations. Multivariable logistic regression showed that stoma dysfunction, including high CI score (OR 3.32), financial burden from the stoma (OR 1.98), unemployment (OR 2.74), being single/widowed (OR 1.35) and young age (OR 1.01 per year) predicted reduced stoma-related HRQoL., Conclusion: Overall HRQoL is preserved in patients with a colostomy after rectal cancer, but a quarter of the patients interviewed reported impaired HRQoL. Differences among several countries were reported and socioeconomic factors correlated with reduced quality of life., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Melon (Cucumis melo) has emerged as an alternative model to tomato for studying fruit ripening due to the coexistence of climacteric and non-climacteric varieties. Previous characterization of a major quantitative trait locus (QTL), ETHQV8.1, that is able to trigger climacteric ripening in a non-climacteric background resulted in the identification of a negative regulator of ripening CTR1-like (MELO3C024518) and a putative DNA demethylase ROS1 (MELO3C024516) that is the orthologue of DML2, a DNA demethylase that regulates fruit ripening in tomato. To understand the role of these genes in climacteric ripening, in this study we generated homozygous CRISPR knockout mutants of CTR1-like and ROS1 in a climacteric genetic background. The climacteric behavior was altered in both loss-of-function mutants in two growing seasons with an earlier ethylene production profile being observed compared to the climacteric wild type, suggesting a role of both genes in climacteric ripening in melon. Single-cytosine methylome analyses of the ROS1-knockout mutant revealed changes in DNA methylation in the promoter regions of the key ripening genes such as ACS1, ETR1, and ACO1, and in transcription factors associated with ripening including NAC-NOR, RIN, and CNR, suggesting the importance of ROS1-mediated DNA demethylation for triggering fruit ripening in melon., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fruit ripening is one of the main processes affecting fruit quality and shelf life. In melon there are both climacteric and non-climacteric genotypes, making it a suitable species to study fruit ripening. In the current study, in order to fine tune ripening, we have pyramided three climacteric QTLs in the non-climacteric genotype "Piel de Sapo": ETHQB3.5 , ETHQV6.3 and ETHQV8.1 . The results showed that the three QTLs interact epistatically, affecting ethylene production and ripening-related traits such as aroma profile. Each individual QTL has a specific role in the ethylene production profile. ETHQB3.5 accelerates the ethylene peak, ETHQV6.3 advances the ethylene production and ETHQV8.1 enhances the effect of the other two QTLs. Regarding aroma, the three QTLs independently activated the production of esters changing the aroma profile of the fruits, with no significant effects in fruit firmness, soluble solid content and fruit size. Understanding the interaction and the effect of different ripening QTLs offers a powerful knowledge for candidate gene identification as well as for melon breeding programs, where fruit ripening is one of the main objectives., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Background: Although surgical site infections after a craniotomy (SSI-CRANs) are a serious problem that involves significant morbidity and costs, information on their prevention is scarce. We aimed to determine whether the implementation of a care bundle was effective in preventing SSI-CRANs., Methods: A historical control study was used to evaluate the care bundle, which included a preoperative shower with 4% chlorhexidine soap, appropriate hair removal, adequate preoperative systemic antibiotic prophylaxis, the administration of 1 g of vancomycin powder into the subgaleal space before closing, and a postoperative dressing of the incisional surgical wound with a sterile absorbent cover. Patients were divided into 2 groups: preintervention (January 2013 to December 2015) and intervention (January 2016 to December 2017). The primary study end point was the incidence of SSI-CRANs within 1 year postsurgery. Propensity score matching was performed, and differences between the 2 study periods were assessed using Cox regression models., Results: A total of 595 and 422 patients were included in the preintervention and intervention periods, respectively. The incidence of SSI-CRANs was lower in the intervention period (15.3% vs 3.5%; P < .001). Using a propensity score model, 421 pairs of patients were matched. The care bundle intervention was independently associated with a reduced incidence of SSI-CRANs (adjusted odds ratio, 0.23; 95% confidence interval, .13-.40; P < .001)., Conclusions: The care bundle intervention was effective in reducing SSI-CRAN rates. The implementation of this multimodal preventive strategy should be considered in centers with high SSI-CRAN incidences., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Neck cannulation is the most common cannulation strategy performed to provide veno-arterial extracorporeal membrane oxygenation support in paediatric patients, especially in small children. Upper limb ischaemia is a rare complication of neck cannulation and is likely caused by arterial cannula malposition. We describe a case of right arm ischaemia caused by extrinsic compression of the right subclavian artery by the venous drainage cannula inserted through the right internal jugular vein. Upper limb hypoperfusion was resolved immediately after changing the venous drainage cannula from the right jugular vein to the right femoral vein., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Study Objectives: To investigate the association between sleep and cognitive decline of patients with mild-moderate Alzheimer's disease., Methods: Observational, prospective study, including consecutive patients diagnosed with mild-moderate Alzheimer's disease. Cerebrospinal fluid was collected for amyloid-beta, total-tau, and phospho-tau levels determination. Also, overnight polysomnography was performed, followed by neuropsychological evaluations at baseline and after 12 months of follow-up. Principal component analysis revealed two profiles of patients in terms of sleep: one with a propensity to deepen the sleep (deep sleepers) and the other with a propensity to spend most of the time in the lighter sleep