To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical ...outcomes similar to those of 14-day schemes.
A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis.
248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments.
7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.
The Mediterranean diet is a well-recognized healthy diet that has shown to induce positive changes in gut microbiota. Lifestyle changes such as diet along with physical activity could aid in weight ...loss and improve cardiovascular risk factors.
To investigate the effect of an intensive lifestyle weight loss intervention on gut microbiota.
This is a substudy of the PREDIMED-Plus (Prevención con Dieta Mediterránea-Plus), a randomized controlled trial conducted in overweight/obese men and women (aged 55–75 y) with metabolic syndrome. The intervention group (IG) underwent an intensive weight loss lifestyle intervention based on an energy-restricted Mediterranean diet (MedDiet) and physical activity promotion, and the control group (CG) underwent a non-energy-restricted MedDiet for 1 y. Anthropometric, biochemical, and gut microbial 16S rRNA sequencing data were analyzed at baseline (n = 362) and 1-y follow-up (n = 343).
IG participants had a weight loss of 4.2 (IQR, –6.8, –2.5) kg compared with 0.2 (IQR, –2.1, 1.4) kg in the CG (P < 0.001). Reductions in BMI, fasting glucose, glycated hemoglobin, and triglycerides and an increase in HDL cholesterol were greater in IG than in CG participants (P < 0.05). We observed a decrease in Butyricicoccus, Haemophilus, Ruminiclostridium 5, and Eubacterium hallii in the IG compared with the CG. Many genera shifted in the same direction within both intervention groups, indicating an overall effect of the MedDiet. Decreases in Haemophilus, Coprococcus 3, and few other genera were associated with a decrease in adiposity parameters in both intervention groups. Changes in Lachnospiraceae NK4A136 were positively associated with changes in MedDiet adherence.
Weight loss induced by an energy-restricted MedDiet and physical activity induce changes in gut microbiota. The role of MedDiet-induced changes on the host might be via short-chain fatty acid producing bacteria, whereas with energy restriction, these changes might be modulated with other mechanisms, which need to be explored in future studies. This trial was registered at http://www.isrctn.com/ISRCTN89898870 as ISRCT 89898870.
Previous studies have shown beneficial associations between fruit and vegetable (FV) consumption and cardiometabolic risk factors. However, variety in FV, which may play an important role on ...cardiovascular health due to the different nutrient and phytochemical content among the different groups and subgroups of FV has been poorly investigated. We longitudinally investigated associations between 1-year changes in variety and quantity of FV and concurrent changes in cardiometabolic risk factors in elderly subjects with overweight/obesity and metabolic syndrome.
a one-year data longitudinal analysis of 6647 PREDIMED-plus study participants (48% women) was conducted. Data were collected at baseline, six months and 1-year of follow-up. Variety and quantity of FV were estimated using a food frequency questionnaire and continuous scores for variety were created based on items/month of FV. Linear mixed-models adjusted for potential confounders were performed to estimate associations (β-coefficients and 95% confidence interval) between 1-year changes in FV variety and/or quantity and concurrent changes in cardiometabolic risk factors.
Two points increment in the FV variety score over one year was associated with a concurrent decrease in glucose (-0.33 mg/dL (0.58, -0.07)), body weight (-0.07 kg (-0.13, -0.02)) and waist circumference (WC) (-0.08 cm (-0.16, -10.01)). An increment of 100 g/d of FV over one year was associated with a concurrent decrease in triglycerides (-0.50 mg/dL (-0.93, -0.08)), glucose (-0.21 mg/dL (-0.32, -0.11)), body weight (-0.11 kg (-0.15, -0.07)) and WC (-0.10 cm (-0.14, -0.06)) over 1-year. Changes in FV consumption which led to higher quantity and variety over one year were associated with downward changes in glucose (-1.26 mg/dL (-2.09, -0.43)), body weight (-0.40 kg (-0.58, -0.23)) and WC (-0.50 cm (-0.73, -0.28)).
Greater variety, in combination with higher quantity of FV was significantly associated with a decrease in several cardiometabolic risk factors among elderly subjects at high cardiovascular risk.
•Eggs, fish and seafood, and fruits and vegetables contributed the most to the PFOS dietary intake.•Dietary intake of PFOS was associated with fasting plasma glucose and HbA1c at baseline.•Dietary ...intake of PFOS was associated with an increase in HOMA-IR and BMI after 1-year of follow-up.
Endocrine disruptors (EDs) have emerged as potential contributors to the development of type-2 diabetes. Perfluorooctane sulfonate (PFOS), is one of these EDs linked with chronic diseases and gathered attention due to its widespread in food.
To assess at baseline and after 1-year of follow-up associations between estimated dietary intake (DI) of PFOS, and glucose homeostasis parameters and body-mass-index (BMI) in a senior population of 4600 non-diabetic participants from the PREDIMED-plus study.
Multivariable linear regression models were conducted to assess associations between baseline PFOS-DI at lower bound (LB) and upper bound (UB) established by the EFSA, glucose homeostasis parameters and BMI.
