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Antimalarial drug resistance is a major constraint for malaria control and elimination efforts. Artemisinin-based combination therapy is now the mainstay for malaria treatment. However, delayed parasite clearance following treatment with artemisinin derivatives has now spread in the Greater Mekong Sub region and may emerge or spread to other malaria endemic regions. This spread is of great concern for malaria control programmes, as no alternatives to artemisinin-based combination therapies are expected to be available in the near future. There is a need to strengthen surveillance systems for early detection and response to the antimalarial drug resistance threat. Current surveillance is mainly done through therapeutic efficacy studies; however these studies are complex and both time- and resource-intensive. For multiple common antimalarials, parasite drug resistance has been correlated with specific genetic mutations, and the molecular markers associated with antimalarial drug resistance offer a simple and powerful tool to monitor the emergence and spread of resistant parasites. Different techniques to analyse molecular markers associated with antimalarial drug resistance are available, each with advantages and disadvantages. However, procedures are not adequately harmonized to facilitate comparisons between sites. Here we describe the target product profiles for tests to analyse molecular markers associated with antimalarial drug resistance, discuss how use of current techniques can be standardised, and identify the requirements for an ideal product that would allow malaria endemic countries to provide useful spatial and temporal information on the spread of resistance.

BACKGROUND:Accurate and efficient detection of sub-microscopic malaria infections is crucial for enabling rapid treatment and interruption of transmission. Commercially available malaria LAMP kits have excellent diagnostic performance, though throughput is limited by the need to prepare samples individually. Here, we evaluate the clinical performance of a newly developed high throughput (HTP) sample processing system for use in conjunction with the Eiken malaria LAMP kit. METHODS:The HTP system utilised dried blood spots (DBS) and liquid whole blood (WB), with parallel sample processing of 94 samples per run. The system was evaluated using 699 samples of known infection status pre-determined by gold standard nested PCR. RESULTS:The sensitivity and specificity of WB-HTP-LAMP was 98.6% (95% CI, 95.7-100), and 99.7% (95% CI, 99.2-100); sensitivity of DBS-HTP-LAMP was 97.1% (95% CI, 93.1-100), and specificity 100% against PCR. At parasite densities greater or equal to 2 parasites/μL, WB and DBS HTP-LAMP showed 100% sensitivity and specificity against PCR. At densities less than 2 p/μL, WB-HTP-LAMP sensitivity was 88.9% (95% CI, 77.1-100) and specificity was 99.7% (95% CI, 99.2-100); sensitivity and specificity of DBS-HTP-LAMP was 77.8% (95% CI, 54.3-99.5) and 100% respectively. CONCLUSIONS:The HTP-LAMP system is a highly sensitive diagnostic test, with the potential to allow large scale population screening in malaria elimination campaigns.

BACKGROUND:New field applicable diagnostic tools are needed for highly sensitive detection of residual malaria infections in pre-elimination settings. Field performance of a high throughput DNA extraction system for loop mediated isothermal amplification (HTP-LAMP) was therefore evaluated for detecting malaria parasites among asymptomatic individuals in Zanzibar. METHODS:HTP-LAMP performance was evaluated against real-time PCR on 3008 paired blood samples collected on filter papers in a community-based survey in 2015. RESULTS:The PCR and HTP-LAMP determined malaria prevalences were 1.6% (95%CI 1.3-2.4) and 0.7% (95%CI 0.4-1.1), respectively. The sensitivity of HTP-LAMP compared to PCR was 40.8% (CI95% 27.0-55.8) and the specificity was 99.9% (CI95% 99.8-100). For the PCR positive samples, there was no statistically significant difference between the geometric mean parasite densities among the HTP-LAMP positive (2.5 p/μL, range 0.2-770) and HTP-LAMP negative (1.4 p/μL, range 0.1-7) samples (p = 0.088). Two lab technicians analysed up to 282 samples per day and the HTP-LAMP method was experienced as user friendly. CONCLUSIONS:Although field applicable, this high throughput format of LAMP as used here was not sensitive enough to be recommended for detection of asymptomatic low-density infections in areas like Zanzibar, approaching malaria elimination.

Loop-mediated isothermal DNA amplification (LAMP) methodology offers an opportunity for point-of-care (POC) molecular detection of asymptomatic malaria infections. However, there is still little evidence on the feasibility of implementing this technique for population screenings in isolated field settings.Overall, we recruited 1167 individuals from terrestrial ('road') and hydric ('riverine') communities of the Peruvian Amazon for a cross-sectional survey to detect asymptomatic malaria infections. The technical performance of LAMP was evaluated in a subgroup of 503 samples, using real-time Polymerase Chain Reaction (qPCR) as reference standard. The operational feasibility of introducing LAMP testing in the mobile screening campaigns was assessed based on field-suitability parameters, along with a pilot POC-LAMP assay in a riverine community without laboratory infrastructure.LAMP had a sensitivity of 91.8% (87.7-94.9) and specificity of 91.9% (87.8-95.0), and the overall accuracy was significantly better among samples collected during road screenings than riverine communities (p≤0.004). LAMP-based diagnostic strategy was successfully implemented within the field-team logistics and the POC-LAMP pilot in the riverine community allowed for a reduction in the turnaround time for case management, from 12-24 hours to less than 5 hours. Specimens with haemolytic appearance were regularly observed in riverine screenings and could help explaining the hindered performance/interpretation of the LAMP reaction in these communities.LAMP-based molecular malaria diagnosis can be deployed outside of reference laboratories, providing similar performance as qPCR. However, scale-up in remote field settings such as riverine communities needs to consider a number of logistical challenges (e.g. environmental conditions, labour-intensiveness in large population screenings) that can influence its optimal implementation.

Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artefacts, as viability and metabolism are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compounds on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodology to measure in vitro the direct effect of antimalarial compounds over the parasite viability, which is based on limiting serial dilution of treated parasites and re-growth monitoring. This methodology allows to precisely determine the killing rate of antimalarial compounds, which can be quantified by the parasite reduction ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to determine compound killing activities that might be otherwise missed by traditional, metabolism-based techniques. The analysis of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compounds based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compounds, which are crucially needed for the control and possibly the eradication of malaria.

