A Methodology Based on Machine Learning and Soft Computing to Design More Sustainable Agriculture Systems.

Advances in new technologies are allowing any field of real life to benefit from using these ones. Among of them, we can highlight the IoT ecosystem making available large amounts of information, cloud computing allowing large computational capacities, and Machine Learning techniques together with the Soft Computing framework to incorporate intelligence. They constitute a powerful set of tools that allow us to define Decision Support Systems that improve decisions in a wide range of real-life problems. In this paper, we focus on the agricultural sector and the issue of sustainability. We propose a methodology that, starting from times series data provided by the IoT ecosystem, a preprocessing and modelling of the data based on machine learning techniques is carried out within the framework of Soft Computing. The obtained model will be able to carry out inferences in a given prediction horizon that allow the development of Decision Support Systems that can help the farmer. By way of illustration, the proposed methodology is applied to the specific problem of early frost prediction. With some specific scenarios validated by expert farmers in an agricultural cooperative, the benefits of the methodology are illustrated. The evaluation and validation show the effectiveness of the proposal.

Assessment of single-nucleotide variant discovery protocols in RNA-seq data from human cells exposed to mycotoxins.

Food and feed contamination by nonlegislated mycotoxins beauvericin (BEA) and enniatin B (ENB) is a worldwide health concern in the present. The principal objective of this work is to assess some of the existing protocols to discover the single nucleotide variants (SNVs) in transcriptomic data obtained by RNA-seq from Jurkat cells in vitro samples individually exposed to BEA and ENB at three concentration levels (1.5, 3 and 5 µM). Moreover, previous transcriptomic results will be compared with new findings obtained using a different protocol. SNVs rs201003509 in BEA exposed cells and the rs36045790 in ENB were found in the differentially expressed genes in all doses compared to controls by means of the Genome Analysis Toolkit (GATK) Best Practices workflow. SNV-RNA-seq complementary pipeline did not show any SNV. Concerning gene expression, discrepant results were found for 1.5 µM BEA exposed cells compared with previous findings. However, 354 overlapped differentially expressed genes (DEGs) were identified in the three ENB concentrations used, with 147 matches with respect to the 245 DEGs found in the previous results. In conclusion, the two discovery SNVs protocols based on variant calling from RNA-seq used in this work displayed very different results and there were SNVs found manually not identified by any pipeline. Additionally, the new gene expression analysis reported comparable but non identical DEGs to the previous transcriptomic results obtained from these RNA-seq data.

Polidocanol foam sclerotherapy in the treatment of hemorrhoidal disease in patients with bleeding disorders: a multicenter, prospective, cohort study.

BACKGROUND: The management of hemorrhoidal disease (HD) in patients with bleeding disorders (BD) is challenging. Polidocanol foam sclerotherapy (PFS) is associated with a low rate of bleeding complications. The aim of this study was to compare the efficacy and safety of PFS in the treatment of HD in patients with and without BD. METHODS: This prospective, multicenter, cohort study enrolled patients with (group B) and without (group A) BD, with symptomatic internal HD grades I-III over an 18-month period. All patients were treated with PFS. Patients with congenital BD did not undergo prior replacement therapy and those with acquired BD due to antithrombotic drugs, did not discontinue therapy. Efficacy outcomes included therapeutic success and HD recurrence during a 1-year follow-up period. To evaluate safety the complications related to PFS were recorded. RESULTS: We included 228 patients (group A: 155, group B: 73; male/female: 114/114; mean age: 59.4 ± 15.9 years). The baseline hemorrhoidal disease bleeding grade (p < 0.001) and Sodergren hemorrhoidal symptom severity score (p = 0.019) were higher for group B. The overall therapeutic success rate was 93.4% with an average number of sessions of 1.51 ± 0.74, significantly higher for group B (1.68 ± 0.86 vs 1.43 ± 0.65, p = 0.013). Complications occurred in 11.4% of the patients, with bleeding reported in 4.8%. The majority of complications were mild (96.2%). No significant differences between the two groups were observed for therapeutic success, recurrence, or complication rate. CONCLUSIONS: Patients with BD may have more symptomatic HD at baseline. Even so, PSF showed similar effectiveness and safety in patients with BD compared to patients without BD.

