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Background Mycetoma is recognized as a neglected tropical disease and there are still therapeutic challenges, especially in cases recalcitrant to standard therapy or with high risk of dissemination. Subcultures have been used previously to decrease the virulence of human pathogens. Previous reports have demonstrated that after carrying out 200 subcultures of Nocardia brasiliensis, a decrease in virulence was observed. Aim To evaluate the effect of attenuated N. brasiliensis strains on the development of lesions in an established mycetoma infection. Methods Female 8-12-week-old BALB/c mice were injected with N. brasiliensis suspension to establish a mycetoma. Sixty mice were selected and divided into three groups: two of these groups were inoculated in the dorsum with N. brasiliensis subcultured 200 and 400 times, respectively, while the third group served as control. The thickness of each lesion was measured with calipers every week for 12 weeks. Results After 12 weeks, we observed that inoculation of 1 × 105 colony-forming units of attenuated N. brasiliensis strains was able to modify the natural history of the infection, with a decrease in the size of the lesions, particularly with P400, compared with the control group (P Conclusion In this experimental evaluation of an immunomodulatory therapy with attenuated N. brasiliensis strains in a murine model, there was a greater stability in the size of the lesion over time in BALB/c mice inoculated with the P400 strain. This treatment could open the possibility of using the attenuated strain as immunomodulatory therapy in patients recalcitrant to standard therapy, with high risk of dissemination or who develop drug-related adverse effects.

Purpose: To evaluate the effect of autologous serum eyedrops treatment on corneal expression of the MUC5AC in patients with limbal deficiency. Methods: A prospective and comparative interventional case series study of 42 eyes of 21 patients was performed before and 8 weeks after treatment with autologous serum. All patients underwent a complete ophthalmic assessment of the tear film and ocular surface, corneal impression cytology (IC) and MUC5AC detection by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Results: Forty-one of the 42 eyes studied were available for both conventional cytology and MUC5AC analysis prior to and after treatment. Differences between outcomes obtained by impression cytology and MUC5AC detection were found in 9 of 82 samples (11%). We found changes in the corneal expression of MUC5AC after treatment in 19 of 41 eyes (46.3%): 18 of them (94.7%) changed from positive to negative expression, and 1 eye (5.3%) changed from negative to positive MUC5AC expression after autologous serum eyedrops. These changes were related with the corneal involvement prior to treatment (15 of them (78.9%) occurred in patients with slight corneal involvement), and with the improvement in the degree of squamous metaplasia after treatment (P = .001 and P = .003, respectively). Conclusions: The treatment significantly improved tear stability, squamous metaplasia, and subjective patient perception. Autologous serum eyedrops treatment diminished the corneal expression of MUC5AC mainly in patients with slight corneal involvement before treatment.

Salmonella enterica serovar Typhi (S. Typhi) porins, OmpC and OmpF, are potent inducers of the immune response against S. Typhi in mice and humans. Vaccination with porins induces the protection against 500 LD50 of S. Typhi, life-lasting bactericidal antibodies and effector T cell responses in mice, however, the nature of the memory T cell compartment and its contribution to protection remains unknown. In this work, we firstly observed that vaccination with porins induces in situ (skin) CD4+ and CD8+ T cell responses. Analysis of the porin-specific functional responses of skin CD4+ and CD8+ T cells showed IFN-gamma- and IL-17-producing cells in both T cell populations. The memory phenotype of porin-specific T cells indicated the presence of resident and effector memory phenotypes in the skin, and a central memory phenotype in the skin-draining lymph node. In addition, we demonstrated that vaccination with porins via skin reduces the bacterial burden following challenge. Finally, evaluating the role of the circulating T cell memory population in protection, we showed that circulating memory CD4+ and CD8+ T cells are crucial in porin-mediated protection against S. Typhi. Overall, this study highlights the importance of inducing circulating memory T cell responses in order to achieve the optimal protection provided by porins, showing a mechanism that could be sought in the rational development of vaccines.

Nowadays there is not an effective drug for the treatment of infections caused by human adenovirus (HAdV) which supposes a clinical challenge, especially for paediatric and immunosuppressed patients. Here, we describe the design, synthesis and biological evaluation as anti-adenovirus agents of a new library (57 compounds) of diester, monoester and triazole derivatives based on 3-amino-1,2-propanediol skeleton. Seven compounds (17, 20, 26, 34, 44, 60 and 66) were selected based on their high anti-HAdV activity at low micromolar concentration (IC50 from 2.47 to 5.75 µM) and low cytotoxicity (CC50 from 28.70 to >200 µM). In addition, our mechanistic assays revealed that compounds 20 and 44 might be targeting specifically the HAdV DNA replication process, and compound 66 would be targeting HAdV E1A mRNA transcription. For compounds 17, 20, 34 and 60, the mechanism of action seems to be associated with later steps after HAdV DNA replication., This work has been supported by Ministerio de Ciencia, Innovación y Universidades, Plan Estatal 2017-2020 Retos - Proyectos I + D + i (PID2019-104767RB-I00); Ministerio de Economía y Competitividad, Plan Nacional I + D + i 2013-2016, Retos-Proyectos (CTQ2016-78580-C2-2-R); Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by European Development Regional Fund “A way to achieve Europe”, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía.

