The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. OBJECTIVE: The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. METHODS: This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). RESULTS: Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. CONCLUSIONS: A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Comparison of Mechanical Insufflation-Exsufflation and Hypertonic Saline and Hyaluronic Acid With Conventional Open Catheter Suctioning in Intubated Patients.

BACKGROUND: Open respiratory secretion suctioning with a catheter causes pain and tracheobronchial mucosal injury in intubated patients. The goal of mechanical insufflation-exsufflation (MI-E) is to move secretions proximally and noninvasively by generating a high peak expiratory air flow. Nebulized hypertonic saline with hyaluronic acid (HS-HA) may facilitate suctioning by hydration. We assessed the safety and tolerance of a single session of airway clearance with MI-E and HS-HA in critically ill intubated patients. METHODS: Adults with a cuffed artificial airway were randomized to (1) open suctioning, (2) open suctioning after HS-HA, (3) MI-E, or (4) MI-E with HS-HA. Adverse events, pain and sedation/agitation scores, and respiratory and hemodynamic variables were collected before, during, and 5-min and 60-min post intervention. RESULTS: One-hundred twenty subjects were enrolled and completed the study. Median (interquartile range [IQR]) Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22 (16-28); median (IQR) age was 69.0 (57.0-75.7) y, and 90 (75%) were male. Baseline respiratory and hemodynamic variables were comparable. Adverse events occurred in 30 subjects (25%), with no between-group differences. Behavioral pain equivalents and Richmond Agitation-Sedation Scale were higher during suctioning in groups 1 (P < .001) and 2 (P < .001). Independent predictive variables for higher pain and agitation/sedation scores were study groups 1 and 2 and simultaneous analgosedation, respectively. Noradrenaline infusion rates were lower at 60 min in groups 2 and 4. PaO2 /FIO2 had decreased at 5 min after open suctioning in group 1 and increased at 60 min in group 3. CONCLUSIONS: We observed no difference in adverse events. MI-E avoids pain and agitation.

In vitro evaluation of the osteogenic and antimicrobial potential of porous wollastonite scaffolds impregnated with ethanolic extracts of propolis.

Context: The development of porous devices using materials modified with various natural agents has become a priority for bone healing processes in the oral and maxillofacial field. There must be a balance between the proliferation of eukaryotic and the inhibition of prokaryotic cells to achieve proper bone health. Infections might inhibit the formation of new alveolar bone during bone graft augmentation. Objective: This study aimed to evaluate the in vitro osteogenic behavior of human bone marrow stem cells and assess the antimicrobial response to 3D-printed porous scaffolds using propolis-modified wollastonite. Methodology: A fractional factorial design of experiments was used to obtain a 3D printing paste for developing scaffolds with a triply periodic minimal surface (TPMS) gyroid geometry based on wollastonite and modified with an ethanolic propolis extract. The antioxidant activity of the extracts was characterized using free radical scavenging methods (DPPH and ABTS). Cell proliferation and osteogenic potential using Human Bone Marrow Stem Cells (bmMSCs) were assessed at different culture time points up to 28 days. MIC and inhibition zones were studied from single strain cultures, and biofilm formation was evaluated on the scaffolds under co-culture conditions. The mechanical strength of the scaffolds was evaluated. Results: Through statistical design of experiments, a paste suitable for printing scaffolds with the desired geometry was obtained. Propolis extracts modifying the TPMS gyroid scaffolds showed favorable cell proliferation and metabolic activity with osteogenic potential after 21 days. Additionally, propolis exhibited antioxidant activity, which may be related to the antimicrobial effectiveness of the scaffolds against S. aureus and S. epidermidis cultures. The mechanical properties of the scaffolds were not affected by propolis impregnation. Conclusion: These results demonstrate that propolis-impregnated porous wollastonite scaffolds might have the potential to stimulate bone repair in maxillofacial tissue engineering applications.

Antibacterial and osteoinductive properties of wollastonite scaffolds impregnated with propolis produced by additive manufacturing.

