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BACKGROUND Invasive pneumococcal disease (IPD) is the most important bacterial infection in young children, and the introduction of pneumococcal conjugate vaccines has changed its presentation. This study compared the incidence, characteristics and serotype distribution of IPD before and after the introduction of the pneumococcal conjugate vaccine (PCV13). METHODS Prospective enrolment of patients with IPD aged less than 60 months and admitted to either of 2 tertiary care hospitals between January 2007 and December 2009 (pre-PCV13 period) and January 2012 and June-2016 (PCV13 period). RESULTS We identified 493 cases, 319 in the pre-PCV13 period and 174 in the PCV13 period. The incidence of IPD decreased from 89.7 to 34.4 casos per 100 000 habitantes ( -62%; P

Vaccination in patients with special medical situations remains a major challenge for health professionals. In recent years, vaccination of these groups has gained special importance because of the conceptual expansion of vaccines associated with early stages of life and the availability of specific vaccines for these patients (adjuvanted or high-burden). On the other hand, new scientific evidence on the definition of new immunopreventable risks is improving the indications and uses of vaccines. In addition, the use of new technologies, as well as indirect information sources for the identification of these patients, contribute significantly to the increase in vaccination coverage.

AIM Non-malignant portal vein thrombosis (PVT) is a complication of liver cirrhosis. The aim of this study was to evaluate the annual incidence of PVT and related risk factors. METHODS We retrospectively reviewed clinical, laboratory, and radiological data collected prospectively from September 2016 to September 2017. A follow-up of 36 months was performed in a subset of patients to determine the cumulative incidence of PVT and related complications. RESULTS The study included 567 patients. The incidence of PVT at 12, 24, and 36 months was 3.7%, 0.8%, and 1.4%, respectively. Patients with PVT were compared with patients without PVT, and showed differences in albumin (p = 0.04), aspartate aminotransferase (p = 0.04), hemoglobin (p = 0.01), and prothrombin activity (p = 0.01). The presence of hydropic decompensation (57.1% vs. 30.1%; p 0.004), gastroesophageal varices (76.2% vs. 39.5%; p = 0.05), variceal bleeding (52.4% vs. 22.7%; p

INTRODUCTION The effect of branched-chain amino acid (BCAA) supplementation on muscle mass in patients with cirrhosis and sarcopenia is unknown. METHODS This is a pilot, prospective, randomized, and double-blind study of a cohort of 32 patients with cirrhosis and sarcopenia diagnosed by computed tomography scan who underwent a nutritional and physical activity intervention for 12 weeks. They were divided into 2 groups (placebo: 17 patients; BCAA: 15 patients). The study protocol was registered at ClinicalTrials.gov (NCT04073693). RESULTS Baseline characteristics were similar in both groups. After treatment, only the BCAA group presented a significant improvement in muscle mass (43.7 vs 46 cm2/m2; P = 0.023). Seventeen patients (63%) presented improvement in muscle mass overall, which was more frequent in the BCAA group (83.3 vs 46.7%; P = 0.056). Regarding frailty, there was a significant improvement in the Liver Frailty Index in the global cohort (n = 32) after the 12 weeks (4.2 vs 3.9; P < 0.001). This difference was significant in both groups: in the placebo group (4.2 vs 3.8; P < 0.001) and in the BCAA group (4.2 vs 3.9; P < 0.001). After treatment, the BCAA group had a higher increase in zinc levels than the placebo group (Δzinc: 12.3 vs 5.5; P = 0.026). In addition, there was a trend for greater improvement of albumin levels in the BCAA group (Δalbumin: 0.19 vs 0.04; P = 0.091). DISCUSSION BCAA supplementation improves muscle mass in cirrhotic patients with sarcopenia.

The status of serotonin 5HT2A receptors (5HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3 H]lysergic acid diethylamide (LSD) and the antagonist [ 3 H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3 H]LSD binding. However, [3 H] MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3 H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT2ARs in schizophrenia. This study was supported by the Spanish State Research Agency, Ministry of Science and ERD Funds (SAF-2009-08460, SAF-2017-88126-R, RYC-2017-22412 and CTQ-2017-87637-R), and the Basque Government (SAIOTEK S-PE13UN019 and IT-1211-19). Part of this work was conducted under the Maria de Maeztu Units of Excellence Programme (Grant MDM-2017-0720). C.M. and A.G.-B. were recipients of fellowships from the Marie Slodowska-Curie Programme (European Union’s Horizon 2020, Grant 747487) and the Basque Government predoctoral training Programme, respectively

Amblyopia is the leading cause of vision impairment in children, and its early detection can avoid irreversible consequences for a child's visual ability. In this prospective study, to detect amblyopia risk factors, we examined patients aged 18 to 30 months in primary care settings. Patients were referred to an ophthalmologist for confirmation. The main aims were to detect amblyogenic risk factors and to assess the usefulness of a photoscreener in such settings. Out of 453 patients, 42 (9.3%) presented visual alterations according to the photoscreener, with astigmatism being the most common. The instrument had good sensitivity (89%) and specificity (91%), with a positive predictive value of 76% and a negative predictive value of 96%. Overall, 38% of the patients required follow-up, and 47% needed glasses. The automated screening device allowed these children to be diagnosed at an early stage.Conclusions: The use of a photoscreener to screen 2-year-old children in primary care settings was helpful and accurate. What is Known: • Early detection of amblyopic risk factors is important to avoid vision defects. However, it is very difficult to measure visual acuity using visual charts in children younger than 4 years old. What is New: • Instrument-based screening in children aged 18 to 30 months allows excellent detection of early amblyopia risk factors in primary care settings.