[Introduction] We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score., [Methods] Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS., [Results] Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15–1.48], P < 0.001), albumin (sHR 0.90 [0.86–0.93], P < 0.001), genetic score (sHR 1.90 [1.57–2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57–4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group., [Discussion] The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.

Hemophilia and other hereditary coagulopathies tend to be associated with a huge negative impact both for individuals who suffer the disease and for their families. In this respect, hemophilia carriers feel the need to make reproductive decisions which will inevitably affect their children, their families and from themselves. Genetic and reproductive counseling is of the essence to alleviate these women's distress. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) allow couples at high-risk of transmitting genetic diseases like hemophilia and other hereditary coagulopathies to prevent the birth of children with the disease. The main difference between prenatal diagnosis and PGD is related to the time at which diagnosis is made. Prenatal diagnosis is done when the woman is pregnant, and both the performance of the technique and its result can affect the course of pregnancy. PGD is a diagnostic procedure in which embryos created in vitro are analyzed for genetic defects before being transferred to the uterus. Performance of both prenatal diagnosis and PGD is subject to a few prerequisites: the establishment of an exact clinical diagnosis, an understanding of the parental genetic alterations that are responsible for the disease and technical feasibility of genetic diagnosis. These couples should be provided with complete, up-to-date and easy-to-understand information.

OBJECTIVE Choroidal thickness (CT) has been evaluated as a marker of systemic inflammation in ankylosing spondylitis (AS). This study evaluates the CT of AS patients before and after 6 months of biological treatment. METHODS This longitudinal multicenter study evaluated CT in 44 AS patients. The correlations between CT and C-reactive protein (CRP) with disease activity indices were calculated. The concordance between CT and CRP was determined. We assessed factors associated with response to treatment. Clinically important improvement was defined as a decrease in Ankylosing Spondylitis Disease Activity Score of 1.1 points or greater. RESULTS Forty-four eyes in patients aged 18 to 65 years were included. Mean CT values were significantly higher at baseline than after 6 months of treatment (baseline: 355.28 ± 80.46 μm; 6 months: 341.26 ± 81.06 μm; p < 0.001). There was a 95% concordance between CT and CRP at baseline and 6 months. Clinically important improvement was associated with lower baseline CT and age as independent factors (odds ratios, 0.97 [95% confidence interval, 0.91-0.93; p = 0.009] and 0.81 [95% confidence interval, 0.7-0.95; p = 0.005]), with baseline CT of less than 374 μm (sensitivity 78%, specificity 78%, area under the curve 0.70, likelihood ratio 3.6). CONCLUSIONS Choroidal thickness decreased significantly after 6 months of biological treatment in all treatment groups. Choroidal thickness and CRP had a 95% concordance. A high CT was associated with a risk of biological treatment failure. Choroidal thickness can be considered a useful biomarker of inflammation and a factor associated with response to treatment in AS.

Hepatitis C virus (HCV) is the main agent responsible for chronic liver disease. Recent advances in anti-HCV treatment strategies have significantly increased the viral clearance rate (>90%). However, sustained antiviral responses vary in different cohorts, and high costs limit the broad use of direct-acting antivirals (DAAs). The goal of this study is to evaluate the inhibitory ability of well characterized (LC-QTOF-MS/MS) aqueous extracts obtained from edible mushrooms (Agaricus bisporus) to diminish HCV viral replication. Our data have demonstrated an in vitro inhibitory effect of A. bisporus extracts on NS3/4A protease and HCV replication. Fractionation by ultra-filtration and sequential liquid–liquid extraction showed that the compounds responsible for the inhibition are water-soluble with low molecular weights (

Author summary Patients who are immunocompromised or have cognitive or physical disabilities are at a higher risk of being affected with infections such as crusted scabies. This is a rare skin hyperinfestation by Sarcoptes scabiei var. hominis. The main characteristic of this dermatosis is a thick crust due to the high concentration of mites; in addition, other manifestations such as papules, excoriations, and burrows may be absent. In severe cases, thick yellow-brown crusts and plaques with deep fissures are present. Diagnosis can be made by observing mites, ova, or feces from skin scrapings. Multiple therapies can be used in patients with this condition. Management with patient isolation is important to prevent institutional outbreaks. This disease can have high mortality, primarily due to sepsis. Awareness of this condition and its serious consequences is important to reduce its mortality and morbidity.