stage (light sleepers)., Results: The cohort included 125 patients with a median [IQR] of 75.0 [72.0;80.0] years. Deep and light sleepers did not present differences in relation to the cerebrospinal fluid pathological markers and to the cognitive function at the baseline. However, there was a significant difference of -1.51 (95% CI: -2.43 to -0.59) in the Mini-mental state examination after 12 months of follow-up. Accordingly, sleep depth and cognitive decline presented a dose-response relationship (p-for-trend = 0.02). Similar outcomes were observed in relation to the processing speed (Stroop words test, p-value = 0.016) and to the executive function (Verbal fluency test, p-value = 0.023)., Conclusions: Considering the increased cognitive decline presented by light sleepers, the sleep profile may have a predictive role in relation to the cognitive function of patients with mild-moderate Alzheimer's disease. The modifiable nature of sleep sets this behavior as a possible useful intervention to prevent a marked cognitive decline., Clinical Trial Information: Role of Hypoxia Ans Sleep Fragmentation in Alzheimer's Disease. and Sleep Fragmentation. Completed. NCT02814045., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis., Methods: A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy., Results: Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018)., Conclusions: Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events., Clinical Trials Registration: NCT01898338., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Study Objectives: The majority of studies investigating the association between sleep and Alzheimer's disease (AD) biomarkers have been performed in healthy participants. Our objective was to investigate the association between sleep and several biomarkers that reflect distinct aspects of AD physiopathology., Methods: The cohort included 104 individuals with mild-moderate AD. The participants were submitted to one-night polysomnography, and cerebrospinal fluid was collected in the following morning to measure the selected biomarkers associated with amyloid deposition, tau pathology, neurodegeneration, axonal damage, synaptic integrity, neuroinflammation, and oxidative damage., Results: There was a positive correlation between neurofilament light (NF-L) and the time spent in stage 1 of non-rapid eyes movement (NREM) (N1) sleep and a negative correlation between this marker and the time spent in stage 3 of NREM (N3) sleep. Accordingly, we observed that deep sleep was associated with lower levels of NF-L, whereas light sleep increased the probability of having higher levels of this marker. Furthermore, chitinase-3-like-1 (YKL-40) was negatively correlated with sleep efficiency, the time spent in stage 2 of NREM (N2) sleep, and the time spent in N3 sleep. Conversely, there was a positive correlation between N3 sleep and the oxidative protein damage markers N-ε-(carboxyethyl)lysine and N-ε-(malondialdehyde)lysine., Conclusions: There were significant correlations between sleep parameters and AD biomarkers related to axonal damage and neuroinflammation, such as NF-L and YKL-40. A lack of deep sleep was associated with higher levels of NF-L. This highlights a potential role for NF-L as a biomarker of sleep disruption in patients with mild-moderate AD in addition to its role in predicting neurodegeneration and cognitive decline., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Context: Lynch syndrome (LS) is the most common inherited colorectal and endometrial cancer syndrome, caused by germline mutations in DNA mismatch repair (MMR) genes. It is also characterized by an increased risk of other tumors with lower prevalence, such as adrenal cortical carcinoma (ACC), an endocrine tumor with an incidence of <2 cases/million individuals/year. Most ACC developed during childhood are associated with hereditary syndromes. In adults, this association is not as well established as in children. Previous studies showed a 3.2% prevalence of LS among patients with ACC., Evidence Acquisition: The objective of this study is to determine the prevalence of ACC in a Spanish LS cohort and their molecular and histological characteristics. This retrospective study includes 634 patients from 220 LS families registered between 1999 and 2018., Evidence Synthesis: During the follow-up period, 3 patients were diagnosed with ACC (0.47%); all were carriers of a MSH2 germline mutation. The 3 ACC patients presented loss of expression of MSH2 and MSH6 proteins. One tumor analysis showed loss of heterozygosity of the MSH2 wildtype allele. Our findings support previous data that considered ACC as a LS spectrum tumor., Conclusion: MMR protein immunohistochemistry screening could be an efficient strategy to detect LS in patients with ACC., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Melon is as an alternative model to understand fruit ripening due to the coexistence of climacteric and non-climacteric varieties within the same species, allowing the study of the processes that regulate this complex trait with genetic approaches. We phenotyped a population of recombinant inbred lines (RILs), obtained by crossing a climacteric (Védrantais, cantalupensis type) and a non-climcteric variety (Piel de Sapo T111, inodorus type), for traits related to climacteric maturation and ethylene production. Individuals in the RIL population exhibited various combinations of phenotypes that differed in the amount of ethylene produced, the early onset of ethylene production, and other phenotypes associated with ripening. We characterized a major QTL on chromosome 8, ETHQV8.1, which is sufficient to activate climacteric ripening, and other minor QTLs that may modulate the climacteric response. The ETHQV8.1 allele was validated by using two reciprocal introgression line populations generated by crossing Védrantais and Piel de Sapo and analyzing the ETHQV8.1 region in each of the genetic backgrounds. A Genome-wide association study (GWAS) using 211 accessions of the ssp. melo further identified two regions on chromosome 8 associated with the production of aromas, one of these regions overlapping with the 154.1 kb interval containing ETHQV8.1. The ETHQV8.1 region contains several candidate genes that may be related to fruit ripening. This work sheds light into the regulation mechanisms of a complex trait such as fruit ripening.

