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Purpose: We assessed the potential association between N-acetyl-cysteine (NAC) and clinical outcomes in critically ill subjects with COVID-19-related ARDS., Material and Methods: We included subjects with confirmed COVID-19 who were admitted to our ICU between March 1, 2020, and January 31, 2021, due to ARDS and necessitating invasive mechanical ventilation (IMV). Subjects who received standard of care (SOC) were compared with subjects who additionally received NAC 600 mg bid orally., Results: A total of 243 subjects were included in this study. The results indicate significantly improved survival rates in the NAC plus SOC group, both in the unadjusted analysis and after adjusting for confounding factors such as ARDS severity (HR 0.48, 95% CI 0.32-0.70)., Conclusions: We found that oral administration of NAC was associated with reduced mortality in critically ill patients with COVID-19 related ARDS., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The optimal dose of rabbit anti-thymocyte globulin (r-ATG) in renal transplantation is still under debate. We previously reported that a low-dose r-ATG induction of 3 mg/kg can be used safely and effectively in low-risk kidney transplants with good results in the first year after transplantation compared to basiliximab induction., Aims: The purpose of this study is to evaluate the long-term impact of this trial of low-dose r-ATG versus basiliximab on post-transplant outcomes (patient and graft survival, biopsy-proven acute rejection incidence [BPAR], infectious complications, and side effects)., Methods: Observational study (three-year follow-up) of a 12-month single-center, open-label RCT in de novo kidney allograft recipients assigned to receive either thymoglobulin or basiliximab before transplantation., Results: Patients in the basiliximab group (BG) underwent more kidney transplant biopsies than patients in the low-dose r-ATG group (TG) (50 vs. 31.8%, p = 0.07). Although the 12-month cumulative incidence of BPAR was lower in BG, by the end of the three-year follow-up period this incidence was higher (22%) than in the low-dose TG (15%) (p = ns). Steroids were withdrawn more frequently in the TG group and sirolimus was most frequently indicated. Graft function and graft survival were higher in the low-dose TG than in the BG at three-year follow-up but not statistically significant. Patient survival was similar between groups (>90%)., Conclusions: These three-year follow-up data confirm the efficacy and favorable safety aspects of the low-dose r-ATG (3 mg/kg) in low-risk kidney transplantation., (Copyright © 2024 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8 + T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8 + T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity., Competing Interests: Declaration of interests C.R.S. is a founder of Adendra Therapeutics and owns stock options and/or is a paid consultant for Adendra Therapeutics, Bicara Therapeutics, Montis Biosciences, and Bicycle Therapeutics, all unrelated to this work. C.R.S. also has an additional appointment as Visiting Professor in the Faculty of Medicine at Imperial College London and holds honorary professorships at University College London and King’s College London. H.B. received a research grant from Nimbus Therapeutics for unrelated work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting Il31 and its receptor Il31ra in a mouse model of house dust mite (HDM)-induced allergic dermatitis. Il31 -deficient mice displayed a deficit in HDM dermatitis-associated scratching, consistent with its well-established role as a pruritogen. In contrast, Il31 deficiency increased the number and proportion of cutaneous type 2 cytokine-producing CD4 + T cells and serum IgE in response to HDM. Furthermore, Il4ra + monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in Il31ra -deficient HDM dermatitis skin. Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin. Our data support a model wherein IL-31 activation of IL31RA + pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which can mediate neurogenic inflammation, inhibit CD4 + T cell proliferation, and reduce T cell production of the type 2 cytokine IL-13. Together, these results illustrate a previously unrecognized neuroimmune pathway that constrains type 2 tissue inflammation in the setting of chronic cutaneous allergen exposure and may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.

T cells typically recognize their ligands using a defined cell biology-the scanning of their membrane microvilli (MV) to palpate their environment-while that same membrane scaffolds T cell receptors (TCRs) that can signal upon ligand binding. Chimeric antigen receptors (CARs) present both a therapeutic promise and a tractable means to study the interplay between receptor affinity, MV dynamics and T cell function. CARs are often built using single-chain variable fragments (scFvs) with far greater affinity than that of natural TCRs. We used high-resolution lattice lightsheet (LLS) and total internal reflection fluorescence (TIRF) imaging to visualize MV scanning in the context of variations in CAR design. This demonstrated that conventional CARs hyper-stabilized microvillar contacts relative to TCRs. Reducing receptor affinity, antigen density, and/or multiplicity of receptor binding sites normalized microvillar dynamics and synapse resolution, and effector functions improved with reduced affinity and/or antigen density, highlighting the importance of understanding the underlying cell biology when designing receptors for optimal antigen engagement., (© 2022 Beppler et al.)