Background and objective Ankylosing spondylitis (AS) is an inflammatory disease, and choroidal thickness (CT) has been proposed and evaluated as a potential marker of systemic inflammation associated with AS and other inflammatory diseases. This study compared CT measurements taken from patients with severe AS disease activity without eye inflammation with those taken from healthy subjects. Methods This cross-sectional, multicenter study compared CT in 44 patients with high AS disease activity, and no history of eye inflammation with CT in 44 matched healthy subjects aged between 18 and 65 years. In the AS group, the correlation between CT and C-reactive protein, human leukocyte antigen (HLA) B27 positivity, disease duration, and disease activity was calculated. Results Mean CT values of patients with AS were significantly higher in the right eye, the left eye, and the thickest choroid eye. The right eye mean CT was 338.3 ± 82.8 μm among patients with AS and 290.5 ± 71.2 μm among healthy subjects (p = 0.005). The left eye mean CT was 339.5 ± 84.7 μm for patients with AS and 298.4 ± 68.9 μm for healthy subjects (P = 0.015). The thickest choroid eye CT was 358.4 ± 82.1 μm among patients with AS and 314.1 ± 65.2 μm among healthy subjects (P = 0.006). We did not find a significant correlation between CT and disease activity, C-reactive protein, human leukocyte antigen B27 positivity, or disease duration. Conclusions Patients with active AS but without a history of eye inflammation had a thicker choroid than healthy subjects. This finding suggests that CT is a marker of systemic inflammation in patients with inflammatory disease, regardless of known eye symptoms.

Background and Aims SARS-CoV-2 is mainly a respiratory virus that has relevant systemic effects. We assessed the impact of the baseline liver function (AST, ALT, and bilirubin) on COVID-19-related outcomes, including on mortality, intensive care unit admission, and non-fatal severe complications. Methods After a systematic review of the relevant studies, odds ratio, mean difference, sensitivity, specificity, and positive and negative likelihood ratios, were calculated for the prediction of relevant COVID-19 outcomes by performing a meta-analysis using fixed and random effects models. A Fagan nomogram was used to assess the clinical utility. Heterogeneity was explored by sensitivity analysis and univariable meta-regression. Results Twenty-six studies were included (22 studies and 5271 patients for AST, 20 studies and 5440 subjects for ALT, and 9 studies and 3542 patients for bilirubin). The outcomes of the studies were: survival (n=8), intensive care unit admission (n=4), and non-fatal severe complications (n=16). AST>ULN (OR 3.10 (95 %CI 2.61-3.68)), ALT>ULN (OR 2.15 (95 %CI 1.43-3.23)), and bilirubin >ULN (OR 2.78 (95 %CI 1.88-4.13)) were associated with an increased prevalence of severe complications, with 78 %, 77 % and 94 % of specificity, respectively. The mean difference between mild and severe COVID-19 was 10.7 U/L (95 %CI 5.8-15.6) for AST, 8 U/L (95 %CI 1.0-15) for ALT, and 0.3 mg/dL (95 %CI 0.16-0.45) for bilirubin. Conclusions Patients showing liver injury had significantly higher risks of developing severe COVID-19 compared to those with normal liver function tests at admission. We should include the assessment of AST, ALT, and total bilirubin routinely in patients affected by SARS-CoV-2 in order to anticipate those at risk of developing COVID-19-related outcomes., This project has been partially funded by the “Consejería de Salud de la Junta de Andalucía” (PI-0075-2014), the “Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).

Spectral-domain optical coherence tomography (SD-OCT) is the most useful tool to measure choroidal thickness (CT). CT may be increased in ocular and systemic diseases. However, there are concerns relating reproducibility and external validity of OCT. The aim of this study was to assess the inter-observer and intra-observer variability of manual OCT measurements.CT was manually measured in the central choroid of 40 eyes from 21 subjects (11 healthy and 10 with ankylosing spondylitis) using RTVue-100 OCT (Optovue Inc., Fremont, CA, EE.UU.). Measurements were performed by 9 independent ophthalmologists from 6 different centers. To assess the inter-observer variability, the intra-class correlation coefficient (ICC) method was calculated. Also, intra-observer variability was assessed in 2 of the ophthalmologists.The mean subfoveal CT was 364.9±85.1μm (range, 170 to 572). The inter-observer ICC was 0.823 (CI 95%, 0.749 to 0.888, p0.001). The intra-observer ICCs were 0.885 (CI 95%, 0.783 to 0.939, p0.001) and 0.925 (CI 95%, 0.859 to 0.960. p0.001).In this study, manual measurements of CT with OCT showed a good concordance. These results suggest that manual OCT is a valid tool for multicenter studies.

Capecitabine is a prodrug used primarily as a chemotherapeutic agent. Despite its good tolerance, it has several adverse effects, including the appearance of eruptive nevi. We present the case of a patient, with a history of EC IV breast adenocarcinoma and superficial extension melanoma, which developed 2 weeks after the start of therapy with capecitabine multiple eruptive palmoplantar pigmented lesions, with diverse benign dermatoscopic patterns. With the increasing incidence of solid tumors, these agents are being more used. It is important that the treating physician knows its adverse effects and apply non-invasive diagnostic tools like dermoscopy to avoid unnecessary biopsies.