Biocompatible ceramic scaffolds offer a promising approach to address the challenges in bone reconstruction. Wollastonite, well-known for its exceptional biocompatibility, has attracted significant attention in orthopedics and craniofacial fields. However, the antimicrobial properties of wollastonite have contradictory findings, necessitating further research to enhance its antibacterial characteristics. This study aimed to explore a new approach to improve in vitro biological response in terms of antimicrobial activity and cell proliferation by taking advantage of additive manufacturing for the development of scaffolds with complex geometries by 3D printing using propolis-modified wollastonite. The scaffolds were designed with a TPMS (Triply Periodic Minimal Surface) gyroid geometric shape and 3D printed prior to impregnation with propolis extract. The paste formulation was characterized by rheometric measurements, and the presence of propolis was confirmed by FTIR spectroscopy. The scaffolds were comprehensively assessed for their mechanical strength. The biological characterization involved evaluating the antimicrobial effects against Staphylococcus aureus and Staphylococcus epidermidis, employing Minimum Inhibitory Concentration (MIC), Zone of Inhibition (ZOI), and biofilm formation assays. Additionally, SaOs-2 cultures were used to study cell proliferation (Alamar blue assay), and potential osteogenic was tested (von Kossa, Alizarin Red, and ALP stainings) at different time points. Propolis impregnation did not compromise the mechanical properties of the scaffolds, which exhibited values comparable to human trabecular bone. Propolis incorporation conferred antibacterial activity against both Staphylococcus aureus and Staphylococcus epidermidis. The implementation of TPMS gyroid geometry in the scaffold design demonstrated favorable cell proliferation with increased metabolic activity and osteogenic potential after 21 days of cell cultures.

NS1-Specific Antibody Response Facilitates the Identification of Children With Dengue and Zika in Hyperendemic Areas.

BACKGROUND: Infections by dengue virus (DENV) and Zika virus (ZIKV) have some similar symptoms and a cross-reactive immune response, although with different risk populations and outcomes. Here, we evaluated the virological characteristics and the nonstructural protein 1 (NS1)-specific antibody responses to DENV and ZIKV in children suspected of dengue in different epidemiological moments in Colombia. METHODS: Viral RNA, circulating NS1 and IgM/IgG specific for DENV and ZIKV were performed by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) in 301 children suspected of dengue enrolled in a hospital setting during the ZIKV epidemic and a primary healthcare setting during a DENV epidemic. For the detection of DENV and ZIKV-specific IgM, an NS1-based ELISA was validated using characterized pediatric samples. Clinical and laboratory parameters were also evaluated. RESULTS: DENV RNA or NS1 antigen was detected in the plasma of 62% of children, and in none, the ZIKV RNA was found. NS1-based ELISA for DENV and ZIKV IgM showed a sensitivity/specificity of 90/84% and 73/98%, respectively. Of 114 children without detectable viremia or antigenemia, 30.7%, 17.5%, 22% and 30% were IgM-DENV+, IgM-ZIKV+, IgM-DENV+ZIKV+ and IgM-DENV-ZIKV-, respectively. The ZIKV/DENV IgM-NS1 ratio allows the identification of the infecting ortho flavivirus in 88% of the children with IgM-DENV+ZIKV+, confirming a high predominance of DENV infections in the 2 pediatric settings. CONCLUSION: Overall, 88% of the children with clinical suspicion of dengue had an identifiable ortho flaviviral infection, with 80% caused by DENV, 7% by ZIKV and 0.7% classified as recent infections or coinfection, demonstrating active viral cocirculation in the pediatric population of southern Colombia. The IgM-NS1 detection improved the identification of ortho flaviviral infections in children without viremia or antigenemia, suggesting it is a helpful complementary tool for medical personnel in tropical regions with high viral cocirculation and different clinical scenes.

Secondary exposure to heavy metal in genetically susceptible mice leads to acceleration of autoimmune response.