Conventional dendritic cells type 1 (cDC1) are critical for inducing protective CD8 + T cell responses to tumour and viral antigens. In many instances, cDC1 access those antigens in the form of material internalised from dying tumour or virally-infected cells. How cDC1 extract dead cell-associated antigens and cross-present them in the form of peptides bound to MHC class I molecules to CD8 + T cells remains unclear. Here we review the biology of dendritic cell natural killer group receptor-1 (DNGR-1; also known as CLEC9A), a C-type lectin receptor highly expressed on cDC1 that plays a key role in this process. We highlight recent advances that support a function for DNGR-1 signalling in promoting inducible rupture of phagocytic or endocytic compartments containing dead cell debris, thereby making dead cell-associated antigens accessible to the endogenous MHC class I processing and presentation machinery of cDC1. We further review how DNGR-1 detects dead cells, as well as the functions of the receptor in anti-viral and anti-tumour immunity. Finally, we highlight how the study of DNGR-1 has opened new perspectives into cross-presentation, some of which may have applications in immunotherapy of cancer and vaccination against viral diseases., Competing Interests: Declaration of Competing Interest C.R.S. is a founder of Adendra Therapeutics and owns stock options and/or is a paid consultant for Adendra Therapeutics, Bicara Therapeutics, Montis Biosciences, Bicycle Therapeutics and Sosei Heptares. C.R.S. has an additional appointment as a Visiting Professor in the Faculty of Medicine at Imperial College London and holds honorary professorships at University College London and King’s College London., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute kidney injury (AKI) is associated with poor outcomes in patients infected with SARS-CoV-2. Sepsis, direct injury to kidney cells by the virus, and severe systemic inflammation are mechanisms implicated in its development. We investigated the association between inflammatory markers (C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase, and ferritin) in patients infected with SARS-CoV-2 and the development of AKI., Methods: A prospective cohort study performed at the Civil Hospital (Dr. Juan I. Menchaca) Guadalajara, Mexico, included patients aged >18 years with a diagnosis of SARS-CoV-2 pneumonia confirmed by RT-PCR and who did or did not present with AKI (KDIGO) while hospitalized. Biomarkers of inflammation were recorded, and kidney function was estimated using the CKD-EPI formula., Results: 291 patients were included (68% males; average age, 57 years). The incidence of AKI was 40.5% (118 patients); 21% developed stage 1 AKI, 6% developed stage 2 AKI, and 14% developed stage 3 AKI. The development of AKI was associated with higher phosphate ( p = 0.002) (RR 1.39, CI 95% 1.13-1.72), high procalcitonin levels at hospital admission ( p = 0.005) (RR 2.09, CI 95% 1.26-3.50), and high APACHE scores ( p = 0.011) (RR 2.0, CI 95% 1.17-3.40). The survival analysis free of AKI according to procalcitonin levels and APACHE scores demonstrated a lower survival in patients with procalcitonin >0.5 ng/ml ( p = 0.001) and APACHE >15 points ( p = 0.004)., Conclusions: Phosphate, high procalcitonin levels, and APACHE levels >15 were predictors of AKI development in patients hospitalized with COVID-19., Competing Interests: All the authors declare no conflicts of interest., (Copyright © 2022 Jorge Andrade Sierra et al.)

Persistent antigenic signaling leads to T cell exhaustion, a dysfunctional state arising in many chronic infections and cancers. Little is known concerning mechanisms limiting exhaustion in immune-stimulatory diseases such as asthma. We report that membrane-associated RING-CH1 (MARCH1), the ubiquitin ligase that mediates surface turnover of MHC class II (MHCII) and CD86 in professional APCs, plays an essential role in restraining an exhaustion-like program of effector CD4 + T cells in a mouse model of asthma. Mice lacking MARCH1 or the ubiquitin acceptor sites of MHCII and CD86 exhibited increased MHCII and CD86 surface expression on lung APCs, and this increase promoted enhanced expression of immune-inhibitory receptors by effector CD4 + T cells and inhibited their proliferation. Remarkably, ablation of MARCH1 in mice with established asthma reduced airway infiltration of eosinophils and Th2 cells. Thus, MARCH1 controls an exhaustion-like program of effector CD4 + T cells during allergic airway inflammation and may serve as a therapeutic target for asthma., (Copyright © 2022 The Authors.)