Introduction: Patients with invasive pneumococcal disease (IPD) may require admission into paediatric intensive care units (PICU). The aim of this study is to analyse the epidemiological, clinical, and microbiological characteristics associated with IPD that may require admission to the PICU. Material and methods: A prospective study was conducted on cases of IPD diagnosed in three Paediatric Hospitals in Barcelona between January 2012 and June 2016. An analysis was made of the associations between the admission to PICU and the epidemiological, clinical, and microbiological variables. Results: A total of 263 cases with IPD were included, of which 19% (n = 50) required admission to PICU. Patients with septic shock (7; 100%), meningitis (16; 84.2%), and those with complicated pneumonia (23; 15.2%) were admitted to the PICU. The most frequent complications were pulmonary (35.2%) and neurological (39.5%). The ratio between admission and non-admission to PICU was 4.7 times higher in subjects with an underlying disease. The serotypes associated with PICU admission were 19A (23% of the total of this serotype), serotype 14 (20%), serotype 3 (17%), and serotype 1 (12.5%). Conclusions: IPD required PICU admission in cases of septic shock and meningitis, and less so with complicated pneumonia. The percentage of admissions is greater in children with an underlying disease. Admission into the PICU involves a longer stay, complications during the acute phase, as well as sequelae, particularly neurological ones. The serotypes of the patients that were admitted to PICU were predominantly vaccine serotypes. Resumen: Introducción: La enfermedad neumocócica invasora (ENI) puede requerir ingreso en la unidad de cuidados intensivos pediátricos (UCIP). El objetivo de este trabajo es analizar las características epidemiológicas, clínicas y microbiológicas asociadas a la ENI que predisponen el ingreso en la UCIP. Material y métodos: Estudio prospectivo de casos diagnosticados con ENI en tres hospitales pediátricos de Barcelona entre enero de 2012 y junio de 2016. Se analizaron las asociaciones entre el ingreso en la UCIP y las variables epidemiológicas, clínicas y microbiológicas. Resultados: Se incluyeron 263 casos con ENI. El 19% (n = 50) requirió ingreso en la UCIP. El 100% (7) de los pacientes con shock séptico, 84,2% (16) con meningitis y 15,2% (23) con neumonía complicada ingresaron en la UCIP. Las complicaciones más frecuentes fueron pulmonares (35,2%) y neurológicas (39,5%). La razón entre ingreso y no ingreso en la UCIP fue 4,17 veces mayor en los sujetos con enfermedad de base. Los serotipos asociados al ingreso en la UCIP fueron el 19A (23% del total de este serotipo), el 14 (20%), el 3 (17%) y el serotipo 1 (12,5%). Conclusiones: La ENI requiere ingreso en la UCIP en caso de shock séptico y meningitis, no así, de entrada, la neumonía complicada. El porcentaje de ingresos es mayor en los niños con enfermedad de base. El ingreso en la UCIP conlleva una estancia más prolongada, así como complicaciones durante la fase aguda y secuelas, sobre todo, neurológicas. Los serotipos de los pacientes que ingresaron en la UCIP fueron, predominantemente, serotipos vacunales.

Clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg, persists 24 weeks after sustained virological response (SVR) in up to 78% of patients with HCV-related cirrhosis treated with direct-acting antivirals. These patients remain at risk of decompensation. However, long-term paired clinical and hemodynamic data are not available for this population.We conducted a prospective multicenter study in 226 patients with HCV-related cirrhosis and CSPH who achieved SVR after antiviral therapy. Patients with CSPH 24 weeks after end of treatment (SVR24) were offered another hemodynamic assessment 96 weeks after end of treatment (SVR96).All patients were clinically evaluated. Out of 176 patients with CSPH at SVR24, 117 (66%) underwent an HVPG measurement at SVR96. At SVR96, 55/117 (47%) patients had HVPG10 mmHg and 53% had CSPH (65% if we assume persistence of CSPH in all 59 non-evaluated patients). The proportion of high-risk patients (HVPG ≥16 mmHg) diminished from 41% to 15%. Liver stiffness decreased markedly after SVR (median decrease 10.5 ± 13 kPa) but did not correlate with HVPG changes (30% of patients with liver stiffness measurement13.6 kPa still had CSPH). Seventeen (7%) patients presented with de novo/additional clinical decompensation, which was independently associated with baseline HVPG ≥16 mmHg and history of ascites.Patients achieving SVR experienced a progressive reduction in portal pressure during follow-up. However, CSPH may persist in up to 53-65% of patients at SVR96, indicating persistent risk of decompensation. History of ascites and high-risk HVPG values identified patients at higher risk of de novo or further clinical decompensation.As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly.

Introduction: The incidence of serogroup C invasive meningococcal disease (IMD) has decreased since the introduction of systematic vaccination in 2000 The aim of this study is to determine the number serogroup C IMD cases diagnosed since then and the vaccine failures. Patients and methods: A retrospective analysis was performed on patients diagnosed with IMD by culture or polymerase chain reaction (PCR) in a maternity and childhood hospital in Barcelona between 2001 and 2018. An analysis was made of the number of vaccine doses and the age received, as well as on the medical records and vaccine cards. Results: There were 128 confirmed cases of IMD (7.1 cases/year; 70.3 in

Background: Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer’s disease. Objective: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer’s disease using positron emission tomography (PET). Methods: Female mice (AβPPswe/PS1A246E/TTR+/–) were divided into 3 groups (n = 7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100 mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age = 14 months. Results: Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age = 5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages = 5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age = 14 months. Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions.

Acute retinal necrosis is a rare yet devastating disease, with significant ocular morbidity. Over the past several decades, initial treatment regimens have shifted from intravenous antivirals requiring hospital admission to the routine use of oral antivirals with intravitreal antivirals for immediate local control. Given the rarity of this disease process and a lack of large-scale research trials, debate continues over recommended practice guidelines. In this paper, we review current diagnostic criteria and recommend a treatment algorithm based on available evidence.

Background & Aims Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. Methods This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. Results One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23–37%) on US and 47.7% (95% CI 39–56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38–62%) and 85.3% (95% CI 75–92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. Conclusion While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. Lay summary Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

Background To evaluate the influence of the disease activity on radiographic progression in axial spondyloarthritis (axSpA) patients treated with TNF inhibitors (TNFi). Methods The study included 101 axSpA patients from the Spanish Register of Biological Therapy in Spondyloarthritides (REGISPONSERBIO), which had clinical data and radiographic assessment available. Patients were classified into 2 groups based on the duration of TNFi treatment at baseline: (i) long-term treatment (≥4 years) and (ii) no long-term treatment (< 4 years). Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. Disease activity differences between patients’ groups at each time point were assessed using a linear mixed-effect model. Results Radiographic progression was defined as an increase in ≥2 mSASSS units. At inclusion, approximately half of the patients (45.5%) were receiving long-term treatment with TNFi (≥4 years). In this group of subjects, a significant difference in averaged Ankylosing Spondylitis disease Activity Score (ASDAS) across follow-up was found between progressors and non-progressors (2.33 vs 1.76, p=0.027, respectively). In patients not under long-term TNFi treatment (54.5%) though, no significant ASDAS differences were observed between progressors and non-progressors until the third year of follow-up. Furthermore, no significant differences were found in progression status, when disease activity was measured by Bath Ankylosing spondylitis Disease Activity Index (BASDAI) and C reactive protein (CRP). Conclusions Patients on long-term TNFi treatment with a mean sustained low disease activity measures by ASDAS presented lower radiographic progression than those with active disease.