[Background] The management of clopidogrel in hyper-responders has not been well described. We report the treatment and dose adjustment individualization with clopidogrel oral solution (COS) in hyper-responder patients with an unruptured intracranial aneurysm treated with a stent., [Methods] A prospective study (2015–2018) in patients receiving clopidogrel prior to endovascular treatment was performed. Platelet reactivity after clopidogrel therapy was evaluated with the VerifyNow PRU test. Initial values ≤80 PRU (P2Y12 reactivity units) were classified as a hyper-response according to prior evidence. Patients were treated with clopidogrel for 7–10 days before stent treatment. Seven days post-procedure the dose of COS was gradually reduced (30 mg–20 mg–10 mg–5 mg) every 5 days to 5 mg (1 mL)/day., [Results] Twenty patients with 24 aneurysms were classified as having a hyper-response to clopidogrel. Mean age was 55.2 years (range 42–64) and 80% were women. Mean baseline PRU value and the percentage of platelet inhibition were 16.4±11.5 PRU and 92.05±7.5%, respectively. The mean time used to decrease the dose of clopidogrel to 5 mg/day was 27±4.3 days. Modified dosing strategies were shown to increase the final PRU values and to decrease the percentage of platelet inhibition (137.42±27.4 and 41.5±14.8%, respectively). Two of the 20 patients with dose adjustment of oral solution of clopidogrel (5 mg/day) in our cohort exhibited a delayed conversion to hypo-response. No patients suffered thromboembolic events related to the dose adjustment of clopidogrel with 5 mg/day during the follow-up., [Conclusion] Reduction of the daily maintenance dose of clopidogrel in hyper-responder patients could provide a similar antiplatelet effect to the standard dose of clopidogrel, allowing a PRU value in the optimal range.

Purpose: The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D. Patients and Methods: Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day −5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays. Results: We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, Pinteraction < 0.001). Conclusions: Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.

Purpose To analyze the biological stability of autologous serum eyedrops after lyophilization. Design Prospective, comparative experimental study. Methods This was a comparative study with serum obtained from 12 healthy volunteers. The concentrations of different epitheliotropic factors (eg, transforming growth factor-β [TGF-β1], epidermal growth factor [EGF], platelet-derived growth factor AB [PDGF-AB], and albumin) were measured in fresh and lyophilized serum. The samples were studied after serum preparation (fresh serum) and immediately after saline solution reconstitution of lyophilized serum (0), 15, and 30 days later. The biological effects of both serum samples were also compared on conjunctival and corneal cell cultures. The pH, osmolarity, and serum density were also determined. Results No significant differences were found in the concentration of growth factors between fresh serum and re-dissolved serum samples after lyophilization. The concentration of growth factors remained stable during 1 month at 4°C in re-dissolved lyophilized form with saline solution. No differences were found related to osmolarity, pH, and density between fresh and lyophilized serum. In addition, no differences were found on the conjunctival and corneal cells proliferation and differentiation in cells cultures between either serum preparation. Conclusions The properties of autologous serum remain after lyophilization. The lyophilized serum can be easily stored without temperature restrictions and easily reconstituted for preparation of eyedrops for standard clinical use.

Myotonic dystrophy type 1 (DM1) is the most common adult muscular dystrophy and presents an autosomal dominant inheritance. A reproductive option for the families affected is preimplantation genetic diagnosis (PGD). One limitation of this option is the nonoptimal response to ovarian stimulation of the women with DM1, although controversial results exist regarding this subject. In this study, we have analyzed the results of the PGD program applied to DM1 at our institution. A total of 35 couples have been included in our program since 2010, and 59 cycles have been performed. The percentage of transfers per cycle was 64.4% and the live birth rate per cycle was 18.6%. Interestingly, statistically significant differences were observed for the clinical results in the group of couples with an affected female versus the group with an affected male or versus a group of couples with different referral reasons. Specifically, both the percentage of mature oocytes out of the total oocytes retrieved and the percentage of fertilization were considerably lower in the group of DM1 females. Our findings would suggest the possibility of achieving less favourable PGD outcomes in women with DM1 in comparison with other pathologies, although the underlying mechanism remains unknown., This work was supported by the Project PI-105-2011, funded by “Fundación Pública Andaluza Progreso y Salud,” within the Regional Ministry of Health of the Autonomous Government of Andalucia.

Background Information on F12 mutation hereditary angioedema (HAE) is still limited, but Spain is now recognized as having one of the highest concentrations of cases in Western Europe. Objective To describe unique features of HAE in Spanish carriers of the F12 mutation and investigate a potential role for angiotensin-converting enzyme (ACE) and aminopeptidase-P polymorphisms in disease expression. Methods This was a prospective observational cohort study of 35 individuals (80% females) from 9 unrelated families carrying the p.Thr309Lys mutation. We analyzed detailed medical records and complement activity (C4, C1q, C1 inhibitor) and screened for mutations in exon 9 of the F12 gene and 2 polymorphisms: XPNPEP2 c-2399A and the ACE insertion/deletion polymorphism. Results The p.Thr309Lys mutation was found in all individuals. Three of the 9 index patients had a clinically negative family history, and 72% of males and 29% of females were asymptomatic. Sixteen females (44% estrogen dependent, 56% estrogen sensitive) were clearly symptomatic. The most common locations of attacks were the abdomen (63%), face (25%), and peripheral structures (6%). Triggers other than hyperestrogenic states included stress and minor trauma or pressure. Short-term treatment with C1-inhibitor concentrate and icatibant and long-term prophylaxis with tranexamic acid were useful. The combination of the I allele and A allele was detected in 17% of patients. Conclusion The polymorphisms analyzed were not a major determinant of disease expression in our population. We recommend searching for F12 mutations in women with edema attacks without associated wheals and with normal C1-inhibitor levels, particularly when they develop symptoms during hyperestrogenic states or are of Western European or African origin.