Localization of interleukin-6 signaling complex in epithelialized apical lesions of endodontic origin.

OBJECTIVES: We aimed to determine the immunolocalization patterns of the interleukin (IL)-6 signaling complex in epithelialized and non-epithelialized apical lesions of endodontic origin (ALEOs). MATERIALS AND METHODS: Epithelialized (n = 8) and non-epithelialized (n = 7) ALEOs were obtained from teeth with indication of extraction in patients with clinical diagnosis of apical periodontitis. All tissues were subjected to routine processing for histopathologic examination and primary antibodies for IL-6, IL-6 receptor (R), and glycoprotein (gp)-130 were used for immunohistochemistry and double immunofluorescence co-localization. RESULTS: IL-6, IL-6R, and gp-130 were immunolocalized in endothelial cells and mononuclear leukocytes in a diffuse pattern within the connective tissue of epithelialized and non-epithelialized ALEOs. In the epithelialized lesions, two different patterns were identified: IL-6 signaling complex was localized within the proliferating epithelium in a diffuse intracellular pattern and in a cell membrane localization pattern within the mature epithelial lining, showing a decreased intensity towards the surface layers. CONCLUSIONS: IL-6, IL-6R, and gp-130 localized to mononuclear inflammatory cells, vascular endothelial cells, and immature proliferating epithelia in a diffuse pattern and in mature lining epithelia in a localized cell membrane pattern, supporting a role for epithelial proliferation during cyst formation. Additional cell membrane co-localization of IL-6 receptor complex suggests classic signaling involvement in addition to trans-signaling.

Impact of Nutritional Stress on Honeybee Gut Microbiota, Immunity, and Nosema ceranae Infection.

Honeybees are important pollinators, having an essential role in the ecology of natural and agricultural environments. Honeybee colony losses episodes reported worldwide and have been associated with different pests and pathogens, pesticide exposure, and nutritional stress. This nutritional stress is related to the increase in monoculture areas which leads to a reduction of pollen availability and diversity. In this study, we examined whether nutritional stress affects honeybee gut microbiota, bee immunity, and infection by Nosema ceranae, under laboratory conditions. Consumption of Eucalyptus grandis pollen was used as a nutritionally poor-quality diet to study nutritional stress, in contraposition to the consumption of polyfloral pollen. Honeybees feed with Eucalyptus grandis pollen showed a lower abundance of Lactobacillus mellifer and Lactobacillus apis (Firm-4 and Firm-5, respectively) and Bifidobacterium spp. and a higher abundance of Bartonella apis, than honeybees fed with polyfloral pollen. Besides the impact of nutritional stress on honeybee microbiota, it also decreased the expression levels of vitellogenin and genes associated to immunity (glucose oxidase, hymenoptaecin and lysozyme). Finally, Eucalyptus grandis pollen favored the multiplication of Nosema ceranae. These results show that nutritional stress impacts the honeybee gut microbiota, having consequences on honeybee immunity and pathogen development. Those results may be useful to understand the influence of modern agriculture on honeybee health.

Epigenetic regulation of TLR2-mediated periapical inflammation.

AIM: To determine the methylation pattern of TLR2 gene promoter and its association with the transcriptional regulation of periapical inflammatory and angiogenic responses in symptomatic and asymptomatic forms of apical periodontitis. METHODOLOGY: In this cross-sectional study, apical lesions were obtained from volunteers with asymptomatic apical periodontitis (AAP) (n = 17) and symptomatic apical periodontitis (SAP) (n = 17) scheduled for tooth extraction, and both total RNA and DNA were extracted. DNA was bisulfite-treated, a region of CpG island within the TLR2 gene was amplified by qPCR and the products were sequenced. Additionally, the mRNA expression of TLR2, TLR4, IL-6, IL-12, TNFalpha, IL-23, IL-10, TGFbeta, VEGFA and CDH5 was analysed by qPCR. The data were analysed with chi-square tests, Mann-Whitney or unpaired t-tests, and Spearman´s correlation; variable adjustments were performed using multiple linear regression (P < 0.05). RESULTS: TLR2 depicted a hypomethylated DNA profile at the CpG island in SAP when compared with AAP, along with upregulated expression of TLR2, with pro-inflammatory cytokines IL-6 and IL-23, and the angiogenesis marker CDH5 (P < 0.05). TLR2 methylation percentage negatively correlated with mRNA levels of IL-23 and CDH5 in apical periodontitis. Lower methylation frequencies of single CpG dinucleotides -8 and -10 localized in close proximity to nuclear factor κB (NFκB) binding within the TLR2 promoter were identified in SAP versus AAP (P < 0.05). Finally, unmethylated -10 and -8 single sites demonstrated up-regulation of IL-23, IL-10 and CDH5 transcripts compared to their methylated counterparts (P < 0.05). CONCLUSIONS: TLR2 gene promoter hypomethylation was linked to transcriptional activity of pro-inflammatory cytokines and angiogenic markers in exacerbated periapical inflammation. Moreover, unmethylated single sites in close proximity to NFκB binding were involved in active transcription of IL-23, IL-10 and CDH5.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome.

STUDY QUESTION: Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. WHAT IS KNOWN ALREADY: PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown. STUDY DESIGN, SIZE, DURATION: Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 µg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women. LIMITATIONS, REASONS FOR CAUTION: While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.

Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma.

BACKGROUND: Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. OBJECTIVES: To investigate the role of the mitochondrial proteins, ß-subunit of the H+ -ATP synthase (ß-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. MATERIALS AND METHODS: The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. RESULTS: The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival. CONCLUSIONS: A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.

Comparison of epidemiological, clinical and microbiological characteristics of bloodstream infection in children with solid tumours and haematological malignancies.

Bloodstream infection (BSI) is a serious complication in immunocompromised hosts. This study compares epidemiological, clinical and microbiological characteristics of BSI among children with haematological malignancies (HM) and solid tumours (ST). The study was conducted from October 2012 through to November 2015 at a referral hospital for cancer care and included the first BSI episode detected in 210 patients aged 18 years or less. BSI cases were prospectively detected by daily laboratory-based surveillance. The Centers for Disease Control and Prevention definitions for primary or secondary BSI were used. A higher proportion of use of corticosteroids (P = 0.02), chemotherapy (P = 0.01) and antibiotics (P = 0.05) before the BSI diagnosis; as well as of neutropenia (P < 0.001) and mucositis (P < 0.001) at the time of BSI diagnosis was observed in patients with HM than with ST. Previous surgical procedures (P = 0.03), mechanical ventilation (P = 0.01) and bed confinement (P < 0.001) were more frequent among children with ST. The frequency of use of temporary (P = 0.01) and implanted vascular lines (P < 0.01) was significantly higher in children with ST than with HM while the tunnelled line (P = 0.01) use was more frequent in children with HM as compared to ST. Most (n = 181) BSI cases were primary BSI. BSI associated with a tunnelled catheter was more frequent in children with HM (P < 0.01), whereas BSI associated with an implanted (P < 0.01) or temporary central line (P < 0.02) was more common in patients with ST. BSI associated with mucosal barrier injury was more frequent (P = 0.01) in children with HM. Indication for intensive care was more frequent in children (P = 0.05) with ST. Mortality ratio was similar in children with ST and HM, and length of hospital stay after BSI was higher in patients with HM than with ST (median of 19 vs. 13 days; P = 0.02). Infection caused by Gram-negative bacteria (P = 0.04) and polymicrobial infections (P = 0.05) due to Gram-positive cocci plus fungus was more common in patients with HM. These findings suggest that the characteristics of BSI acquisition and mortality can be cancer-specific.

mTOR pathway activation in large vessel vasculitis.

BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry.

BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Very low level viraemia and risk of virological failure in treated HIV-1-infected patients.

OBJECTIVES: The aim of the study was to investigate whether very low level viraemia (VLLV) (20-50 HIV-1 RNA copies/mL) was associated with increased risk of virological failure (VF) as compared with persistent full suppression (< 20 copies/mL). METHODS: From the VACH Cohort database, we selected those patients who started antiretroviral therapy (ART) after January 1997 and who achieved effective viral suppression [two consecutive viral loads (VLs) < 50 copies/mL] followed by full suppression (at least one VL <20 copies/mL). We carried out survival analyses to investigate whether the occurrence of VLLV rather than maintaining full suppression at < 20 copies/mL was associated with virological failure (two consecutive VLs > 200 copies/mL or one VL > 200 copies/mL followed by a change of ART regimen, administrative censoring or loss to follow-up), adjusted for nadir CD4 cell count, sex, age, ethnicity, transmission group, type of ART and time on effective suppression at < 50 copies/mL. RESULTS: Of 21 480 patients who started ART, 13 674 (63.7%) achieved effective suppression at < 50 copies/mL, of whom 4289 (31.4%) further achieved full suppression at < 20 copies/mL after May 2009. A total of 2623 patients (61.1%) remained fully suppressed thereafter, while 1666 had one or more episodes of VL detection > 20 copies/mL (excluding virological failure). A total of 824 patients had VLLV after suppression at < 20 copies/mL. VLLV was not associated with virological failure as compared with persistent full suppression [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.44-1.00], independently of the number of blips recorded (from one to 18). CONCLUSIONS: In our population of HIV-infected patients on ART who achieved viral suppression at < 20 copies/mL, the risk of virological failure was no different for patients who remained fully suppressed compared with those who experienced subsequent episodes of VLLV.

Waterborne disease outbreak detection: an integrated approach using health administrative databases.

Hundreds of waterborne disease outbreaks (WBDO) of acute gastroenteritis (AGI) due to contaminated tap water are reported in developed countries each year. Such outbreaks are probably under-detected. The aim of our study was to develop an integrated approach to detect and study clusters of AGI in geographical areas with homogeneous exposure to drinking water. Data for the number of AGI cases are available at the municipality level while exposure to tap water depends on drinking water networks (DWN). These two geographical units do not systematically overlap. This study proposed to develop an algorithm which would match the most relevant grouping of municipalities with a specific DWN, in order that tap water exposure can be taken into account when investigating future disease outbreaks. A space-time detection method was applied to the grouping of municipalities. Seven hundred and fourteen new geographical areas (groupings of municipalities) were obtained compared with the 1,310 municipalities and the 1,706 DWN. Eleven potential WBDO were identified in these groupings of municipalities. For ten of them, additional environmental investigations identified at least one event that could have caused microbiological contamination of DWN in the days previous to the occurrence of a reported WBDO.

Spontaneous convexity subarachnoid haemorrhage: Clinical series of 3 patients with associated cerebral amyloid angiopathy. / Hemorragia subaracnoidea espontánea de la convexidad cerebral: una serie clínica de 3 pacientes asociada con angiopatía amiloide cerebral.