Compared to those in the lowest tertile, participants in the highest tertile of baseline PFOS-DI in LB and UB showed higher levels of HbA1c β-coefficient(CI) 0.01 %(0.002 to 0.026), and 0.06 mg/dL(0.026 to 0.087), both p-trend ≤ 0.001, and fasting plasma glucose in the LB PFOS-DI 1.05 mg/dL(0.050 to 2.046),p-trend = 0.022. Prospectively, a positive association between LB of PFOS-DI and BMI 0.06 kg/m2(0.014 to 0.106) per 1-SD increment of energy-adjusted PFOS-DI was shown. Participants in the top tertile showed an increase in HOMA-IR 0.06(0.016 to 0.097), p-trend = 0.005 compared to participants in the reference tertile after 1-year of follow-up.
This is the first study to explore the association between DI of PFOS and glucose homeostasis. In this study, a high baseline DI of PFOS was associated with a higher levels of fasting plasma glucose and HbA1c and with an increase in HOMA-IR and BMI after 1-year of follow-up.
Background: In adult rats we study the short- and long-term effects of focal blue light-emitting diode (LED)-induced phototoxicity (LIP) on retinal thickness and Iba-1+ activation. Methods: The left ...eyes of previously dark-adapted Sprague Dawley (SD) rats were photoexposed to a blue LED (20 s, 200 lux). In vivo longitudinal monitoring of retinal thickness, fundus images, and optical retinal sections was performed from 1 to 30 days (d) after LIP with SD-OCT. Ex vivo, we analysed the population of S-cone and Iba-1+ cells within a predetermined fixed-size circular area (PCA) centred on the lesion. Results: LIP resulted in a circular focal lesion readily identifiable in vivo by fundus examination, which showed within the PCAs a progressive thinning of the outer retinal layer, and a diminution of the S-cone population to 19% by 30 d. In parallel to S-cone loss, activated Iba-1+ cells delineated the lesioned area and acquired an ameboid morphology with peak expression at 3 d after LIP. Iba-1+ cells adopted a more relaxed-branched morphology at 7 d and by 14–30 d their morphology was fully branched. Conclusion: LIP caused a progressive reduction of the outer retina with loss of S cones and a parallel dynamic activation of microglial cells in the lesioned area.
We studied short- and long-term effects of intravitreal injection of
-methyl-d-aspartate (NMDA) on melanopsin-containing (m
) and non-melanopsin-containing (Brn3a
) retinal ganglion cells (RGCs). In ...adult SD-rats, the left eye received a single intravitreal injection of 5µL of 100nM NMDA. At 3 and 15 months, retinal thickness was measured in vivo using Spectral Domain-Optical Coherence Tomography (SD-OCT). Ex vivo analyses were done at 3, 7, or 14 days or 15 months after damage. Whole-mounted retinas were immunolabelled for brain-specific homeobox/POU domain protein 3A (Brn3a) and melanopsin (m), the total number of Brn3a
RGCs and m
RGCs were quantified, and their topography represented. In control retinas, the mean total numbers of Brn3a
RGCs and m
RGCs were 78,903 ± 3572 and 2358 ± 144 (mean ± SD;
= 10), respectively. In the NMDA injected retinas, Brn3a
RGCs numbers diminished to 49%, 28%, 24%, and 19%, at 3, 7, 14 days, and 15 months, respectively. There was no further loss between 7 days and 15 months. The number of immunoidentified m
RGCs decreased significantly at 3 days, recovered between 3 and 7 days, and were back to normal thereafter. OCT measurements revealed a significant thinning of the left retinas at 3 and 15 months. Intravitreal injections of NMDA induced within a week a rapid loss of 72% of Brn3a
RGCs, a transient downregulation of melanopsin expression (but not m
RGC death), and a thinning of the inner retinal layers.
Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of liver alterations that can result in severe disease and even death. Consumption of ultra-processed foods (UPF) has been associated ...with obesity and related comorbidities. However, the link between UPF and NAFLD has not been sufficiently assessed. We aimed to investigate the prospective association between UPF consumption and liver health biomarkers. Methods: We followed for 1 year 5867 older participants with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus trial. A validated 143-item semi-quantitative food frequency questionnaire was used to evaluate consumption of UPF at baseline, 6, and 12 months. The degree of processing for foods and beverages (g/day) was established according to the NOVA classification system. The non-invasive fatty liver index (FLI) and hepatic steatosis index (HSI) were used to evaluate liver health at three points in time. The associations between changes in UPF consumption (percentage of total daily dietary intake (g)) and liver biomarkers were assessed using mixed-effects linear models with repeated measurements. Results: In this cohort, UPF consumption at baseline was 8.19% (SD 6.95%) of total daily dietary intake in grams. In multivariable models, each 10% daily increment in UPF consumption in 1 year was associated with significantly greater FLI (β 1.60 points, 95% CI 1.24;1.96 points) and HSI (0.43, 0.29; 0.57) scores (all p-values < 0.001). These associations persisted statistically significant after adjusting for potential dietary confounders and NAFLD risk factors. Conclusions: A higher UPF consumption was associated with higher levels of NAFLD-related biomarkers in older adults with overweight/obesity and MetS.