Background: Mortality rates from Staphylococcus aureus bacteremia are high and have only modestly improved in recent decades. We compared the efficacies of a β-lactam in combination with daptomycin (BL/D-C) and β-lactam monotherapy (BL-M) in improving clinical outcomes in methicillin-susceptible S. aureus (MSSA) bacteremia., Methods: A retrospective cohort study of MSSA bacteremia was performed in a tertiary hospital from January 2011 to December 2017. Patients receiving BL/D-C and BL-M were compared to assess 7-, 30-, and 90-day mortality rates. A 1:2 propensity score matching analysis was performed. Differences were assessed using Cox regression models., Results: Of the 514 patients with MSSA bacteremia, 164 were excluded as they had received combination therapies other than BL/D-C, had pneumonia, or died within 48 hours of admission. Of the remaining 350 patients, 136 and 214 received BL/D-C and BL-M, respectively. BL/D-C patients had higher Pitt scores and persistent bacteremia more often than BL-M patients. In the raw analysis, there were no differences in mortality rates between groups. After propensity score matching, there were no significant differences between the BL/D-C (110 patients) and BL-M (168 patients) groups for all-cause mortality rates at 7 days (8.18% vs 7.74%; P = 1.000), 30 days (17.3% vs 16.1%; P = .922), and 90 days (22.7% vs 23.2%; P = 1.000), even in a subanalysis of patients with high-risk source of infection and in a subgroup excluding catheter-related bacteremia., Conclusions: BL/D-C failed to reduce mortality rates in patients with MSSA bacteremia. Treatment strategies to improve survival in MSSA bacteremia are urgently needed., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs., Methods: A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes., Results: A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p <0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients., Conclusions: In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined.

Background: It has been suggested that there is an increased risk of treatment failure in episodes of MRSA bloodstream infection (BSI) caused by strains with high vancomycin MICs. However, it is unknown if this phenomenon may also act as a risk factor for the development of infective endocarditis (IE)., Methods: We analysed 207 episodes of catheter-related (CR)-BSI recruited from June 2008 to December 2009 within a prospective study on MRSA BSI in 21 Spanish hospitals. Vancomycin susceptibility was centrally tested. The impact of high vancomycin MIC values (≥1.5 mg/L by Etest) on the subsequent development of IE was investigated by Cox regression., Results: High vancomycin MIC values were observed in 46.9% of the isolates. Initial therapy consisted of vancomycin [99 episodes (44.7%)], daptomycin [25 (12.1%)], linezolid [18 (8.7%)] and other antistaphylococcal agents [16 (7.7%)]. Haematogenous complications occurred in 41 patients (19.8%), including 10 episodes complicated by IE. Early (48 h) and late (30 day) all-cause mortality were 3.4% and 25.1%, respectively. High vancomycin MIC isolates were more common among patients that developed IE compared with those free from this complication [90.9% (9/10) versus 44.7% (88/197); P  = 0.007]. This association remained significant after adjusting for multiple confounders (including initial antibiotic therapy and catheter removal) in different models (minimum hazard ratio: 9.18; 95% CI: 1.16-72.78; P  = 0.036). There were no differences in mortality according to vancomycin MIC values., Conclusions: Decreased susceptibility to vancomycin acted as a predictor of the development of IE complicating MRSA CR-BSI., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Objectives: To describe a group of patients referred because of abnormal sleep behaviors that were suggestive of rapid eye movement (REM) sleep behavior disorder (RBD) in whom video-polysomnography ruled out RBD and showed the reported behaviors associated with vigorous periodic limb movements during sleep (PLMS)., Aims and Methods: Clinical history and video-polysomnography review of patients identified during routine visits in a sleep center., Results: Patients were 15 men and 2 women with a median age of 66 (range: 48-77) years. Reported sleep behaviors were kicking (n = 17), punching (n = 16), gesticulating (n = 8), falling out of bed (n = 5), assaulting the bed partner (n = 2), talking (n = 15), and shouting (n = 10). Behaviors resulted in injuries in 3 bed partners and 1 patient. Twelve (70.6%) patients were not aware of displaying abnormal sleep behaviors that were only noticed by their bed partners. Ten (58.8%) patients recalled unpleasant dreams such as being attacked or chased. Video-polysomnography showed (1) frequent and vigorous stereotyped PLMS involving the lower limbs, upper limbs, and trunk (median PLMS index 61.2; median PLMS index in NREM sleep 61.9; during REM sleep only 8 patients had PLMS and their median PLMS index in REM sleep was 39.5); (2) abnormal behaviors (e.g., punching, groaning) during some of the arousals that immediately followed PLMS in NREM sleep; and (3) ruled out RBD and other sleep disorders such as obstructive sleep apnea. Dopaminergic agents were prescribed in 14 out of the 17 patients and resulted in improvement of abnormal sleep behaviors and unpleasant dreams in all of them. After dopaminergic treatment, follow-up video-polysomnography in 7 patients showed a decrease in the median PLMS index from baseline (108.9 vs. 19.2, p = .002) and absence of abnormal behaviors during the arousals., Conclusions: Abnormal sleep behaviors and unpleasant dreams simulating RBD symptomatology may occur in patients with severe PLMS. In these cases, video-polysomnography ruled out RBD and identified prominent PLMS followed by arousals containing abnormal behaviors. Our cases represent an objectively documented subtype of periodic limb movement disorder causing abnormal sleep behaviors., (© Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objectives: A high proportion of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia die within a few days of the onset of infection. However, predictive factors for early mortality (EM) have barely been examined. The aim of this study was to determine the predictive factors for EM in patients with MRSA bacteraemia., Methods: All episodes of MRSA bacteraemia were prospectively followed in 21 Spanish hospitals from June 2008 to December 2009. Epidemiology, clinical data, therapy and outcome were recorded. All MRSA strains were analysed in a central laboratory. Mortality was defined as death from any cause occurring in the 30 days after the onset of MRSA bacteraemia. EM was defined as patients who died within the first 2 days, and late mortality (LM) for patients who died after this period. Multivariate analyses were performed by using logistic regression models., Results: A total of 579 episodes were recorded. Mortality was observed in 179 patients (31%): it was early in 49 (8.5%) patients and late in 130 (22.5%). Independent risk factors for EM were [OR (95% CI)] initial Pitt score >3 [3.99 (1.72-3.24)], previous rapid fatal disease [3.67 (1.32-10.24)], source of infection lower respiratory tract or unknown [3.76 (1.31-10.83) and 2.83 (1.11-7.21)], non-nosocomial acquisition [2.59 (1.16-5.77)] and inappropriate initial antibiotic therapy [3.59 (1.63-7.89)]. When predictive factors for EM and LM were compared, inappropriate initial antibiotic therapy was the only distinctive predictor of EM, while endocarditis and lower respiratory tract sources both predicted LM., Conclusions: In our large cohort of patients several factors were related to EM, but the only distinctive predictor of EM was inappropriate initial antibiotic therapy.