Understanding the factors affecting species distributions is a central topic in ecology and biogeography. However, most research on this topic has focused on species inhabiting terrestrial environments. At broad scales, abiotic variables consistently serve as primary determinants of species' distributions. In this study, we investigated the explanatory power of different abiotic variables in determining the distribution patterns of sea snakes on a global scale. Additionally, as the boundaries of realized thermal niches have significant implications for the ecology of species and their geographic distributions, we evaluated the asymmetry of realized thermal limits (i.e., differences in variances between the upper and lower limits of the realized thermal niche). We obtained 10 marine environmental variables from global databases along with >5000 occurrence records for 51 sea snake species in 4 genera across the group's entire known geographic range. Using these data, we employed correlative ecological niche modeling to analyze the influence of the individual variables in explaining species' distributions. To estimate the realized thermal limits of each species, we extracted the mean, minimum, and maximum temperature values at four depths (superficial, mean benthic, minimum benthic, and maximum benthic) for each occurrence record of the species. We then evaluated the asymmetry of the realized thermal niche by measuring and comparing the variances in the upper and lower limits. Both analyses (the importance of variables and realized thermal limit asymmetry) were performed at three taxonomic levels (sea snakes as a lineage of marine-adapted elapids [true sea snakes + sea kraits], subfamily, and genus) and two spatial resolutions. Overall, we found that temperature, silicate, nitrate, salinity, and phosphate concentrations were the most influential factors in explaining the spatial distribution patterns of sea snakes, regardless of taxonomic level or spatial resolution. Similarly, we observed that the realized thermal limits were asymmetric, with a higher variance in the lower limits, and that asymmetry decreased as the taxonomic level and spatial resolution increased.

Human-induced climate change impacts the oceans, increasing their temperature, changing their circulation and chemical properties, and affecting marine ecosystems. Like most marine species, sole has a biphasic life cycle, where one planktonic larval stage and juvenile/adult stages occur in a different ecological niche. The year-class strength, usually quantified by the end of the larvae stage, is crucial for explaining the species' recruitment. We implemented an experimental system for rearing larvae under laboratory conditions and experimentally investigated the effects of temperature and feeding frequencies on survival, development (growth), and metamorphosis success of S. solea larvae. Specific questions addressed in this work include: what are the effects of feeding regimes on larvae development? How does temperature impact larvae development? Our results highlight that survival depends on the first feeding, that the onset of metamorphosis varies according to rearing temperature and that poorly fed larvae take significantly longer to start (if they do) metamorphosing. Moreover, larvae reared at the higher temperature (a +4°C scenario) showed a higher incidence in metamorphosis defects. We discuss the implications of our results in an ecological context, notably in terms of recruitment and settlement. Understanding the processes that regulate the abundance of wild populations is of primary importance, especially if these populations are living resources exploited by humans.

The objective of this study was to investigate the feelings and experiences of infertile women with deep infiltrating endometriosis during and after a first pregnancy achieved by in-vitro fertilization (IVF). We conducted a qualitative monocentric study between May and November 2020. Semi-structured interviews were undertaken with infertile women with deep infiltrating endometriosis who achieved a first pregnancy by IVF and delivered at least two years prior to the interview. Data analysis was performed using an inductive approach to identify recurrent categories and themes. Fifteen interviews were conducted to reach data saturation. Pregnancy appeared to improve all components of the experience of endometriosis that were explored (psychological and physical well-being, social relationships, professional life, and sexuality). This improvement was only temporary and all symptoms and negative aspects of the women's quality of life reappeared after a variable period.

Aim Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Results Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 pConclusions These experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.

BackgroundSeveral studies have proposed personalized strategies based on women's individual breast cancer risk to improve the effectiveness of breast cancer screening. We designed and internally validated an individualized risk prediction model for women eligible for mammography screening.MethodsRetrospective cohort study of 121,969 women aged 50 to 69 years, screened at the long-standing population-based screening program in Spain between 1995 and 2015 and followed up until 2017. We used partly conditional Cox proportional hazards regression to estimate the adjusted hazard ratios (aHR) and individual risks for age, family history of breast cancer, previous benign breast disease, and previous mammographic features. We internally validated our model with the expected-to-observed ratio and the area under the receiver operating characteristic curve.ResultsDuring a mean follow-up of 7.5 years, 2,058 women were diagnosed with breast cancer. All three risk factors were strongly associated with breast cancer risk, with the highest risk being found among women with family history of breast cancer (aHR: 1.67), a proliferative benign breast disease (aHR: 3.02) and previous calcifications (aHR: 2.52). The model was well calibrated overall (expected-to-observed ratio ranging from 0.99 at 2 years to 1.02 at 20 years) but slightly overestimated the risk in women with proliferative benign breast disease. The area under the receiver operating characteristic curve ranged from 58.7% to 64.7%, depending of the time horizon selected.ConclusionsWe developed a risk prediction model to estimate the short- and long-term risk of breast cancer in women eligible for mammography screening using information routinely reported at screening participation. The model could help to guiding individualized screening strategies aimed at improving the risk-benefit balance of mammography screening programs.

BACKGROUND:Patients with a history of tuberculosis (TB) have a high probability of recurrence because long-term cure is not always maintained in successfully treated patients. The aim of this study was to identify the probability of TB recurrence and its predictive factors in a cohort of socially vulnerable patients who completed treatment in the TB referral center in Catalonia, which acts as the center for patients with social and health problems. METHODS:This retrospective open cohort study included all patients diagnosed with TB who were admitted and successfully treated in Serveis Clínics between 2000 and 2016 and who remained disease-free for a minimum of 1 year after treatment completion. We calculated the incidence density of TB recurrences per person-years of follow-up. We also estimated the cumulative incidence of TB recurrence at 1, 2, 5, and 10 years of follow-up. Bivariate analysis was conducted using Kaplan-Meier curves. Multivariate analysis was conducted using Cox regression. Hazard ratios (HR) were calculated with their 95% confidence intervals (95%CI). RESULTS:There were 839 patients and 24 recurrences (2.9%), representing 0.49 per 100 person-years. The probability of a recurrence was 0.63% at 1 year of follow-up, 1.35% at 2 years, and 3.69% at 5 years. The multivariate analysis showed that the predictive factors of recurrence were age older than 34 years (aHR = 3.90; CI = 1.06-14.34 at age 35-45 years and aHR = 3.88; CI = 1.02-14.80 at age >45 years) and resistance to at least one anti-TB drug (aHR = 2.91; CI = 1.11-7.65). CONCLUSIONS:Attention should be paid to socially vulnerable persons older than 34 years with a previous episode of resistant TB. Surveillance resources should be directed toward adequately treated patients who nevertheless have a high risk of recurrence.

