There is an unmet need for new treatments for allergic conjunctivitis.
To assess the activity of reproxalap, a novel reactive aldehyde species modulator, in a real-world model of seasonal allergen ...exposure.
The INVIGORATE Trial, a prospective, quadruple-masked, vehicle-controlled, crossover, sequence-randomized Phase 3 trial, tested the efficacy of reproxalap in adults with a history of moderate to severe allergic conjunctivitis, ragweed pollen allergy, and allergen chamber-induced ocular itching and redness. Patients were randomly assigned (1:1) to receive 0.25% reproxalap ophthalmic solution or vehicle, followed by a 2-week washout period before crossing over to the other test article. The primary endpoint was ocular itching from 110 to 210 minutes after chamber entry; the key secondary endpoint was ocular redness over the chamber duration (0-4 scales for both endpoints).
Of the 95 randomly assigned patients, 89 completed all visits (reproxalap to vehicle: n = 46; vehicle to reproxalap: n = 43). Primary and key secondary endpoints were met: reproxalap significantly reduced ocular itching (mean SE: -0.50 0.03, p < 0.001) and redness (-0.14 0.01, p < 0.001) relative to vehicle. Responder analyses confirmed the clinical relevance of both end points. Reproxalap was safe and well tolerated. No clinically significant changes in safety assessments were observed. No serious or severe treatment-emergent adverse events (TEAEs) were reported. The most commonly reported TEAE was mild and transient installation site irritation after reproxalap versus vehicle administration.
In this well-controlled allergen chamber trial, reproxalap was statistically superior to vehicle across typical symptoms and signs of allergic conjunctivitis.
NCT04207736.
Summary Few studies are available to inform duration of intravenous antibiotics for children and when it is safe and appropriate to switch to oral antibiotics. We have systematically reviewed ...antibiotic duration and timing of intravenous to oral switch for 36 paediatric infectious diseases and developed evidence-graded recommendations on the basis of the review, guidelines, and expert consensus. We searched databases and obtained information from references identified and relevant guidelines. All eligible studies were assessed for quality. 4090 articles were identified and 170 studies were included. Evidence relating antibiotic duration to outcomes in children for some infections was supported by meta-analyses or randomised controlled trials; in other infections data were from retrospective series only. Criteria for intravenous to oral switch commonly included defervescence and clinical improvement with or without improvement in laboratory markers. Evidence suggests that intravenous to oral switch can occur earlier than previously recommended for some infections. We have synthesised recommendations for antibiotic duration and intravenous to oral switch to support clinical decision making and prospective research.
Previous research supports gene-environment interactions for polymorphisms in the corticotropin hormone receptor 1 gene (CRHR1) and the serotonin transporter gene linked polymorphic region (5-HTTLPR) ...in predicting depression, but it has rarely considered genetic influences on stress sensitization processes, whereby early adversities (EA) increase depressive reactivity to proximal stressors later in life. The current study tested a gene-environment-environment interaction (G × E × E; specifically, gene-EA-proximal stress interaction) model of depression in a 20-year longitudinal study. Participants were assessed prospectively for EA up to age 5 and recent chronic stress and depressive symptoms at age 20 and genotyped for CRHR1 single nucleotide polymorphism rs110402 and 5-HTTLPR. EA predicted stronger associations between recent chronic stress and depression, and the effect was moderated by genes. CRHR1 A alleles and 5-HTTLPR short alleles were associated with greater stress sensitization (i.e., greater depressive reactivity to chronic stress for those also exposed to high levels of EA). The results are consistent with the notion that EA exposure results in neurobiological and cognitive-emotional consequences (e.g., altered hypothalamic-pituitary-adrenal axis functioning), leading to emotional distress in the face of recent stressors among those with certain genetic characteristics, although further research is needed to explore explanatory mechanisms.
Unlimited generation of chimeric antigen receptor (CAR) T cells from human-induced pluripotent stem cells (iPSCs) is an attractive approach for “off-the-shelf” CAR T cell immunotherapy. Approaches to ...efficiently differentiate iPSCs into canonical αβ T cell lineages, while maintaining CAR expression and functionality, however, have been challenging. We report that iPSCs reprogramed from CD62L+ naive and memory T cells followed by CD19-CAR engineering and 3D-organoid system differentiation confers products with conventional CD8αβ-positive CAR T cell characteristics. Expanded iPSC CD19-CAR T cells showed comparable antigen-specific activation, degranulation, cytotoxicity, and cytokine secretion compared with conventional CD19-CAR T cells and maintained homogeneous expression of the TCR derived from the initial clone. iPSC CD19-CAR T cells also mediated potent antitumor activity in vivo, prolonging survival of mice with CD19+ human tumor xenografts. Our study establishes feasible methodologies to generate highly functional CAR T cells from iPSCs to support the development of “off-the-shelf” manufacturing strategies.
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•3D-organoid culture supports differentiation of CAR+ iPSCs into functional CAR T cells•iPSC-derived CAR T cells demonstrate conventional αβ T cell phenotypes•iPSC-derived CAR T cells show lower CAR expression and a homogeneous TCR repertoire•iPSC-derived CAR T cells demonstrate potent antitumor activity in vitro and in vivo
Wang et al. establish feasible methodologies to generate highly functional CAR T cells from T-cell-derived iPSCs using 3D-organoid cultures, thereby supporting the development of “off-the-shelf” manufacturing strategies.
Numerous studies have supported an association between maternal depression and child psychiatric outcomes, but few have controlled for the confounding effects of both maternal and offspring ...co-morbidity. Thus, it remains unclear whether the correspondence between maternal and offspring depressive and anxiety disorders is better explained by associations between shared features of maternal and offspring internalizing disorders or by specific effects exerted by unique aspects of individual disorders.