P27(Kip1) (p27) is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors. Recently, a new function of p27 as transcriptional regulator has been reported. It has been shown that p27 regulates the expression of target genes mostly involved in splicing, cell cycle, respiration and translation. We report here that p27 directly binds to the transcriptional coactivator PCAF by a region including amino acids 91-120. PCAF associates with p27 through its catalytic domain and acetylates p27 at lysine 100. Our data showed that overexpression of PCAF induces the degradation of p27 whereas in contrast, the knockdown of PCAF stabilizes the protein. A p27 mutant in which K100 was substituted by arginine (p27-K100R) cannot be acetylated by PCAF and has a half-life much higher than that of p27WT. Moreover, p27-K100R remains stable along cell-cycle progression. Ubiquitylation assays and the use of proteasome inhibitors indicate that PCAF induces p27 degradation via proteasome. We also observed that knockdown of skp2 did not affect the PCAF induced degradation of p27. In conclusion, our data suggest that the p27 acetylation by PCAF regulates its stability.

Dicentric analysis is considered as a 'gold standard' method for biological dosimetry. However, due to the radiation-induced mitotic delay or inability to reach mitosis of heavily damaged cells, the analysis of dicentrics is restricted to doses up to 4-5 Gy. For higher doses, the analysis by premature chromosome condensation technique has been proposed. Here, it is presented a preliminary study is presented in which an alternative method to analyse dicentrics after high dose exposures to ionising radiation (IR) is evaluated. The method is based on the effect of caffeine in preventing the G2/M checkpoint allowing damaged cells to reach mitosis. The results obtained indicate that the co-treatment with Colcemid and caffeine increases significantly increases the mitotic index, and hence allows a more feasible analysis of dicentrics. Moreover in the dose range analysed, from 0 to 15 Gy, the dicentric cell distribution followed the Poisson distribution, and a simulated partial-body exposure has been clearly detected. Overall, the results presented here suggest that caffeine has a great potential to be used for dose-assessment after high dose exposure to IR.

