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ABSTRACT NIM‐1324 is an oral investigational new drug for autoimmune disease that targets the Lanthionine Synthetase C‐like 2 (LANCL2) pathway. Through activation of LANCL2, NIM‐1324 modulates CD4+ T cells to bias signaling and cellular metabolism toward increased immunoregulatory function while providing similar support to phagocytes. In primary human immune cells, NIM‐1324 reduces type I interferon and inflammatory cytokine (IL‐6, IL‐8) production. Oral NIM‐1324 was assessed for safety, tolerability and PK in normal healthy volunteers in a randomized, double‐blind, placebo‐controlled trial. Subjects (n = 57) were randomized into five single ascending dose (SAD) cohorts (250, 500, 750, 1000, 1500 mg, p.o.) and three multiple ascending dose (MAD) cohorts (250, 750, 1500 mg QD for 7 days, p.o.). NIM‐1324 did not increase total AE rates in individual cohorts or pooled active groups in SAD or MAD with no SAEs in the study. Oral NIM‐1324 dosing does not result in any clinically significant findings by biochemistry, coagulation, ECG, hematology, or urinalysis when compared to placebo. Plasma exposure, as measured by area under the curve from 0 to 24 h (AUC0‐24), scaled dose proportionally over 250–1000 mg. At 250 mg, NIM‐1324 successfully engaged the target with an upregulation of Lancl2 and key transcriptional biomarkers in whole blood. In conclusion, NIM‐1324 treatment is well‐tolerated up to daily oral doses of at least 1500 mg (nominal), a ≥ six‐fold margin over the anticipated therapeutic dose, and 1000 mg (maximum observed exposure), at least a four‐fold margin over the anticipated therapeutic dose with no dose limiting toxicities.

IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit.MethodsAdolescent patients (N = 206) (≥ 12 to

The overuse and misuse of antibiotics have accelerated the selection of antibiotic-resistant bacteria, significantly impacting human, animal, and environmental health. As aquatic environments are vulnerable to antibiotic resistance, suitable management practices should be adopted to tackle this phenomenon. Here we show an effective, nature-based solution for reducing antibiotic resistance from actual wastewater. We utilize a bioreactor that relies on benthic (biofilms) and planktonic microbial communities to treat secondary effluent from a small urban wastewater treatment plant (

Abstract Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea, and its clinical symptoms can span from asymptomatic colonization to pseudomembranous colitis and even death. The current standard of care for CDI is antibiotic treatment to achieve bacterial clearance; however, 15 to 35% of patients experience recurrence after initial response to antibiotics. We have conducted a comprehensive, global colonic transcriptomics analysis of a 10-day study in mice to provide new insights on the local host response during CDI and identify novel host metabolic mechanisms with therapeutic potential. The analysis indicates major alterations of colonic gene expression kinetics at the acute infection stage, that are restored during the recovery phase. At the metabolic level, we observe a biphasic response pattern characterized by upregulated glycolytic metabolism during the peak of inflammation, while mitochondrial metabolism predominates during the recovery/healing stage. Inhibition of glycolysis via 2-Deoxy-d-glucose (2-DG) administration during CDI decreases disease severity, protects from mortality, and ameliorates colitis in vivo. Additionally, 2-DG also protects intestinal epithelial cells from C. difficile toxin damage, preventing loss of barrier integrity and secretion of proinflammatory mediators. These data postulate the pharmacological targeting of host immunometabolic pathways as novel treatment modalities for CDI.

Introduction Pre-eclampsia affects ~5%–7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal–fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35–37 weeks’ gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35–37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes.Methods and analysis We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35–37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect).Ethics and dissemination The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences.Trial registration number NCT04766866.

This study examines the extent to which extra-linguistic factors such as language dominance, order of acquisition and language of instruction are deterministic for multilingual transfer selection and subsequent development. We test two groups of Catalan-Spanish bilinguals acquiring English as an L3 in a controlled setting. We first examine judgements and interpretations of negative quantifiers and negative polarity items after 16 hours of exposure, establishing the participants own baselines for development. Eleven months later, we test those that continued learning English to explore what factors modulate their development. Data suggest that holistic structural similarity is the most deterministic factor for initial transfer selection. Results of TIME 2 reveal that developmental sequencing, however, is dynamic and non-uniform, differing at the individual level by language-dominance in Catalan or Spanish.