[This corrects the article DOI: 10.1371/journal.pone.0208112.].

BackgroundA higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. The main objective was to assess clinical and laboratory differences in hospitalized COVID-19 patients according to occurrence of PE.MethodsThis retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset, were compared between PE and non-PE patients.ResultsNinety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD 13.7) vs 69.9 (SD 12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD 8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). No patients met ISTH DIC criteria. Any parameter was statistically significant or clinically relevant except for D-Dimer when comparing both groups. Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1-11208.9] vs 626.0 [374.0-2382.2]; p = 0.004); week 3 (3893.1 [1388.2-6694.0] vs 1184.4 [461.8-2447.8]; p = 0.003); and week 4 (2736.3 [1202.1-8514.1] vs 1129.1 [542.5-2834.6]; p = 0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02-23.05] vs 1.57 [0.64-2.71], p = 0.003); ROC curve AUC was 0.879 (p = 0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively.ConclusionsAmong hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared.

ContextClassical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL).MethodsTwenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point.ResultsNeither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject.ConclusionsIn absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

Cancer progression results from a complex interplay between tumor cells and the extracellular milieu. In breast carcinoma, the stromal microenvironment has been suggested to play a major role in promoting tumor growth, progression, and invasion. The stroma of 154 resected specimens of invasive breast carcinoma of no special type was quantified using a digital image analyzer. Statistical analyses were performed between the quantity of stroma and survival, as well as between progression-free survival and clinicopathological data. Levels of myofibroblastic stroma varied from 0-46%, with a median of 15.1% and a standard deviation of 7.5. The myofibroblastic stromal reaction was statistically greater in grade 2 and 3 tumors (p = 0.029). Furthermore, there was a trend for worse progression-free survival in the group of node-negative tumors with strong smooth-muscle actin stromal expression (Log rank = 0.075). The present study demonstrates that the myofibroblastic reaction of breast invasive carcinoma of no special type is not merely a passive reaction, but seems to be an integral part of the neoplastic process by facilitating tumor progression and invasion. Additional, larger studies on mechanisms of stromal change are needed and may potentially lead to novel treatments.

BACKGROUND:The effectiveness of breast cancer screening is still under debate. Our objective was to systematically review studies assessing personalized breast cancer screening strategies based on women's individual risk and to conduct a risk of bias assessment. METHODS:We followed the standard methods of The Cochrane Collaboration and PRISMA declaration and searched the MEDLINE, EMBASE and Clinical Trials databases for studies published in English. The quality of the studies was assessed using the ISPOR-AMCP-NPC Questionnaire and The Cochrane Risk of Bias Tool. Two independent reviewers screened full texts and evaluated the risk of bias. RESULTS:Out of the 1533 initially retrieved citations, we included 13 studies. Three studies were randomized controlled trials, while nine were mathematical modeling studies, and one was an observational pilot study. The trials are in the recruitment phase and have not yet reported their results. All three trials used breast density and age to define risk groups, and two of them included family history, previous biopsies, and genetic information. Among the mathematical modeling studies, the main risk factors used to define risk groups were breast density, age, family history, and previous biopsies. Six studies used genetic information to define risk groups. The most common outcome measures were the gain in quality-adjusted life years (QALY), absolute costs, and incremental cost-effectiveness ratio (ICER), while the main outcome in the observational study was the detection rate. In all models, personalized screening strategies were shown to be effective. The randomized trials were of good quality. The modeling studies showed moderate risk of bias but there was wide variability across studies. The observational study showed a low risk of bias but its utility was moderate due to its pilot design and its relatively small scale. CONCLUSIONS:There is some evidence of the effectiveness of screening personalization in terms of QUALYs and ICER from the modeling studies and the observational study. However, evidence is lacking on feasibility and acceptance by the target population. REVIEW REGISTRATION:PROSPERO: CRD42018110483.

Background and aimsThe DE-PLAN was a European multicenter study, with the primary objective of testing whether a community-based lifestyle modification programme could serve as a means of primary prevention for type 2 diabetes (T2D) in high-risk individuals (based on the FINDRISC questionnaire). The aim of this study was to examine the impact of a 1-year community-based lifestyle intervention on health-related quality of life (HRQOL) in individuals from four participating European centers (Athens, Barcelona, Krakow, Kaunas), through a post-hoc analysis.Materials and methodsEach center was allowed to implement different intervention strategies specifically tailored to the needs of their corresponding population sample. Before and after the intervention, participants underwent clinical evaluation, anthropometric measurements, an oral glucose tolerance test and lipid profile measurements. Health-related quality of life was assessed using the validated HRQOL-15D questionnaire. A difference of ±0.015 in the 15D questionnaire score was set as the threshold of clinically meaningful change.ResultsData from 786 participants (67% females, mean age 59.7±9.4 years, BMI 31.5±4.5 kg/m2) with complete data regarding the HRQOL were analyzed (Athens: 104, Barcelona: 434, Krakow: 175, Kaunas: 70). After 1 year, a significant overall improvement in HRQOL was shown, as depicted by a change of 15D score from baseline value (0.88±0.9) to post-intervention (0.90±0.87, PConclusionA community-based lifestyle intervention programme aiming at T2D prevention, applied on a heterogeneous population and with varied methods, was shown to improve overall health-related quality of life to a clinically meaningful degree.