The development of Next-Generation Sequencing (NGS) has provided useful diagnostic, prognostic, and therapeutic strategies for individualized management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Consequently, NGS is rapidly being established in clinical practice. However, the technology’s complexity, bioinformatics analysis, and the different available options difficult a broad consensus between different laboratories in its daily routine introduction. This collaborative study among Spanish centers was aimed to assess the feasibility, pros, and cons of our customized panel and other commercial alternatives of NGS-targeted approaches. The custom panel was tested in three different sequencing centers. We used the same samples to assess other commercial panels (OncomineTM Childhood Cancer Research Assay, Archer®FusionPlex® ALL, and Human Comprehensive Cancer Panel GeneRead Panel v2®). Overall, the panels showed a good performance in different centers and platforms, but each NGS approach presented some issues, as well as pros and cons. Moreover, a previous consensus on the analysis and reporting following international guidelines would be preferable to improve the concordance in results among centers. Our study shows the challenges posed by NGS methodology and the need to consider several aspects of the chosen NGS-targeted approach and reach a consensus before implementing it in daily practice.

Aim To emphasize that nurses need to be fully protected to carry out their vital role, particularly during pandemics, yet the lack of a standardized and systematic collection of high‐quality disaggregated data on nurses health inhibits our ability to assess this within and across countries. Background Nurses are the largest workforce group in the health sector, yet only 59 countries worldwide report on nurse COVID‐19 infections and related deaths, and the standardized, systematic collection of disaggregated health data is not yet in place. Sources of evidence Medline, International Council of Nurses, World Health Organization, Centers of Disease Control and Prevention and the experiences of the authors. Discussion Inconsistent recording and definitions of nurses, precarious and informal employment conditions, limited transparent and reliable data, lack of mass testing and long‐standing structural issues and biases have affected nursing for too long. Conclusions These issues are reflected in the limited capacity of many national public health information systems to collect, monitor and report on the health of the largest group of health workers. Political will, accountability and public data transparency at different levels are essential to adequately protect nurses at work. Implications for nursing practice, and nursing and health policy Building on current momentum in the nursing field, immediate political action is required to strengthen existing nursing and midwifery policies, standards and regulatory capacity, as well as existing public health services and information and surveillance systems. The generation of up‐to‐date, context‐specific knowledge is needed to inform and monitor political decisions related to the protection of nurses, and the improvement of their employment conditions, as well as to strengthen accountability for these areas at various levels.

Objective After the introduction of 13-valent pneumococcal conjugate vaccine (PCV13), a decrease of serotype-3 invasive pneumococcal disease (IPD) has not been homogenously observed around Europe. The aim of the study is to analyze the incidence of serotype-3 IPD in our area (Catalonia, Spain) and describe what microbiological and clinical characteristics distinguish serotype-3 IPD from nonserotype-3 IPD. Methods This study is a prospective observational study performed in three hospitals of Barcelona (Spain), from January 2012 to June 2016. Patients younger than 18 years with a diagnosis of IPD were included. Epidemiological, clinical, and microbiological data were collected. Results A total of 253 cases of IPD were included; of these, 53 were caused by serotype 3. The incidence rate of serotype-3 IPD remained stable over the study years (risk ratio [RR] = 0.64; 95% confidence interval [CI]: 0.3–1.38). In 92.5% (49/53) of the cases of serotype-3 IPD, the diagnosis was pneumonia and 89.8% (44/49) of them reported a complicated pneumonia. Also, 98.1% (52/53) were detected by positive real-time polymerase chain reaction (PCR) in blood or pleural effusion. Seventeen patients were properly vaccinated with PCV13 before the infection. Conclusion After the introduction of PCV13 a global decline of invasive pneumococcal disease has been reported, specially, due to a decrease of serotypes 1 and 19A cases. Serotype-3 Streptococcus pneumoniae IPD remained stable throughout the years of study, being currently the main serotype causing IPD in our area. Serotype 3 causes mostly pneumonia and physicians must be aware of possible complications. Real-time PCR have a significantly higher diagnostic yield for serotype 3 compared with culture. Some vaccination failures were observed.

Objective Different adipokines have been reported to play a role in the development, progression, and severity of knee osteoarthritis, but this association may be mediated by obesity. The aim of this study was to evaluate separately the associations of leptin and adiponectin with clinical severity and inflammatory markers in nonobese and obese women with knee osteoarthritis. Design Cross-sectional study with systematic inclusion of 115 women with symptomatic primary knee osteoarthritis. Age, physical exercise, symptoms duration, and body mass index were collected. Radiographic severity was evaluated according to Kellgren-Lawrence scale. Pain and disability were assessed by WOMAC-total, -pain, -function subscales. Two adipokines (leptin and adiponectin) and 3 inflammatory markers (TNF-α, hsCRP, and IL-6) were measured by ELISA in synovial fluid and serum. Results Synovial fluid adiponectin was associated with WOMAC pain, function, and total and with synovial fluid IL-6 in nonobese female knee osteoarthritis after controlling by confounders (partial correlation coefficient [PCC] = 0.395, 0.387, 0.427, and 0.649, respectively). Synovial fluid and serum leptin were significantly associated with IL-6 (PCC = 0.354) after controlling by confounders but associations with clinical severity and the rest of inflammatory markers were mitigated after control. Conclusions Adiponectin in synovial fluid was associated with clinical severity and local inflammatory markers in knee osteoarthritis women, while leptin relation was attenuated when controlled by confounders.

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objectives: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat)

Summary After the continued decline in measles morbidity and mortality during this century, since 2017 there has been, for various reasons (vaccination reticence is very important), a re-emergence of the disease around the world, when walking towards its eradication. Clinicians should suspect measles to anyone susceptible to fever and a clinical flulike presentation of several days of evolution, with the subsequent appearance of a generalized maculopapulous rash. When a measles case is suspected, epidemiological surveillance service shall be urgently declared, the specific IgM shall be determined and the patient isolated. If the case is confirmed, an epidemiological survey and post-exposure prophylaxis of the susceptible contacts will be carried out. Routine vaccination in childhood with a triple viral vaccine with two doses from 12 months and in all persons with any age is essential, and vaccine coverage of 95% or more in the population is essential.

