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An outbreak of Clostridium difficile infection (CDI) caused by ribotype 027 (B1/NAP1) began in our hospital in November 2014, and produced 141 episodes in the following months. The aim of this study is to describe this outbreak, assess risk factors for recurrence of CDI-027 and to analyze the implementation of a novel treatment strategy. This is a prospective study of all patients with CDI-027, from November 2014 to November 2015. The epidemiological data were collected daily for each patient. We compared clinical characteristics and treatment between patients with and without recurrence of CDI-027. Interestingly, liver cirrhosis was present in 22% of the patients, and most of them received prophylaxis for hepatic encephalopathy with rifaximin. Patients were also taking antimicrobial drugs (93.6%) and proton pump inhibitors (80.1%). Overall, 27 (23.5%) patients had a first recurrence of CDI-027. Liver cirrhosis increased the risk of recurrence (44.4% vs 14.8%). Patients treated with a prolonged oral vancomycin regimen vs the conventional regimen (oral metronidazole or 10 days of vancomycin) had fewer recurrences (8.6 versus 44.7% [p ≤ 0.01]; OR, 0.91; 95% CI, 0.028-0.294) and less attributable mortality (0% versus 7.1%; p = 0.058). We report an outbreak of CDI-027, mainly in patients with liver cirrhosis. Recurrence of CDI-027 was more common in those patients. A novel approach involving high-dose prolonged vancomycin taper as a first-line treatment, together with a bundle of outbreak measures, seemed to reduce the number of cases of CDI-027, recurrences, and attributable mortality. Nevertheless, this approach warrants further investigation.

Die transrektale Sonografie mit systematischer Biopsie gilt derzeit als Standard fur die Diagnose eines Prostatakarzinoms. Allerdings ist das Verfahren nicht immer prazise – hochgradige Erkrankungen konnen ubersehen und niedrig maligne Veranderungen ubertherapiert werden. Die Fusionsbiopsie konnte eine Alternative darstellen, aber dazu muss sie zuverlassig reproduzierbar sein. Das haben Mediziner aus den USA gepruft.

Summary Background Faecal microbiota transplantation (FMT) is a highly effective approach for refractory and recurrent Clostridioides difficile infection (CDI). Despite its excellent efficacy, FMT is not yet a routine procedure in most centres. There is very little experience with FMT based on lyophilized capsules, and data from European institutions are lacking. This article describes our experience with FMT to treat recurrent CDI using lyophilized oral capsules. Methods A prospectively recorded single-centre case series of patients with recurrent CDI who underwent FMT between January 2018 and May 2019 were analysed. The primary outcome was defined as resolution of CDI without recurrences over a two-month period. Overall resolution was defined as resolution of diarrhoea without recurrence of CDI within two months after a further cycle of FMT. The FMT process involved oral ingestion of four or five lyophilized capsules in a single dose. All stool donors were rigorously screened. Findings FMT was performed in 32 patients. Primary cure was achieved in 81.3% of patients, and the overall cure rate was 87.5%. FMT via lyophilized capsules was well tolerated. No FMT procedure-related adverse events and no further complications were observed for lyophilized-capsule FMT. Conclusions This initial clinical experience suggests that FMT based on oral lyophilized preparations is a safe, well-tolerated, and highly effective treatment for recurrent CDI. Administration of oral lyophilized capsules seems feasible in hospital routine and will enable FMT to be more widely used.

En este documento se presenta el diseño, implementación y operación de un módulo didáctico desarrollado con la finalidad de obtener una adecuada capacitación en el aprendizaje de los Sistemas Solares Fotovoltaicos. Al verificar el desempeño del equipo, se observaron sus capacidades tales como: potencia de suministro, medición de parámetros eléctricos utilizando puntos de prueba distribuidos en el panel de monitoreo, posibilidad de expansión de capacidad mediante la interconexión con módulos de características similares. Al poner el sistema a disposición de la comunidad académica de la institución, se mejoró el proceso de enseñanza aprendizaje, facilitando la labor del docente e incrementando la motivación del estudiante a adquirir conocimientos en este tema. Basándose en la idea de pasar de trabajar con celdas solares de aplicaciones de laboratorio a un sistema fotovoltaico de aplicaciones prácticas en el suministro de energía eléctrica, y de los sistemas de simulación a uno

