A global rise in alluvial mining increases sediment load in tropical rivers.

Increasing gold and mineral mining activity in rivers across the global tropics has degraded ecosystems and threatened human health1,2. Such river mineral mining involves intensive excavation and sediment processing in river corridors, altering river form and releasing excess sediment downstream2. Increased suspended sediment loads can reduce water clarity and cause siltation to levels that may result in disease and mortality in fish3,4, poor water quality5 and damage to human infrastructure6. Although river mining has been investigated at local scales, no global synthesis of its physical footprint and impacts on hydrologic systems exists, leaving its full environmental consequences unknown. We assemble and analyse a 37-year satellite database showing pervasive, increasing river mineral mining worldwide. We identify 396 mining districts in 49 countries, concentrated in tropical waterways that are almost universally altered by mining-derived sediment. Of 173 mining-affected rivers, 80% have suspended sediment concentrations (SSCs) more than double pre-mining levels. In 30 countries in which mining affects large (>50 m wide) rivers, 23 ± 19% of large river length is altered by mining-derived sediment, a globe-spanning effect representing 35,000 river kilometres, 6% (±1% s.e.) of all large tropical river reaches. Our findings highlight the ubiquity and intensity of mining-associated degradation in tropical river systems.

Multifractality in spin glasses.

We unveil the multifractal behavior of Ising spin glasses in their low-temperature phase. Using the Janus II custom-built supercomputer, the spin-glass correlation function is studied locally. Dramatic fluctuations are found when pairs of sites at the same distance are compared. The scaling of these fluctuations, as the spin-glass coherence length grows with time, is characterized through the computation of the singularity spectrum and its corresponding Legendre transform. A comparatively small number of site pairs controls the average correlation that governs the response to a magnetic field. We explain how this scenario of dramatic fluctuations (at length scales smaller than the coherence length) can be reconciled with the smooth, self-averaging behavior that has long been considered to describe spin-glass dynamics.

Dispersal history of SARS-CoV-2 in Galicia, Spain.

The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron-BA.1 variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the United States became increasingly significant. The number of detected introductions varied from 96 and 101 for Alpha and Delta to 39 for Omicron-BA.1. Most of these introductions left a low number of descendants (<10), suggesting a limited impact on the evolution of the pandemic in Galicia. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

Feasibility of allogeneic hematopoietic stem cell transplantation in advanced age.

Although it is known that increasing age is associated with increased morbidity and mortality in allogeneic transplantation (allo-HSCT), individualization of the process may allow to perform it in progressively older patients.This study analyzed the outcome of 97 patients older than 60 years with a first allo-HSCT performed at our institution between 2011 and 2019.Median age was 66 years (range 60-79) and 15.4% were older than 70 years. The most frequent diagnosis was acute leukemia (50.5%), and 58.8% received a myeloablative conditioning. With a median follow-up of 33.9 months (range 7.9-111.5), at 3-years overall survival (OS) was 50%; progression-free survival (PFS), 46%; cumulative incidence of relapse, 22%; and non-relapse mortality (NRM), 32%. There were no significant differences in OS (p = 0.415), PFS (p = 0.691), cumulative incidence of relapse (p = 0.357) or NRM (p = 0.658) between patients of 60-64 years (n = 37), 65-69 (n = 45) and ≥ 70 years (n = 15). No differences were observed either depending on the intensity of the conditioning regimen in terms of OS (p = 0.858), PFS (p = 0.729), cumulative incidence of relapse (p = 0.416) or NRM (p = 0.270).In conclusion, older adults can safely and effectively undergo allo-HSCT with proper patient selection and individualized transplantation procedures.

Targeted bacterial conjugation mediated by synthetic cell-to-cell adhesions.