Background: Central obesity, due to the accumulation of visceral fat(VF), is one of the main risk factors for venous thrombosis. The aim of this study was to determine if VF may be a risk factor for development of portal vein thrombosis(PVT) in cirrhotic patients.Methods: A total of 214 cirrhotic patients at the outpatient clinic were consecutively included, undergoing an anthropometric evaluation, blood tests and bioimpedance.Results: Median MELDscore was10. Prior liver decompensation occurred in 44.9% of patients and 35.6% of patients had large esophageal varices. Mean body mass index was 28.7 Kg/m2 (39.3%were obese) and mean waist circumference(WC) was 103.8 cm. A 7.5% of patients had PVT at the time of inclusion. PVT was more frequent in males(93.8 vs. 68.2%, p = 0.03). Patients with PVT had a higher WC(111.9 vs. 103.2 cm, p = 0.02) and VF (17.1 vs. 14.5, p = 0.04). PVT was also more frequent in patients with prior decompensation (81.3 vs. 41.9%, p < 0.01) and with large esophageal varices(62.5 vs. 33.3%, p = 0.02). In the simplified multivariate analysis, PVT was independently associated with the presence of portal hypertension(OR 13, 95%CI 1.6-108.3, p = 0.02) and VF(OR 1.2, 95%CI 1.03-1.3, p = 0.01).Conclusion: VF was independently associated with PVT in cirrhotic patients. VF may be more reliable than conventional anthropometric measurements for cirrhotic patients.

Background: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. Aim: To evaluate sociodemographic factors as risk factors in severity of HCPS. Patients and Methods: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. Results: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. Conclusion: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Introduction and aims. To determine the prevalence of minimal hepatic encephalopathy (MHE) in patients with liver cirrosis (LC) due to hepatitis C virus (HCV) infection and to evaluate the impact of sustained viral response (SVR) on MHE. Material and methods. We performed a prospective study using MHE screening and follow-up on patients with HCV and LC. The patients were evaluated at the beginning of treatment and 24 weeks after treatment. Results. 64 patients were included. 51.6% were male, the median age was 62years, Child-Pugh classification A/B/C 93.8%/4.7%/1.6% and median MELD was 8.3. Prior hydropic decompensation was present in 11 patients. Median values of liver stiffness, as measured by transient elastography (TE) were 22.8 KPa. Indirect signs of portal hypertension (PH) were present in 53.1% of patients, with a mean of 11.9 mmHg among the ones with a measurement of the hepatic venous pressure gradient. The prevalence of MHE before treatment was 26.6%. After treatment, 98.4% of patients achieved SVR. The presence of MHE at 24weeks post-treatment had an statistically significant association with the presence of pre-treatment MHE (80% vs. 21.6%; p < 0.01), higher MELD scores at 24-weeks post-treatment (9.8 vs. 8; p = 0.02), higher Child-Pugh scores at 24-weeks post-treatment (p = 0.04), higher baseline INR levels (1.4 vs. 1.1; p < 0.001) and with the presence of indirect signs of PH (100% vs. 47.1%; p = 0.02). During follow-up, those patients without MHE at 24weeks post-treatment had a higher probability of experiencing an improvement in post-treatment TE (80.9% vs. 40%, p = 0.04). Conclusion. We found that SVR may lead to MHE resolution in a considerable proportion of patients, which has potential implications for disease prognosis.

Background To evaluate the performance of the extended modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) incorporating information from anteroposterior (AP) lumbar radiographs as compared to the conventional mSASSS in detection of radiographic spinal progression in patients with axial spondyloarthritis (axSpA) Methods A total of 210 patients with axSpA, 115 with radiographic axSpA (r-axSpA), and 95 with non-radiographic axSpA (nr-axSpA), from the GErman SPondyloarthritis Inception Cohort (GESPIC), were included in the analysis based on the availability of spinal radiographs (cervical spine lateral, lumbar spine lateral, and AP views), at baseline and year 2. Two trained readers independently scored lateral cervical and lumbar spine images according to the mSASSS system (0–3 per vertebral corner, 0–72 in total). In addition, all vertebral corners of vertebral bodies visible on lumbar AP radiographs (lower T12 to upper S1) were assessed according to the same scoring system that resulted in a total range for the extended mSASSS from 0 to 144. Reliability and sensitivity to detect radiographic spinal progression of the extended mSASSS as compared to the conventional mSASSS were evaluated. Results The reliability of conventional and extended scores was excellent with intraclass correlation coefficients (ICCs) of 0.926 and 0.927 at baseline and 0.920 and 0.933 at year 2, respectively. The mean ± SD score for mSASSS and extended mSASSS at baseline were 4.25 ± 8.32 and 8.59 ± 17.96, respectively. The change score between baseline and year 2 was 0.73 ± 2.34 and 1.19 ± 3.73 for mSASSS and extended mSASSS, respectively. With the extended mSASSS, new syndesmophytes after 2 years were detected in 4 additional patients, new syndesmophytes or growth of existing syndesmophytes in 5 additional patients, and progression by ≥ 2 points in the total score in 14 additional patients meaning a 25%, 28%, and 46% increase in the proportion of patients with progression according to the respective definition as compared to the conventional score. Conclusions Incorporation of lumbar AP radiographs in the assessment of structural damage in the spine resulted into detection of additional patients with radiographic spinal progression not captured by the conventional mSASSS score.

BACKGROUND & AIMS: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD). METHODS: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. RESULTS: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (

Recurrence is a major cause of death among BRCA1/2 mutation carriers with breast (BrCa) and ovarian cancers (OvCa). We performed multi-omic sequencing on 67 paired primary and recurrent BrCa and OvCa from 27 BRCA1/2 mutation carriers to identify potential recurrence-specific drivers. PARP1 amplifications were identified in recurrences (FDR q = 0.05), and PARP1 was significantly overexpressed across primary BrCa and recurrent BrCa and OvCa, independent of amplification status. RNA-seq analysis found two BRCA2 isoforms, BRCA2-201/Long and BRCA2-001/Short, predicted sensitive and insensitive to nonsense-mediated decay, respectively. BRCA2-001/Short was expressed more frequently in recurrences and associated with reduced overall survival in breast cancer (87 vs. 121 months; HR = 2.5 [1.18–5.5]). Loss of heterozygosity (LOH) status was discordant in 25% of patient’s primary and recurrent tumors, with switching between both LOH and lack of LOH found. Our study revealed multiple potential drivers of recurrent disease in BRCA1/2 mutation-associated cancer, improving our understanding of tumor evolution and suggesting potential biomarkers.

Este artículo se encuentra disponible en la página web de la revista en la siguiente URL: https://journals.lww.com/jped/Fulltext/2021/39020/Basic_behavior_guidance_techniques__A_survey_of.4.aspx Background: Over the last 20–30 years social trends, educational and parenting patterns, and the ethical and legal factors guiding them have led to the revaluation and even abandonment of some traditionally used behavior guidance techniques (BGTs). Aims: To profile the professionals providing specialized pediatric treatments in Spain and understand changes in their preferences and use of basic BGTs, and the evolution of these preferences. Settings and Design: A cross‑sectional, descriptive, and correlational study was designed. Methods: One hundred and twenty‑six dentists completed a previously validated survey. Statistical Analysis: Descriptive statistics and Chi‑square tests were performed to analyze the questionnaire data. Results: The most common BGTs were “Tell/Show/Do” (98%) and positive reinforcement (92.1%), and the most abandoned BGT was: “hand‑over‑mouth” (15%), because it was rejected by parents and because of potential legal problems and psychological consequences for the patients. Of note, 37% of the professionals allowed the patient’s parents to be present during the treatment. Conclusions: There has been a notable decrease in the use of certain BGTs in Spain, especially hand‑over‑mouth and voice control, because they are becoming less socially acceptable as the way society relates to and educates children changes.