BackgroundThe local infectious origin and the putative role of Cutibacterium acnes (CA) of a particular subtype of discopathy (Modic 1) are still debated.PurposeTo establish the association of CA in intervertebral disc (IVD) and Modic 1 discopathy in patients with low back pain.MethodsThe prevalence of bacteria in IVD samples obtained by anterior approach in patient with chronic low back pain harboring Modic type 1, 2 or no Modic changes was compared to that measured in IVD samples obtained by posterior approach for sciatica. From 45 patients included in the study, 77 discs samples were obtained: 58 by anterior approach (32 Modic 1/2 changes, 26 without Modic change) and 19 by posterior approach. Conventional microbial cultures, universal 16S rRNA molecular detection and a CA specific PCR were performed.Results12 /77 (15.6%) disc samples were culture positive. Among the 10 CA positive cultures, 5 out of 58 (8.6%) were identified from specimens obtained by anterior approach and 5/19 (26.3%) from posterior approach (p = 0.046). Moreover, the percentage of CA culture positive sample was statistically no different between the patient with or without Modic changes. The CA prevalence was lower through molecular, culture-free approaches: the universal 16S rRNA PCR was positive for 6 specimens, including one CA positive sample and the CA specific PCR was positive for one specimen obtained by posterior approach.ConclusionsIn spine surgery the prevalence of CA in culture was significantly higher in IVD samples collected through a posterior approach compared to an anterior approach, suggesting a contamination process. This study did not support the CA related local infectious origin of Modic 1 discopathy.

BackgroundThe survival rates from breast cancer in Africa are poor and yet the incidence rates are on the rise. In this study, we hypothesized that, in Africa, a continent with great disparities in socio-economic status, race, tumor biology, and cultural characteristics, the survival rates from breast cancer vary greatly based on region, tumor biology (hormone receptor), gender, and race. We aimed to conduct the first comprehensive systematic review and meta-analysis on region, gender, tumor-biology and race-specific 5-year breast cancer survival rates in Africa and compared them to 20-year survival trends in the United States.MethodsWe searched MEDLINE, EMBASE, and Cochrane Library to identify studies on breast cancer survival in African published before October 17, 2018. Pooled 5-year survival rates of breast cancer were estimated by random-effects models. We explored sources of heterogeneity through subgroup meta-analyses and meta-regression. Results were reported as absolute difference (AD) in percentages. We compared the survival rates of breast cancer in Africa and the United States.FindingsThere were 54 studies included, consisting of 18,970 breast cancer cases. There was substantial heterogeneity in the survival rates (mean 52.9%, range 7-91%, I2 = 99.1%; p for heterogeneity ConclusionRegional, sub-regional, gender, and racial disparities exist, influencing the survival rates of breast cancer in Africa. Therefore, region and race-specific public health interventions coupled with prospective genetic studies are urgently needed to improve breast cancer survival in this region.

Mass spectrometry imaging (MSI) is a molecular imaging technique that maps the distribution of molecules in biological tissues with high spatial resolution. The most widely used MSI modality is matrix-assisted laser desorption/ionization (MALDI), mainly due to the large variety of analyte classes amenable for MALDI analysis. However, the organic matrices used in classical MALDI may impact the quality of the molecular images due to limited lateral resolution and strong background noise in the low mass range, hindering its use in metabolomics. Here we present a matrix-free laser desorption/ionization (LDI) technique based on the deposition of gold nanolayers on tissue sections by means of sputter-coating. This gold coating method is quick, fully automated, reproducible, and allows growing highly controlled gold nanolayers, necessary for high quality and high resolution MS image acquisition. The performance of the developed method has been tested through the acquisition of MS images of brain tissues. The obtained spectra showed a high number of MS peaks in the low mass region (m/z below 1000 Da) with few background peaks, demonstrating the ability of the sputtered gold nanolayers of promoting the desorption/ionization of a wide range of metabolites. These results, together with the reliable MS spectrum calibration using gold peaks, make the developed method a valuable alternative for MSI applications.

BACKGROUND AND AIM:Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series. METHODS:All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures. RESULTS:One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed. CONCLUSION:DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.

The DE-PLAN-CAT project (Diabetes in Europe-Prevention using lifestyle, physical activity and nutritional intervention-Catalonia) has shown that an intensive lifestyle intervention is feasible in the primary care setting and substantially reduces the incidence of diabetes among high-risk Mediterranean participants. The DP-TRANSFERS project (Diabetes Prevention-Transferring findings from European research to society) is a large-scale national programme aimed at implementing this intervention in primary care centres whenever feasible.A multidisciplinary committee first evaluated the programme in health professionals and then participants without diabetes aged 45-75 years identified as being at risk of developing diabetes: FINDRISC (Finnish Diabetes Risk Score)>11 and/or pre-diabetes diagnosis. Implementation was supported by a 4-channel transfer approach (institutional relationships, facilitator workshops, collaborative groupware, programme website) and built upon a 3-step (screening, intervention, follow-up) real-life strategy. The 2-year lifestyle intervention included a 9-hour basic module (6 sessions) and a subsequent 15-hour continuity module (10 sessions) delivered by trained primary healthcare professionals. A 3-level (centre, professionals and participants) descriptive analysis was conducted using cluster sampling to assess results and barriers identified one year after implementation.The programme was started in June-2016 and evaluated in July-2017. In all, 103 centres covering all the primary care services for 1.4 million inhabitants (27.9% of all centres in Catalonia) and 506 professionals agreed to develop the programme. At the end of the first year, 83 centres (80.6%) remained active and 305 professionals (60.3%) maintained regular web-based activities. Implementation was not feasible in 20 centres (19.4%), and 5 main barriers were prioritized: lack of healthcare manager commitment; discontinuity of the initial effort; substantial increase in staff workload; shift in professional status and lack of acceptance. Overall, 1819 people were screened and 1458 (80.1%) followed the lifestyle intervention, with 1190 (81.6% or 65.4% of those screened) participating in the basic module and 912 in the continuity module (62.5% or 50.1%, respectively).A large-scale lifestyle intervention in primary care can be properly implemented within a reasonably short time using existing public healthcare resources. Regrettably, one fifth of the centres and more than one third of the professionals showed substantial resistance to performing these additional activities.