Background: Today bacterial resistance is a global problem, it is estimated that in 2050 it could reach 10 million deaths per year. Bacterial resistance can be caused by different mechanisms, in the case of beta-lactams they include the production of flow pumps, the modification or reduction of porin production, alteration of penicillin-binding proteins and production of an enzyme capable of inactivating the antibiotic., Objective: To describe the main bacterial agents reported in the Hospital para el Niño de Toluca and their sensitivity pattern., Material and Methods: This is an observational, descriptive, retrospective cohort study, evaluated from January 1, 2018 to December 31, 2020, in hospitalized patients under 18 years of age, with confirmed infections from blood culture specimens, urine culture, fluid cerebrospinal and secretions., Results: 599 patients with positive cultures were reported. The five most frequently isolated agents were Staphylococci aureus, Escherichia coli, Klebsiella sp, Candida sp and Enterococci sp, Pseudomonas third in frequency in 2019 and fifth in 2020. The main isolated gram positive coconut was S. epidermidis with 52.3% in 2020 , while the BGN report an increase in positive ESBL organisms by 21.5% for 2020., Conclusions: S aureus, E coli, Klebsiella, Candida, and pseudomonas remain the main causative agents of infection. The GNBs showed an increase in frequency up to 21.5%, showing high resistance in fourth grade cephalosporins, gentamicin, ciprofloxacin and meropenem., (© 2022 Revista Medica del Instituto Mexicano del Seguro Social.)

Introduction: Nutritional risk is highly prevalent in patients with COVID-19. Relevant data on nutritional assessment in the critically ill population are scarce. This study was conducted to evaluate the modified Nutrition Risk in the Critically Ill (mNUTRIC)-Score as a mortality risk factor in mechanically ventilated patients with COVID-19., Methods: We conducted this retrospective observational study in critically ill patients with COVID-19. Patients' characteristics and clinical information were obtained from electronic medical records. The nutritional risk for each patient was assessed at the time of mechanical ventilation using the mNUTRIC-Score. The major outcome was 28-day mortality., Results: Ninety-eight patients were analyzed (mean age, 57.22 ± 13.66 years, 68.4% male); 46.9% of critically ill COVID-19 patients were categorized as being at high nutrition risk (mNUTRIC-Score of ≥5). A multivariate logistic regression model indicated that high nutritional risk has higher 28-day hospital mortality (OR = 4.206, 95% CI: 1.147-15.425, p =0.030). A multivariate Cox regression analysis showed that high-risk mNUTRIC-Score had a significantly increased full-length mortality risk during hospitalization (OR = 1.991, 95% CI: 1.219-3.252, p =0.006)., Conclusion: The mNUTRIC-Score is an independent mortality risk factor during hospitalization in critically ill COVID-19 patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Francisco G. Yanowsky-Escatell et al.)

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222-deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Wigton et al.)

Type 2 T helper (T H 2) cells are protective against parasitic worm infections but also aggravate allergic inflammation. Although the role of dendritic cells (DCs) in T H 2 cell differentiation is well established, the underlying mechanisms are largely unknown. Here, we show that DC induction of T H 2 cells depends on membrane-associated RING-CH-1 (MARCH1) ubiquitin ligase. The pro-T H 2 effect of MARCH1 relied on lymph node (LN)–resident DCs, which triggered T cell receptor (TCR) signaling and induced GATA-3 expression from naïve CD4 + T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of MHCII and CD86, the two substrates of MARCH1, failed to develop T H 2 cells. These findings suggest that T H 2 cell development depends on ubiquitin-mediated clearance of antigen-presenting and costimulatory molecules by LN-resident DCs and consequent control of TCR signaling.