The behaviour of Pseudomonas fluorescens EPS62e was investigated in apple and pear orchards under Mediterranean climatic conditions. The trials studied the influence of weather conditions, plant host species, presence of indigenous microbial community and spread from treated to nontreated trees on colonization and survival. Population dynamics were assessed by real-time PCR and CFU-counting methods. With inoculated flowers, weather conditions were optimal for colonization, and EPS62e established high and stable population levels around 10(8) CFU per organ, according to both methods of analysis. The plant host species did not influence the colonization rate, and the biocontrol agent dominated the microbial communities of blossoms, representing up to 100% of the total cultivable population. With inoculated leaves, the EPS62e population decreased to nondetectable levels 30 days after treatment according to both methods used. EPS62e spread moderately in the orchard, being detected in nontreated flowers of trees 15-35 m from the inoculation site. The combined use of real-time PCR and CFU-counting methods of analysis permitted the identification of three physiological states for EPS62e in the field, which consisted of active colonization, survival and entry into a viable but nonculturable state, and cell death.

Background: In the setting of a large endemic of Acinetobacter baumannii infections, treatment of those due to carbapenem-resistant strains, susceptible only to colistin, has become a major problem in our hospital during the past years. Successful results have been reported using colistin, but clinical experience with this antibiotic is limited. In our experimental studies using these strains in a mouse pneumonia model, the best results were observed with a combination of rifampicin and imipenem., Methods: From July 2000 to September 2001, we performed a pilot study with patients suffering from serious infections due to carbapenem-resistant A. baumannii. Patients were treated with a rifampicin/imipenem combination and followed up prospectively. Cultures were repeated during and after treatment, and in vitro activity of rifampicin was monitored. Genotyping of these strains was performed by means of PFGE., Results: Ten patients were selected: four with ventilator-associated pneumonia, and six with other infections (one catheter-related bacteraemia, five surgical infections). Three patients died, two of whom were considered therapeutic failures. In five of the seven patients who were cured, other procedures were also performed such as surgical drainage or catheter removal. In vitro development of high resistance to rifampicin was shown in seven (70%). PFGE demonstrated that initial isolates and high-resistant strains belonged to the same clones., Conclusions: The results of our study argue against the use of a rifampicin/imipenem combination for the treatment of carbapenem-resistant A. baumannii infections. However, combinations of rifampicin with other antibiotics merit further studies.

Pseudomonas fluorescens EPS62e has been selected in a screening procedure for its high efficacy controlling Erwinia amylovora infections in flowers, immature fruits and young pear plants. We developed two monitoring methods which allowed specific detection and quantification of EPS62e by combining classical microbiological techniques with molecular tools. RAPD and unspecific-PCR fingerprints were used to differentiate EPS62e from other P. fluorescens strains. Differential amplified fragments from EPS62e were sequence characterized as SCAR markers and two primer pairs were designed and selected for their specificity against EPS62e. A SCAR primer pair was evaluated and validated for the assessment of population dynamics of EPS62e on pear plants under greenhouse conditions using plating and most probable number assays coupled to PCR. Both techniques were useful in monitoring the biological control agent. The population level of EPS62e after treatment was 7 log CFU(gf.w.)(-1), which in turn decreased progressively to 4-5 log CFU(gf.w.)(-1) after 17 days and then remained stable until the end of the assay 11 days later. The limit of detection of both monitoring methods developed was around 3 log CFU(gf.w.)(-1), thus, providing a reliable tool for the analysis of EPS62e in greenhouse or field trials, and the assessment of threshold population levels for efficient biocontrol of fire blight.