Alterations of species phenology in response to climate change are now unquestionable. Until now, most studies have reported precocious occurrence of life cycle events as a major phenological response. Desynchronizations of biotic interactions, in particular predator-prey relationships, are however assumed to strongly impact ecosystems' functioning, as formalized by the Match-Mismatch Hypothesis (MMH). Temporal synchronicity between juvenile fish and zooplankton in estuaries is therefore of essential interest since estuaries are major nursery grounds for many commercial fish species. The Gironde estuary (SW France) has suffered significant alterations over the last three decades, including two Abrupt Ecosystem Shifts (AES), and three contrasted intershift periods. The main objective of this study was to depict modifications in fish and zooplankton phenology among inter-shift periods and discuss the potential effects of the resulting mismatches at a community scale. A flexible Bayesian method was used to estimate and compare yearly patterns of species abundance in the estuary among the three pre-defined periods. Results highlighted (1) an earlier peak of zooplankton production and entrance of fish species in the estuary and (2) a decrease in residence time of both groups in the estuary. Such species-specific phenological changes led to changes in temporal overlap between juvenile fish and their zooplanktonic prey. This situation questions the efficiency and potentially the viability of nursery function of the Gironde estuary, with potential implications for coastal marine fisheries of the Bay of Biscay.

Worldwide use of formalin-fixed paraffin-embedded blocks (FFPE) is extensive in diagnosis and research. Yet, there is a lack of optimized/standardized protocols to process the blocks and verify the quality and presence of the targeted tissue. In the context of an international study on head and neck cancer (HNC)-HPV-AHEAD, a standardized protocol for optimizing the use of FFPEs in molecular epidemiology was developed and validated. First, a protocol for sectioning the FFPE was developed to prevent cross-contamination and distributed between participating centers. Before processing blocks, all sectioning centers underwent a quality control to guarantee a satisfactory training process. The first and last sections of the FFPEs were used for histopathological assessment. A consensus histopathology evaluation form was developed by an international panel of pathologists and evaluated for four indicators in a pilot analysis in order to validate it: 1) presence/type of tumor tissue, 2) identification of other tissue components that could affect the molecular diagnosis and 3) quality of the tissue. No HPV DNA was found in sections from empty FFPE generated in any histology laboratories of HPV-AHEAD consortium and all centers passed quality assurance for processing after quality control. The pilot analysis to validate the histopathology form included 355 HNC cases. The form was filled by six pathologists and each case was randomly assigned to two of them. Most samples (86%) were considered satisfactory. Presence of >50% of invasive carcinoma was observed in all sections of 66% of cases. Substantial necrosis (>50%) was present in 0.85) between first and last sections and fair to high between pathologists (kappa/pabak 0.21-0.72). The protocol allowed to correctly process without signs of contamination all FFPE of the study. The histopathology evaluation of the cases assured the presence of the targeted tissue, identified the presence of other tissues that could disturb the molecular diagnosis and allowed the assessment of tissue quality.

Bisphenol A (BPA) exposure has been suspected to be associated with deleterious effects on health including obesity and metabolically-linked diseases. Although bisphenols F (BPF) and S (BPS) are BPA structural analogs commonly used in many marketed products as a replacement for BPA, only sparse toxicological data are available yet. Our objective was to comprehensively characterize bisphenols gene targets in a human primary adipocyte model, in order to determine whether they may induce cellular dysfunction, using chronic exposure at two concentrations: a "low-dose" similar to the dose usually encountered in human biological fluids and a higher dose. Therefore, BPA, BPF and BPS have been added at 10 nM or 10 μM during the differentiation of human primary adipocytes from subcutaneous fat of three non-diabetic Caucasian female patients. Gene expression (mRNA/lncRNA) arrays and microRNA arrays, have been used to assess coding and non-coding RNA changes. We detected significantly deregulated mRNA/lncRNA and miRNA at low and high doses. Enrichment in "cancer" and "organismal injury and abnormalities" related pathways was found in response to the three products. Some long intergenic non-coding RNAs and small nucleolar RNAs were differentially expressed suggesting that bisphenols may also activate multiple cellular processes and epigenetic modifications. The analysis of upstream regulators of deregulated genes highlighted hormones or hormone-like chemicals suggesting that BPS and BPF can be suspected to interfere, just like BPA, with hormonal regulation and have to be considered as endocrine disruptors. All these results suggest that as BPA, its substitutes BPS and BPF should be used with the same restrictions.

Fatigue is a common and bothersome symptom in inflammatory bowel disease (IBD) patients. The study was aimed to determine the relationship of biological and psychological factors with IBD-related fatigue.Consecutive clinically inactive IBD outpatients receiving immunosuppressants or biological drugs were enrolled between January and December 2013. Patients completed a Fatigue score (FACIT-F), various psychological, quality of life (IBDQ-9), and IBD activity scores. Biological parameters were assessed, including levels of interleukins (IL-5, IL-8 and IL-12) and micronutrients.We prospectively recruited 202 patients (28% ulcerative colitis and 72% Crohn's disease) for the study. Fatigue measured by FACIT-F score was prevalent in the studied population (54%, 96/177) and higher than in the general population. In the univariate analysis no relation was found between IL levels or micronutrient deficiencies and fatigue. Fatigue was significantly related to female sex, Crohn's disease, joint disorders, body mass index (BMI), psychological tests, thiopurine use, and anti-TNF treatment. All these variables were included in the multivariate analysis. Female sex (OR: 4.8), high BMI (OR:1.2) and higher depression rates (OR:1.2) were predictors of increased fatigue. High IBDQ-9 score (OR: 0.82) was significantly related to lower degrees of fatigue.Fatigue was prevalent in quiescent IBD patients with moderate-to-severe disease. It was associated with high levels of depression, low quality of life, and female sex. No association was found with the other biological and psychological factors evaluated.