Background: It has recently been argued that asthma does not increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. If so, the prevalence of asthma in subjects diagnosed with COVID-19 should be lower than in the general population., Objective: To determine the prevalence of asthma in Mexican children and adults with SARS-CoV-2 infection., Methods: A public database of the Epidemiological Surveillance System for Viral Respiratory Disease in Mexico was analyzed. Those who underwent the real-time reverse transcriptase-polymerase chain reaction-SARS-CoV-2 (rtRT-PCR-SARS-CoV-2) test from February 27 to June 21, 2020, were included. In addition to the prevalence of asthma, some factors associated with it were investigated., Results: Data from 417,366 subjects were analyzed. Asthma prevalence in children, adults, and global were 3.7%, 3.3%, and 3.3%, respectively. Although the asthma prevalence was lower in SARS-CoV-2 positive over negative patients, significant differences were only found in adults (2.8% vs. 3.7% respectively; odds ratio (OR) = 0.74; 95% confidence interval (CI): 0.71-0.77); but not in children (3.5% vs. 3.8%, respectively; OR = 0.91; 95%CI: 0.76-1.10). Multivariate analysis showed in younger than 18 years that girls and immunosuppression were factors associated with a decrease in the odds to develop asthma. In adults, asthma was positively associated with females, obesity, smoking, immunosuppression, chronic obstructive pulmonary disease, arterial hypertension, and cardiovascular disease., Conclusion: The prevalence of asthma in child and adult were lower than those previously reported. Our study seems to support the hypothesis that asthma patients have a lower risk of SARS-CoV-2 infection. Further studies are required to demonstrate the consistency of our findings., Competing Interests: The authors declare no potential conflicts of interest.

Context: Thymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established., Objective: Demonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression DESIGN, SETTING, PARTICIPANTS: Prospective randomized study in kidney transplant patients (12/2016-05/2018)., Inclusion Criteria: Recipients > 18 years, first living donor transplant., Exclusion Criteria: Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm 3 , platelets < 75,000 cells/mm 3 and malignancy., Intervention: Group A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids., Main Outcome Measures: Biopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months., Results: 100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns)., Conclusion: Low-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The response to the COVID-19 crisis across most research institutions mandated ceasing nonessential research activities in order to minimize the spread of the virus in our communities. With minimal notice, experiments were terminated, cell lines were frozen, mouse colonies were culled, and trainees were prevented from performing bench research. Still, despite the interruption of experimental productivity, the shutdown has proven for many PIs and trainees that doing and thinking science are not activities that are bound to the laboratory. Furthermore, the shutdowns have solidified important emerging trends and forced us to further innovate to get the most out of working remotely. We hope that some of these innovations, hard-gained in this difficult time, will persist and develop into new paradigms-lessons that will improve our science and our relationship to the climate and community beyond the current pandemic., (© 2020 Freedman et al.)