Background:Choroidal thickness (CT) has been proposed and evaluated as a potential marker of systemic inflammation associated with inflammatory diseases as Ankylosing spondylitis (AS). Patients with active AS have a thicker choroid than healthy subjects, regardless of eye inflammation. The evolution of choroid after treatment is poorly known.Objectives:This study evaluates the CT of patients with severe AS disease activity before and after six months of biological therapy.Methods:This prospective multicenter study evaluates the CT in 44 patients with high AS disease activity, naïve for biological treatment, and no history of eye inflammation before and after six months of biological therapy, aged from 18 to 65 years. The correlations between the CT and C-reactive protein (CRP) with the disease activity indices and scales as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), night pain and Patient Global Assessment (PGA) were calculated at baseline and after six months of biological therapy. The concordance between the CT and CRP was determined. Finally, we assessed potential predictors of response to treatment. Clinically important improvement was defined as a decrease in ASDAS score ≥ 1.1 points.Results:Globally, 44 eyes of 44 patients aged between 18-65 years were included in the study, 12 (27%) women. The biological treatments prescribed were: Adalimumab 13 (29.5%), Certolizumab 9 (20.5%), Secukinumab 10 (20%), Etanercept 8 (18%), Infliximab 3 (6.8%), and Golimumab 1 (2.2%).Mean CT values were significantly higher at baseline than after six months of treatment (baseline 355.28±80.46 µm; 6 months, 341.26±81.06 µm) (pCT decreased both in patients on biological treatment without effect in eye (Secukinumab and Etanecept; p=0.024) and in patients on treatment with effect in eye (other; p=0.005). Also, CRP, BASDAI, night pain and PGA decreased after six months of treatment ((pMultivariable analysis showed that clinically important improvement was associated with higher CT and age as independent factors (OR 0.97, CI95% 0.91-0.93; p=0.009, and OR 0.81, CI95% 0.7-0.95; p=0.005). Clinically important improvement was associated with basal CT >374 µm (sensitivity 78 %, [CI 95% 60-90], specificity 78% [CI 95% 52-92], area under the curve of ROC, 0.70, likelihood ratio 3.6).Conclusion:CT decreased significantly after six months of biological treatment. CT and CPR had a 95% concordance. A high CT is associated with risk of failure to biological treatment. CT can be considered as a useful biomarker of inflammation and predictor of response to treatment in AS.References:[1]Karkucak M, Kalkisim A, Kola M, et al. SAT0408 anti Tnf-α therapy provides beneficial effects on choroidal thickness increase in patients with active ankylosing spondylitis: a possible mechanism of infliximab effectiveness in suppressing uveitis attacks.Ann Rheum Dis. 2016;75:817.Disclosure of Interests:None declared

Supplementary information:Rights and permissions.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Behcet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p. Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P=0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P=0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA., This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (PI16/01373), Fondos FEDER and Plan Andaluz de Investigacion (CTS-0197).

Colorectal cancers are the third most common malignant tumors worldwide and are associated with an increased economic expenditure for healthcare systems due to its high diagnostic, therapeutic, and follow-up costs. Elective surgical resection is the gold standard for CRCs curative treatment, but up to 30% of CRC patients are presenting at emergency setting. Emergency surgery for CRC increases postoperative morbidity, mortality, length of admissions, and costs. Moreover, curative resection rates are lower and recurrences higher after emergency operations. There is substantial heterogeneity in the methodologies and quality of the published economic evaluations of CRC, and emergency surgery may represent an underestimated cost burden to healthcare systems and society worldwide. Novel strategies to separately evaluate, reduce, and improve the quality for the emergent management of colorectal cancer should be explored as a global health target.