The cognitive-motor performance (CMP), defined here as the capacity to rapidly use sensory information and transfer it into efficient motor output, represents a major contributor to performance in almost all sports, including soccer. Here, we used a high-technology system (COGNIFOOT) which combines a visual environment simulator fully synchronized with a motion capture system. This system allowed us to measure objective real-time CMP parameters (passing accuracy/speed and response times) in a large turf-artificial grass playfield. Forty-six (46) young elite soccer players (including 2 female players) aged between 11 and 16 years who belonged to the same youth soccer academy were tested. Each player had to pass the ball as fast and as accurately as possible towards visual targets projected onto a large screen located 5.32 meters in front of him (a short pass situation). We observed a linear age-related increase in the CMP: the passing accuracy, speed and reactiveness of players improved by 4 centimeters, 2.3 km/h and 30 milliseconds per year of age, respectively. These data were converted into 5 point-scales and compared to the judgement of expert coaches, who also used a 5 point-scale to evaluate the same CMP parameters but based on their experience with the players during games and training. The objectively-measured age-related CMP changes were also observed in expert coaches' judgments although these were more variable across coaches and age categories. This demonstrates that high-technology systems like COGNIFOOT can be used in complement to traditional approaches of talent identification and to objectively monitor the progress of soccer players throughout a cognitive-motor training cycle.

Screening with faecal occult blood tests reduces colorectal cancer-related mortality; however, age, sex and socioeconomic factors affect screening outcomes and could lead to unequal mortality benefits. The aim of this study was to describe the main outcomes of the population-based Barcelona colorectal cancer screening programme (BCRCSP) by deprivation.Retrospective study of the eligible population of the first round of the BCRCSP. Participants' postal addresses were linked with the MEDEA database to obtain the deprivation quintiles (Dq). Chi-squared tests were used to compare proportions across variables and logistic regression was used to estimate the adjusted effects of age, sex and deprivation on uptake, FIT positivity, colonoscopy adherence and advanced neoplasia detection rate.Overall uptake was 44.7%, higher in Dq2, 3 and 4 (OR 1.251, 1.250 and 1.276, respectively) than in the least deprived quintile (Dq 1), and lowest in Dq5 (OR 0.84). Faecal immunochemical test (FIT) positivity and the percentage of people with detectable faecal haemoglobin below the positivity threshold increased with deprivation. The advanced neoplasia detection rate was highest in Dq4.Unlike most regions where inequalities are graded along the socioeconomic continuum, inequalities in the uptake of colorectal cancer screening in Spain seem to be concentrated first in the most disadvantaged group and second in the least deprived group. The correlation of deprivation with FIT-positivity and faecal haemoglobin below the positivity threshold is worrying due to its association with colorectal cancer and overall mortality.

Recently, there has been multi-agency promotion of entomophagy as an environmentally-friendly source of food for the ever increasing human population especially in the developing countries. However, food quality and safety concerns must first be addressed in this context. We addressed these concerns in the present study using the edible stink bug Encosternum delegorguei, which is widely consumed in southern Africa. We analysed for mycotoxins, and health beneficials including antioxidants, amino acids and essential fatty acids using liquid chromatography coupled to quadrupole time of flight mass spectrometry (LC-Qtof-MS) and coupled gas chromatography (GC)-MS. We also performed proximate analysis to determine nutritional components. We identified the human carcinogen mycotoxin (aflatoxin B1) at low levels in edible stink bugs that were stored in traditonally woven wooden dung smeared baskets and gunny bags previously used to store cereals. However, it was absent in insects stored in clean zip lock bags. On the other hand, we identified 10 fatty acids, of which 7 are considered essential fatty acids for human nutrition and health; 4 flavonoids and 12 amino acids of which two are considered the most limiting amino acids in cereal based diets. The edible stink bug also contained high crude protein and fats but was a poor source of minerals, except for phosphorus which was found in relatively high levels. Our results show that the edible stink bug is a nutrient- and antioxidant-rich source of food and health benefits for human consumption. As such, use of better handling and storage methods can help eliminate contamination of the edible stink bug with the carcinogen aflatoxin and ensure its safety as human food.

We analyzed the effects of the clinical hyperbaric oxygen therapy (HBOT) on the plasma antioxidant response and levels of endothelin-1, Interleukine-6 (IL-6) and vascular endothelial growth factor (VEGF) in patients with chronic wounds (20.2±10.0 months without healing). They received 20 HBOT sessions (five sessions/week), and blood samples were obtained at sessions 1, 5 and 20 before and 2 hours after the HBOT. An additional blood sample was collected 1 month after wound recovery. Serum creatine kinase activity decreased progressively in accordance with the wound healing. Plasma catalase activity significantly increased after the first and fifth sessions of HBOT. Plasma myeloperoxidase activity reported significantly lower values after sessions. Plasma VEGF and IL-6 increased after sessions. Endothelin-1 levels were progressively decreasing during the HBOT, being significant at the session 20. Plasma malondialdehyde concentration was significantly reduced at the last session. Both creatine kinase activity and malondialdehyde levels were maintained lower 1 month after wound recovery respect to initial values. In conclusion, HBOT enhanced the plasma antioxidant defenses and may contribute to activate the healing resolution, angiogenesis and vascular tone regulation by increasing the VEGF and IL-6 release and the endothelin-1 decrease, which may be significant factors in stimulating wound healing.

The bradykinin (BK) B1 receptor (B1R) is a peculiar G protein coupled receptor that is strongly regulated to the point of being inducible in immunopathology. Limited clinical evidence suggests that its expression in peripheral blood mononuclear cells is a biomarker of active inflammatory states. In an effort to develop a novel imaging/diagnostic tool, we report the rational design and testing of a fusion protein that is a ligand of the human B1R but not likely to label peptidases. This ligand is composed of a fluorescent protein (FP) (enhanced green FP [EGFP] or mCherry) prolonged at its N-terminus by a spacer peptide and a classical peptide agonist or antagonist (des-Arg9-BK, [Leu8]des-Arg9-BK, respectively). The design of the spacer-ligand joint peptide was validated by a competition assay for [3H]Lys-des-Arg9-BK binding to the human B1R applied to 4 synthetic peptides of 18 or 19 residues. The labeling of B1R-expressing cells with EGFP or mCherry fused with 7 of such peptides was performed in parallel (microscopy). Both assays indicated that the best design was FP-(Asn-Gly)n-Lys-des-Arg9-BK; n = 15 was superior to n = 5, suggesting benefits from minimizing steric hindrance between the FP and the receptor. Cell labeling concerned mostly plasma membranes and was inhibited by a B1R antagonist. EGFP-(Asn-Gly)15-Lys-des-Arg9-BK competed for the binding of [3H]Lys-des-Arg9-BK to human recombinant B1R, being only 10-fold less potent than the unlabeled form of Lys-des-Arg9-BK to do so. The fusion protein did not label HEK 293a cells expressing recombinant human BK B2 receptors or angiotensin converting enzyme. This study identifies a modular C-terminal sequence that can be adapted to protein cargoes, conferring high affinity for the BK B1R, with possible applications in diagnostic cytofluorometry, histology and drug delivery (e.g., in oncology).