Background: Pretransplant anti-HLA antibodies are a risk factor for graft rejection and loss, and its percentage estimate is known as panel-reactive antibody (PRA). Our objective was to evaluate the influence of PRA on the survival of renal grafts from living donors over a period of 10 years., Methods: Retrospective analysis was completed in all living donor transplants with PRA class I and class II from October 2008 to December 2018 with follow-up until June 2019. The methods used for the PRA were flow cytometry and Luminex. Graft survival (not censored) was evaluated by Kaplan-Meier (log-rank) and Cox regression. P < .05 was considered significant., Results: The study included 393 patients. PRA class I mean was 9.8 ± 20% (0%-98%) and class II mean was 8.6 ± 17.8% (0%-97.8%). Of the patients, 81.9% had a PRA <20% for any class. Uncensored graft survival at 1, 5, and 10 years was 90.3%, 76.2%, and 69.3%, respectively. Mean estimated uncensored graft survival in PRA <20% patients (103.9 ± 2.7, 95% confidence interval [CI] 96.6-11.2) was higher than that of PRA >20% patients (61.5 ± 5.7, 95% CI 50.3-72.8) (P = .005 log-rank). Cox regression (univariate) was statistically significant for PRA class I (Exp [B] 1.01, 95% CI 1.003-1.02, P = .009) and for PRA >20% any class (Exp [B] 2.074, 95% CI 1.222-3.520, P = .007)., Conclusion: PRA class I and PRA >20% any class are associated with lower graft survival. PRA must be considered to determine immunologic risk and to choose an immunosuppressive regimen in kidney transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In Mexico during 2018, 15,072 patients were waiting for a deceased donor kidney transplant, and 969 deceased donor kidney transplants were performed. There is no annual data report of the waiting list activity in Mexico. Herein, we analyzed our kidney transplant waiting list activity in 2018., Methods: We performed a waiting list analysis in our unit during 2018. Patient and status characteristics (active, deceased, inactive, or transplant) were registered. Differences between status were determined. A P < .05 was considered statistically significant., Results: In total, 467 patients were waiting, and 74 patients were included on the list (57.7% male, mean age 38.5 ± 11.3 years and mean BMI 24.9 ± 4.7 kg/m 2 ); 92.8% were state residents. The most common end-stage renal disease diagnosis was unknown (40.9%). In total, 94.9% were on dialysis (mean time 5.1 ± 3.14 years), and for 90.9%, this was the first transplant. PRA class I and class II were 19.9% ± 30.6% and 12.9% ± 27.1%, respectively. Mean EPTS was 19.8% ± 9.4%. Mean waiting time was 2.88 ± 2.3 years. In total, 21 deceased donor patients (3.9%) were transplanted; 57 (10.5%) patients had an inactive status, and 3 (0.6%) received a living donor kidney transplant with a proven mortality of 1.8% (n = 10). Patients who underwent deceased donor transplant were younger and had more time on dialysis, lower PRA class I, and more time on the waiting list (P < .05 by analysis of variance)., Conclusion: There are more patients included on the list than patients off the list. There are significant differences between patients who received a transplant and inactive and active patients that needs to be shortened., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The Living Kidney Donor Profile Index (LKDPI) was recently created. This model predicts recipient risk of graft loss after living donor transplant. Herein, we applied the LDKPI to our population to analyze its performance., Methods: A retrospective analysis of all living donor kidney transplants from 2003 to 2018 from 2 transplant centers in Veracruz, Mexico, was used. LKDPI was calculated in a webpage (www.transplantmodels.com). Donor and recipient demographics and transplant data included in the model were registered. Pearson correlation between the LKDPI percentage and death-censored graft survival was performed. Kaplan-Meier survival (log-rank) and Cox regression analysis were compared between the LKPDI quartiles. P < .05 was considered statistically significant., Results: In total, 821 transplants were included (mean age 31.7 ± 10.5 years, 62.5% male, n = 513). Mean follow-up was 64.7 ± 46.2 months. Mean estimated survival (Kaplan-Meier) was 128.9 ± 3 months (95% confidence interval [CI], 123-134). Ten-year death-censored graft survival was 61.4%. Median LKPDI was -2%, and mean LKDPI was -2.6% ± 14.6% (range, -50% to 42%). Pearson coefficient correlation between the LKDPI and death-censored graft survival was 0.024 (P = .4). Area under the curve (receiver operating characteristic [ROC]) for the LKDPI and death-censored graft loss was 0.54 (95% CI, 0.505-0.591) (P = .04). Recipients with the lowest LKDPI had lower risk of death-censored graft loss than other quartiles (P = .014 log-rank). Cox regression analysis was significant for the lower LKDPI quartile (<20%) (Exp B = 0.35; 95% CI, 0.14-0.9; P = .03)., Conclusion: The LKDPI applies with moderate discrimination predictive power in our population. The best LKDPI patient has better death-censored graft survival. Further studies might continue to validate the LKDPI in other cohorts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction. The synthesis of LT was biphasic and followed by antifibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts (IMR-90) induced profibrotic signaling in naive fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl LT in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cell removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+ cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs. This study demonstrates for the first time to our knowledge that senescent cells secrete functional LTs, significantly contributing to the LT pool known to cause or exacerbate IPF.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly. There are currently no licensed RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab is restricted to high-risk infants in part due to its modest efficacy. Although it is widely agreed that an effective RSV vaccine will require the induction of a potent neutralizing antibody response against the RSV fusion (F) glycoprotein, little is known about the specificities and functional activities of RSV F-specific antibodies induced by natural infection. Here, we have comprehensively profiled the human antibody response to RSV F by isolating and characterizing 364 RSV F-specific monoclonal antibodies from the memory B cells of three healthy adult donors. In all donors, the antibody response to RSV F is comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, the antibodies targeting this new site display convergent sequence features, thus providing a future means to rapidly detect the presence of these antibodies in human vaccine samples. Many of the antibodies that bind preF-specific surfaces are over 100 times more potent than palivizumab, and several cross-neutralize human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine candidates and offer new options for passive prophylaxis.