Exposure to mercury (Hg) and silver (Ag) has been shown to induce autoimmune diseases in genetically susceptible rodents. Here, A.SW mice were initially exposed to HgCl2, AgNO3 or tap water (control) for 3 weeks. After 13 weeks of stoppage, all mice had secondary exposure to 203HgCl2. After secondary exposure, higher and earlier ANoA titers were observed in mice initially exposed to Hg or Ag compared to control. Further, mice initially exposed to Ag showed higher total IgG1 and IgG2a, Whole Body Retention and lymph nodes and spleen accumulation of Hg compared to mice initially exposed to Hg and controls. These findings showed an earlier and stronger immunological response in A.SW mice compared with control, following re-exposure to heavy metals indicating an immunological memory. Additionally, secondary exposure to a different heavy metal may aggravate the effects of exposure of at least one of the metals indicating cross-reactivity.

The Quantitative Impact of Using 3D Printed Anatomical Models for Surgical Planning Optimization: Literature Review.

3D printing has entered the medical field as a visualization tool that allows the manufacture of three-dimensional (3D) models that physically represent the anatomy of a patient in need of analysis to improve surgical results. This article analyzes the literature around reported study cases that make use of anatomical models for their surgical processes' planning, focusing on obtaining the quantitative results of each one of them. A search of case studies was carried out in the main medical databases such as PubMed, ScienceDirect, SpringerLink, among others; to obtain the most relevant results of the 56 selected articles, the information of each study was analyzed and categorized. These articles presented figures and data about the benefits that are considered more representative to measure the positive impact of this technology. These benefits are summarized in variables such as the decrease in surgical time, greater accuracy in the diagnosis of pathology, blood loss reduction, and decreasing operating room costs; owed to an improvement in the surgery planning. It was found that in all the cases analyzed there was an improvement in the surgical results related to these variables, which were summarized in macro figures that combine this improvement quantitatively. In the analyzed studies, it was evident that there is great potential in the use of 3D printing for presurgical planning, being as the results of these analyzed interventions were better when using this technology. In addition, it was found that the results obtained initially, before applying the inclusion and exclusion criteria, were mostly of a qualitative nature; expressing the perception of researchers regarding the positive use of this tool in the field and evidencing an opportunity for this research to focus on concrete and technical information to show in numerical terms the effectiveness of this tool, to demonstrate the cost-benefit that it has for the field.

A Specific Pattern and Dynamics of Circulating Cytokines Are Associated with the Extension of Lung Injury and Mortality in Colombian Adults with Coronavirus Disease-19.

Increased systemic levels of inflammatory cytokines have been associated with the development of pathophysiologic events during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To further explore differences in the pattern and dynamics of plasma cytokines in individuals with coronavirus disease-19 (COVID-19), and the relationship with disease mortality, here we evaluated the plasma levels of proinflammatory and regulatory cytokines in Colombian patient survivors and nonsurvivors of SARS-CoV-2 infection. Individuals with confirmed COVID-19, with other respiratory diseases requiring hospitalization, and healthy controls, were included. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-γ, IL-10, soluble tumor necrosis factor receptor I (sTNFRI), and transforming growth factor-ß1 were measured by a bead-based assay or enzyme-linked immunosorbent assay and clinical, laboratory, and tomographic parameters were registered during hospitalization. The levels of most of the evaluated cytokines were increased in COVID-19 individuals relative to healthy controls. The levels of IL-6, IL-10, and sTNFRI were directly associated with the development of respiratory failure, immune dysregulation, and coagulopathy, as well as with COVID-19 mortality. Particularly, the early, robust, and persistent increase of circulating IL-6 characterized COVID-19 nonsurvivors, while survivors were able to counteract the inflammatory cytokine response. In addition, IL-6 systemic levels positively correlated with the tomographic extension of lung damage in individuals with COVID-19. Thus, an exacerbated inflammatory cytokine response, particularly mediated by IL-6 added to the inefficiency of regulatory cytokines, distinguishes COVID-19-associated tissue disturbances, severity, and mortality in Colombian adults.

Reinforcement of Calcium Phosphate Cement with Hybrid Silk Fibroin/Kappa-Carrageenan Nanofibers.