The effect of a selective decontamination of the digestive tract (SDD) regimen including polymyxin and tobramycin on several body site reservoirs was compared between a test group and a control group in intensive care unit (ICU) patients with faecal multi-resistant Acinetobacter baumannii colonization. SDD significantly reduced faecal and pharyngeal carriage when compared with the control group at the end of ICU stay (48% versus 91%, P = 0.001, and 38.5% versus 78%, P = 0.01, respectively), but failed to reduce axillary colonization (75% versus 78%, P = 0.6). In addition, the isolation of A. baumannii from new clinical samples was lower in patients with SDD (45.5% versus 81%, P = 0.05). No resistance to polymyxin was observed. We conclude that the digestive tract reservoir of A. baumannii in ICU patients may be decreased by a SDD regimen.

Study Objectives: To measure the sleep spindle characteristics in patients with unilateral thalamic stroke., Design: A prospective study of patients with thalamic stroke and age-matched healthy controls., Setting: Department of Neurology of a University Hospital., Participants: Thirteen patients (mean age: 67 years, SD: 13,44) with an isolated, unilateral acute thalamic stroke and 18 healthy age-matched volunteers., Interventions: A polysomnogram recording from 14 scalp EEG electrodes performed during 2 consecutive nights, the second or third week after the stroke. Only the sleep of the second night was analyzed., Measurements and Results: Sleep spindles were counted during two separate 10-minute epochs of stage II. Spindles appearing synchronously in both sides with similar amplitude were called "bilateral." Spindles with twice the amplitude in one side than the other were "right" or "left-side predominant". There were 8 patients with posterolateral, 3 with global and 2 with anterior lesions. Eight were right and 5 left-sided. The number of spindles was similar in patients (39.8 +/- 23.4 in 20 minutes) than controls (26.07 +/- 29.07; p=0.173). Spindles with a centroparietal (34%) and centroparieto-occipital localization (22%) were the most frequent. In controls approximately 66% of the spindles had a bilateral and symmetric distribution over the scalp, 23% of the spindles were predominantly left-sided and 5% were predominantly right-sided. In patients, bilateral spindles decreased (p<0.0001) but asymmetric spindles did not change., Conclusion: Unilateral acute thalamic stroke does not decrease sleep spindles ipsilaterally; rather, it seems to produce a bilateral diminution in their number.

From March 1995 to March 1997, sulbactam was prospectively evaluated in patients with non-life-threatening multiresistant Acinetobacter baumannii infections. During this period, 47 patients were treated with sulbactam; of them, five were excluded because they had received < or =48 h of sulbactam therapy. A total of 42 patients, 27 males and 15 females with a mean age of 60+/-15 years, were finally evaluated. Infections were as follows: surgical wound, 19; tracheobronchitis, 12; urinary tract, 7; catheter-related bacteraemia, 2; and pneumonia, 2. Eighteen patients received intravenous sulbactam alone (1 g every 8 h) and 24 patients received intravenous sulbactam/ampicillin (1 g:2 g every 8 h) with no major adverse effects. Of the 42 patients, 39 improved or were cured and showed A. baumannii eradication and one patient had persistence of wound infection after 8 days of sulbactam/ampicillin requiring surgical debridement. Two patients died after 3 days of therapy (one of the deaths was attributable to A. baumannii infection). The in-vitro activity of the sulbactam/ampicillin combination was by virtue of the antimicrobial activity exhibited by sulbactam. Killing curves showed that sulbactam was bacteriostatic; no synergy was observed between ampicillin and sulbactam. Our results indicate that sulbactam may prove effective for non-life-threatening A. baumannii infections. Its role in the treatment of severe infections is unknown. However, the current formulation of sulbactam alone may allow its use at higher doses and provide new potential synergic combinations, particularly for those infections by A. baumannii resistant to imipenem.

