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Background Caprine tuberculosis (TB) is a zoonosis caused by members of the Mycobacterium tuberculosis complex (MTBC). Caprine TB control and eradication programmes have traditionally been based on intradermal tuberculin tests and slaughterhouse surveillance. However, this strategy has limitations in terms of sensitivity and specificity. Different factors may affect the performance of the TB diagnostic tests used in goats and, subsequently, the detection of TB-infected animals. In the present study, the effect of two of the factors that may affect the performance of the techniques used to diagnose TB in goats, the topical administration of corticosteroids and a recent pre-sensitisation with tuberculin, was analysed. Methods The animals (n = 151) were distributed into three groups: (1) a group topically treated with corticosteroids 48 h after intradermal tuberculin tests (n = 53); (2) a group pre-sensitised with bovine and avian purified protein derivatives (PPDs) 3 days before the intradermal tuberculin test used for TB diagnosis (n = 48); and (3) a control group (n = 50). All the animals were tested using single and comparative intradermal tuberculin (SIT and CIT, respectively) tests, an interferon-gamma release assay (IGRA) and a P22 ELISA. Results The number of SIT test reactors was significantly lower in the group treated with corticosteroids when compared to the pre-sensitised (p p = 0.036) groups. In contrast, pre-sensitisation with bovine and avian PPDs did not cause a significant reduction in the number of SIT and CIT test reactors compared with the control group. In fact, a higher number of reactors was observed after the prior tuberculin injection in the pre-sensitised group (p > 0.05). No significant effect was observed on IGRA and P22 ELISA due to corticosteroids administration. Nevertheless, a previous PPD injection affected the IGRA performance in some groups. Conclusions The application of topical corticosteroid 24 h before reading the SIT and CIT tests can reduce the increase in skin fold thickness and subsequently significantly decrease the number of positive reactors. Corticosteroids used can be detected in hair samples. A previous pre-sensitisation with bovine and avian PPDs does not lead to a significant reduction in the number of intradermal tests reactors. These results are valuable in order to improve diagnosis of caprine TB and detect fraudulent activities in the context of eradication programs.

BACKGROUND: Perioperative fluid therapy management is changing due to the incorporation of different fluids, surgical techniques, and minimally invasive monitoring systems. The objective of this study was to explore fluid therapy management during the perioperative period in our country. METHODS: We designed the Fluid Day study as a cross-sectional, multicentre, observational study. The study was performed in 131 Spanish hospitals in February 2019. We included adult patients undergoing general anaesthesia for either elective or non-elective surgery. Demographic variables were recorded, as well as the type and total volume of fluid administered during the perioperative period and the monitorization used. To perform the analysis, patients were categorized by risk group. RESULTS: We recruited 7291 patients, 6314 of which were included in the analysis; 1541 (24.4%) patients underwent high-risk surgery, 1497 (23. 7%) were high risk patients, and 554 (8.7%) were high-risk patients and underwent high-risk surgery; 98% patients received crystalloids (80% balanced solutions); intraoperative colloids were used in 466 patients (7.51%). The hourly intraoperative volume in mL/kg/h and the median [Q1; Q3] administered volume (mL/kg) were, respectively, 6.67 [3.83; 8.17] ml/Kg/h and 13.9 [9.52;5.20] ml/Kg in low-risk patients undergoing low- or intermediate-risk surgery, 6 [4.04; 9.08] ml/Kg/h and 15.7 [10.4;24.5] ml/Kg in high- risk patients undergoing low or intermediate-risk surgery, 6.41 [4.36; 9.33] ml/Kg/h and 20.2 [13.3;32.4] ml/Kg in low-risk patients undergoing high-risk surgery, and 5.46 [3.83; 8.17] ml/Kg/h and 22.7[14.1;40.9] ml/Kg in high-risk patients undergoing high- risk surgery . We used advanced fluid monitoring strategies in 5% of patients in the intraoperative period and in 10% in the postoperative period. CONCLUSIONS: The most widely used fluid was balanced crystalloids. Colloids were used in a small number of patients. Hourly surgery volume tended to be more restrictive in high-risk patients but confirms a high degree of variation in the perioperatively administered volume. Scarce monitorization was observed in fluid therapy management. TRIAL REGISTRATION: Clinical Trials: NCT03630744.

BACKGROUND: Health-related quality of life (HRQoL) is greatly affected by prostate cancer (PCa) and associated treatments. This study aimed to measure the impact of radiotherapy on HRQoL and to further validate the Spanish version of the 16-item Expanded Prostate Cancer Index Composite (EPIC-16) in routine clinical practice. METHODS: An observational, non-interventional, multicenter study was conducted in Spain with localized PCa patients initiating treatment with external beam radiotherapy (EBRT) or brachytherapy (BQT). Changes from baseline in EPIC-16, University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), and patient-perceived health status were longitudinally assessed at end of radiotherapy (V2) and 90 days thereafter (V3). Psychometric evaluations of the Spanish EPIC-16 were conducted. RESULTS: Of 516 patients enrolled, 495 were included in the analysis (EBRT, n = 361; BQT, n = 134). At baseline, mean (standard deviation [SD]) EPIC-16 global scores were 11.9 (7.5) and 10.3 (7.7) for EBRT and BQT patients, respectively; scores increased, i.e., HRQoL worsened, from baseline, by mean (SD) of 6.8 (7.6) at V2 and 2.4 (7.4) at V3 for EBRT and 4.2 (7.6) and 3.9 (8.2) for BQT patients. Changes in Spanish EPIC-16 domains correlated well with urinary, bowel, and sexual UCLA-PCI domains. EPIC-16 showed good internal consistency (Cronbach's alpha = .84), reliability, and construct validity. CONCLUSION: The Spanish EPIC-16 questionnaire demonstrated sensitivity, strong discriminative properties and reliability, and validity for use in clinical practice. EPIC-16 scores worsened after radiotherapy in different HRQoL domains; however, a strong tendency towards recovery was seen at the 3-month follow-up visit.