Calcium phosphate cements (CPCs) offer a promising solution for treating bone defects due to their osteoconductive, injectable, biocompatible, and bone replacement properties. However, their brittle nature restricts their utilization to non-load-bearing applications. In this study, the impact of hybrid silk fibroin (SF) and kappa-carrageenan (k-CG) nanofibers as reinforcements in CPC was investigated. The CPC composite was fabricated by incorporating electrospun nanofibers in 1, 3, and 5% volume fractions. The morphology, mineralization, mechanical properties, setting time, injectability, cell adhesion, and mineralization of the CPC composites were analyzed. The results demonstrated that the addition of the nanofibers improved the CPC mixture, leading to an increase in compressive strength (14.8 ± 0.3 MPa compared to 8.1 ± 0.4 MPa of the unreinforced CPC). Similar improvements were seen in the bending strength and work fracture (WOF). The MC3T3-E1 cell culture experiments indicated that cells attached well to the surfaces of all cement samples and tended to join their adjacent cells. Additionally, the CPC composites showed higher cell mineralization after a culture period of 14 days, indicating that the SF/k-CG combination has potential for applications as a CPC reinforcement and bone cell regeneration promoter.

Impact of the 21-Gene Assay in Patients with High-Clinical Risk ER-Positive and HER2-Negative Early Breast Cancer: Results of the KARMA Dx Study.

BACKGROUND: The 21-gene Oncotype DX Breast Recurrence Score® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2- early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. METHODS: Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1-2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians' confidence levels in their final recommendations. RESULTS: A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians' confidence in their final recommendations increased in 34% of cases. CONCLUSIONS: Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.

Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype.

GAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype. Methods: GAD autoantibodies, GADA subclasses, GAD65-induced cytokine secretion (Luminex panel) and proliferation of peripheral mononuclear cells were analyzed in T1D patients (n=109) who received either three intra-lymphatic injections (one month apart) with 4 µg GAD-alum and oral vitamin D supplementation (2000 IE daily for 120 days), or placebo. Results: Higher GADA, GADA subclasses, GAD65-induced proliferation and cytokine secretion was observed in actively treated patients after the second injection of GAD-alum compared to the placebo group. Following the second injection of GAD-alum, actively treated subjects with DR3DQ2 haplotype had higher GAD65-induced secretion of several cytokine (IL4, IL5, IL7, IL10, IL13, IFNγ, GM-CSF and MIP1ß) and proliferation compared to treated individuals without DR3DQ2. Stratification of samples from GAD-alum treated patients according to C-peptide preservation at 15 months revealed that "good responder" individuals with better preservation of C-peptide secretion, independently of the HLA haplotype, had increased GAD65-induced proliferation and IL13 secretion at 3 months, and a 2,5-fold increase of IL5 and IL10 as compared to "poor responders". The second dose of GAD-alum also induced a more pronounced cytokine secretion in "good responders" with DR3DQ2, compared to few "good responders" without DR3DQ2 haplotype. Conclusion: Patients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD65-induced IL13 secretion and proliferation that seems to be associated with a better clinical outcome. If confirmed in the ongoing larger randomized double-blind placebo-controlled clinical trial (DIAGNODE-3), including only patients carrying DR3DQ2 haplotype, these results might be used as early surrogate markers for clinical efficacy.

Ambient exposures to selected volatile organic compounds and the risk of prostate cancer in Montreal.

Little is known about environmental factors that may increase the risk of prostate cancer. We estimated associations between incident prostate cancer and environmental concentrations of five ambient volatile organic compounds (VOCs): benzene; n-decane; ethylbenzene; hexane; and 1,2,4-trimethylbenzene. Methods: This study is based on a population-based case-control study of incident prostate cancer (PROtEuS) in men ≤ 75 years of age living in Montreal, Canada, in 2005 to 2012. We included 1172 cases and 1177 population controls. We had personal information, lifetime residential addresses, occupational exposures, and a variety of area-wide covariables. We inferred concentrations of the five VOCs using Bayesian geostatistical models using data from a dense environmental survey conducted in Montreal in 2005 to 2006. We used different sets of adjustments to estimate odds ratios (OR) and confidence intervals. Results: We found nonlinear associations such that the ORs increased monotonically and then either flattened or fell off with increased exposures. The model that contained other environmental variables and contextual variables led to lower ORs and results were similar when we restricted analyses to controls recently screened or tested for prostate cancer or cases with low- or high-grade tumors. A change from the 5th to 25th percentile in mean environmental benzene levels led to an adjusted OR of 2.00 (95% confidence interval = 1.47, 2.71). Conclusion: We found positive associations between prostate cancer and concentrations of benzene and ethylbenzene, independently of previous testing for prostate cancer or tumor grade, suggesting that exposure to certain ambient VOCs may increase incidence.