Genetic interventions on microbiomes, for clinical or biotechnological purposes, remain challenging. Conjugation-based delivery of genetic cargo is still unspecific and limited by low conjugation rates. Here we report an approach to overcome these problems, based on a synthetic bacterial adhesion system. Mating assemblers consist on a synthetic adhesion formed by the expression on the surface of donor and target cells of specific nanobodies (Nb) and their cognate antigen (Ag). The Nb-Ag bridge increased 1-3 logs transfer of a variety of plasmids, especially in liquid media, confirming that cell-cell docking is a main determinant limiting mating efficiency. Synthetic cell-to-cell adhesion allows efficient conjugation to targeted recipients, enhancing delivery of desired genes to a predefined subset of prey species, or even specific pathogenic strains such as enterohemorrhagic Escherichia coli (EHEC), within a bacterial community. The synthetic conjugation enhancer presented here optimizes plasmid delivery by selecting the target hosts with high selectivity.

Visual outcomes after treatment of craniopharyngioma in children: A systematic review.

OBJECTIVE: Craniopharyngiomas (CP) are rare brain tumors that often result in visual impairment due to their proximity to the optic pathway. The optimal management approach to preserve visual function in these patients remains controversial. We sought to investigate visual outcomes of children with craniopharyngiomas based on treatment modality. METHODS: A systematic review was performed according to PRISMA guidelines. PubMed, Embase, and Scopus databases were searched in December 2022 for relevant articles. Articles were screened by title/abstract for relevance, then by full-text. Relevant demographic, intervention, and outcome data were extracted from included studies. RESULTS: A total of 59 studies were included, representing 2655 patients. The overall visual status (OVS) of patients receiving surgery alone was improved in 27.6% of reported outcomes, unchanged in 50.3%, and deteriorated in 22.1%. The OVS for patients receiving radiation alone was improved in 21.1%, unchanged in 42.1%, and deteriorated in 36.8%. Patients receiving surgery plus adjuvant radiotherapy had OVS improvement in 27.4%, unchanged in 63.2%, and deteriorated in 9.4%. Of those receiving intracystic bleomycin, 23.1% had improvement in OVS, 46.2% remained unchanged, and 30.8% deteriorated. Of patients receiving interferon-α, 34.8% improved, 54.5% remained unchanged, and 10.6% deteriorated. CONCLUSION: OVS most frequently remained unchanged regardless of intervention. The greatest improvement in OVS was seen in those receiving interferon-α or surgery alone. The greatest OVS deterioration was noted with radiation alone. Future standardized, randomized, large-scale studies with focused assessment of ophthalmologic findings are key to further understanding the impact different interventions have on visual outcomes in these children.

Resident training in interventional pathology: Ultrasound-guided fine-needle aspiration and rapid on site evaluation-5 years of teaching experience in a single university hospital.

INTRODUCTION: Despite the established role of the interventional pathologist, their diagnostic performance is difficult to establish. At least in Spain training of pathology residents in ultrasound-guided interventional procedures for specimen collection is limited or absent in most institutions. We present our teaching experience in the instruction of ultrasound-guided fine-needle aspiration (FNA) to pathology residents in a tertiary-level hospital. MATERIALS AND METHODS: The training of pathology residents who rotated through the interventional unit of the pathology department and the application of ultrasound-guided FNA and rapid on-site evaluation (U-ROSE) was documented over 5 years. The training period was broken down into learning phases and included the number of ultrasound-guided FNA performed, anatomical location, and their diagnostic performance, among other aspects. RESULTS: Nineteen (19) pathology residents were trained in U-ROSE, and performed a total of 4003 procedures, with a mean of 211 per resident. In 53% of cases only one pass was required for an adequated sample. The specimen was diagnostic in more than 97% of cases. The most frequently sampled anatomical sites were the thyroid gland (n = 2347), followed by lymph node (n = 667), soft tissues (n = 663) and salivary glands (n = 322). CONCLUSION: The results support the training programme followed by pathology residents in learning U-ROSE, which is essential to lay the foundations for the future interventional pathologist.

The global challenge of reducing mercury contamination from artisanal and small-scale gold mining (ASGM): evaluating solutions using generic theories of change.