Fecal colonization with multiresistant Acinetobacter baumannii was evaluated in 189 consecutive patients in intensive care units (ICUs) during two different 2-month periods (October-November 1993 and May-June 1994). Rectal swabs were obtained weekly from admission to discharge from the ICU. Overall, 77 patients (41%) had multiresistant A. baumannii fecal colonization; colonization was detected in 55 (71%) of the patients within the first week of their ICU stay. Clinical infections due to multiresistant A. baumannii occurred more frequently in patients with fecal colonization than in those without fecal colonization (26% vs. 5%, respectively; P < .001). The reinforcement of isolation measures between study periods reduced both the number of fecal carriers of multiresistant A. baumannii (from 52% to 31%; P < .01) and the number of patients with multiresistant A. baumannii infections (from 17% to 11%; no statistical significance). The digestive tract of ICU patients could be an important epidemiologic reservoir for multiresistant A. baumannii infections in hospital outbreaks. Further prospective studies should be undertaken to define the relative significance of digestive tract colonization compared with other body site colonizations.

For 16 years we prospectively observed 530 adult patients with brucellosis to analyze the characteristics of and risk factors for relapse. Clinical and laboratory findings from 86 relapsed patients were milder during the relapse episode when compared with those for the same patients during the initial disease. Blood cultures were positive for Brucella melitensis in 65% of cases during relapse and in approximately 80% of cases during the initial disease. Risk factors that were identified as being independently associated with relapse (by logistic regression analysis) were "less-effective" antibiotic therapy (OR, 8.3; 95% CI, 4.6-15.1), positive blood cultures during initial disease (OR, 2.7; 95% CI, 1.2-6.2), < or = 10-day duration of the disease before treatment (OR, 1.9; 95% CI, 1.1-3.6), male sex (OR, 1.8; 95% CI, 1.02-3.8) and a platelet count of < or = 150 x 10(3)/mm3 (OR, 1.7; 95% CI, 1.1-2.8). These data show that relapse of brucellosis is sometimes difficult to diagnose and that it can be an insidious disease. In addition to inappropriate antibiotic therapy, other factors, such as those indicating a more aggressive disease and/or a deficient immunologic response, seem to play an important role in the relapse of brucellosis.

Pasteurella piscicida grown in a glucose-rich medium produces a capsule that can be see under light and electron microscopy. The capsular polysaccharide was purified and characterized by chemical and HPLC analysis. The polymer has the composition glucose/mannose/N-acetylgalactosamine/galacturonic acid/acetic acid in the molar ratios of approximately 2.5:1.3:0.5:0.4:2.5. The polysaccharide was immunogenic in rabbits and did not cross-react with antibodies against the O-antigen lipopolysaccharide.

Between 1974 and 1989 we prospectively observed 530 patients with brucellosis. The findings for 62 patients (42 males and 20 females; mean age, 34.7 years) with 63 episodes in which the sacroiliac joint was involved (the most frequent osteoarticular location [11.7%]) were analyzed. Ten of the older patients (mean age, 55.3 years) had concomitant spondylitis. Systemic symptoms were usually important, and characteristic pain and findings of sacroiliitis were observed in approximately 75% of cases. Blood cultures were positive for Brucella melitensis for 44 patients. The most frequent radiographic findings were blurring of articular margins (42 cases) and widening of the sacroiliac space (20 cases). No radiographic anomalies were detected in 13 cases. Results of 99mTc and gallium-67 bone scans were abnormal in approximately 90% of cases (abnormalities were often mild). Overall, clinical, radiographic, and isotopic bone scan findings were sensitive and useful, although they were occasionally minimal or difficult to evaluate, making diagnostic findings confusing or misleading. Brucellar sacroiliitis is a mild disease associated with a good outcome similar to that observed for patients with uncomplicated brucellosis.

Aeromonas salmonicida grown in a medium with excess glucose as carbon source produces both capsular and exocellular polysaccharides. The capsular polysaccharide is composed of glucose, mannose, rhamnose, N-acetylmannosamine and mannuronic acid in the molar ratios of approximately 5:3:0.75:2:1. The extracellular polysaccharide is similarly constituted, but in the molar ratios of approximately 4.75:10.5:1.5:2:1. The capsular and exocellular polysaccharides did not cross-react with monoclonal antibodies against the A-layer or the O-antigen lipopolysaccharide.