To establish the effectiveness of an educational intervention to improve nurses' knowledge on pediatric nasogastric intubation.Multicenter, quasi-experimental, pre- and post-test study using a theoretical educational intervention based on bibliographic evidence and assessment of its effectiveness after 4 months.Delivered questionnaires: 1019. Valid questionnaires: 557 (54.66 %) pre-test and 246 (24.14 %) post-test. Pre- and post-test answers indicated that the implied risk always entailed by the procedure had been perceived by 53.2 % and then increased to 70.7 % (p0.001). Nasogastric (NG) tube size was chosen using tables by 4.3 % of participants, and increased to 24.6 % (p0.001). The length of NG tube to be inserted as measured by the nose-ear-midumbilicus distance (NEMU) method increased from 34.2 % to 81.3 % (p0.001). Confirmation of NG tube placement prior to use increased from 73.1 % to 86.5 % (p0.001). Confirmation of the five rights (patient, drug, dosage, route, and timing) prior to NG tube use increased from 85.6 % to 91 %. In relation to confirmation methods, the perception that auscultation was unsafe improved from 11.7 % to 31.1 % (p0.001), and its use reduced from 95.1 % to 81.6 %. The perception that the measurement of gastric pH was safe increased from 71.3 % to 91.1 % (p0.001), and its use rose from 7.6 % to 54.3 % (p0.001).The educational intervention was effective to increase nurses' knowledge on pediatric nasogastric intubation.Objetivo. Eficacia de una intervención educativa para mejorar el conocimiento de las/os enfermeras/os sobre el sondaje gástrico en pediatría. Métodos. Estudio multicéntrico cuasi experimental pre- y postest mediante intervención educativa teórica basada en la evidencia bibliográfica y la evaluación de su eficacia a los 4 meses. Resultados. Cuestionarios entregados: 1019. Válidos: 557 (54,66 %) pretest, 246 (24,14 %) postest. Las respuestas pre- y postest fueron que el riesgo implícito que conllevaba siempre el procedimiento había sido percibido por el 53,2 % y aumentó al 70,7 % (p0,001). El 4,3 % elegía el tamaño de la sonda gástrica (SG) mediante tablas y se elevó al 24,6 % (p0,001). La longitud de la SG por introducir medida mediante el método nariz-oreja-distancia media xifoides-ombligo (nose-ear-mid-umbilicus; NEMU, por sus siglas en inglés) ascendió del 34,2 % al 81,3 % (p0,001). La comprobación de la ubicación de la SG previa a su uso pasó del 73,1 % al 86,5 % (p0,001). La comprobación de los cinco correctos (paciente, medicamento, dosis, vía y hora) previa a la utilización de la SG aumentó del 85,6 % al 91 %. Como métodos de comprobación, mejoró la percepción de inseguridad de la auscultación del 11,7 % al 31,1 % (p0,001), y disminuyó su uso del 95,1 % al 81,6 %. Creció la percepción de seguridad de la medición del pH gástrico del 71,3 % al 91,1 % (p0,001), y aumentó su uso del 7,6 % al 54,3 % (p0,001). Conclusiones. La intervención educativa resultó eficaz para incrementar el conocimiento de enfermería sobre el sondaje gástrico pediátrico.

CD4+ T cells are major players in the immune response against several diseases; including AIDS, leishmaniasis, tuberculosis, influenza and cancer. Their activation has been successfully achieved by administering antigen coupled with antibodies, against DC-specific receptors in combination with adjuvants. Unfortunately, most of the adjuvants used so far in experimental models are unsuitable for human use. Therefore, human DC-targeted vaccination awaits the description of potent, yet nontoxic adjuvants. The nontoxic cholera B subunit (CTB) can be safely used in humans and it has the potential to activate CD4+ T cell responses. However, it remains unclear whether CTB can promote DC activation and can act as an adjuvant for DC-targeted antigens. Here, we evaluated the CTB's capacity to activate DCs and CD4+ T cell responses, and to generate long-lasting protective immunity. Intradermal (i.d.) administration of CTB promoted late and prolonged activation and accumulation of skin and lymphoid-resident DCs. When CTB was co-administered with anti-DEC205-OVA, it promoted CD4+ T cell expansion, differentiation, and infiltration to peripheral nonlymphoid tissues, i.e., the skin, lungs and intestine. Indeed, CTB promoted a polyfunctional CD4+ T cell response, including the priming of Th1 and Th17 cells, as well as resident memory T (RM) cell differentiation in peripheral nonlymphoid tissues. It is worth noting that CTB together with a DC-targeted antigen promoted local and systemic protection against experimental melanoma and murine rotavirus. We conclude that CTB administered i.d. can be used as an adjuvant to DC-targeted antigens for the induction of broad CD4+ T cell responses as well as for promoting long-lasting protective immunity.

Sporotrichosis is a chronic subcutaneous mycosis caused by the Sporothrix schenckii species complex and it is considered an emerging opportunistic infection in countries with tropical and subtropical climates. The host’s immune response has a main role in the development of this disease. However, it is unknown the features of the memory cellular immune response that could protect against the infection. Our results show that i.d. immunization in the ears of mice with inactivated S. schenckii conidia (iC) combined with the cholera toxin (CT) induces a cellular immune response mediated by circulating memory CD4+ T cells, which mainly produce interleukin 17 (IL-17). These cells mediate a strong delayed-type hypersensitivity (DTH) reaction. Systemic and local protection against S. schenckii was mediated by circulating CD4+ T cells. In contrast, the infection induces a potent immune response in the skin mediated by CD4+ T cells, which have an effector phenotype that preferentially produce interferon gamma (IFN-γ) and mediate a transitory DTH reaction. Our findings prove the potential value of the CT as a potent skin adjuvant when combined with fungal antigens, and they also have important implications for our better understanding of the differences between the memory immune response induced by the skin immunization and those induced by the infection; this knowledge enhances our understanding of how a protective immune response against a S. schenckii infection is developed.