Mercury contamination from artisanal and small-scale gold mining (ASGM) currently accounts for 37% of the global total, often affecting tropical regions where regulations, if they exist, are often poorly enforced. Ingestion by people and other animals damages the nervous, reproductive, and cognitive systems. Despite the efforts of many organizations and governments to curb mercury releases from ASGM, it is increasing globally. There are many possible interventions, all with significant complexity and cost. Therefore, we recommend taking an established systematic approach to articulate the current situation and construct theories of change (ToC) for different possible interventions for any government or organization trying to solve this problem. Here we present a high-level situation analysis and generic ToC to support a more coordinated approach that explicitly builds upon previous experience to identify organization- and situation-appropriate engagement on this issue. We then illustrate the use of these generic models to construct a specific ToC with a policy-focused entry point. This includes interventions through (1) engagement with the global Minamata Convention on Mercury; (2) support for existing national laws and policies connected to ASGM and mercury contamination; and (3) engagement of indigenous people and local communities with governments to meet the governments' legal obligations. By methodically articulating assumptions about interventions, connections among actions, and desired outcomes, it is possible to create a more effective approach that will encourage more coordination and cooperation among governments and other practitioners to maximize their investments and support broad environmental and socio-political outcomes necessary to address this pernicious problem.

Mercury bioaccumulation in bats in Madre de Dios, Peru: implications for Hg bioindicators for tropical ecosystems impacted by artisanal and small-scale gold mining.

Mercury (Hg) endangers human and wildlife health globally, primarily due to its release from artisanal small-scale gold mining (ASGM). During gold extraction, Hg is emitted into the environment and converted to highly toxic methylmercury by microorganisms. In Madre de Dios (MDD), Peru, ASGM dominates the economy and has transformed rainforests into expansive deforested areas punctuated by abandoned mining ponds. The aim of this study was to evaluate the use of bats as bioindicators for mercury pollution intensity in tropical terrestrial ecosystems impacted by ASGM. We collected 290 bat fur samples from three post-ASGM sites and one control site in Madre de Dios. Our results showed a wide Hg distribution in bats (0.001 to 117.71 mg/kg) strongly influenced by feeding habits. Insectivorous and piscivorous bats from ASGM sites presented elevated levels of Hg surpassing the mercury small mammal threshold for small mammals (10 mg/kg). We observed the highest reported fur mercury concentrations for insectivorous Neotropical bats reported to date (Rhynchonycteris naso, 117 mg/kg). Our findings further confirm that Hg emissions from ASGM are entering local food webs and exposing wildlife species at several trophic levels to higher levels of Hg than in areas not impacted by mining. We also found that three bat genera consistently showed increased Hg levels in ASGM sites relative to controls indicating potential usefulness as bioindicators of mercury loading in terrestrial ecosystems impacted by artisanal and small-scale gold mining.

Elevated mercury exposure in bird communities inhabiting Artisanal and Small-Scale Gold Mining landscapes of the southeastern Peruvian Amazon.

Artisanal and Small-Scale Gold Mining (ASGM) represents a significant source of anthropogenic mercury emissions to the environment, with potentially severe implications for avian biodiversity. In the Madre de Dios department of the southern Peruvian Amazon, ASGM activities have created landscapes marred by deforestation and post-mining water bodies (mining ponds) with notable methylation potential. While data on Hg contamination in terrestrial wildlife remains limited, this study measures Hg exposure in several terrestrial bird species as bioindicators. Total Hg (THg) levels in feathers from birds near water bodies, including mining ponds associated with ASGM areas and oxbow lakes, were analyzed. Our results showed significantly higher Hg concentrations in birds from ASGM sites with mean ± SD of 3.14 ± 7.97 µg/g (range: 0.27 to 72.75 µg/g, n = 312) compared to control sites with a mean of 0.47 ± 0.42 µg/g (range: 0.04 to 1.89 µg/g, n = 52). Factors such as trophic guilds, ASGM presence, and water body area significantly influenced feather Hg concentrations. Notably, piscivorous birds exhibited the highest Hg concentration (31.03 ± 25.25 µg/g, n = 12) exceeding known concentrations that affect reproductive success, where one measurement of Chloroceryle americana (Green kingfisher; 72.7 µg/g) is among the highest ever reported in South America. This research quantifies Hg exposure in avian communities in Amazonian regions affected by ASGM, highlighting potential risks to regional bird populations.