The aims of the present study were to explore the expression pattern of haem biosynthesis enzymes in circulating cells of patients affected by two types of porphyria (acute intermittent, AIP, and variegate porphyria, VP), together with the antioxidant enzyme pattern in AIP in order to identify a possible situation of oxidative stress. Sixteen and twelve patients affected by AIP and VP, respectively, were analysed with the same numbers of healthy matched controls. Erythrocytes, neutrophils and peripheral blood mononuclear cells (PBMCs) were purified from blood, and RNA and proteins were extracted for quantitative real time PCR (qRT-PCR) and Western-blot analysis, respectively. Porhobilinogen deaminase (PBGD) and protoporphyrinogen oxidase (PPOX) gene and protein expression was analysed. Antioxidant enzyme activity and gene expression were additionally determined in blood cells, together with protein carbonyl content in plasma. PBMCs isolated from AIP patients presented low mRNA levels of PBGD when compared to controls, while PBMCs isolated from VP patients presented a decrease in PPOX mRNA. PPOX protein content was higher in AIP patients and lower in VP patients, compared to healthy controls. Regarding antioxidant enzymes, PBMCs and erythrocyte superoxide dismutase (SOD) presented statistically significant higher activity in AIP patients compared to controls, while catalase activity tended to be lower in these patients. No differences were observed regarding antioxidant gene expression in white blood cells. Circulating cells in AIP and VP patients present altered expression of haem biosynthetic enzymes, which could be useful for the differential diagnosis of these two types of porphyria in certain difficult cases. AIP patients present a condition of potential oxidative stress similar to VP patients, evidenced by the post-transcriptional activation of SOD and possible catalase impairment.

BACKGROUND:In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). METHODS AND FINDINGS:We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). CONCLUSIONS:Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

The systematic creation of gaps within canopies results in fragmentation and the architecture of fragmented canopies differs substantially from non-fragmented canopies. Canopy fragmentation leads to spatial heterogeneity in hydrodynamics and therefore heterogeneity in the sheltering of canopy communities. Identifying the level of instability due to canopy fragmentation is important for canopies in coastal areas impacted by human activities and indeed, climate change. The gap orientation relative to the wave direction is expected to play an important role in determining wave attenuation and sheltering. Initially we investigated the effect of a single transversal gap within a canopy (i.e. a gap oriented perpendicular to the wave direction) on hydrodynamics, which was compared to fully vegetated canopies (i.e. no gaps) and also to bare sediment. The wave velocity increased with gap width for the two canopy densities studied (2.5% and 10% solid plant fraction) reaching wave velocities found over bare sediments. The turbulent kinetic energy (TKE) within the gap also increased, but was more attenuated by the adjacent vegetation than the wave velocity. As expected, denser canopies produced a greater attenuation of both the wave velocity and the turbulent kinetic energy within an adjacent gap, compared to sparse canopies. Using non-dimensional analysis and our experimental data, a parameterization for predicting TKE in a canopy gap was formulated, as a function of easily measured variables. Based on the experimental results, a fragmented canopy model was then developed to determine the overall mixing level in such canopies. The model revealed that canopies with large gaps present more mixing than canopies with small gaps despite having the same total gap area in the canopy. Furthermore, for the same total gap area, dense fragmented canopies provide more shelter than sparse fragmented canopies.

Quercus robur and Q. petraea are major European forest tree species. They have been affected by powdery mildew caused by Erysiphe alphitoides for more than a century. This fungus is a biotrophic foliar pathogen that diverts photosynthetate from the plant for its own nutrition. We used a dendrochronological approach to investigate the effects of different levels of infection severity on the radial growth of young oak trees. Oak infection was monitored at individual tree level, at two sites in southwestern France, over a five-year period (2001-2005). Mean infection severity was almost 75% (infected leaf area) at the end of the 2001 growing season, at both sites, but only about 40% in 2002, and 8%, 5% and 2% in 2003, 2004 and 2005, respectively. Infection levels varied considerably between trees and were positively related between 2001 and 2002. Increment cores were taken from each tree to assess annual ring widths and increases in basal area. Annual radial growth was standardised to take the effect of tree size into account. Annual standardised radial growth was significantly and negatively correlated with infection severity in the same year, for both 2001 and 2002, and at both sites. The decrease in growth reached 70-90% for highly infected trees. The earlywood width was poorly correlated with infection severity, but the proportion of latewood in tree rings was lower in highly infected trees (60%) than in less heavily infected trees (85%). Infection in 2001 and 2002 was found to have a cumulative effect on radial growth in these years, together with a delayed effect detectable in 2003. Thus, even non-lethal pathogens like powdery mildew can have a significant impact on tree functioning. This impact should be taken into account in growth and yield models, to improve predictions of forest net primary production.