Calciphylaxis, also known as calcific uremic arteriolopathy and uremic small artery disease with medial wall calcification and intimal hyperplasia, is a multifactorial cutaneous vascular disease characterized by chronic, painful, non-healing wounds that occur frequently in patients with chronic kidney disease, predominantly in those with end-stage renal disease. The pathogenesis remains unclear, and the development of calciphylaxis lesions depends on medial calcification, intimal fibrosis of arterioles and thrombotic occlusion. Despite an increase in reports of calciphylaxis in the literature and clinical recognition of demographic characteristics and risk factors associated with calciphylaxis, it remains a poorly understood disease with high morbidity and mortality. In this review, we analyze and summarize the clinical manifestations, pathogenesis and pathophysiology, histopathology, differential diagnosis, diagnostic workup and treatment modalities for calciphylaxis. Because of the lack of consensus regarding the optimal approach to and treatment of this disorder, a high degree of clinical suspicion, early diagnosis, and multimodal and multidisciplinary treatment in collaboration with dermatology, nephrology, wound care, nutrition and pain management specialties may improve survival in patients with calciphylaxis.

Background Eosinophilic esophagitis (EoE) is an antigen-driven disease mediated by an abnormal immune Th2 response. Objective The objective of this article is to investigate genes associated with regulating immune responses leading to disease susceptibility. Methods Twenty-seven tag single nucleotide polymorphisms (tSNPs) selected in five candidate genes ( TLR3, TLR4, FOXP3, FLG and TSLP) were genotyped in 218 EoE patients and 376 controls. Skin prick tests were carried out in EoE patients with a panel of 17 aeroallergens and 22 plant- and animal-derived foods. Results Five tSNPs located in the TSLP locus and one tSNP located in the TLR3 locus were significantly associated with EoE. The interactions between TLR3 and TSLP loci were analyzed. TLR3+/TSLP– and TLR3–/TSLP+ individuals showed a significantly reduced susceptibility to EoE compared to TLR3–/TSLP– individuals (OR = 0.66, p = 0.036 and OR = 0.23, p = 0.00014, respectively). Likewise, TLR3+/TSLP+ individuals showed the most decreased susceptibility of developing EoE (OR = 0.16, p = 0.0001). However, the interaction gain attributed to the combination of both genes was negative (IG = –4.52%), which indicated redundancy or independent effect. Additionally, TLR3 locus was found to be associated with aeroallergen and food sensitization in EoE patients (OR = 9.67, pc = 0.025 and OR = 0.53, pc = 0.048, respectively). Conclusion TLR3 constitutes a novel genetic susceptibility locus for developing EoE, and the effects would be independent of TSLP.

The expression of activation-induced cytidine deaminase, B-aggressive lymphoma, cyclin D1 and serine/threonine kinase 15 genes, among others, is increased in B cells from patients with chronic hepatitis C virus (HCV) infection. It is unknown whether the level of expression of these genes in B cells is increased in patients with hepatitis C who have achieved a sustained virological response (SVR) but who have persistent, detectable HCV RNA, so-called occult infection. Eighty-three patients who achieved and SVR, 27 with detectable HCV and 56 without detectable HCV RNA, 28 chronic hepatitis C patients and 32 healthy controls were studied. RNA was extracted from B cells, and gene expression levels were measured by RT-PCR. Patients with chronic HCV and those who achieved an SVR (with and without persistent low-level HCV RNA) showed a statistically significant higher expression compared to healthy controls, of activation-induced cytidine deaminase (P = 0.004, P < 0.001 and P = 0.002, respectively), B-aggressive lymphoma (P < 0.001, P = 0.001 and P = 0.006) and cyclin D1 (P = 0.026, P = 0.001; P = 0.038). For activation-induced cytidine deaminase patients with an SVR and 'occult infection' had a statistically significantly higher expression level than patients with and SVR without 'occult infection' (P = 0.014). The higher expression levels found for activation-induced cytidine deaminase, together with other genes indicates that these B lymphomagenesis-related genes are upregulated following HCV therapy and this is more marked when HCV can be detected in PBMCs.