Spatial modeling of ambient concentrations of volatile organic compounds in Montreal, Canada.

Volatile organic compounds (VOCs) are components of the complex mixture of air pollutants within cities and can cause various adverse health effects. Therefore, it is necessary to understand their spatial distribution for exposure assessment in epidemiological studies. Objectives: The objective was to model measured concentrations of five VOCs within the city of Montreal, Canada, developing spatial prediction models that can be used in health studies. Methods: We measured concentrations using 3M 3500 Organic Vapor Monitors, over 2-week periods, for three monitoring campaigns between 2005 and 2006 in over 130 locations in the city. Using GC/MSD (Gas Chromatography/Mass Selective Detector), we measured concentrations of benzene, n-decane, ethylbenzene, hexane, and trimethylbenzene. We fitted four different models that combine land-use regression and geostatistical methods to account for the potential spatial structure that remains after accounting for the land-use variables. The fitted models also accounted for possible variations in the concentration of air pollutants across campaigns. Results: The highest concentrations for all VOCs were found in December with hexane being the most abundant followed by ethylbenzene. We obtained predicted surfaces for the VOCs for the three campaigns and mean surfaces across campaigns. We found higher concentrations of some VOCs along highways and in the Eastern part of Montreal, which is a highly industrialized area. Conclusions: Each of the fitted models captured the spatial and across-campaigns variability for each VOC, and we found that different VOCs required different model structures.

Combination of the Focus-Forming Assay and Digital Automated Imaging Analysis for the Detection of Dengue and Zika Viral Loads in Cultures and Acute Disease.

Optimized methods for the detection of flavivirus infections in hyperendemic areas are still needed, especially for working with patient serum as a starting material. The focus-forming assay (FFA) reveals critical aspects of virus-host interactions, as it is a quantitative assay to determine viral loads. Automated image analysis provides evaluations of relative amounts of intracellular viral protein at the single-cell level. Here, we developed an optimized FFA for the detection of infectious Zika virus (ZIKV) and dengue virus (DENV) viral particles in cell cultures and clinical serum samples, respectively. Vero-76 cells were infected with DENV-2 (16681) or ZIKV (PRVA BC59). Using a panel of anti-DENV and anti-ZIKV NS1-specific monoclonal antibodies (mAbs), the primary mAbs, concentration, and the optimal time of infection were determined. To determine whether intracellular accumulation of NS1 improved the efficiency of the FFA, brefeldin A was added to the cultures. Focus formation was identified by conventional optical microscopy combined with CellProfiler™ automated image analysis software. The FFA was used with spike assays for ZIKV and clinical specimens from natural infection by DENV-1 and DENV-2. mAb 7744-644 for ZIKV and mAb 724-323 for DENV used at a concentration of 1 µg/ml and a time of 24 hours postinfection produced the best detection of foci when combining conventional counting and automated digital analysis. Brefeldin A did not improve the assessment of FFUs or their digitally assessed intensity at single-cell level. The FFA showed 95% ZIKV recovery and achieved the detection of circulating DENV-1 and DENV-2 in the plasma of acutely ill patients. The combination of the two techniques optimized the FFA, allowing the study of DENV and ZIKV in culture supernatants and clinical specimens from natural infection in hyperendemic areas.

Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2.

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 µg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Hourly Analysis of Mechanical Ventilation Parameters in Critically Ill Adult Covid-19 Patients: Association with Mortality.

Objective: There exists controversy about the pathophysiology and lung mechanics of COVID-19 associated acute respiratory distress syndrome (ARDS), because some report severe hypoxemia with preserved respiratory system mechanics, contrasting with "classic" ARDS. We performed a detailed hourly analysis of the characteristics and time course of lung mechanics and biochemical analysis of patients requiring invasive mechanical ventilation (IMV) for COVID-19-associated ARDS, comparing survivors and non-survivors. Methods: Retrospective analysis of the data stored in the ICU information system of patients admitted in our hospital ICU that required IMV due to confirmed SARS-CoV-2 pneumonia between March 5th and April 30th, 2020. We compare respiratory system mechanics and gas exchange during the first ten days of IMV, discriminating volume and pressure controlled modes, between ICU survivors and non-survivors. Results: 140 patients were included, analyzing 11 138 respiratory mechanics recordings. Global mortality was 38.6%. Multivariate analysis showed that age (OR 1.092, 95% (CI 1.014-1.176)) and need of renal replacement therapies (OR 10.15, (95% CI 1.58-65.11)) were associated with higher mortality. Previous use of Angiotensin Converting Enzyme inhibitor (ACEI)/angiotensin-receptor blockers (ARBs) also seemed to show an increased mortality (OR 4.612, (95% CI 1.19-17.84)) although this significance was lost when stratifying by age. Respiratory variables start to diverge significantly between survivors and non-survivors after the 96 to 120 hours (hs) from mechanical ventilation initiation, particularly respiratory system compliance. In non survivors, mechanical power at 24 and 96 hs was higher regardless ventilatory mode. Conclusions: In patients admitted for SARS-CoV-2 pneumonia and requiring mechanical ventilation, non survivors have different respiratory system mechanics than survivors in the first 10 days of ICU admission. We propose a checkpoint at 96-120 hs to assess patients improvement or worsening in order to consider escalating to extracorporeal therapies.

Violencia institucional de género en el sistema jurídico colombiano / Institutional Gender-Based Violence in the Colombian Legal System

Resumen En este texto se develan los modos en que se expresa la violencia género en las estructuras jurídicas de tratamiento legal a las denuncias de las mujeres víctimas de maltratos en relaciones de pareja en Colombia. Las actuaciones y fallos judiciales referidos a estos casos derivan en acciones de revictimización e inoperancia de la justicia, que perpetúan las lógicas de dominación masculina y de daño moral a las mujeres. Mientras el sistema normativo colombiano no reconozca que en sí mismo, constituye una de las estructuras elementales del patriarcado, será ineficaz en garantizarles a las mujeres una vida libre de violencias.

Abstract: This text unveils the ways in which gender violence is expressed in the legal structures of legal treatment to the complaints of women victims of abuse in intimate partner relationships in Colombia. Judicial actions and rulings in these cases result in actions of revictimization and ineffectiveness of justice, which perpetuate the logic of male domination and moral damage to women. As long as the Colombian normative system does not recognize that it constitutes one of the elemental structures of patriarchy, it will be ineffective in guaranteeing women a life free of violence.

Acute recurrent pancreatitis complicated by pancreatic-portal venous fistulisation, secondary chronic portal vein thrombosis, multiple hepatic abscesses and newly diagnosed cirrhosis.

Pancreatic-portal vein fistula, portal vein thrombosis and liver abscesses are rare complications of acute pancreatitis which occur in the setting of localised inflammation of the pancreatic tissues and surrounding structures. We discuss a 34-year-old woman with a medical history of intermittently controlled HIV and alcohol use disorder who presents with severe epigastric pain diagnosed with acute pancreatitis. Concerning CT findings showing hypoattenuating liver lesions likely to be abscesses and multiple pancreatic pseudocysts led us to order an MRI which showed thrombosis of the portal vein, porto-pancreatic pseudocyst fistulation and cirrhotic changes. Patient was treated conservatively in the hospital and ultimately given a course of antibiotics for hepatic abscesses. Workup for new diagnosis of cirrhosis revealed positive antimitochondrial antibodies, raising suspicion for autoimmune hepatitis possibly triggered by immune reconstitution in the setting of HIV infection. Patient was discharged on oral antibiotic therapy and home antiretroviral therapy.