BACKGROUND:Prediction of massive transfusion (MT) is challenging in management of trauma patients. However, MT and its prediction were poorly studied in obese patients. The main objective was to assess the relationship between obesity and MT needs in trauma patients. The secondary objectives were to validate the Trauma Associated Severe Hemorrhage (TASH) score in predicting MT in obese patients and to use a grey zone approach to optimize its ability to predict MT. METHODS AND FINDINGS:An observational retrospective study was conducted in a Level I Regional Trauma Center Trauma in obese and non-obese patients. MT was defined as ≥10 U of packed red blood cells in the first 24h and obesity as a BMI≥30 kg/m². Between January 2008 and December 2012, 119 obese and 791 non-obese trauma patients were included. The rate of MT was 10% (94/910) in the whole population. The MT rate tended to be higher in obese patients than in non-obese patients: 15% (18/119, 95%CI 9‒23%) versus 10% (76/791, 95%CI 8‒12%), OR, 1.68 [95%CI 0.97‒2.92], p = 0.07. After adjusting for Injury Severity Score (ISS), obesity was significantly associated with MT rate (OR, 1.79[95%CI 1.00‒3.21], p = 0.049). The TASH score was higher in the obese group than in the non-obese group: 7(4-11) versus 5(2-10) (p

AIM:To calculate the incremental cost of nosocomial bacteremia caused by the most common organisms, classified by their antimicrobial susceptibility. METHODS:We selected patients who developed nosocomial bacteremia caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa. These microorganisms were analyzed because of their high prevalence and they frequently present multidrug resistance. A control group consisted of patients classified within the same all-patient refined-diagnosis related group without bacteremia. Our hospital has an established cost accounting system (full-costing) that uses activity-based criteria to analyze cost distribution. A logistic regression model was fitted to estimate the probability of developing bacteremia for each admission (propensity score) and was used for propensity score matching adjustment. Subsequently, the propensity score was included in an econometric model to adjust the incremental cost of patients who developed bacteremia, as well as differences in this cost, depending on whether the microorganism was multidrug-resistant or multidrug-sensitive. RESULTS:A total of 571 admissions with bacteremia matched the inclusion criteria and 82,022 were included in the control group. The mean cost was € 25,891 for admissions with bacteremia and € 6,750 for those without bacteremia. The mean incremental cost was estimated at € 15,151 (CI, € 11,570 to € 18,733). Multidrug-resistant P. aeruginosa bacteremia had the highest mean incremental cost, € 44,709 (CI, € 34,559 to € 54,859). Antimicrobial-susceptible E. coli nosocomial bacteremia had the lowest mean incremental cost, € 10,481 (CI, € 8,752 to € 12,210). Despite their lower cost, episodes of antimicrobial-susceptible E. coli nosocomial bacteremia had a major impact due to their high frequency. CONCLUSIONS:Adjustment of hospital cost according to the organism causing bacteremia and antibiotic sensitivity could improve prevention strategies and allow their prioritization according to their overall impact and costs. Infection reduction is a strategy to reduce resistance.

To estimate the long-term need for colonoscopies after a positive fecal immunochemical test (FIT) and post-polypectomy surveillance in the context of a population-based colorectal cancer (CRC) screening program.A discrete-event simulation model was built to reproduce the process of CRC screening and post-polypectomy surveillance following European guidelines in a population of 100,000 men and women aged 50-69 years over a 20-year period. Screening consisted of biennial FIT and colonoscopy in participants with positive results. The model was mainly fed using data from the first and second rounds of a Spanish program (2010-2013). Data on post-polypectomy surveillance results were obtained from the literature. A probabilistic multivariate sensitivity analysis was performed on the effect of participation, FIT positivity, and adherence to surveillance colonoscopies. The main outcome variables were the number of colonoscopies after a positive FIT, surveillance colonoscopies, and the overall number of colonoscopies.An average yearly number of 1,200 colonoscopies after a positive FIT were predicted per 100,000 inhabitants with a slight increase to 1,400 at the end of the 20-year period. Surveillance colonoscopies increased to an average of 1,000 per 100,000 inhabitants in the long-term, showing certain stabilization in the last years of the 20-year simulation horizon. The results were highly sensitive to FIT positivity.Implementing a population-based CRC screening program will increase the demand for colonoscopies, which is expected to double in 20 years, mainly due to an increase in surveillance colonoscopies.

The direct negative effects of invasive plant species on agriculture and biodiversity are well known, but their indirect effects on human health, and particularly their interactions with disease-transmitting vectors, remains poorly explored. This study sought to investigate the impact of the invasive Neotropical weed Parthenium hysterophorus and its toxins on the survival and energy reserves of the malaria vector Anopheles gambiae. In this study, we compared the fitness of An. gambiae fed on three differentially attractive mosquito host plants and their major toxins; the highly aggressive invasive Neotropical weed Parthenium hysterophorus (Asteraceae) in East Africa and two other adapted weeds, Ricinus communis (Euphorbiaceae) and Bidens pilosa (Asteraceae). Our results showed that female An. gambiae fitness varied with host plants as females survived better and accumulated substantial energy reserves when fed on P. hysterophorus and R. communis compared to B. pilosa. Females tolerated parthenin and 1-phenylhepta-1, 3, 5-triyne, the toxins produced by P. hysterophorus and B. pilosa, respectively, but not ricinine produced by R. communis. Given that invasive plants like P. hysterophorus can suppress or even replace less competitive species that might be less suitable host-plants for arthropod disease vectors, the spread of invasive plants could lead to higher disease transmission. Parthenium hysterophorus represents a possible indirect effect of invasive plants on human health, which underpins the need to include an additional health dimension in risk-analysis modelling for invasive plants.

Soil microbial communities undergo rapid shifts following modifications in environmental conditions. Although microbial diversity changes may alter soil functioning, the in situ temporal dynamics of microbial diversity is poorly documented. Here, we investigated the response of fungal and bacterial diversity to wheat straw input in a 12-months field experiment and explored whether this response depended on the soil management history (grassland vs. cropland). Seasonal climatic fluctuations had no effect on the diversity of soil communities. Contrastingly fungi and bacteria responded strongly to wheat regardless of the soil history. After straw incorporation, diversity decreased due to the temporary dominance of a subset of copiotrophic populations. While fungi responded as quickly as bacteria, the resilience of fungal diversity lasted much longer, indicating that the relative involvement of each community might change as decomposition progressed. Soil history did not affect the response patterns, but determined the identity of some of the populations stimulated. Most strikingly, the bacteria Burkholderia, Lysobacter and fungi Rhizopus, Fusarium were selectively stimulated. Given the ecological importance of these microbial groups as decomposers and/or plant pathogens, such regulation of the composition of microbial successions by soil history may have important consequences in terms of soil carbon turnover and crop health.