Our aim was to assess the relationship between serum adalimumab levels, anti-drug antibodies (ADA) and disease activity in patients with axial spondylarthritis (SpA). We have carried out a ...single-centre cross-sectional study. adalimumab and ADA levels were analysed with ELISA and correlated with SpA activity using BASDAI and ASDAS scores. Adalimumab cut-off value was calculated to discriminate inactive disease/low disease activity (BASDAI < 4; ASDAS < 2.1) from moderate/high disease activity (BASDAI ≥ 4; ASDAS ≥ 2.1), using a receiver operating characteristic (ROC) curve. Up to January 2016, 51 consecutive patients were included. The median (range) age was 46.6 (18–68) and 47.1% were women. ADA prevalence was 27.5%, with none detected in the 21.6% receiving concomitant disease-modifying antirheumatic drugs (DMARDs) (
p
= 0.021). Adalimumab level was normal (> 3 mg/l) in 36 patients (70.6%), all without ADA. Fifteen patients (29.4%) had subtherapeutic adalimumab levels (< 3 mg/l), with ADA in 14 (93%). Median adalimumab (mg/l) was significantly higher in patients with inactive disease/low disease activity: BASDAI < 4 vs ≥ 4: 9.5 vs 2.6 (
p
< 0.01); ASDAS-CRP < 2.1 vs ≥ 2.1: 9.3 vs 0.3 (
p
< 0.001); ASDAS-ESR < 2.1 vs ≥ 2.1: 9.9 vs 3.0 (
p
< 0.001), and this finding was consistent with the result of the multivariate model. Patients with inactive disease/low disease activity presented significantly lower ADA levels. The adalimumab level cut-offs and area under the curve (AUC) obtained in the ROC curves were: ASDAS-CRP (< 2.1) 4.6 mg/l (AUC 81.2%; 95% CI 67.5–94.9;
p
< 0.001); ASDAS-ESR (< 2.1) 7.7 mg/l (AUC 82.4%; 95% CI 69.3–95.5;
p
< 0.001); BASDAI (< 4) 6.4 mg/l (AUC 73.5%; 95% CI 58.6–88.3;
p
< 0.01). In conclusion, presence of ADA in axial SpA patients treated with adalimumab was associated with lower serum drug levels. ADA levels were lower and adalimumab levels were higher in patients with inactive disease/low disease activity based on BASDAI and ASDAS indices. Concomitant treatment with MTX reduces de likelihood of finding ADA. Serum adalimumab levels above 4.6 mg/l are recommended to avoid compromising efficacy.
Purpose: To evaluate the optimal therapeutic window of 7,8‐Dihydroxyflavone (DHF), an agonist of TrkB receptor, as a neuroprotectant for degenerative retinal ganglion cells (RGCs) due to an ...excitotoxic damage with N‐methyl‐D‐aspartic acid (NMDA).
Methods: In adult albino Sprague–Dawley rats, NMDA (5 μl of 100 nM) was intravitreally injected into the left eye (day 0) and the animals were sacrificed after 7 days. In these animals, the treatment regimen of systemically administered DHF (5 mg/kg) was evaluated in four groups of increasing dose range (n = 8/group): a single injection of DHF (day −1), two injections (days −1 and 0), four injections (days −1, 0, 1 and 2) and seven injections (day −1 and one daily injection until processing). The number of Brn3a+RGCs was automatically quantified in whole‐mounted retinas. Once the optimal dose of DHF was stablished, the time course of Brn3a+RGCs degeneration was analysed at 3, 7 and 14 days after NMDA administration (n = 8/time‐point) and their treatment with 4 injections of DHF or vehicle (0.9% NaCl containing 1% DMSO). The number of Brn3a+RGCs in injured retinas was quantified and the spatial distribution was assessed with isodensity maps. As control, intact retinas were used.
Results: Seven days after NMDA injury, DHF treatment increases the percentage of surviving Brn3a+RGCs from 27% to 68% when retinas were treated with one injection to four injections, respectively (p < 0.05). No significant changes were found between four or seven DHF injections, indicating that the optimal treatment regimen for DHF is four injections and showing a rescue of Brn3a+RGCs over the entire retinal surface. Using this DHF dose at different time‐points after NMDA injury, DHF treatment rescues most Brn3a+RGCs degeneration at 3 days and it decreases up to 56% at 14 days.
Conclusions: DHF prevents RGC death following NMDA excitotoxic damage.
Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection ...rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients.
We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype–phenotype correlation.
We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25–26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1–0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype.
In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.
•To date, the total spectrum of pathogenic variants in Mexican patients with cystic fibrosis is ninety-five.•10 novel pathogenic variants are described that will help to deep into the pathophysiology of the disease.•In the Mexican population, it is necessary to combine different tools for the molecular diagnosis of CF.
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