INTRODUCTION: Convexity subarachnoid haemorrhage (cSAH) is a rare type of spontaneous, non-traumatic, and nonaneurysmal SAH characterised by blood collections in one or more cortical sulci in the convexity of the brain; the aetiology varies. We report a clinical case series of 3 patients with cSAH associated with probable cerebral amyloid angiopathy (CAA) who presented with focal sensory seizures and responded well to corticosteroid treatment. PATIENTS: Case 1 was a 67-year-old man reporting right-sided paroxysmal sensory episodes with Jacksonian progression, cheiro-oral symptoms, and motor dysphasia. Case 2 was a 79-year-old man reporting left-sided paroxysmal episodes with cheiro-oral signs and dysarthria. Case 3 was a 71-year-old woman also reporting recurrent left cheiro-oral signs and dysarthria. None of the patients had headache or clinical dementia. Aneurysms were ruled out using MR angiography. RESULTS: Brain CT scan detected an isolated hyperintensity in a sulcus of the frontal convexity; brain gradient echo T2-weighted MRI sequences showed meningeal haemosiderosis and microbleeds. However, no atrophy was identified in medial temporal lobes including the hippocampal formation. All patients had low levels of beta-amyloid in CSF, low values on the Hulstaert index and high levels of phosphorylated tau protein. Patients were initially treated with prednisone and levetiracetam, but symptoms recurred in 2 patients after prednisone was discontinued. CONCLUSIONS: We present a series of 3 patients with cSAH associated with CAA, characterised by a stereotypical syndrome responding well to corticoid treatment; there were no cases of headache or clinical dementia.

[Compliance with recommendations in secondary prevention of stroke in primary care]. / Seguimiento de las recomendaciones en prevención secundaria cerebrovascular en atención primaria.

OBJECTIVE: Knowing compliance with secondary prevention recommendations of stroke in primary care and to identify factors associated with compliance. DESIGN: Multi-centre cross-sectional. SETTING: Health primary care centres in a metropolitan area (944,280 inhabitants). PARTICIPANTS: Patients aged 18years and over with ischemic brain disease diagnosis prior to 6months before the study. MAIN MEASUREMENTS: Clinical history records of demographic variables, risk factors and cardiovascular comorbidity, drugs, blood pressure values (BP), LDL-cholesterol and medical visits by doctor and nurses after the event. Good adherence was considered when BP <140/90 mmHg, LDL-cholesterol <100 mg/dL, smoking abstention and preventive drugs prescription (anti-platelet/anticoagulants, statins and angiotensin-converting-enzyme inhibitors/angiotensin-receptor-antagonists or diuretics) during the last 18months. RESULTS: A total of 21,976 patients, mean age 73.12 years (SD: 12.13), 48% women, 72.7% with stroke. Co-morbidity: hypertension 70.8%, dyslipidemia 55.1%, DM 30.9%, atrial fibrillation 14.1%, ischemic heart disease 13.5%, chronic renal failure 12.5%, heart failure 8.8%, peripheral arterial disease 6.2%, dementia 7.8%. No record was found for smoking in 3.7%, for BP in 3.5% and for LDL in 6.5%. Optimal control: abstention smoking in 3.7%, BP <140/90 in 65.7% and LDL <100 mg/dL in 41.0%. TREATMENT: 86.2% anti-platelet/anticoagulants, 61.3% statins and 61.8% angiotensin-converting-enzyme inhibitors, angiotensin-receptor-antagonists or diuretic. Registration and risk factors control was higher in 66-79years aged and lower in 18-40years aged. CONCLUSIONS: The implementation of clinical guidelines recommendations for stroke prevention in primary care must be improved, especially among younger population. Organizational changes and more active involvement by professionals and strategies against therapeutic inertia must be taken.

Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report and literature review.

Osteoporosis remains a chronic and common disease associated with high medical costs. Pharmacological therapy has shown to be a good strategy to significantly reduce fracture risk. While literary evidence for bone protection in the short and medium term is strongly in it's favor, there are concerns about long-term treatment with antiresorptive drugs. Increased risk of atypical femoral fractures (AFFs) have been demonstrated in several studies following the long-term use of bisphosphonate. Denosumab offers an alternative approach to the treatment of osteoporosis, however, it is also an antiresorptive drug. We present a case of simultaneous bilateral atypical femoral fractures in a patient with denosumab treatment. These findings highlight the need to reevaluate the optimal antiresorptive therapy duration, as well as the safety of transition from bisphosphonates to denosumab and the need for continued monitoring in the prevention of AFFs.