Background: The standard treatment of diabetic ketoacidosis involves intravenous infusion of regular insulin until recovery of the episode: this is associated with high costs. Coadministration of insulin glargine from the onset of management may prove beneficial, potentially avoiding rebound hyperglycemia, and hopefully improving the time to resolution of the disease., Methods: We searched MEDLINE, EMBASE, and CENTRAL for randomized controlled trials comparing coadministration of insulin glargine versus standard treatment in patients with diabetic ketoacidosis. To be eligible, studies must assess the efficacy of insulin glargine and report clinically important outcomes. Two reviewers extracted data, assessed risk of bias and summarized strength of evidence using the GRADE approach., Results: Four studies (135 participants during hospital follow-up) were included in this review. Low-quality evidence from three trials suggested that subcutaneously administered insulin glargine, in addition to the standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis (MD -4.19 hours; 95% CI: -7.81 to 0.57; p = 0.02). There was neutral difference between the two groups regarding length of hospital stay and hypoglycemic episodes., Conclusions: subcutaneously administered insulin glargine, in addition to standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis, with neutral effects on hypoglycemic episodes.

Background: Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of uncontrolled diabetes that mainly occurs in individuals with autoimmune type 1 diabetes, but it is not uncommon in some people with type 2 diabetes. The treatment of DKA is traditionally accomplished by the administration of intravenous infusion of regular insulin that is initiated in the emergency department and continued in an intensive care unit or a high-dependency unit environment. It is unclear whether people with DKA should be treated with other treatment modalities such as subcutaneous rapid-acting insulin analogues., Objectives: To assess the effects of subcutaneous rapid-acting insulin analogues for the treatment of diabetic ketoacidosis., Search Methods: We identified eligible trials by searching MEDLINE, PubMed, EMBASE, LILACS, CINAHL, and the Cochrane Library. We searched the trials registers WHO ICTRP Search Portal and ClinicalTrials.gov. The date of last search for all databases was 27 October 2015. We also examined reference lists of included randomised controlled trials (RCTs) and systematic reviews, and contacted trial authors., Selection Criteria: We included trials if they were RCTs comparing subcutaneous rapid-acting insulin analogues versus standard intravenous infusion in participants with DKA of any age or sex with type 1 or type 2 diabetes, and in pregnant women., Data Collection and Analysis: Two review authors independently extracted data, assessed studies for risk of bias, and evaluated overall study quality utilising the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the I² statistic. We synthesised data using random-effects model meta-analysis or descriptive analysis, as appropriate., Main Results: Five trials randomised 201 participants (110 participants to subcutaneous rapid-acting insulin analogues and 91 to intravenous regular insulin). The criteria for DKA were consistent with the American Diabetes Association criteria for mild or moderate DKA. The underlying cause of DKA was mostly poor compliance with diabetes therapy. Most trials did not report on type of diabetes. Younger diabetic participants and children were underrepresented in our included trials (one trial only). Four trials evaluated the effects of the rapid-acting insulin analogue lispro, and one the effects of the rapid-acting insulin analogue aspart. The mean follow-up period as measured by mean hospital stay ranged between two and seven days. Overall, risk of bias of the evaluated trials was unclear in many domains and high for performance bias for the outcome measure time to resolution of DKA.No deaths were reported in the included trials (186 participants; 3 trials; moderate- (insulin lispro) to low-quality evidence (insulin aspart)). There was very low-quality evidence to evaluate the effects of subcutaneous insulin lispro versus intravenous regular insulin on the time to resolution of DKA: mean difference (MD) 0.2 h (95% CI -1.7 to 2.1); P = 0.81; 90 participants; 2 trials. In one trial involving children with DKA, the time to reach a glucose level of 250 mg/dL was similar between insulin lispro and intravenous regular insulin. There was very low-quality evidence to evaluate the effects of subcutaneous insulin aspart versus intravenous regular insulin on the time to resolution of DKA: MD -1 h (95% CI -3.2 to 1.2); P = 0.36; 30 participants; 1 trial. There was low-quality evidence to evaluate the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin on hypoglycaemic episodes: 6 of 80 insulin lispro-treated participants compared with 9 of 76 regular insulin-treated participants reported hypoglycaemic events; risk ratio (RR) 0.59 (95% CI 0.23 to 1.52); P = 0.28; 156 participants; 4 trials. For insulin aspart compared with regular insulin, RR for hypoglycaemic episodes was 1.00 (95% CI 0.07 to 14.55); P = 1.0; 30 participants; 1 trial; low-quality evidence. Socioeconomic effects as measured by length of mean hospital stay for insulin lispro compared with regular insulin showed a MD of -0.4 days (95% CI -1 to 0.2); P = 0.22; 90 participants; 2 trials; low-quality evidence and for insulin aspart compared with regular insulin 1.1 days (95% CI -3.3 to 1.1); P = 0.32; low-quality evidence. Data on morbidity were limited, but no specific events were reported for the comparison of insulin lispro with regular insulin. No trial reported on adverse events other than hypoglycaemic episodes, and no trial investigated patient satisfaction., Authors' Conclusions: Our review, which provided mainly data on adults, suggests on the basis of mostly low- to very low-quality evidence that there are neither advantages nor disadvantages when comparing the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin for treating mild or moderate DKA.