BACKGROUND: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

Background In recent years, the identification of genetic and phenotypic biomarkers of cancer for prevention, early diagnosis and patient stratification has been a main objective of research in the field. Different multivariable models that use biomarkers have been proposed for the evaluation of individual risk of developing breast cancer. Methods This is a case control study based on a population-based cohort. We describe and evaluate a multivariable model that incorporates 92 Single-nucleotide polymorphisms (SNPs) (Supplementary Table S1) and five different phenotypic variables and which was employed in a Spanish population of 642 healthy women and 455 breast cancer patients. Results Our model allowed us to stratify two groups: high and low risk of developing breast cancer. The 9th decile included 1% of controls vs 9% of cases, with an odds ratio (OR) of 12.9 and a p-value of 3.43E-07. The first decile presented an inverse proportion: 1% of cases and 9% of controls, with an OR of 0.097 and a p-value of 1.86E-08. Conclusions These results indicate the capacity of our multivariable model to stratify women according to their risk of developing breast cancer. The major limitation of our analysis is the small cohort size. However, despite the limitations, the results of our analysis provide proof of concept in a poorly studied population, and opens up the possibility of using this method in the routine screening of the Spanish population.

Background In April 2014 the UK government launched the ‘NHS Visitor and Migrant Cost Recovery Programme Implementation Plan’ which set out a series of policy changes to recoup costs from ‘chargeable’ (largely non-UK born) patients. In England, approximately 75% of tuberculosis (TB) cases occur in people born abroad. Delays in TB treatment increase risk of morbidity, mortality and transmission in the community. We investigated whether diagnostic delay has increased since the Cost Recovery Programme (CRP) was introduced. Methods There were 3342 adult TB cases notified on the London TB Register across Barts Health NHS Trust between 1st January 2011 and 31st December 2016. Cases with missing relevant information were excluded. The median time between symptom onset and treatment initiation before and after the CRP was calculated according to birthplace and compared using the Mann Whitney test. Delayed diagnosis was considered greater or equal to median time to treatment for all patients (79 days). Univariable logistic regression was used to manually select exposure variables for inclusion in a multivariable model to test the association between diagnostic delay and the implementation of the CRP. Results We included 2237 TB cases. Among non-UK born patients, median time-to-treatment increased from 69 days to 89 days following introduction of CRP (p p = 0.307). The multivariable logistic regression model showed non-UK born patients were more likely to have a delay in diagnosis after the CRP (adjOR 1.37, 95% CI 1.13–1.66, p value 0.001). Conclusion Since the introduction of the CRP there has been a significant delay for TB treatment among non-UK born patients. Further research exploring the effect of policies restricting access to healthcare for migrants is urgently needed if we wish to eliminate TB nationally.

Leishmaniasis, considered by the World Health Organization as one of the most important tropical diseases, is endemic in the Mediterranean Basin. The aim of this study was to evaluate epidemiological and clinical characteristics of cutaneous (CL) and mucocutaneous leishmaniasis (MCL) in La Fe University Hospital, Valencia, Spain. The particular focus was on diagnosis techniques and clinical differences according to the immunological status of the patients.

BACKGROUND: Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. METHODS: We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. RESULTS: While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. CONCLUSIONS: Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity.

Background Medication Errors (MEs) are considered the most common type of error in pediatric critical care services. Moreover, the ME rate in pediatric patients is up to three times higher than the rate for adults. Nevertheless, information in pediatric population is still limited, particularly in emergency/critical care practice. The purpose of this study was to describe and analyze MEs in the pediatric critical care services during the prescription stage in a Mexican secondary-tertiary level public hospital. Methods A cross-sectional study to detect MEs was performed in all pediatric critical care services [pediatric emergency care (PEC), pediatric intensive care unit (PICU), neonatal intensive care unit (NICU), and neonatal intermediate care unit (NIMCU)] of a public teaching hospital. A pharmacist identified MEs by direct observation as the error detection method and MEs were classified according to the updated classification for medication errors by the Ruiz-Jarabo 2000 working group. Thereafter, these were subclassified in clinically relevant MEs. Results In 2347 prescriptions from 301 patients from all critical care services, a total of 1252 potential MEs (72%) were identified, and of these 379 were considered as clinically relevant due to their potential harm. The area with the highest number of MEs was PICU (n = 867). The ME rate was > 50% in all pediatric critical care services and PICU had the highest ME/patient index (13.1). The most frequent MEs were use of abbreviations (50.9%) and wrong speed rate of administration (11.4%), and only 11.7% of the total drugs were considered as ideal medication orders. Conclusion Clinically relevant medication errors can range from mild skin reactions to severe conditions that place the patient's life at risk. The role of pharmacists through the detection and timely intervention during the prescription and other stages of the medication use process can improve drug safety in pediatric critical care services.

Background Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2–23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. Discussion Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. Trial registration Clinicaltrials.gov, NCT03130114. Registered on April 26 2017.

BACKGROUND: There are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19(-) either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22(+)CD19(-) B-ALL relapses and CD19(-) preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied. METHODS: Here, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays. RESULTS: Conformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy. CONCLUSIONS: We report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22(high) and CD22(low) ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22-CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL.