Small Extracellular Vesicles and Oxidative Pathophysiological Mechanisms in Retinal Degenerative Diseases.

This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles' cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.

[Congenital cytomegalovirus infection, is more prevalent in our country in newborns exposed to HIV?] / La infección congénita por citomegalovirus, ¿es más prevalente en nuestro medio en neonatos expuestos al VIH?

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) has been considered more prevalent among HIV-exposed children during pregnancy. Spanish national guidelines recommend the cCMV screening in these newborns. Nowadays, pregnant women have a better control of HIV infection compared to previous decades. We aim to analyze the prevalence and associated risk factors to cCMV in these children. METHODS: A retrospective cross-sectorial study was performed. All newborns exposed to HIV were assisted in a third-level hospital (2014-2020). Epidemiological and clinical data of the mother and newborn were recorded. Shell vial urine culture and/or CRP were performed along the two first weeks of life for the neonatal screening of cCMV. RESULTS: Overall 69 newborns were enrolled. A high proportion (82.4%) of the mothers had been diagnosed with HIV before getting pregnant. All women received ART during the pregnancy. Median T-CD4 lymphocytes before delivery was 641/mm3 (IQR: 480-865) and the viral load was undetectable in 83.6%. Serological test for CMV along the first trimester of pregnancy was performed in 73.5% (positive IgG in 96%). There were no congenital cases of HIV neither cCMV (CI 95%:0-5.3%). CONCLUSIONS: The cCMV prevalence in newborns exposed to HIV was 0%, lower than reported before, probably related to a better and earlier ART during pregnancy, leading to a better immunological status.

Evaluation of a lateral flow immunoassay to detect CTX-M extended-spectrum ß-lactamases (ESBL) directly from positive blood cultures for its potential use in Antimicrobial Stewardship programs.

OBJECTIVE: Bloodstream infections (BSI) caused by extended-spectrum beta-lactamases Enterobacteriaceae (ESBL-E) are associated with high rates of treatment failure and increased mortality, especially when appropriate antimicrobial therapy is delayed. Our aim was to evaluate the anticipation of ESBLs detection and the potential improvement of the time response of the Vitek 2 System (BioMérieux; France). METHODS: We compared this lateral flow immunoassay when used directly on fluid from positive blood cultures to the VITEK2 AST system. We evaluated 80 isolates, 61 tested directly on fluid from positive blood cultures and 19 tested on fluid from blood cultures spiked with known ESBL positive and negative organisms. RESULTS: The concordance between the CTX-LFIA and the reference method (Vitek 2) had a Cohen´s Kappa coefficient of 0.97, indicating a particularly good correlation between both compared methods. CONCLUSIONS: This lateral flow immunoassay can be more rapid than the Vitek 2 for earlier presumptive identification of CTX-M ESBLs and can be useful to anticipate results and the adjustment of antimicrobial therapy.

Predictors of mortality and clinical characteristics among carbapenem-resistant or carbapenemase-producing Enterobacteriaceae bloodstream infections in Spanish children.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging problem in the paediatric population worldwide with high mortality rates in bloodstream infection (BSI). OBJECTIVES: To evaluate predictors of 30 day mortality in CRE BSI in a paediatric cohort. METHODS: A retrospective observational single-centre study (December 2005-August 2018) was conducted. Cases of CRE BSI in children 0 to 16 years were included. Microbiological identification (MALDI Biotyper) and antimicrobial susceptibility testing (Vitek2® and MicroScan panel NBC44) according to EUCAST breakpoints were performed. PCR OXVIKP® was used to confirm carbapenemase genes (OXA-48, VIM, KPC, NDM). Demographic characteristics, underlying diseases, source of bacteraemia, antimicrobial therapy and outcomes were collected from medical records. Survival analysis to establish predictors of 30 day mortality was performed. RESULTS: Thirty-eight cases were included; 76.3% were hospital-acquired infections and 23.7% related to healthcare. All patients had at least one underlying comorbidity and 52.6% were recipients of an organ transplant. VIM carbapenemase was the predominant mechanism (92.1%). Previous CRE colonization or infection rate was 52.6%. Intestinal tract (26.3%) and vascular catheter (21.1%) were the most common sources of infection. Crude mortality within 30 days was 18.4% (7/38); directly related 30 day mortality was 10.5%. Conditions associated with an increment in 30 day mortality were intensive care admission and inadequate empirical therapy (P < 0.05). Combination-antibiotic targeted treatment and a low meropenem MIC were not related to improved survival. CONCLUSIONS: CRE BSI mortality rate is high. The most important factor related to 30 day survival in our CRE BSI cohort in children was empirical treatment that included at least one active antibiotic.

Bloodstream infection due to Herbaspirillum sp.: case series and review of literature.

Herbaspirillum species are Gram-negative bacteria belonging to the class Betaproteobacteria, order Burkholderiales. The phylogenetic and phenotypic similarities among these groups easily lead to species misidentification. Herbaspirillum bacteraemia is an uncommon clinical entity. The objective of this review is to collect information to contribute to the management of this infection. We describe our own case series and review the cases reported in the literature. Cancer appears as the major underlying disease. The main source of bacteraemia was respiratory. Phenotypic identification methods often misidentify this species. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and molecular methods identify at genus level, but species assignment is not reliable. Herbaspirillum spp. showed a highly susceptible antimicrobial profile. ß-Lactams showed good activity with low MIC values, except ampicillin. All isolates were resistant to colistin, suggesting an intrinsic resistance mechanism. Herbaspirillum spp. is an uncommon pathogen. MALDI-TOF MS or molecular methods are necessary to achieve a reliable genus identification. These species are not multidrug resistant. Piperacillin/tazobactam or ceftazidime might be a good treatment for this microorganism.

Does the Antitumor Necrosis Factor-α Therapy Decrease the Vertebral Fractures Occurrence in Inflammatory Bowel Disease?

BACKGROUND/OBJECTIVE: Osteoporosis and osteoporotic fracture risk are extraintestinal manifestations of the inflammatory bowel disease, whose etiopathogenic mechanisms have not been determined yet. Anti-tumor necrosis factor (TNF)-α are used in treatment of inflammatory bowel disease (IBD), but it is unknown if they play a role in osteoporotic fracture prevention. The objective of this study was to know if anti-TNF decreases fracture risk or modifies bone mineral density. To determine the possible risk factors associated with fractures, and assess the incidence of vertebral fractures in IBD patients. METHODS: Longitudinal prospective cohort study (7 yr of follow-up); which included 71 IBD patients, 23 received anti-TNF-α; the remaining 48 received conventional treatment, constituted the control group. Patients participated in a questionnaire which gathered risk factors associated with the development of osteoporosis and fractures. Radiographs of the dorsolumbar-spine were performed and also a bone density measurement. Their biochemical and bone remodeling parameters were determined. RESULTS: Although patients who did not receive anti-TNF-α, suffered more fractures but biologic therapy did not reduce the risk of new vertebral fractures. The increase of bone mass was significantly higher the group treated with anti-TNF-α. The increase in the lumbar spine was of 8% and in the femoral neck was of 6.7%. The only determinant factor for the incidence of vertebral fractures was a history of previous fractures (odds ratio of 12.8; confidence interval 95% 2.37-69.9; p = 0.003). The incidence of vertebral fractures in IBD patients was considerably high: 26.7/700 patient-yr. CONCLUSIONS: Anti-TNF-α, although increased bone mass in these patients, did not reduce the risk of new vertebral fractures. In this study, patients with IBD have a considerably high incidence of fractures. Only the existence of previous vertebral fractures was a predictive factor for consistent fractures.

A dynamically young and perturbed Milky Way disk.

The evolution of the Milky Way disk, which contains most of the stars in the Galaxy, is affected by several phenomena. For example, the bar and the spiral arms of the Milky Way induce radial migration of stars1 and can trap or scatter stars close to orbital resonances2. External perturbations from satellite galaxies can also have a role, causing dynamical heating of the Galaxy3, ring-like structures in the disk4 and correlations between different components of the stellar velocity5. These perturbations can also cause 'phase wrapping' signatures in the disk6-9, such as arched velocity structures in the motions of stars in the Galactic plane. Some manifestations of these dynamical processes have already been detected, including kinematic substructure in samples of nearby stars10-12, density asymmetries and velocities across the Galactic disk that differ from the axisymmetric and equilibrium expectations13, especially in the vertical direction11,14-16, and signatures of incomplete phase mixing in the disk7,12,17,18. Here we report an analysis of the motions of six million stars in the Milky Way disk. We show that the phase-space distribution contains different substructures with various morphologies, such as snail shells and ridges, when spatial and velocity coordinates are combined. We infer that the disk must have been perturbed between 300 million and 900 million years ago, consistent with estimates of the previous pericentric passage of the Sagittarius dwarf galaxy. Our findings show that the Galactic disk is dynamically young and that modelling it as time-independent and axisymmetric is incorrect.