The metastatic spread of tumor cells from the primary site to anatomically distant organs leads to a poor patient prognosis. Increasing evidence has linked adhesive interactions between circulating tumor cells (CTCs) and endothelial cells to metastatic dissemination. Microscale biomimetic flow devices hold promise as a diagnostic tool to isolate CTCs and develop metastatic therapies, utilizing E-selectin (ES) to trigger the initial rolling adhesion of tumor cells under flow. To trigger firm adhesion and capture under flow, such devices also typically require antibodies against biomarkers thought to be expressed on CTCs. This approach is challenged by the fact that CTCs are now known to exhibit heterogeneous expression of conventional biomarkers. Here, we describe surfactant-nanotube complexes to enhance ES-mediated capture and isolation of tumor cells without the use of capture antibodies. While the majority of tumor cells exhibited weaker rolling adhesion on halloysite nanotubes (HNT) coated with ES, HNT functionalization with the sodium dodecanoate (NaL) surfactant induced a switch to firm cellular adhesion under flow. Conversely, surfactant-nanotube complexes significantly reduced the number of primary human leukocytes captured via ES-mediated adhesion under flow. The switch in tumor cell adhesion was exploited to capture and isolate tumor cells in the absence of EpCAM antibodies, commonly utilized as the gold standard for CTC isolation. Additionally, HNT-NaL complexes were shown to capture tumor cells with low to negligible EpCAM expression, that are not efficiently captured using conventional approaches., (© 2015 Wiley Periodicals, Inc.)

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Continuous use of insecticides for the control of dengue transmission may lead to decreased susceptibility levels in mosquito vector populations. Timely monitoring is necessary to ensure detection of any potential resistance problems., Objective: To determine the susceptibility status of Aedes aegypti to insecticides used in public health in Caldas, Colombia, during 2007 and 2011., Materials and Methods: Susceptibility tests to the organophosphates temephos, malathion, fenitrothion and pirimiphos methyl, as well as to the pyrethroid deltamethrin, were carried out using standard World Health Organization and Centers for Disease Control and Prevention protocols., Results: In 2007, resistance to temephos was detected in Ae. aegypti populations from La Dorada with resistance ratios of 11.5 and 13.3, prompting the Caldas Health Department to suspend the use of this larvicide. A reduction in resistance ratios to temephos was observed in 2011, as well as an apparent resistance to pirimiphos methyl. All Ae. aegypti populations tested were susceptible to deltamethrin, malathion and fenitrothion in both years., Conclusion: Evaluating the resistance ratios during two distinct periods allowed a decrease in resistance to be detected after suspension of the use of temephos. Surveillance of mosquito populations for changes in susceptibility levels to the insecticides used in dengue control programs is therefore recommended.

Background: Non-ST elevation acute coronary syndromes (NSTEACS) represent a spectrum of disease including unstable angina and non-ST segment myocardial infarction (NSTEMI). Despite treatment with aspirin, beta-blockers and nitroglycerin, unstable angina/NSTEMI is still associated with significant morbidity and mortality. Although evidence suggests that low molecular weight heparin (LMWH) is more efficacious compared to unfractionated heparin (UFH), there is limited data to support the role of heparins as a drug class in the treatment of NSTEACS. This is an update of a review last published in 2008., Objectives: To determine the effect of heparins (UFH and LMWH) compared with placebo for the treatment of patients with non-ST elevation acute coronary syndromes (unstable angina or NSTEMI)., Search Methods: For this update the Cochrane Heart Group Trials Search Co-ordinator searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (2013, Issue 12), MEDLINE (OVID, 1946 to January week 1 2014), EMBASE (OVID, 1947 to 2014 week 02), CINAHL (1937 to 15 January 2014) and LILACS (1982 to 15 January 2014). We applied no language restrictions., Selection Criteria: Randomized controlled trials of parenteral UFH or LMWH versus placebo in people with non-ST elevation acute coronary syndromes (unstable angina or NSTEMI)., Data Collection and Analysis: Two review authors independently assessed quality of studies and independently extracted data., Main Results: There were no new included studies for this update. Eight studies (3118 participants) were included in this review. We found no evidence for difference in overall mortality between the groups treated with heparin and placebo (risk ratio (RR) = 0.84, 95% confidence interval (CI) 0.36 to 1.98). Heparins compared with placebo, reduced the occurrence of myocardial infarction in patients with unstable angina and NSTEMI (RR = 0.40, 95% CI 0.25 to 0.63, number needed to benefit (NNTB) = 33). There was a trend towards more major bleeds in the heparin studies compared to control studies (RR = 2.05, 95% CI 0.91 to 4.60). From a limited data set, there appeared to be no difference between patients treated with heparins compared to control in the occurrence of thrombocytopenia (RR = 0.20, 95% CI 0.01 to 4.24). Assessment of overall risk of bias in these studies was limited as most of the studies did not give sufficient detail to allow assessment of potential risk of bias., Authors' Conclusions: Compared with placebo, patients treated with heparins had a similar risk of mortality, revascularization, recurrent angina, and thrombocytopenia. However, those treated with heparins had a decreased risk of myocardial infarction and a higher incidence of minor bleeding. Overall, the evidence assessed in this review was classified as low quality according to the GRADE approach. The results presented in this review must therefore be interpreted with caution.