In response to myocardial infarction (MI), neutrophils (PMNs) are early responders that initiate the inflammatory reaction. Because macrophages and fibroblasts show polarization states after MI, we hypothesized PMNs also undergo phenotypic changes over the MI time course. The objective of the current study was to map the continuum of polarization phenotypes in cardiac neutrophils over the first week of MI. C57BL/6J male mice (3–6 months old) underwent permanent coronary artery ligation to induce MI, and PMNs were isolated from the infarct region at days 1, 3, 5, and 7 after MI. Day 0 served as a no MI negative control. Aptamer proteomics was performed on biological replicates (n = 10–12) for each time point. Day (D)1 MI neutrophils had a high degranulation profile with increased matrix metalloproteinase (MMP) activity. D3 MI neutrophil profiles showed upregulation of apoptosis and induction of extracellular matrix (ECM) organization. D5 MI neutrophils further increased their ECM reorganization profile. D7 MI neutrophils had a reparative signature that included expression of fibronectin, galectin-3, and fibrinogen to contribute to scar formation by stimulating ECM reorganization. Of note, fibronectin was a key modulator of degranulation, as it amplified MMP-9 release in the presence of an inflammatory stimulus. Our results indicate that neutrophils selectively degranulate over the MI time course, reflective of both their intrinsic protein profiles as well as the ECM environment in which they reside. MMPs, cathepsins, and ECM proteins were prominent neutrophil degranulation indicators. Electronic supplementary material The online version of this article (10.1007/s00395-019-0746-x) contains supplementary material, which is available to authorized users.

Recently, impressive results have been provided by pre-trained convolutional neural networks combined with the transfer learning technique. They have quickly become a great option to classify general image datasets. However, to the best of our knowledge, the majority of works do not explore if these pre-trained architectures are well-suited to specific contexts like the medical image domain (e.g. breast lesions). We focus on breast lesions, because it is one of the most common types of cancer affecting women worldwide, and its early diagnosis is crucial to the success of the treatment. In this paper, we propose a methodology capable of analyzing different approaches, regarding description (e.g through handcrafted and deep features) and classification (e.g. through end-to-end networks and traditional classifiers) to automatically answer the best tuning according to a given mammographic image dataset. Our methodology can also apply a data augmentation method to improve the learning of the networks. It increases the number of training samples to cope with unbalancing and overfitting problems that are intrinsic to the breast lesion classification task. We validate our methodology on public image datasets and our results show classification accuracies of up to 94.34%.

Background The use of daptomycin has increased in Spain since its approval and there is a great variability in the dosage and the criteria for its use in clinical practice. Purpose This study was aimed at reporting the real use of daptomycin in clinical practice, including its efficacy and tolerability as a first measure for the establishment of improvement actions. Material and methods Observational, retrospective study including all patients who started treatment with daptomycin during the period 1 January 2017 and 31 December 2017 in a Spanish tertiary hospital. The following variables were collected: age, sex, comorbidities, type of infection, dosage, microbiological results, analytical parameters such as creatinine or creatine phosphokinase (CPK), adverse events and clinical outcome. Results Overall, 176 patients (61.9% men), median age of 70 years (IQR: 57–79), began treatment with daptomycin during 2017. The median of the Charlson comorbidity index was 3 (IQR: 2–6). Daptomycin was mainly used to treat skin and soft-tissue infections (37.5%), fever without source (17.6%), osteoarticular infection (12.5%) and endocarditis (11.4%). A total of 63 patients (35.8%) presented a concomitant bacteremia. Daptomycin was prescribed empirically in 58.0% of patients. At the end of the follow-up, microbiological results were available in 89.2% of the total treated patients. Staphylococcus aureus was the most frequently isolated microorganism (58 microbiological isolates, only 10 resistant to methicillin). 43.8% of patients received doses≤6 mg/kg/day, whereas 23.9% received doses≥10 mg/kg/day. Infradosification was observed in at least 49 patients (27.8%), who received doses≤5 mg/kg/day. Daptomycin was administered for a median of 6 days (IQR: 3–13). CPK was only monitored in 47.7% of patients treated with daptomycin for ≥7 days. Clinical evolution was satisfactory in 77.7% of patients. Total mortality was 17.6% and mortality related to the infection was 7.4%. Five patients discontinued treatment due to adverse events (urticaria, cholestasis, increased CPK and rhabdomyolysis). No cases of resistance to the drug were reported. Conclusion Daptomycin is a well-tolerated and effective drug but is often prescribed empirically or in infections not caused by S. aureus methicillin resistant. The follow-up of patients treated with daptomycin should be considered a priority intervention within the Antimicrobial Stewardship Programmes. References and/or acknowledgements PMID: 29261926. No conflict of interest.