To validate in a cohort of 214 rheumatoid arthritis patients a panel of 10 plasmatic microRNAs, which we previously identified and that can facilitate earlier diagnosis of cardiovascular disease in rheumatoid arthritis patients. We identified 10 plasma miRs that were downregulated in male rheumatoid arthritis patients and in patients with acute myocardial infarction compared to controls suggesting that these microRNAs could be epigenetic biomarkers for cardiovascular disease in rheumatoid arthritis patients. Six of those microRNAs were validated in independent plasma samples from 214 rheumatoid arthritis patients and levels of expression were associated with surrogate markers of cardiovascular disease (carotid intima-media thickness, plaque formation, pulse wave velocity and distensibility) and with prior cardiovascular disease. Multivariate analyses adjusted for traditional confounders and treatments showed that decreased expression of microRNA-425-5p in men and decreased expression of microRNA-451 in women were significantly associated with increased (β = 0.072; p = 0.017) and decreased carotid intima-media thickness (β = −0.05; p = 0.013), respectively. MicroRNA-425-5p and microRNA-451 also increased the accuracy to discriminate patients with pathological carotid intima-media thickness by 1.8% (p = 0.036) in men and 3.5% (p = 0.027) in women, respectively. In addition, microRNA-425-5p increased the accuracy to discriminate male patients with prior cardiovascular disease by 3% (p = 0.008). Additionally, decreased expression of microRNA-451 was significantly associated with decreased pulse wave velocity (β = −0.72; p = 0.035) in overall rheumatoid arthritis population. Distensibility showed no significant association with expression levels of the microRNAs studied. We provide evidence of a possible role of microRNA-425-5p and microRNA-451 as useful epigenetic biomarkers to assess cardiovascular disease risk in patients with rheumatoid arthritis.

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD. J.L., P. R. and A.M thank the Spanish Ministry of Economy and Competitiveness (Project numbers: CTQ2017-87637-R, SAF2017-87670-R, PID2019-107989RB-I00 and RYC-2017-22412, respectively) and the Basque Government (project number: 2019RTE00214647-2019222012) for financial support. L.R., U.K. and S.G. thank the Slovenian Research Agency (projects J1-9166, Z1-9195, L1-8157 and NC-0009; research programs P1-0230 and P1-0208 for core financing). M.M. thanks Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP Number 112 201501 00410, P-UE Number 22920160100046CO) and Universidad de Buenos Aires (UBA, UBACyT Number 20020150100012BA) for financial support. Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720), and co-financed by the Interreg Atlantic Area Programme through the European Regional Development Fund. A. G. was supported by a grant from Ministerio de Ciencia, Innovación y Universidades (RTI2018-094678-A-I00) and he is a Ramón y Cajal fellow (RYC-2016-19466). E.C-Z. thanks the Basque Government (KK-2020/00034) for financial support.

Background Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). Patients and methods This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Background: Gestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity. Methods: We did an individual participant data (IPD) meta-analysis of mother–offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI. Findings: 160 757 mother–offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0–4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0–9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0–17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score −0·05 SD score [95% CI −0·09 to −0·01]), and this association strengthened following additional adjustment for maternal BMI. Interpretation: Although lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications. Funding: EU's Horizon 2020 research and innovation programme (LifeCycle Project). This study has received support from the US National Institute of Health (R01 DK10324) and European Research Council under the European Union’s Seventh 22 Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The Swedish Research Council, The Swedish Heart and Lung Foundation, The Swedish Research Council for Working Life and Social Welfare, the Swedish Asthma and Allergy Association Research Foundation, The Swedish Research Council Formas, Stockholm County Council, and the European Commission’s Seventh Framework 29 Program MeDALL under grant agreement No. 261357. This study has received support from the British Heart Foundation (CS/16/4/32482), US National Institute of Health (R01 DK10324) and European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007- 2013), project EarlyNutrition under grant agreement n°289346, the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and the European Union’s Horizon 2020 research and innovation programme under grant agreement 733206 (LifeCycle Project). European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements Early Nutrition n° 289346 and by funds from the Norwegian Research Council's MILPAAHEL programme, project No.213148. This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249). The "Rhea" project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-28.1.2.1.4 envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX) and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). ROLO is supported by the Health Research Board Ireland, the Health Research Centre for Health and Diet Research, and the European Union's Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. The SWS is supported by grants from the Medical Research Council, National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, and the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition (grant 289346). Study participants were drawn from a cohort study funded by the Medical Research Council and the Dunhill Medical Trust.

Objectives The presence of phytosterols in vegetable-based lipid emulsions has been associated with alterations in the results of liver function tests (LFTs). Serum levels of phytosterols are under strict genetic control. T-allele carriers in rs41360247 and C-allele carriers in rs4245791 of ABCG8genes are associated with higher phytosterolemia. The objective of this study was to determine the association between these single-nucleotide polymorphisms (SNPs) and LFT result alterations in an adult hospitalized population treated with parenteral nutrition. Methods This is a substudy of a previous clinical trial (EudraCT 2014-003597-17). It included adult hospitalized patients who had received at least 7 d of parenteral nutrition with 0.8 g/kg/d of an olive/soybean lipid emulsion, randomized 1:1 to receive the same olive/soybean emulsion or 100% fish oil at a dose of 0.4 g/kg/d for 7 d. Plasma phytosterols and their fractions, rs41360247 and rs4245791 of ABCG8 genes, and LFT were determined. Analyses of variance were performed to determine the association between the SNPs and LFT values, as well as total phytosterol values and their fractions. Simple linear regressions were performed to analyze LFT variations and the different interactions of the SNPs studied with phytosterols and their fractions. Interactions of the synergic variable plasma phytosterol and its fractions with SNPs allow us to study the interaction of the SNPs with phytosterols with a regression. Results We included 19 participants. In the multivariate model, total phytosterols, sitosterol, and lanosterol were positively associated with increases in γ-glutamyltransferase. Significant increases with stigmasterol were associated with the T allele of rs41360247, whereas campesterol showed only a tendency to increase that was not significant. Increases in alkaline phosphatase were associated with T-rs41360247 independent of the presence of phytosterols. With stigmasterol, C-allele carriers of rs4245791 showed a tendency to increase, and also for sitosterol and lanosterol, although independent of the SNP analyzed. Increases in alanine aminotransferase were positively associated with total phytosterol and sitostanol, whereas lanosterol and stigmasterol were associated with the presence of the T allele of rs41360247. Conclusions With both SNPs rs41360247 and rs4245791, the alteration in parameters of liver function in adult patients with short-term parenteral nutrition is conditional.

Approximately 75% of patients with carpal tunnel syndrome (CTS) are diagnosed as idiopathic. Despite this, the presence of an underlying cause such as an anatomical variant or a systemic disease must always be suspected, especially in cases of bilateral presentation without an obvious cause, recurrence or complications. The anatomical variant known as the bifid median nerve (BMN) is a very rare abnormality that can occasionally lead to CTS. On the other hands, transthyretin-associated amyloidosis (ATTR) is one of the possible causes of bilateral CTS. We report a case where these two very rare pathologies converge as the cause of bilateral CTS and a review of the literature. We report a 71-year-old male with prior history of lumbar canal stenosis, bilateral trigger finger, rupture of the supraspinatus muscle tendon and of the long portion of the right biceps brachial. He also had 8-year-old bilateral CTS that recurred after CTS surgery. He was surgically re-intervened and was diagnosed incidentally with BMN and an ultrasound of the other hands also showed BMN. Because of all the prior musculoskeletal history, a biopsy of the transverse carpal ligament was taken showing ATTR deposits that led to the diagnosis of cardiac ATTR wild type. This case highlights the natural history of the multiple musculoskeletal manifestations related to ATTR and the importance of performing intraoperative biopsies in patients with CTS surgery as this can lead to early diagnosis of cardiac ATTR.

Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN, and RAS mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: NOTCH1 mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of CDKN2A/B had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients.

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient’s data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44, 95% CI, 0.21–0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient’s survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

INTRODUCTION: Liver enzyme elevation has been reported for SARS-CoV-2 disease (COVID-19) in heterogeneous cohorts, mainly from China. Comprehensive reports from other countries are needed. We dissect the pattern, evolution and predictive value of such abnormalities in a cohort from Madrid, Spain. METHODS: Retrospective study with prospective 14-day follow-up of 373 patients with confirmed COVID-19 in five Madrid hospitals, including 50 outpatients. COVID-19 severe course was defined as need of mechanical ventilation. RESULTS: A total of 33.1% hospitalised patients showed baseline AST elevation and 28.5% showed ALT elevation, contrasting with 12% and 8% of outpatients (P≤0.001). Baseline AST, ALT and GGT levels correlated with LDH and C-reactive protein levels (CRP) (r≤0.598, P

Este artículo se encuentra disponible en la siguiente URL: https://journals.sagepub.com/doi/pdf/10.1177/20587384211031107 To assess the effects of a probiotic upon oral health indices in adolescents and to establish relationships between these indices and dietary habits and oral hygiene. Twenty-seven adolescents between 12 and 18 years of age were randomized into two groups. The study group received tablets containing Lactobacillus reuteri DSM 17938/ATCC 5289 for 28 days, while the control group received tablets without any bacteria. Streptococcus mutans, Lactobacillus sp., and salivary pH were assessed at baseline and at 7, 14, 21, 28, and 45 days. The plaque, gingivitis, and bleeding indices were recorded at baseline and at 14, 28, and 45 days. Dietary and oral hygiene habits were also evaluated by means of a questionnaire. A less marked rise in S. mutans was recorded in the study group. Improvements were observed in terms of plaque, gingivitis, and bleeding, though statistical significance was not reached. Oral pH increased in the study group, though not to a significant degree. Poorer eating habits were significantly correlated to increased plaque. The study parameters decreased with the two strains of L. reuteri DSM 17938 and ATCC PTA 5289, though the results failed to reach statistical.

Adenosine A(l) receptors (A(l)ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A(l)ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A(1)ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [F-18]CPFPX and immunohistochemistry (IHC). In addition, the role of AIARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [F-18]DPA-714 (TSPO) and [F-18]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [F-18]CPFPX signal and IHC showed the overexpression of A(l)ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the AAR agonist ENBA showed a significant decrease in both [F-18]DPA-714 and [F-18]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A(l)AR promoted the reduction of the brain lesion, as measured with T2W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A(l)AR expression after cerebral ischemia in rats and the application of [F-18]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A(l)AR playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats. The authors would like to thank A. Leukona and V. Salinas for technical support in the radiosynthesis. This study was funded by grants from the Spanish Ministry of Education and Science/FEDER RYC-201722412, SAF2016-75292-R, SAF2017-87670-R and PID2019-107989RB-I00, the Basque Government (IT1203/19, BIO18/IC/006) and CIBERNED. Maria Ardaya holds a fellowship from the University of Pais Vasco. Ana Joya acknowledges funding from Fundacio La Marato de TV3 (17/C/2017). Juan Jose Gutierrez acknowledges funding from Euskampus Fundazioa. Jordi Llop also acknowledges The Spanish Ministry of Economy and Competitiveness (Grant CTQ2017-87637-R). Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720).

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.

International Variceal Bleeding Observational Study Group and Baveno Cooperation., [Background & Aims] Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis., [Methods] A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization., [Results] A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9)., [Conclusion] Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Supported by grants from the Spanish Ministry of Science and Innovation (SAF-2016-75767-R to JC.G-P, SAF 2017-86343-R awarded to A.A, Instituto de Salud Carlos III PIE 15/00027 to JC.G-P, PI17/00398 to V.H.G, PI18/01901 to R.B and PI20/01302 to A.A, and Commissioner for Universities and Research of the Generalitat de Catalunya (AGAUR SGR 2017 awarded to JC.G-P). CIBEREHD is funded by the Instituto de Salud Carlos III with grants cofinanced by the European Development Regional Fund “A way to achieve Europe” (EDRF).

Effects of mercury on maturing immune system have been reported, however the association with respiratory and allergy problems during infancy remains unclear. The aim of this study is to evaluate the association between pre and postnatal mercury exposure and respiratory and allergy problems among preschool children and to examine the role of potential modifying factors. Study subjects were children participant in Spanish Childhood and Environment Project (INMA, 2003-2008). We measured total mercury levels in cord blood (n = 1868) and hair at 4 years of age (n = 1347). Respiratory outcomes (wheezing, severe wheezing, chestiness, persistent cough, eczema and otitis) were obtained by questionnaires administered to parents. Associations were investigated by logistic regression adjusted for socio-demographic and lifestyle-related variables in each cohort and subsequent meta-analysis. We tested effect modification by factors related to individual susceptibility, diet and co-exposure with other pollutants. The geometric mean of cord blood and hair total mercury was 8.20 μg/L and 0.97 μg/g, respectively. No statistically significant association between pre or postnatal mercury exposure and respiratory and allergy outcomes was found. Notwithstanding, lower maternal intake of fruits and vegetables increased the risk of some respiratory outcomes due to the prenatal exposure to mercury (pint < 0.05). Moreover, an inverse association between prenatal mercury exposure and some respiratory outcomes was observed among children with higher maternal exposure to organocholorine compounds or smoking (pint < 0.05). Also, sex and postnatal smoking exposure modulated mercury postnatal effects on persistent cough (pint < 0.05). In conclusion, no association between pre and postnatal mercury exposure and respiratory and allergy problems among the whole population at study was found. However, diet and other toxicants could modulate this relation, especially during prenatal period. More research on this topic is warranted due to the limited evidence. This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI04/2018, PI04/1436, PI05/1079, PI05/1052, PI06/1213, PI06/0867, PI07/0314, PI08/1151, PI09/00090, PI09/02647, PI09/2311, PI11/01007, PI11/02591, PI11/02038, PI13/2429, PI13/02187, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, PI18/01142, PI18/0909, PI19/1338; Miguel Servet-FEDER: CP15/0025; Miguel Servet-FSE: MS15/0025, MS20/0006), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), BEST/2020/059, AICO/2020/285 and GV/2020/058, Alicia Koplowitz Foundation 2017, Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació la Marató de TV3 (090430), CIBERESP, Obra Social Cajastur/Fundación Liberbank, Universidad de Oviedo, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain).

Preemptive TIPS Individual Data Metanalysis, International Variceal Bleeding Study and Baveno Cooperation Study groups., [Background & Aims] Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS., [Method] We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients., [Results] Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323–0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307–0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253–0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy., [Conclusions] In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy., Juan Carlos García-Pagán received support in part through grants from the Spanish Ministry of Education and Science (SAF-2016–75767-R and PIE 15/00027) and from the “Commissioner for Universities and Research of the Generalitat de Catalunya” (AGAUR SGR 2017). CIBERehd is funded by the Instituto de Salud Carlos III. Edilmar Alvarado-Tapias and Anna Baiges are recipients of a "Río Hortega" fellowship grant from the Instituto de Salud Carlos III. The study was partially supported by a GORE grant for statistical support.

Background The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. Patients and methods In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. Results The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. Conclusion Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. Trial registration ClinicalTrials.gov identifier: NCT02624973. 2020 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under theCC BY license(http://creativecommons.org/licenses/by/4.0/).

Background: COVID-19 pathophysiology and the predictive factors involved are not fully understood, but lymphocytes dysregulation appears to play a role. This paper aims to evaluate lymphocyte subsets in the pathophysiology of COVID-19 and as predictive factors for severe disease. Patient and methods: A prospective cohort study of patients with SARS-CoV-2 bilateral pneumonia recruited at hospital admission. Demographics, medical history, and data regarding SARS-CoV-2 infection were recorded. Patients systematically underwent complete laboratory tests, including parameters related to COVID-19 as well as lymphocyte subsets study at the time of admission. Severe disease criteria were established at admission, and patients were classified on remote follow-up according to disease evolution. Linear regression models were used to assess associations with disease evolution, and Receiver Operating Characteristic (ROC) and the corresponding Area Under the Curve (AUC) were used to evaluate predictive values. Results: Patients with critical COVID-19 showed a decrease in CD3+CD4+ T cells count compared to non-critical (278 (485 IQR) vs. 545 (322 IQR)), a decrease in median CD4+/CD8+ ratio (1.7, (1.7 IQR) vs. 3.1 (2.4 IQR)), and a decrease in median CD4+MFI (21,820 (4491 IQR) vs. 26,259 (3256 IQR)), which persisted after adjustment. CD3+CD8+ T cells count had a high correlation with time to hospital discharge (PC = −0.700 (−0.931, −0.066)). ROC curves for predictive value showed lymphocyte subsets achieving the best performances, specifically CD3+CD4+ T cells (AUC = 0.756), CD4+/CD8+ ratio (AUC = 0.767), and CD4+MFI (AUC = 0.848). Conclusions: A predictive value and treatment considerations for lymphocyte subsets are suggested, especially for CD3CD4+ T cells. Lymphocyte subsets determination at hospital admission is recommended.

BackgroundWe aimed to determine the impact of tocilizumab use in severe COVID-19 pneumonia mortality.MethodsWe performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain, from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by Inverse Probability of the Treatment Weights (IPTW). Tocilizumab effect in patients receiving steroids during the 48h following inclusion was analyzed.ResultsDuring the study period, 506 patients with severe COVID-19 fulfilled inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days (IQR 8-14). Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls (16.8% versus 31.5%, HR 0.514 [95CI 0.355-0.744], p< 0.001; weighted HR 0.741 [95CI 0.619-0.887], p = 0.001). Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment (RRR 46.7%). We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in patients treated with tocilizumab than in those treated with steroids alone (10.9% versus 40.2%, HR 0.511 [95CI 0.352-0.741], p = 0.036; weighted HR 0.6 [95CI 0.449-0.804], p< 0.001) (Interaction p = 0.094).ConclusionsThese results show that survival of patients with severe COVID-19 is higher in patients treated with tocilizumab than in those not treated, and that tocilizumab effect adds to that of steroids administered to non-intubated cases with COVID-19 during the first 48 hours of presenting with respiratory failure despite of oxygen therapy. Randomised controlled studies are needed to confirm these results.SummaryWe investigated in-hospital mortality of patients with severe SARS-CoV-2 pneumonia in a multicenter series of patients treated with tocilizumab compared to controls, and adjusted using IPTW. Our results show a beneficial impact of tocilizumab treatment in SARS-CoV-2 pneumonia, that adds to that of steroids.

Ferritin status during prenatal brain development may influence the risk of attention deficit and hyperactivity disorder (ADHD) symptoms in childhood. We investigated the association of maternal ferritin in pregnancy and ADHD-like symptoms in offspring. A total of 1095 mother-child pairs from three birth cohorts of the INMA Project (Spain) were studied. Maternal plasma ferritin in pregnancy was measured at 11.57 weeks of gestation. Children&prime, s ADHD-like symptoms at ages 4&ndash, 5 years were assessed using the ADHD Rating Scale-IV. The count model of the zero-inflated Poisson regression model showed a significant inverse association between ferritin (continuous variable) and inattention, &beta, = &minus, 0.19 (&minus, 0.32, &minus, 0.07), for boys. Comparing ferritin level by tertiles, significant differences were observed between the first tertile ([1.98, 20.92]) and the second ([20.92, 38.79]) and third tertiles ([38.79, 216.5]) (mg/L).The number of symptoms was lower for those in the third tertile, &beta, 0.3 (&minus, 0.55, &minus, 0.5), and for those in the second one, &beta, 0.37 (&minus, 0.6, &minus, 0.14). The model stratification by sex also showed this inverse association for boys only, &beta, 0.21 (&minus, 0.34, &minus, 0.08). No associations were found between ferritin level and hyperactivity or total ADHD symptoms. High ferritin levels during pregnancy show a protective association with child inattentive-type ADHD symptoms.

Volume 57, no. 8, e00363-19, 2019, [https://doi.org/10.1128/JCM.00363-19][1]. This article was published on 26 July 2019 with the title “Invasive Pneumococcal Disease and Influenza Activity in a Pediatric Population: Impact of PCV13 Vaccination in Pandemic and Nonpandemic Influenza Periods.” The

BACKGROUND Obesity is a risk factor for non-alcoholic fatty liver disease (NAFLD), although obese patients with NAFLD do not always develop significant fibrosis. The distribution of body fat could predict the risk of NAFLD progression. AIM To investigate the role of bioelectrical impedance-estimated visceral fat (VF) in assessing NAFLD severity. METHODS In this cross-sectional study, patients with biopsy-proven NAFLD were prospectively included. All patients underwent anthropometric evaluation, blood tests and bioelectrical impedance analysis. RESULTS Between 2017 and 2020, 119 patients were included [66.4% male, 56 years (SD 10.7), 62.2% obese, 61.3% with metabolic syndrome]. Sixty of them (50.4%) showed significant fibrosis (≥ F2) in liver biopsy. Age, VF and metabolic syndrome were associated with significant fibrosis (61 years vs 52 years, 16.4 vs 13.1, 73.3% vs 49.2%, respectively; P < 0.001 for all). In the multivariate analysis, VF and age were independently associated with significant fibrosis (VF, OR: 1.11, 95%CI: 1.02-1.22, P = 0.02; age, OR: 1.08, 95%CI: 1.03-1.12, P < 0.01). A model including these variables showed and area under the receiver operating characteristic curve (AUROC) of 0.75, which was not inferior to transient elastography or NAFLD fibrosis score AUROCs. We developed a nomogram including age and VF for assessing significant fibrosis in routine practice. CONCLUSION VF is a surrogate marker of liver fibrosis in patients with NAFLD. Bioelectrical impedance analysis is an inexpensive and simple method that can be combined with age to guide patient referral when other resources may be unavailable.

Highlights • Dexamethasone, or alternative steroids, are recommended in severe COVID-19. • The use of tocilizumab in COVID-19, with or without steroids, is still controversial. • Risk for mortality was assessed in 186 COVID-19 patients receiving tocilizumab. • Mortality was associated with older age, chronic heart failure and liver disease. • In tocilizumab-treated patients, the additional use of steroids was beneficial., Objectives To assess the characteristics and risk factors for mortality in patients with severe COVID-19 treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). Methods From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. Results A total of 1,092 COVID-19 patients were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186, 155 (83.3 %) patients were receiving non-invasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (± 4.3) and 4.3 days (± 3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p

Among HIV-infected individuals, screening for bone disease is encouraged to assess reversible risk factors and plan therapeutic interventions.We assessed the usefulness of Fracture Risk Assessment (FRAX) tool to identify candidates for dual X-ray absorptiometry (DXA) scan, or individuals with bone loss progression. We further explored how secondary causes of osteoporosis are reflected on FRAX.Longitudinal study of 217 consecutive individuals (mean, 45.8 years, 24% females) included after DXA scan. FRAX was calculated without/with femoral neck bone mineral density (BMD), checking the box of "secondary osteoporosis" for all the individuals.Low BMD was observed in 133/217 (61%) individuals, of whom 98.5% had not been selected as candidates for DXA by current FRAX thresholds. Specifically, 23% of individuals aged50 had low BMD but none was candidate for DXA. Adding BMD data, FRAX results increased by 50-100%, with 2/217 individuals (1%) above the thresholds. Classical and HIV-related secondary causes of osteoporosis (observed in 98% overall) correlated with low BMD, modifying significantly FRAX results (HCV coinfection, +124%; longer time of HIV infection, +93%; longer time on antiretroviral therapy, +147%; tenofovir exposure +36%). Individuals with lower BMD and higher FRAX results at inclusion had less bone decline in a follow-up DXA after a median of 3.5 years.Currently recommended FRAX thresholds are not useful to select candidates for DXA scan, which could delay its performance in a population with a high prevalence of secondary factors for low BMD. Classical and HIV-related factors alter BMD and fracture risk estimation.

Introduction: Human immunodeficiency virus (HIV) infection and cirrhosis are associated with a senescent phenotype that decreases telomere length. We evaluated the impact of hepatitis C virus (HCV) elimination on telomere length in patients with advanced HCV-related cirrhosis after sustained virological response (SVR), with all-oral direct-acting antiviral agents (DAAs). Methods: Prospective study of 60 HIV/HCV-coinfected and 30 HCV-monoinfected patients with advanced HCV cirrhosis (liver decompensation or liver stiffness measurement (LSM) &ge, 25 kPa, hepatic liver pressure gradient (HVPG) &ge, 10 mmHg, or Child&ndash, Pugh&ndash, Turcotte (CPT) &ge, 7). The relative telomere length (RTL) was quantified by real-time multiplex PCR (MMqPCR) on peripheral blood mononuclear cells at baseline and 48 weeks after HCV treatment. Generalized linear models (GLMs) adjusted for the most relevant clinical and epidemiological variables and mixed GLMs were used. Results: In comparison with HCV-monoinfected patients, HIV/HCV-coinfected patients were younger (p &lt, 0.001), had lower body mass index (BMI) (p = 0.002), and had been exposed less frequently to interferons (p = 0.011). In addition, they were more frequently men (p = 0.011), smokers (p = 0.005), prior intravenous drug users (IVDUs) (p &lt, 0.001), and alcohol abusers (p = 0.005). RTL was significantly lower in HIV/HCV-coinfected patients than in HCV-monoinfected patients, both at baseline (p &lt, 0.001), and at the end of follow-up (p = 0.032). A significant RTL increase over time was found only for HIV/HCV-coinfected patients (p &lt, 0.001), especially in those patients with compensated cirrhosis (p &lt, 0.001). Conclusion: HCV eradication with all-oral DAAs was associated with an increase in telomere length in HIV/HCV-coinfected patients with advanced cirrhosis, particularly in compensated patients. This finding suggests that HCV clearance may have implications in age-related conditions in this population group.