Background: As the anti-biofilm pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics are not well-defined, we have evaluated the PK/PD indices for different regimens of ceftazidime (CAZ; with/without colistin) against Pseudomonas aeruginosa biofilm. Methods: We have used the Center for Disease Control and Prevention Biofilm Reactor with two susceptible (PAO1 and HUB-PAS) and one resistant (HUB-XDR) strains of P. aeruginosa. The regimens were CAZ monotherapies (mimicking a human dose of 2 g/8 h, CAZ-IB; 6 g/daily as continuous infusion at 50 mg/L, CAZ-CI50; and 9 g/daily at 70 mg/L, CAZ-CI70) and CAZ-colistin combinations. Efficacy was correlated with the CAZ PK/PD parameters. Results: CAZ-CI70 was the most effective monotherapy against CAZ-susceptible strains (Δlog CFU/mL 54–0 h = −4.15 ± 0.59 and −3.05 ± 0.5 for HUB-PAS and PAO1, respectively; p ≤ 0.007 vs. other monotherapies), and adding colistin improved the efficacy over CAZ monotherapy. CAZ monotherapies were ineffective against the HUB-XDR strain, and CAZ-CI50 plus colistin achieved higher efficacy than CAZ-IB with colistin. The PK/PD index that correlated best with anti-biofilm efficacy was fAUC0–24h/MIC (r2 = 0.78). Conclusions: CAZ exhibited dose-dependent anti-biofilm killing against P. aeruginosa, which was better explained by the fAUC0–24h/MIC index. CAZ-CI provided benefits compared to CAZ-IB, particularly when using higher doses and together with colistin. CAZ monotherapies were ineffective against the CAZ-resistant strain, independently of the optimized strategy and only CAZ-CI plus colistin appeared useful for clinical practice.

Abstract We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.

En este artículo se muestra que, en comparación con otros cuantificadores negativos del inglés, no se comporta de forma inesperada cuando se aplican los diagnósticos de negación oracional. Se argumenta que esto se puede explicar en un enfoque donde los cuantificadores negativos son objetos sintácticos complejos con un núcleo negativo y un Sintagma Determinante (SD) existencial y que permite que el Ensamble Paralelo genere marcadores sintagmáticos multidominantes. Así, el verbo selecciona sólo la parte existencial del cuantificador negativo, mientras que la Negación (Neg) también se Ensambla (Paralelamente) con ésta. En el caso de no se afirma que, a diferencia de lo que sucede con otros cuantificadores negativos, la Neg sólo se combina con el núcleo D y no con el SD existencial entero. El resultado es una estructura compleja que se ramifica a la izquierda que, como tal, debe transferirse en cuanto se Ensambla, congelando así la Neg en el Sintagma Tiempo (ST). Dado que el ST es el dominio sintáctico al que los diagnósticos de negación oracional son sensibles, no no puede más que comportarse de forma consistente en los diagnósticos de negación oracional, sin mostrar, a diferencia de otros cuantificadores negativos, ninguna asimetría relacionada con la posición en la que ocurre. Palabras clave: cuantificador negativo; negación; multidominancia; asimetría; inglés; no In this article I show that, when compared to other English negative quantifiers, no behaves unexpectedly when diagnostic tests of sentential negation are applied. I argue that this can be accounted for within an approach to negative quantifiers that assumes them to be complex syntactic objects involving a negative head and an existential Determiner Phrase (DP) and that allows Parallel Merge to generate multidominant phrase markers. Within this view, the verb selects just the existential part of the negative quantifier, while Negation (Neg) also (Parallel) Merges with it. In the case of no I claim that, unlike what is the case for other negative quantifiers, Neg only targets the D head rather than the entire existential DP. This results in a complex left-branching structure that, as such, needs to be transferred upon Merge, thus freezing Neg in the Tense Phrase (TP). As TP is the syntactic domain that sentential negation tests are sensitive to, no can do nothing but behave consistently in sentential negation tests, showing, unlike other negative quantifiers, no asymmetry related to the position where it occurs. Keywords: negative quantifier; negation; multidominance; asymmetry; English; no, On the Behaviour of the English Negative Quantifier no in Sentential Negation Tests 1. INTRODUCTION In this article I address a number of polarity-related puzzles that have been reported in [...]