Study question What is the clinical efficacy of an oocyte donation program based on the transportation of frozen semen and embryos between two countries? Summary answer The transnational oocyte donation program is efficient and reliable and it could provide a first-line strategy to overcome the lack of donors in some countries. What is known already While there is increasing need for donated oocytes, in many countries the availability of donors is still insufficient to cover the therapeutic demands, and patients are referred abroad for treatment. Since embryo cryopreservation is reliable and efficient, we propose a strategy based on frozen embryos instead of frozen oocytes to satisfy the increasing demand for cross border oocyte donation. Study design, size, duration This is a retrospective cohort study including 630 patients treated from December 2015 to July 2017. Participants/materials, setting, methods Infertile women were treated with elective vitrified-thawed embryo shipping and embryo transfer (ET) between two IVF clinics, one in Spain and one in Italy. Main results and the role of chance A total of 2617 embryos were created for the 630 patients and the survival rate after warming was 98.5%. After the first ET the live birth rate (LBR) was 30.6%. In 476 patients (75.5%), embryos were transferred at the cleavage stage (Day 2 or 3) and the LBR was 29.2%. Vitrified blastocysts were available for 154 patients (24.5%) and the LBR was 35%. Among patients who did not achieve a pregnancy after the first frozen ET (FET), 92.5% had at least one frozen embryo for successive procedures. 213 patients underwent a second FET. The LBR at the second FET was 30%. The cumulative LBR at the end of the observation period was 39.3%. Limitations, reasons for caution The study design was retrospective. A direct comparison with vitrified oocyte donors cycle and subsequent fresh ET would have permitted to compare this strategy versus the current standard based on vitrified gametes. Wider implications of the findings The LBR found in our study is more than acceptable and seems to be higher than what reported with vitrified oocytes. The transnational fresh oocyte donation program may have several advantages over the shipment of vitrified oocytes: similarly to the fresh oocyte donation program it allows for personalized care in oocyte recipient, which is provided by assigning a flexible number of oocytes, and at the same time it maintains the benefit of a frozen ART program permitting scheduling flexibility. The TOD program is efficient and may be proposed as a first-line strategy for distance and inter-countries oocyte donation programs. Study funding, competing interest(s) None. Trial registration number NA.

Background/objective Spinal arachnoid cysts (SAC) are intradural lesions, which may provoke a compression of the spinal cord and roots. Endoscopic techniques are increasingly used to minimize the surgical access and the postoperative scar tissue. Shunts may also represent an option. The aim of this paper is to illustrate the technique of endoscopic-assisted fenestration and positioning of a cysto-peritoneal diversion in a thoracic SAC using a flexible endoscope and to perform a systematic literature review on this subject. Material and methods We reported our case and we performed a review of the literature, searching for all the adult cases of Type III SACs in English language treated through endoscopic procedures. Results We found 5 articles matching our search criteria and we included 9 adult patients in our analysis. Six patients were females and the most common localization was the thoracic spine. Six patients underwent selective laminectomies followed by endoscopic fenestration without cyst wall resection. Three patients had a percutaneous endoscopic inspection of the cyst and in two cases a cysto-subarachnoid shunt space was performed. Improvement of pre-operative neurological deficit was reported in six patients, no patients experienced clinical deterioration. The mean follow-up was 22 months and no progression or recurrence was reported. Conclusion The implementation of endoscopy allows a minimally invasive treatments with good visualization of cyst anatomy and precise shunt positioning under real-time guidance. Endoscopy is technically demanding but it can offer similar clinical outcomes when compared to microscopic procedures with a limited rate of post-operative complications. The long-term risk of recurrence should be established by prospective studies., Spinal arachnoid cyst, Endoscopy, Outcome, Shunt, Surgery.

The ability to identify different cell populations in a noninvasive manner and without the use of fluorescence labeling remains an important goal in biomedical research. Various techniques have been developed over the last decade, which mainly rely on fluorescent probes or nanoparticles. On the other hand, their applications to single-cell studies have been limited by the lengthy preparation and labeling protocols, as well as issues relating to reproducibility and sensitivity. Furthermore, some of these techniques require the cells to be fixed. Interestingly, it has been shown that different cell types exhibit a unique intracellular environment characterized by specific acidity conditions as a consequence of their distinct functions and metabolism. Here, we leverage a recently developed pH imaging modality and machine learning-based single-cell segmentation and classification to identify different cancer cell lines based on their characteristic intracellular pH. This simple method opens up the potential to perform rapid noninvasive identification of living cancer cells for early cancer diagnosis and further downstream analyses.

Background Cystic fibrosis (CF) patients experience intestinal complications characterized by the accumulation of thick viscous mucus. CF mice were utilized to determine if a novel guluronate oligomer, OligoG, may be a potential therapy in reducing intestinal mucus and subsequent CF-related intestinal manifestations. Methods Intestinal transit, intestinal histology, survival and growth were examined in wildtype and CF mice on regular water and OligoG. Conclusions OligoG improves intestinal transit and survival in CF mice by reducing the accumulation of intestinal mucus. OligoG's ability to directly bind mucin, disrupt mucin interaction and/or sequester calcium allowing for mucin expansion may explain the decrease in mucus accumulation.

This paper examines whether cities with preferential policies have higher inequality in household disposable income per capita than cities without preferential policies in urban China. “Preferential policies” refers to the autonomy and deregulation given to Special Economic Zones (SEZs) and Open Cities, allowing them to experiment with market policies and reforms, as the country moves from a state-controlled economy towards a market-oriented economy. While the effect of these policies on economic growth is extensively documented, their relationship with income inequality remains undetermined. Subgroup decompositions of income inequality, using the China Household Income Project's urban datasets of over 6000 households and 20,000 individuals from of up to 70 cities from 12 provinces, were used to identify income inequality gaps between cities with and without preferential policies. The results reveal that while income inequality increased in urban China from 1988 to 2007, the change was lower for cities awarded preferential policies across regions. Furthermore, the decompositions by region indicate that cities receiving preferential policy treatment had higher income growth but a lesser increase in income inequality than cities without preferential policies in each region. Finally, cities receiving preferential policies were able to increase the share of income of the poorest 40% of households while reducing the share of the richest 10%.

OBJECTIVES Prediction of patients with poor outcome is necessary in order to plan the proper management of Clostridium difficile infection (CDI); however, clinical criteria are insufficient. In a previous study, we observed that high toxigenic C. difficile cfu stool counts at diagnosis were associated with a poor outcome. Our objective was to investigate the role of the PCR toxin B amplification cycle threshold (Ct) in the prediction of CDI poor outcome and to derive and validate a high-risk prediction rule using this marker. METHODS We prospectively included patients with CDI (derivation cohort, January 2013 to June 2014; and validation cohort, December 2014 to May 2015), who were followed for at least 2 months after their last episode/recurrence. All samples were tested with Xpert™ C. difficile. RESULTS For the derivation cohort (n = 129) toxin B Ct was independently associated with poor outcome (P

Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl− secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.

Introduction: Partial lipodystrophy (PL) is a rare disease associated with insulin resistance and metabolic dysfunctions, including NAFLD. Global prevalence of NAFLD is ±25%. In PL patients NAFDL prevalence and severity remains unclear. AIMS To evaluate the presence of hepatic steatosis and/or fibrosis in PL patients using transient elastography (TE) in comparison to a control group. Materials and Methods: Fifteen patients (7 with PL of the limbs, 8 with Familiar Partial Lipodystrophy Dunnigan-type) and 15 (13 women) controls paired to BMI and age were included. We recruited participants aged 18-65 years-old and a BMI≥25 and ≤35kg/m², excluding other causes of steatohepatitis. Anthropometric measures, metabolic parameters and the presence of steatosis/fibrosis using TE(Fibroscan®) were evaluated. According to literature, the adopted cut-off values in TE for Controlled Attenuation Parameter (CAP) and Liver Stiffness Measurement (LSM) are ≥238dB/m and ≥5,8kPa, respectively. Student t-test was used for continuous variables. Main results are presented as Mean ± SD. Results: Mean age was 52.93 and 50.26 years-old in PL and control groups, respectively. BMI was slightly but not significantly higher in control group (30,13kg/m² [SD±2,85] vs. 27,43kg/m² [SD±5,30]). Waist-to-hip ratio did not differ. PL group had higher fasting plasma glucose (116.78mg/dL [SD±39,54] vs. 89,58mg/dL [SD±23,34], p= 0,0476). No differences in hepatic lesion biomarkers or lipid profile was noted, except for a lower HDL-c in PL group (40,64mg/dL [SD±9,45] vs. 49,62mg/dL [SD±12,67], p=0,0432). CAP tended to be higher in PL patients [301,82dB/m (SD±54,88) vs. 262,93dB/m (SD±57,44); p=0,0685] and LSM was significantly higher (7,32kPa [SD±3,71] vs. 4,94kPa [SD±1,58], p=0,0260). Conclusions: Patients with PL presented a trend for increased hepatic steatosis and showed higher values of fibrosis in TE. Therefore, we suggest PL patients should undergo TE for screening of NAFLD. Disclosure L.C. Viola: None. F.O. Matsuura: None. C.M. Valerio: None. A.F. Godoy-Matos: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Other Relationship; Self; Takeda Development Center Americas, Inc., Novo Nordisk Inc.. M.H. Costa: None. J.M. Araujo-Neto: None. M. Dias: None.

Background: Image-based plant phenotyping has become a powerful tool in unravelling genotype-environment interactions. The utilization of image analysis and machine learning have become paramount in extracting data stemming from phenotyping experiments. Yet we rely on observer (a human expert) input to perform the phenotyping process. We assume such input to be a 'gold-standard' and use it to evaluate software and algorithms and to train learning-based algorithms. However, we should consider whether any variability among experienced and non-experienced (including plain citizens) observers exists. Here we design a study that measures such variability in an annotation task of an integer-quantifiable phenotype: the leaf count.Results: We compare several experienced and non-experienced observers in annotating leaf counts in images of Arabidopsis Thaliana to measure intra- and inter-observer variability in a controlled study using specially designed annotation tools but also citizens using a distributed citizen-powered web-based platform. In the controlled study observers counted leaves by looking at top-view images, which were taken with low and high resolution optics. We assessed whether the utilization of tools specifically designed for this task can help to reduce such variability. We found that the presence of tools helps to reduce intra-observer variability, and that although intra- and inter-observer variability is present it does not have any effect on longitudinal leaf count trend statistical assessments. We compared the variability of citizen provided annotations (from the web-based platform) and found that plain citizens can provide statistically accurate leaf counts. We also compared a recent machine-learning based leaf counting algorithm and found that while close in performance it is still not within inter-observer variability.Conclusions: While expertise of the observer plays a role, if sufficient statistical power is present, a collection of non-experienced users and even citizens can be included in image-based phenotyping annotation tasks as long they are suitably designed. We hope with these findings that we can re-evaluate the expectations that we have from automated algorithms: as long as they perform within observer variability they can be considered a suitable alternative. In addition, we hope to invigorate an interest in introducing suitably designed tasks on citizen powered platforms not only to obtain useful information (for research) but to help engage the public in this societal important problem.

Drosophila suzukii (Diptera: Drosophilidae) is an invasive alien species devastating soft fruit crops in newly invaded territories. Little is known about the importance and potential of long-distance dispersal at a regional scale. The goal of this work is to investigate D. suzukii dispersal ability during different times of the season, and along an elevational gradient in a mountain valley in Trentino Province, Italy. We employed a mark–release–recapture strategy using protein markers. Flies were recaptured using fruit-baited traps. The protein-marked flies were positively identified using ELISA procedure. Additional microsatellite analyses were performed on D. suzukii collected during autumn at different elevations to characterize the population structure. Results suggest that a portion of the local D. suzukii population moves from low to high elevations during spring and summer and travels back to low elevations in autumn. Genetic analysis further revealed that samples collected during autumn at different elevations belong to the same population. These results show that D. suzukii are able to fly up to about 9000 m away from the marking point and that seasonal breezes likely facilitate long-distance movement. We suggest that these migrations have multiple functions for D. suzukii, including conferring the ability to exploit gradual changes of temperature, food, and ovipositional resources in spring and autumn, as well as to assist in the search for suitable overwintering sites in late autumn. Our findings help to unveil the complex ecology of D. suzukii in Italian mountainous regions and provide important clues for improving the efficacy of integrated pest management control techniques to combat this pest.

Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon in CFTR mRNA causing early termination of translation, and lead to lack of CFTR function. There are no currently available animal models which contain a nonsense mutation in the endogenous Cftr locus that can be utilized to test nonsense mutation therapies. In this study, we create a CF mouse model carrying the G542X nonsense mutation in Cftr using CRISPR/Cas9 gene editing. The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction. Importantly, CFTR restoration is observed in G542X intestinal organoids treated with G418, an aminoglycoside with translational readthrough capabilities. The G542X mouse model provides an invaluable resource for the identification of potential therapies of CF nonsense mutations as well as the assessment of in vivo effectiveness of these potential therapies targeting nonsense mutations.