Impact of rapid diagnosis of Staphylococcus aureus bacteremia from positive blood cultures on patient management.

We have performed a retrospective, before-after comparison of turnaround time and therapy adjustment parameters before and after the introduction of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) plus mecA polymerase chain reaction (PCR) for the identification of methicillin-resistant Staphylococcus aureus (MRSA) in positive blood cultures. There were 227 episodes of S. aureus bacteremia during the study periods. The pre-MALDI-TOF and post-MALDI-TOF groups included 133 and 94 patients, respectively. The two rapid methods performed sequentially decreased the turnaround time of MRSA identification by nearly 50% (2.06 ± 1.95 vs. 3.95 ± 1.70 days). There was no significant reduction in the length of hospitalization (28.27 ± 32.16 vs. 28.62 ± 28.75 days). In both groups, the adequacy of the empirical antibacterial therapy was similar (59.49% vs. 51.31%), but the optimization of the therapy was more frequent in the post-MALDI-TOF group. Routine implementation of these techniques provides results earlier than conventional methods and increases the proportion of episodes with adequate change of empirical to directed antimicrobial therapy.

Effectiveness and Safety of CT-P13 (Biosimilar Infliximab) in Patients with Inflammatory Bowel Disease in Real Life at 6 Months.

BACKGROUND: CT-P13 is a biosimilar of Remicade®, an agent approved in some countries for use in inflammatory bowel disease (IBD). Controlled clinical trials have demonstrated the efficacy and safety of CT-P13 in rheumatic diseases, but not in IBD. AIMS: To assess the effectiveness and safety of CT-P13 in IBD patients in real clinical practice. METHODS: This is a prospective observational study in patients with moderate to severe Crohn's disease or ulcerative colitis treated with CT-P13. The study was performed in one single center. Patients included were naive or switched to anti-TNF treatment from the reference infliximab (Remicade®) to CT-P13. Efficacy and safety were assessed in naive and switched patients who were in remission at the time of the switch at months 3 and 6 of therapy. RESULTS: 87.5 and 83.9% of switched CD patients who were in remission at the time of the switch continued in remission, and 66.7 and 50% of naive CD patients reached remission, at months 3 and 6. In UC switched cases, 92 and 91.3% of patients in remission at the time of the switch continued in remission, at 3 and 6 months. In naive UC patients, the remission rates were 44.4 and 66.7%, at months 3 and 6. Adverse events occurred in 7.5% of patients during 6 months of study. CONCLUSIONS: CT-P13 was efficacious and well tolerated in patients with CD or UC.

Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. AIM: To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. METHODS: Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. RESULTS: Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. CONCLUSIONS: Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807].

Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis.

BACKGROUND: Several recent studies have shown a strong association between non-alcoholic steatohepatitis (NASH) and chronic kidney disease. AIM: To examine the relationship between changes in liver histology and renal function in patients with NASH. METHODS: The present analysis represents a post hoc analysis of a recently published trial that included 261 patients with NASH who were treated with lifestyle modifications during 52 weeks. Kidney function was evaluated through Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rates (eGFR, mL/min/1.73 m2 ) overtime. We explored correlations between the kidney function and improvement in histological outcomes at 52 weeks. RESULTS: Interestingly, a one-stage reduction in fibrosis (r = 0.20, P < 0.01) and resolution of NASH (r = 0.17, P < 0.01) were significantly correlated with an improvement in the kidney function. The eGFR values significantly increased in patients with fibrosis improvement (+7.6 ± 6.5 mL/min/1.73 m2 ), compared to those without fibrosis improvement (-1.98 ± 6.4 mL/min/1.73 m2 ) (P < 0.01) at end of treatment (EOT). Likewise, NASH resolution was associated with an increase in eGFR compared with patients without NASH resolution (2.32 ± 7.8 mL/min/1.73 m2 vs. -1.04 ± 5.9 mL/min/1.73 m2 , P = 0.04) at EOT. After controlling for the confounders, the association between fibrosis improvement, NASH resolution and eGFR change remained significant (P < 0.05 for both). CONCLUSIONS: Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in NASH. As new drugs for NASH emerge, studies should address whether improvement in histology in response to pharmacotherapies yield the same improvement in kidney function as weight loss.

Cost-effectiveness of clinical remission by treat to target strategy in established rheumatoid arthritis: results of the CREATE registry.

To analyse the cost-effectiveness, in daily clinical practice, of the strategy of treating to the target of clinical remission (CR) in patients with established rheumatoid arthritis (RA), after 2 years of treatment with biological therapy. Adult patients with established RA were treated with biological therapy and followed up for 2 years by a multidisciplinary team responsible for their clinical management. Treatment effectiveness was evaluated by the DAS28 score. The direct costs incurred during this period were quantified from the perspective of the healthcare system. We calculated the cost-effectiveness of obtaining a DAS28 < 2.6, considered as CR. The study included 144 RA patients treated with biological therapies. After 2 years of treatment, 32.6% of patients achieved CR. The mean cost of achieving CR at 2 years was 79,681 ± 38,880 euros. The strategy of treatment to the target of CR is considered the most effective, but in actual clinical practice in patients with established RA, it has a high cost.

Role of assessing liver fibrosis in management of chronic hepatitis C virus infection.

Fibrosis progression is common in hepatitis C. Both host and viral factors influence its natural history. Liver fibrosis is a key predictive factor for advanced disease including endpoints such as liver failure, cirrhosis and hepatocellular carcinoma (HCC). METAVIR fibrosis stages F3-F4 have been considered as the threshold for antiviral therapy. However, this aspect is controversial after the advent of new direct-acting antivirals (DAAs) because they show an excellent efficacy and safety profile. Moreover, in the DAA era, fibrosis stage seems not to be a predictive factor of a sustained virological response (SVR). Viral eradication decreases liver damage by improving the inflammation, as well as by regressing fibrosis irrespective of the treatment regimen. Non-invasive methods are useful in the assessment of liver fibrosis, replacing liver biopsy in clinical practice; but their usefulness for monitoring fibrosis after SVR needs to be demonstrated. Fibrosis regression has been demonstrated after the eradication of hepatitis C virus infection and is associated with a lower risk of hepatic cirrhosis and liver cancer. However, patients showing advanced fibrosis and cirrhosis must be followed-up after SVR, as risks of portal hypertension and HCC remain.

Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference.

BACKGROUND: Blood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. AIMS: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. METHODS: We pre-included new NAFLD patients with biopsy and blood tests from a single-centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary-ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. RESULTS: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864-0.892) for FibroTest and fibrosis stages, 0.846 (0.830-0.862) for ActiTest and activity grades, and 0.822 (0.804-0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820-0.852; P = 0.0001), FIB4 (0.845; 0.829-0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850-0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). CONCLUSIONS: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non-invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis.

Real-world cost-effectiveness of infliximab, etanercept and adalimumab in rheumatoid arthritis patients: results of the CREATE registry.

Biological drugs have proven efficacy and effectiveness in treatment of rheumatoid arthritis (RA), although none has been shown to be superior. Few studies have evaluated the cost-effectiveness of biological drugs in real-life clinical conditions. The objective of this study was to compare the cost-effectiveness of infliximab, etanercept and adalimumab in achieving clinical remission (DAS28 < 2.6) when used as initial biological therapy. Patients were diagnosed with RA who began treatment with infliximab, etanercept or adalimumab in the Reina Sofia Hospital (Cordoba, Spain) between January 1, 2007, and December 31, 2012. Effectiveness was measured as the percentage of patients who achieved clinical remission after 2 years. The cost analysis considered the use of direct health resources (perspective of the healthcare system). Cost-effectiveness was calculated by dividing the total mean cost of each treatment by the percentage of patients who achieved remission. One hundred and thirty patients were included: 55 with infliximab, 44 with adalimumab and 31 with etanercept. After 2 years, 45.2 % of patients with adalimumab achieved clinical remission, versus 29.1 % with infliximab (p = 0.133) and 22.7 % with etanercept (p = 0.040), with no differences between etanercept and infliximab (p = 0.475). The average total cost at 2 years was €29,858, €25,329 and €23,309 for adalimumab, infliximab and etanercept, respectively, while the mean cost (95 %CI) to achieve remission was €66,057 (48,038­84,076), €87,040 (78,496­95,584) and €102,683 (94,559­110,807), respectively. Adalimumab was more efficient than etanercept (p < 0.001) and infliximab (p = 0.026), with no differences between etanercept and infliximab (p = 0.086). Adalimumab was the most cost-effective treatment in achieving clinical remission in real-life clinical conditions in RA patients during the study period.