Information on the long-term effects of non-restrictive antimicrobial stewardship (AMS) strategies is scarce. We assessed the effect of a stepwise, multimodal, non-restrictive AMS programme on broad-spectrum antibiotic use in the intensive care unit (ICU) over an 8-year period. Components of the AMS were progressively implemented. Appropriateness of antibiotic prescribing was also assessed by monthly point-prevalence surveys from 2013 onwards. A Poisson regression model was fitted to evaluate trends in the reduction of antibiotic use and in the appropriateness of their prescription. From 2011 to 2019, a total of 12,466 patients were admitted to the ICU. Antibiotic use fell from 185.4 to 141.9 DDD per 100 PD [absolute difference, −43.5 (23%), 95% CI −100.73 to 13.73; p = 0.13] and broad-spectrum antibiotic fell from 41.2 to 36.5 [absolute difference, −4.7 (11%), 95% CI −19.58 to 10.18; p = 0.5]. Appropriateness of antibiotic prescribing rose by 11% per year [IRR: 0.89, 95% CI 0.80 to 1.00; p = 0.048], while broad-spectrum antibiotic use showed a dual trend, rising by 22% until 2015 and then falling by 10% per year since 2016 [IRR: 0.90, 95% CI 0.81 to 0.99; p = 0.03]. This stepwise, multimodal, non-restrictive AMS achieved a sustained reduction in broad-spectrum antibiotic use in the ICU and significantly improved appropriateness of antibiotic prescribing.

In the current study, we tested the hypothesis that Mild Cognitive Impairment (MCI) patients can be identified based on the analysis of vergence eye movements and pupil responses. We recorded vergence and pupil responses in MCI patients (N = 22) and cognitive healthy elderly (N = 18) while performing a visual oddball task. Based on selected features, a classifier model computed probability scores predicting MCI. MCI patients were re-evaluated in a follow-up visit of 12–18 months. For validating the model, patients with Alzheimer's Disease (AD) (N = 9) were tested. High classification accuracy was obtained (AUC: 0.93). In addition, the probability scores showed significant predictive power of MCI conversion into possible AD. Our results show that MCI can be detected by assessing vergence and pupil responses during a simple and short task. Therefore, these responses could potentially be used as a marker tool for MCI diagnosis and to identify the risk of developing Alzheimer's Disease.

ABSTRACT Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones.

Abstract Psoriasis (PsO) is a complex immune-mediated disease that afflicts 100 million people. Omilancor is a locally-acting, small molecule that selectively activates the Lanthionine Synthetase C-like 2 (LANCL2) pathway, resulting in immunoregulatory effects at the intersection of immunity and metabolism. Topical omilancor treatment in an imiquimod-induced mouse model of PsO ameliorates disease severity, epidermal hyperplasia and acanthosis. Further, pharmacological activation of LANCL2 results in significant downregulation of proinflammatory markers including local reduction of IL17, and infiltration of proinflammatory cell subsets. These therapeutic effects were further validated in an IL-23 PsO model. This model reported increased preservation of homeostatic skin structure, accompanied by a decreased infiltration of proinflammatory T cell subsets. In CD4+ T cells and Th17 cells, the LANCL2 pathway regulates proinflammatory cytokine production, proliferation and glucose metabolism. Metabolically, the loss of Lancl2 resulted in increased glycolytic rates, lactate production and upregulated enzymatic activity of hexokinase and lactate dehydrogenase (LDH). Inhibition of LDH activity abrogated the increased proliferation rate in Lancl2−/− CD4+ T cells. Additionally, topical omilancor treatment decreased the metabolic upregulation in keratinocytes, keratinocyte hyperproliferation and expression of inflammatory markers. Omilancor is a promising topical, LANCL2-targeting therapeutic candidate for the treatment of PsO and other dermatology indications.