Resumen La enfermedad de Crohn (EC) presenta con frecuencia manifestaciones extraintestinales del espectro autoinmune como artritis y artralgias. La enfermedad de Still del adulto es una enfermedad de escasa prevalencia que se presenta con artritis y artralgias, fiebre > 39 °C y persistente y otros sintomas como rash, odinofagia, linfadenopatias o hepatoesplenomegalia. Existen solo 3 casos descritos en la literatura de enfermedad de Still del adulto en pacientes con EC. Se describe un nuevo caso de conectivopatia asociada a enfermedad de Still del adulto en paciente con EC. Aunque poco frecuente, es importante su conocimiento para el diagnostico diferencial de artralgias y fiebre alta persistente en los pacientes con EC.

Drosophila suzukii (Matsumura; Diptera: Drosophilidae) is a key pest of sweet cherry and small fruits worldwide. The present studies were designed to describe the reproductive physiology in both sexes, through dissections of their reproductive organs. We extensively dissected female D. suzukii throughout the season from 2013 to 2016 and classified the reproductive status flies based on five recognizable ovarian maturation stages: 1) no ovaries; 2) unripe ovaries 3) ripening eggs in ovarioles; 4) mature eggs in ovarioles; and 5) mature eggs in the abdomen. Development was examined as a function of calendar days as well as degree-days (DD). Results obtained from winter collections revealed that females collected from November to March contained a lower percentage of mature eggs than females collected from April to September. These data suggest that environmental conditions during the dormant period induce reproductive diapause. Oogenesis likely increased with an increase in mean monthly temperatures and DD. The first overwintered females with mature eggs were dissected as early as 21 February 2014 in Trento (7 DD). Additionally, we found that a low proportion of males (less than 50%) had sperm in their testes between January and March, yet during the same period females already have sperm stored in their spermathecal. Ivy berries was an alternative but unfavorable non-crop host during the late dormant period, as evidenced by emergence of smaller adults when compared to individuals emerging from cherry fruits. This study showed that D. suzukii females have great potential for oviposition early in the season, posing a risk to early season maturing crop hosts.

Mammalian reproduction requires that males and females produce functional haploid germ cells through complex cellular differentiation processes known as spermatogenesis and oogenesis, respectively. While numerous studies have functionally characterized protein-coding genes and small noncoding RNAs (microRNAs and piRNAs) that are essential for gametogenesis, the roles of regulatory long noncoding RNAs (lncRNAs) are yet to be fully characterized. Previously, we and others have demonstrated that intergenic regions of the mammalian genome encode thousands of long noncoding RNAs, and many studies have now demonstrated their critical roles in key biological processes. Thus, we postulated that some lncRNAs may also impact mammalian spermatogenesis and fertility. In this study, we identified a dynamic expression pattern of lncRNAs during murine spermatogenesis. Importantly, we identified a subset of lncRNAs and very few mRNAs that appear to escape meiotic sex chromosome inactivation, an epigenetic process that leads to the silencing of the X- and Y-chromosomes at the pachytene stage of meiosis. Further, some of these lncRNAs and mRNAs show a strong testis expression pattern suggesting that they may play key roles in spermatogenesis. Lastly, we generated a mouse knockout of one X-linked lncRNA, Tslrn1 (testis-specific long noncoding RNA 1), and found that males carrying a Tslrn1 deletion displayed normal fertility but a significant reduction in spermatozoa. Our findings demonstrate that dysregulation of specific mammalian lncRNAs is a novel mechanism of low sperm count or infertility, thus potentially providing new biomarkers and therapeutic strategies.

CANDIPOP Project: B. Padilla, P. Muñoz, J. Guinea, J. R. Paño Pardo, J. García-Rodríguez, C. G. Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos, Gil, V. Buendía, B. P. Gorricho, M. Alonso, F. S. Sanz, J. M. Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J. E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. S. Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodríguez-Baño, A. I. Suarez, A. Loza, A. I. Aller García, E. Martín-Mazuelos, M. R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F. L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J. J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernández, G. Ezpeleta, E. Bereciartua, J. L. Hernández Almaraz, M. Montejo, R. A. Rivas, R. Ayarza, A. M. Planes, I. R. Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martínez-Montauti, M. Sierra, J. P. Horcajada, L.Sorli, J. Gómez, A. Gené, M. Urrea, A. Mularoni, M.Valerio, A. Díaz-Martín, F. Puchades., [Objectives] The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration–time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients., [Methods] We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3–7 days) and late (3–30 days) mortality., [Results] Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48–5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04–0.98; p 0.026)., [Conclusions] High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found., Supported in part by nonrestrictive research grants from Gilead, MSD, Astellas and Pfizer. This study was cofunded by Fundación SEIMC-GESIDA; the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (cofinanced by the European Development Regional Fund (ERDF) ‘A Way to Achieve Europe’); and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). MFR holds a ‘Juan Rodés’ clinical research contract (JR14/00036) and JG a ‘Miguel Servet’ contract (CPII15/00006), both from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III. MFR has received honoraria for talks on behalf of Pfizer and Gilead Sciences. JG has received grant support from Astellas Pharma, MICOLAB, the Mutua Madrileña Foundation and the Spanish Health Research Fund (FIS). He has been paid for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma, Hickma Pharmaceutica and United Medical. BA has received grant support from Gilead Sciences, Pfizer and the Instituto de Salud Carlos III. He has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. BP has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. MCE has received grant support from Astellas Pharma, bioMérieux, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International, the Europea Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), the Ramon Areces Foundation and the Mutua Madrileña Foundation.

CANDIPOP Project from GEIH-GEMICOMED (SEIMC) and REIPI: B. Padilla, P. Muñoz, J. Guinea, J. R. Paño Pardo, J. García-Rodríguez, C. García Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos Gil, V. Buendía, B. P. Gorricho, M. Alonso, F. S. Sanz, J. M. Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J. E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. Sánchez Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodriguez-Baño, A. Isabel Suarez, A. Loza, A. I. Aller García, E. Martín-Mazuelos, M. R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F. L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J. J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernáez, G. Ezpeleta, E. Bereciartua, J. L. Hernández Almaraz, M. Montejo, R. A. Rivas, R. Ayarza, A. M. Planes, I. R. Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martinez-Montauti, M. Sierra, J. P. Horcajada, L. Sorli, J. Gómez, A. Gené, M. Urrea, M. Valerio, A. Díaz-Martín, F. Puchades, A. Mularoni., [Objective] Paradoxical growth (PG) and trailing effect (TE) are frequently observed during antifungal susceptibility testing (AFST). These two phenomena interfere with the determination of the minimal inhibitory concentration (MIC). The aim of this study was to assess the clinical impact of TE and PG., [Methods] We analysed the frequency of TE and PG of 690 Candida isolates collected from a population-based study performed in Spain (CANDIPOP) and correlated the results with clinical outcome of the patients., [Results] Around 70% (484/690) of the isolates exhibited TE to azoles. Candida tropicalis showed the highest presence of TE (39/53 isolates exhibited residual growth >25% of control). No TE was seen in most of the isolates from the psilosis complex. PG was mainly associated with echinocandins. In patients treated with fluconazole within the first 48 hours after blood sampling (n = 221), the presence of TE to azoles tended to be associated with lower 30-day mortality (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.25–1.00) but not with clinical failure (OR 0.85, 95% CI 0.45–1.54). In the subgroup of 117 patients treated with echinocandins, the presence of PG was not associated with patient's response to antifungal treatment (OR for 30-day mortality 1.63, 95% CI 0.76–4.03; OR for clinical failure 1.17, 95% CI 0.53–2.70)., [Conclusions] TE or PG are widely expressed among Candida spp., although they do not seem to influence clinical outcome., C. Rueda was funded by a Sara Borrell contract from the Fondo de Investigaciones Sanitarias (FIS, reference number CD11/00110). O. Zaragoza was funded by grant SAF2014-54336-R from the Spanish Ministry for Economics and Competitivity. The CANDIPOP study was funded by research grants from Gilead, MSD, Astellas and Pfizer and by funding from the Fundacion SEIMC-GESIDA and the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund ‘A way to achieve Europe’ ERDF and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). MC-E has received grant support from Astellas Pharma, bioMerieux, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering-Plough, Soria Melguizo SA, Ferrer International, the Europea Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), the Ramón Areces Foundation and the Mutua Madrileña Foundation.