IgE Reactivity, Work Related Allergic Symptoms, Asthma Severity, and Quality of Life in Bakers with Occupational Asthma.

In Germany, bakers with occupational asthma willing to stay in their job are included in an interdisciplinary program of the Social Accident Insurance for Foodstuff and Catering Industry (BGN). The primary aim is to reduce flour dust exposure, and to provide adequate medical treatment. Our aim was to evaluate the program's effect on the disease's course using routinely collected data. Forty three bakers with allergic occupational asthma and with the available baseline level of IgE (f4, f5) were investigated. Changes in IgE related to wheat and rye flour exposure were measured by ImmunoCAP test during follow-up visits. A questionnaire on work-related allergic complaints (WRAC), the Asthma Control Test (ACT), a 10-point scale of asthma severity grade, and quality of life instruments (EQ-5D-5L, Mini-AQLQ) were administered. We found an improvement of asthma severity in 88.4 % of the bakers. WRAC were reported by 65 %; 77 % had good asthma control (ACT ≥ 20); and 81 % had regular asthma medication. A relevant reduction of ≥2 CAP-classes for both allergens was seen in 12 % of the subjects. Health-related and asthma-specific quality of life was high. We conclude that satisfactory asthma control is probably the result of adequate medical management. In a subgroup of bakers with decreased specific IgE, it may also be attributed to reduced allergen exposure.

Content of Asthmagen Natural Rubber Latex Allergens in Commercial Disposable Gloves.

The use of natural rubber latex (NRL) gloves in many occupations may lead to latex sensitization, allergic asthma, and skin reactions. Due to their good properties and environmental safety NRL gloves are still being used in the healthcare setting, but also in the food industry, by hairdressers, cleaners, etc. The aim of our study was to assess the protein and NRL allergen content in commercial gloves by different methods, including a new assay. Twenty commercially available NRL gloves were analyzed. Protein extraction was performed according to the international standard ASTM D-5712. Total protein content was measured with a modified Lowry method, NRL content with the CAP Inhibition Assay, the Beezhold ELISA Inhibition Assay, and an innovative ELISA with IgY-antibodies extracted from eggs of NRL-immunized hens (IgY Inhibition Assay). We found a high protein content in a range of 215.0-1304.7 µg/g in 8 out of the 20 NRL gloves. Seven of the 20 gloves were powdered, four of them with a high protein content. In gloves with high protein content, the immunological tests detected congruently high levels of NRL allergen. We conclude that a high percentage of commercially available NRL gloves still represent a risk for NRL allergy, including asthma. The modified Lowry Method allows to infer on the latex allergen content.

[Multidose treatment of methotrexate in cornual ectopic pregnancy]. / Protocolo de tratamiento multidosis con metotrexato a pacientes con embarazo-ectópico cornual.

BACKROUND: Ectopic pregnancy represents a common entity when the differential diagnosis of first trimester pathologies is performed. Extratubal location, nonetheless, is an in unfrequent situation that delays and difficults the diagnoses. CASE REPORT: 41-year-old women who goes to clinic for a pregnancy test, which proved positive done. During normal ultrasonographic we observed attached with endometrial 8 mm thick, without gestational sac inside, no free liquid in the bottom of the pouch of Douglas. In the left cornual region had a suggestive image of ectopic pregnancy, of 2.8 cm, with embryo without cardiac activity, tested with Doppler color, according to 6 weeks of amenorrhea was observed. The level of ß-HCG was 17,656 mU/mL, which confirmed the diagnosis of corneal ectopic pregnancy. Multidose protocol of methotrexate and folinic acid was prescribed at a dose of 50 mg on days 1, 3, 5 and 7, and 5 mg in the days 2, 4, 6 and 8, respectively. After 14 days of treatment a new ß-HCG study control was made, which results was 2,519 mU/mL. From that time we take a weekly control studies of the ß-HCG until was negative (six months later). The multidose protocol of methotrexate and folinic acid is an effective treatment in patients with cornual ectopic pregnancy.