Global mercury concentrations in biota: their use as a basis for a global biomonitoring framework.

An important provision of the Minamata Convention on Mercury is to monitor and evaluate the effectiveness of the adopted measures and its implementation. Here, we describe for the first time currently available biotic mercury (Hg) data on a global scale to improve the understanding of global efforts to reduce the impact of Hg pollution on people and the environment. Data from the peer-reviewed literature were compiled in the Global Biotic Mercury Synthesis (GBMS) database (>550,000 data points). These data provide a foundation for establishing a biomonitoring framework needed to track Hg concentrations in biota globally. We describe Hg exposure in the taxa identified by the Minamata Convention: fish, sea turtles, birds, and marine mammals. Based on the GBMS database, Hg concentrations are presented at relevant geographic scales for continents and oceanic basins. We identify some effective regional templates for monitoring methylmercury (MeHg) availability in the environment, but overall illustrate that there is a general lack of regional biomonitoring initiatives around the world, especially in Africa, Australia, Indo-Pacific, Middle East, and South Atlantic and Pacific Oceans. Temporal trend data for Hg in biota are generally limited. Ecologically sensitive sites (where biota have above average MeHg tissue concentrations) have been identified throughout the world. Efforts to model and quantify ecosystem sensitivity locally, regionally, and globally could help establish effective and efficient biomonitoring programs. We present a framework for a global Hg biomonitoring network that includes a three-step continental and oceanic approach to integrate existing biomonitoring efforts and prioritize filling regional data gaps linked with key Hg sources. We describe a standardized approach that builds on an evidence-based evaluation to assess the Minamata Convention's progress to reduce the impact of global Hg pollution on people and the environment.

ProsTAV, a novel blood-based test for biopsy decision management in significant prostate cancer.

BACKGROUND: Current pathways in early diagnosis of prostate cancer (PCa) can lead to unnecessary biopsy procedures. Here, we used telomere analysis to develop and evaluate ProsTAV®, a risk model for significant PCa (Gleason score >6), with the objective of improving the PCa diagnosis pathway. METHODS: This retrospective, multicentric study analyzed telomeres from patients with serum PSA 3-10 ng/mL. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate telomere-associated variables (TAVs) in peripheral blood mononucleated cells. ProsTAV® was developed by multivariate logistics regression based on three clinical variables and six TAVs. The predictive capacity and accuracy of ProsTAV® were summarized by receiver operating characteristic (ROC) curves and its clinical benefit with decision curves analysis. RESULTS: Telomeres from 1043 patients were analyzed. The median age of the patients was 63 years, with a median PSA of 5.2 ng/mL and a percentage of significant PCa of 23.9%. A total of 874 patients were selected for model training and 169 patients for model validation. The area under the ROC curve of ProsTAV® was 0.71 (95% confidence interval [CI], 0.62-0.79), with a sensitivity of 0.90 (95% CI, 0.88-1.0) and specificity of 0.33 (95% CI, 0.24-0.40). The positive predictive value was 0.29 (95% CI, 0.21-0.37) and the negative predictive value was 0.91 (95% CI, 0.83-0.99). ProsTAV® would make it possible to avoid 33% of biopsies. CONCLUSIONS: ProsTAV®, a predictive model based on telomere analysis through TAV, could be used to increase the prediction capacity of significant PCa in patients with PSA between 3 and 10 ng/mL.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Significant increase of CTX-M-15-ST131 and emergence of CTX-M-27-ST131 Escherichia coli high-risk clones causing healthcare-associated bacteraemia of urinary origin in Spain (ITUBRAS-2 project).