OBJECTIVES Enterococcus spp. account for 10% of infective endocarditis (IE). Although daptomycin is a bactericidal drug with in vitro activity against Enterococcus, there is little experience of its use in IE. We analysed the effectiveness of daptomycin in the treatment of enterococcal IE (EIE). METHODS This was a retrospective descriptive study comparing the efficacy of daptomycin versus ampicillin/ceftriaxone versus conventional antibiotic regimens (ampicillin or vancomycin ± gentamicin) in EIE. RESULTS From January 2007 to December 2011, 6 patients with EIE treated with daptomycin monotherapy were compared with 21 patients treated with ampicillin/ceftriaxone and 5 patients treated with ampicillin or vancomycin ± gentamicin. The three groups had similar epidemiological and clinical characteristics. Daptomycin indications were allergy to β-lactams (n = 3), therapy simplification (n = 2), renal failure (n = 2) and Enterococcus faecium resistant to ampicillin/gentamicin (n = 1). Daptomycin MICs ranged from 1 to 2 mg/L and the doses were 6-10 mg/kg/day intravenously. Daptomycin patients had longer duration of bacteraemia (6 versus 1 day, P

Drosophila suzukii causes economic damage to berry and stone fruit worldwide. Laboratory-generated datasets were standardized and combined on the basis of degree days (DD), using Gompertz and Cauchy curves for survival and reproduction. Eggs transitioned to larvae at 20.3DD; larvae to pupae at 118.1DD; and pupae to adults at 200DD. All adults are expected to have died at 610DD. Oviposition initiates at 210DD and gradually increases to a maximum of 15 eggs per DD at 410DD and subsequently decreases to zero at 610DD. These data were used as the basis for a DD cohort-level population model. Laboratory survival under extreme temperatures when DD did not accumulate was described by a Gompertz curve based on calendar days. We determined that the initiation of the reproductive period of late dormant field-collected female D. suzukii ranged from 50 to 800DD from January 1. This suggests that D. suzukii females can reproduce early in the season and are probably limited by availability of early host plants. Finally, we used the DD population model to examine hypothetical stage-specific mortality effects of IPM practices from insecticides and parasitoids at the field level. We found that adulticides applied during the early season will result in the largest comparative population decrease. It is clear from model outputs that parasitism levels comparable to those found in field studies may have a limited effect on population growth. Novel parasitoid guilds could therefore be improved and would be valuable for IPM of D. suzukii.

Prostate Cancer (PCa) remains an exception among solid cancers since organ-sparing procedures are not considered as a standard option. Despite most men harbour low to intermediate risk disease at diagnosis, the vast majority are advised towards radical treatment. We performed a literature review to highlight and discuss why focal therapy (FT) would represent a feasible and attractive option in appropriately selected men. The rationale supporting this strategy relies in epidemiological, pathological, molecular and clinical findings. These include the shift towards the diagnosis of less aggressive and unifocal PCas, the presence of an identifiable index lesion which drives the natural history of the disease together with the absence of significant disease elsewhere in the gland in many patients. New diagnostic tools, especially multiparametric MRI, allow the detection of the index lesion with good accuracy and high reliability. FT might provide acceptable disease control and at the same time substantially reduce treatment related side-effects in those men who are eligible for such strategy. To allow its adoption as a standard of care, future studies need to address current limitations such as the lack of direct comparative research against standard treatment, as well as long-term disease-control outcomes.

The risk factors and clinical features of patients with Candida tropicalis fungaemia have not been fully defined. We performed a case-control study comparing 59 cases of C. tropicalis fungaemia with 177 episodes of fungaemia caused by other species of Candida in our hospital over a 24-year period (January 1985 to December 2008). Patients with C. tropicalis fungaemia were more likely to be older (median age, 67 vs. 56 years; p0.01), to have cancer (45.5% vs. 31.6%, p0.04), and to have the abdomen as the portal of entry (32.2% vs. 11.9%, p0.001), and had a higher in-hospital mortality rate (61% vs. 44%, p0.03). Multivariate analysis showed that the independent risk factors for C. tropicalis fungaemia were cancer (OR 4.5; 95% CI 1.05-3.83; p0.03) and the abdomen as the portal of entry (OR 13.6; 95% CI 1.9-8.2; p

ESGBIS/BICHROME Study Group: C. Campoli, G. Siccardi, S. Ambretti, A. Stallmach, M. Venditti, C. Lucidi, S. Ludovisi, M. De Cueto, M. D. Navarro, E. Lopez Cortes, E. Bouza, M. Valerio, A. Eworo, R. Losito, M. Senzolo, E. Nadal, A. Ottobrelli, M. Varguvic, C. Badia, G. Borgia, I. Gentile, A. R. Buonomo, E. Boumis, A. Beteta-Lopez, A. Rianda, G. Taliani, S. Grieco., [Objectives] To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance., [Methods] Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model., [Results] We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure–SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29–18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93–5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28–1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73–4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48–4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12–0.73; p 0.008)., [Conclusions] MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.