Rotaviruses continue being the most important pathogens responsible of diarrhea in young children worldwide. Seminested reverse transcription polymerase chain reaction (RT-PCR) is used to determine rotavirus genotype; however, this technique employs multistep procedures. The real-time RT-PCR is a fast and reliable tool that can be used as rotavirus genotyping tool, especially in rotavirus outbreaks. In this study, we tested a real-time RT-PCR to identify rotavirus genotype using a panel of 252 samples from patients with diarrheal disease caused by G9P[4] and G12P[8] genotypes, which were identified as emerging rotaviruses in 2 outbreaks in Chiapas, Mexico. Our results show that the real-time RT-PCR assay detected these rotaviruses, and it allowed us to identify mixed genotype infections, G/P combinations, and the viral abundance in some samples in which the seminested assay could not identify them. Therefore, the real-time RT-PCR is a molecular tool that can be great support during rotavirus outbreaks.

espanolfrecuencia y morbimortalidad de las infecciones fungicas ha hecho necesario disponer de nuevos antifungicos. En la ultima decada el consumo de antifungicos se ha incrementado en un 12 % al ano. El aumento de resistencias frente a una gran cantidad de antimicrobianos ha llevado a una creciente demanda de nuevos agentes antifungicos de aplicacion topica u oral para profilaxis y tratamiento. Material y metodos: Se ha realizado un estudio descriptivo y observacional para conocer la sensibilidad in vitro de 38 especies de Candida spp. El metodo utilizado fue Kirby-Bauer o metodo de difusion en agar Sabouraud®. Este metodo ha permitido caracterizar los niveles de resistencia de la terbinafina y otros antifungicos afines a la practica clinica podologica. Los antifungicos estudiados fueron: terbinafina, ketoconazol, fluconazol, itraconazol, nistatina y ciclopirox-olamina. Resultados: Todas las cepas fueron sensibles a ciclopirox-olamina y a clotrimazol. El 2.6 % de las especies de C. albicans fueron resistentes a ketoconazol y un 2.6 % en C. glabrata. El 5.3 % de los casos de C. albicans fueron resistentes a fluconazol y el 10.5 % en C. glabrata, C. guillermondii y C. parapsilosis. En el grupo de estudio de la terbinafina, el 65.8 % de C. albicans fueron resistentes a este antifungico, un 10.5 % de todas las C. tropicalis y un 13.2 % para el resto de especies. En resumen, existe un porcentaje amplio de resistencia de formas levaduriformes a la terbinafina. Conclusiones: Es interesante analizar la cantidad de cepas estudiadas resistentes a los azoles, especialmente a fluconazol y terbinafina. Curiosamente, una gran mayoria de las especies son resistentes a terbinafina, a pesar de ser el antifungico que mas es prescrito en onicomicosis, como se evidencia en la mayor parte de los estudios realizados. EnglishIntroduction: Yeast infections have become very important in recent decades. An increase in the frequency and morbidity and mortality of fungal infections has made it necessary to have new antifungals. In the last decade, the consumption of antifungals has increased by 12 % per year. The increase in resistance to a large number of antimicrobials has led to an increasing demand for new antifungal agents for topical or oral application for prophylaxis and treatment. Material and methods: A descriptive and observational study was carried out to know the in vitro sensitivity of 38 species of Candida spp. The method used was Kirby-Bauer or Sabouraud® agar diffusion method. This method has allowed to characterise the resistance levels of terbinafine and other antifungals related to clinical podiatric practice. The antifungals studied were: terbinafine, ketoconazole, fluconazole, itraconazole, nystatin and cyclopirox-olamine. Results: All strains were sensitive to ciclopirox-olamine and clotrimazole. 2.6 % of C. albicans species were resistant to ketoconazole and 2.6 % in C. glabrata. 5.3 % of the cases of C. albicans were resistant to fluconazole and 10.5 % in C. glabrata, C. guillermondii and C. parapsilosis. In the study group of terbinafine, 65.8 % of C. albicans were resistant to this antifungal, 10.5 % of all C. tropicalis and 13.2 % for the rest of species. In summary, there is a broad percentage of resistance of yeast forms to terbinafine. Conclusions: It is interesting to analyse the amount of strains studied resistant to azoles, especially fluconazole and terbinafine. Interestingly, a large majority of the species are resistant to terbinafine, despite being the antifungal agent that is most prescribed in onychomycosis, as evidenced in most of the studies conducted.

The purpose of this study is to assess the stability of the growth factors (GF) in autologous serum eyedrops under different storage conditions.The concentration of epidermal growth factor (EGF), transforming growth factor-β (TGF-β1), platelet-derived growth factor AB (PDGF-AB), and albumin was measured in fresh and defrosted samples of autologous serum under different storage conditions. The fresh and defrosted samples were cooled at 4 °C, and they were studied immediately after preparation, or after defrosting, and after 1, 2, 3, and 4 weeks. The concentration of GF was also assessed after 1, 3, 6, and 9 months at -20 °C. We also investigated how the different storage conditions influence the biological effects of autologous serum on conjunctival and corneal cell cultures.The concentration of EGF, TGF-β1, PDGF-AB, and albumin remained stable over the 4 weeks at 4 °C, both in fresh and in defrosted samples. Likewise, no statistically significant differences were found between the GF concentration in fresh samples and after 1, 3, 6, and 9 months of freezing at -20 °C. Moreover, no differences were found on the cell proliferation and differentiation between cultured cells with fresh or defrosted samples after 4 weeks at 4 °C or after 1, 3, 6, or 9 months at -20 °C.Long-term storage of autologous serum eyedrops at -20 °C does not affect the concentration of GF, simplifies clinical logistics, and reduces the frequency of blood extractions from the patients.