OBJECTIVES: To assess the microbiological characteristics of Escherichia coli causing healthcare-associated bacteraemia of urinary origin (HCA-BUO) in Spain (ITUBRAS-2 project), with particular focus on ESBL producers and isolates belonging to ST131 high-risk clone (HiRC). Clinical characteristics and outcomes associated with ST131 infection were investigated. METHODS: A total of 222 E. coli blood isolates were prospectively collected from patients with HCA-BUO from 12 tertiary-care hospitals in Spain (2017-19). Antimicrobial susceptibility and ESBL/carbapenemase production were determined. ST131 subtyping was performed. A subset of 115 isolates were selected for WGS to determine population structure, resistome and virulome. Clinical charts were reviewed. RESULTS: ESBL-producing E. coli prevalence was 30.6% (68/222). ST131 represented 29.7% (66/222) of E. coli isolates and accounted for the majority of ESBL producers (46/68, 67.6%). The C2/H30-Rx subclone accounted for most ST131 isolates (44/66) and was associated with CTX-M-15 (37/44) and OXA-1 enzymes (27/44). Cluster C1-M27 was identified in 4/10 isolates belonging to subclade C1/H30-R1 and associated with CTX-M-27. Additionally, ST131 isolates showed a high content of other acquired resistance genes, and clade C/ST131 isolates carried characteristic QRDR mutations. They were categorized as uropathogenic E. coli and had higher aggregate virulence scores. ST131 infection was associated with more complex patients, prior use of cephalosporins and inadequate empirical treatment but was not associated with worse clinical outcomes. CONCLUSIONS: ST131 HiRC is the main driver of ESBL-producing E. coli causing HCA-BUO in Spain, mainly associated with the expansion of subclade CTX-M-15-C2/H30-Rx and the emergence of CTX-M-27-C1/H30-R1 (Cluster C1-M27).

Oxygen saturation during donor warm ischemia time and outcome of donation after circulatory death (DCD) liver transplantation with static cold storage: A review of 1114 cases.

The donor operation and the hemodynamics during declaration resulting in donor warm ischemia time have been linked to the outcomes in donation after circulatory death (DCD) liver transplantation (LT). Scrutiny of the donor hemodynamics at the time of withdrawal of life support concluded that a functional donor warm ischemia time may be associated with LT graft failure. Unfortunately, the definition for functional donor warm ischemia time has not reached a consensus-but has almost always incorporated time spent in a hypoxic state. Herein, we reviewed 1114 DCD LT cases performed at the 20 highest volume centers during 2014 and 2018. Donor hypoxia began within 3 minutes of withdrawal of life support for 60% of cases and within 10 minutes for 95% of cases. Graft survival was 88.3% at 1 year and 80.3% at 3 years. Scrutinizing the time spent under hypoxic conditions (oxygen saturation ≤ 80%) during the withdrawal of life support, we found an increasing risk of graft failure as hypoxic time increased from 0 to 16 minutes. After 16 minutes and up to 50 minutes, we did not find any increased risk of graft failure. In conclusion, after 16 minutes of time in hypoxia, the risk of graft failure in DCD LT did not increase. The current evidence suggests that an over-reliance on hypoxia time may lead to an unnecessary increase in DCD liver discard and may not be as useful for predicting graft loss after LT.

Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx-dependent pyroptosis in intestinal epithelial cells.

Clustering of the enteropathogenic Escherichia coli (EPEC) type III secretion system (T3SS) effector translocated intimin receptor (Tir) by intimin leads to actin polymerisation and pyroptotic cell death in macrophages. The effect of Tir clustering on the viability of EPEC-infected intestinal epithelial cells (IECs) is unknown. We show that EPEC induces pyroptosis in IECs in a Tir-dependent but actin polymerisation-independent manner, which was enhanced by priming with interferon gamma (IFNγ). Mechanistically, Tir clustering triggers rapid Ca2+ influx, which induces lipopolysaccharide (LPS) internalisation, followed by activation of caspase-4 and pyroptosis. Knockdown of caspase-4 or gasdermin D (GSDMD), translocation of NleF, which blocks caspase-4 or chelation of extracellular Ca2+, inhibited EPEC-induced cell death. IEC lines with low endogenous abundance of GSDMD were resistant to Tir-induced cell death. Conversely, ATP-induced extracellular Ca2+ influx enhanced cell death, which confirmed the key regulatory role of Ca2+ in EPEC-induced pyroptosis. We reveal a novel mechanism through which infection with an extracellular pathogen leads to pyroptosis in IECs.