Hematogenous metastasis, the process of cancer cell migration from a primary to distal location via the bloodstream, typically leads to a poor patient prognosis. Selectin proteins hold promise in delivering drug-containing nanocarriers to circulating tumor cells (CTCs) in the bloodstream, due to their rapid, force-dependent binding kinetics. However, it is challenging to deliver such nanocarriers while avoiding toxic effects on healthy blood cells, as many possess ligands that adhesively interact with selectins. Herein, we describe a nanostructured surface to capture flowing cancer cells, while preventing human neutrophil adhesion. Microtube surfaces with immobilized halloysite nanotubes (HNTs) and E-selectin functionalized liposomal doxorubicin (ESPEG L-DXR) significantly increased the number of breast adenocarcinoma MCF7 cells captured from flow, yet also significantly reduced the number of captured neutrophils. Neutrophils firmly adhered and projected pseudopods on surfaces coated only with liposomes, while neutrophils adherent to HNT-liposome surfaces maintained a round morphology. Perfusion of both MCF7 cells and neutrophils resulted in primarily cancer cell adhesion to the HNT-liposome surface, and induced significant cancer cell death. This work demonstrates that nanostructured surfaces consisting of HNTs and ES-PEG L-DXR can increase CTC recruitment for chemotherapeutic delivery, while also preventing healthy cell adhesion and uptake of therapeutic intended for CTCs.

We have synthesized two different fullerene-subphthalocyanine-ferrocene conjugates. The molecules were designed so that the ferrocene unit is linked at the subphthalocyanine axial position through a phenoxy spacer while the C(60) is rigidly held close to the concave face of the macrocycle via a 3-fold C(3)-symmetrical anchoring. The Bingel trisaddition reaction leading to the final products proceeded with very high regioselectivities and full diastereoselectivity. The only difference between both systems is the length of the triple tether employed, which finely regulates the regioselectivity of the trisaddition reaction and the distance between the subphthalocyanine and the C(60) complementary π-π surfaces. Thus, when the tether is connected to the subphthalocyanine through a direct C-C bond, a short π-π distance of 3.25-3.30 Å was calculated. In contrast, when it is connected through a slightly longer C-O-C bond, the distance increases to 3.5-3.6 Å. This π-π distance has a strong influence on the ground-state electronic interactions between the subphthalocyanine and the C(60), as determined from electronic absorption and cyclic voltammetry measurements. In addition, fluorescence and time-resolved transient absorption experiments demonstrated that different mechanisms operate in the two systems after photoexcitation. Despite the similar HOMO-LUMO gaps, only when the two complementary π-π surfaces of the subphthalocyanine and the C(60) are held at a close distance, therefore showing a high degree of orbital overlap, is a multistep electron transfer process triggered, ultimately leading to the long-lived, spatially separated C(60) radical anion and ferrocenium radical cation pair. A full account of the synthesis, characterization, and studies of the ground- and excited-state electronic interactions occurring in these conjugates, as well as in their reference C(60)-subphthalocyanine and subphthalocyanine-ferrocene dyads, is presented in this article.

Very efficient stabilization of the photoinduced charge-transfer state was achieved in simple subphthalocyanine-ferrocene dyads, reaching radical pair lifetimes of about 0.2 ms.