DEAE/Catechol-Chitosan Conjugates as Bioactive Polymers: Synthesis, Characterization, and Potential Applications.

This work provides the first description of the synthesis and characterization of water-soluble chitosan (Cs) derivatives based on the conjugation of both diethylaminoethyl (DEAE) and catechol groups onto the Cs backbone (Cs-DC) in order to obtain a Cs derivative with antioxidant and antimicrobial properties. The degree of substitution [DS (%)] was 35.46% for DEAE and 2.53% for catechol, determined by spectroscopy. Changes in the molecular packing due to the incorporation of both pendant groups were described by X-ray diffraction and thermogravimetric analysis. For Cs, the crystallinity index was 59.46% and the maximum decomposition rate appeared at 309.3 °C, while for Cs-DC, the values corresponded to 16.98% and 236.4 °C, respectively. The incorporation of DEAE and catechol groups also increases the solubility of the polymer at pH > 7 without harming the antimicrobial activity displayed by the unmodified polymer. The catecholic derivatives increase the radical scavenging activity in terms of the half-maximum effective concentration (EC50). An EC50 of 1.20 µg/mL was found for neat hydrocaffeic acid (HCA) solution, while for chitosan-catechol (Cs-Ca) and Cs-DC solutions, concentrations equivalent to free HCA of 0.33 and 0.41 µg/mL were required, respectively. Cell culture results show that all Cs derivatives have low cytotoxicity, and Cs-DC showed the ability to reduce the activity of reactive oxygen species by 40% at concentrations as low as 4 µg/mL. Polymeric nanoparticles of Cs derivatives with a hydrodynamic diameter (Dh) of around 200 nm, unimodal size distributions, and a negative ζ-potential were obtained by ionotropic gelation and coated with hyaluronic acid in aqueous suspension, providing the multifunctional nanoparticles with higher stability and a narrower size distribution.

Polymorphisms indicating risk of inflammatory bowel disease or antigenicity to anti-TNF drugs as biomarkers of response in children.

Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.

Impact of Saccharomyces boulardii CNCM I-745 on Bacterial Overgrowth and Composition of Intestinal Microbiota in Diarrhea-Predominant Irritable Bowel Syndrome Patients: Results of a Randomized Pilot Study.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is associated with diarrhea-predominant irritable bowel syndrome (IBS-D). Probiotics like Saccharomyces boulardii CNCM I-745 (Sb) may be efficacious in balancing the microbiota. This randomized open label study assessed the effect of Sb in patients with bacterial overgrowth associated with IBS-D and its impact on the intestinal microbiota. METHODS: Patients were randomized to receive Sb + dietary advice (Sb + DA) or dietary advice (DA) only for 15 days. SIBO was assessed by the lactulose hydrogen breath test (LHBT). Symptoms were assessed with the IBS Symptom Severity Scale (IBS-SSS) and stool consistency with the Bristol Stool Form Scale. Microbiota and mycobiota were analyzed by 16S rDNA and ITS2. RESULTS: 54 patients were included, among whom 48 (27 Sb + DA, 21 DA) were evaluated. Decrease of hydrogen excretion was slightly higher in Sb + DA group, 41% versus 29% in DA group, and IBS-SSS total score were reduced by -134 and -93, respectively. The proportion of patients with diarrhea was lower in the Sb + DA group than in the DA group (25.9% compared to 47.6%). Bacterial and fungal microbiota showed that Sb treatment was associated with several modifications. Interestingly, F. prausnitzii was more abundant in Sb-treated patients with marked clinical improvement. The safety of S. boulardii CNCM I-745 was excellent. CONCLUSIONS: In patients with SIBO, S. boulardii CNCM I-745 associated with dietary advice reduced bacterial overgrowth and improved digestive symptoms while restoring the intestinal microbiota. The increased abundance of F. prausnitzii coupled with symptom improvement merits further research.