Pairs of mothers and offspring overselected for maternal depression (n = 815) were assessed at offspring age 15 years for anxiety and depressive disorders; 705 completed a follow-up at offspring age 20 years. For both mothers and offspring, structural equation modeling was used to distinguish transdiagnostic internalizing pathology--representing the overlap among all depressive and anxiety disorders--from diagnosis-specific forms of pathology. To discriminate between general versus specific pathways of intergenerational transmission of psychopathology, we examined (a) the general association between the maternal and offspring internalizing factors and (b) the correlations between maternal and offspring diagnosis-specific pathology for each disorder.
For mothers and offspring, a unidimensional latent variable model provided the best fit to the correlations among depressive and anxiety disorders. The maternal transdiagnostic internalizing factor strongly predicted the corresponding factor among offspring. In addition, the unique component of post-traumatic stress disorder among offspring was significantly related to the analogous unique component among mothers, but specific components of other maternal disorders, including depression, did not predict corresponding offspring pathology.
Results suggest that intergenerational transmission of internalizing disorders is largely non-specific.
SignificanceSkin is recognized as an intricate assembly of molecular components, which facilitate cell signaling, metabolism, and protein synthesis mechanisms in order to offer protection, ...regulation, and sensation to the body. Our study takes significant steps to characterize in more detail the complex chemistry of the skin, in particular by generating a better understanding of the uppermost layer, the stratum corneum. Using a state-of-the-art 3D OrbiSIMS technique, we were able to observe the depth distribution, in situ, for a wide range of molecular species. This unprecedented molecular characterization of skin provides information that has the potential to benefit research into fundamental processes, such as those associated with skin aging and disease, and the development and delivery of effective topical formulations.
Objective To determine whether cystic fibrosis (CF) is associated with adverse neonatal outcomes in a recent birth cohort in the US. Study design A retrospective matched cohort study of infants born ...in Washington State from 1996 to 2013 was identified through birth certificate data and linked to statewide hospital discharge data. Infants with CF were identified by hospitalization (through age 5 years) in which a CF-specific International Classification of Diseases, Ninth Revision code was recorded. “Unexposed” infants lacked CF-related International Classification of Diseases, Ninth Revision codes and were randomly selected among births, frequency-matched to “exposed” infants on birth year. Associations of CF with adverse neonatal outcomes (low birth weight LBW, small for gestational age SGA, preterm birth, and infant mortality) were estimated through Poisson regression. We performed extreme value imputation to address possible ascertainment bias. Results We identified 170 infants with CF and 3400 unexposed infants. CF was associated with increased relative risk (95% CI) of 3.5 (2.5-4.9), 1.6 (1.1-2.4), 3.0 (2.2-4.0), and 6.8 (1.7-26.5) for LBW, SGA, preterm birth, and infant death, respectively. The estimated relative risks were similar among infants born from 2006 to 2013, except SGA was no longer associated with CF diagnosis. Results were robust to extreme value imputation and exclusion of infants with meconium ileus. Conclusions Observed associations of CF with LBW, preterm birth, and infant death are unlikely to be due to ascertainment bias. Further work is needed to determine how to prevent these adverse neonatal outcomes.
•A latent internalizing dimension explained correlations among manifest internalizing problems.•Internalizing was correlated modestly with anhedonia and robustly with neuroticism.•Anhedonia was ...virtually unassociated with the major depression, net internalizing.
Developmental research documents that anhedonia, or diminished interest in usual activities, is associated with a diverse array of emotional problems in childhood and adolescence. Meanwhile, official nosologies desginate anhedonia as a more specific characteristic of major depressive disorder. Using a quantitative model of the internalizing domain, we compared the strength of transdiagnostic versus diagnosis-specific pathways from anhedonia to major depression (and other internalizing conditions) during adolescence. We recruited 241 youth ages 14–17 who completed semistructured interviews of anxiety and depressive disorders, as well as several self-report surveys of trait anhedonia and neuroticism. Confirmatory factor analysis of diagnostic correlations revealed good fit for a unidimensional model of the 10 internalizing conditions we assessed. This overarching internalizing dimension was statistically significantly correlated with trait anhedonia (r = 0.17) and neuroticism (r = 0.59). In contrast, anhedonia was virtually unrelated to major depression (r = −0.02), net the internalizing dimension. Thus, in this sample, the connection between anhedonia and major depression was explained by a transdiagnostic dimension presumed to underlie all internalizing problems. Compared to neuroticism, however, anhedonia had a more limited association with internalizing, consistent with established personality models of anxiety and depression. We conclude that these data are consistent with conceptualizing anhedonia predominantly as a transdiagnostic correlate of internalizing conditions, rather than a specific marker of major depression, in developmental psychopathology research and clinical interventions for young people.
Objectives The aim of this study was to evaluate the independent prognostic significance of ischemia change in stable coronary artery disease (CAD). Background Recent randomized trials in stable CAD ...have suggested that revascularization does not improve outcomes compared with optimal medical therapy (MT). In contrast, the nuclear substudy of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial found that revascularization led to greater ischemia reduction and suggested that this may be associated with improved unadjusted outcomes. Thus, the effects of MT versus revascularization on ischemia change and its independent prognostic significance requires further investigation. Methods From the Duke Cardiovascular Disease and Nuclear Cardiology Databanks, 1,425 consecutive patients with angiographically documented CAD who underwent 2 serial myocardial perfusion single-photon emission computed tomography scans were identified. Ischemia change was calculated for patients undergoing MT alone, percutaneous coronary intervention, or coronary artery bypass grafting. Patients were followed for a median of 5.8 years after the second myocardial perfusion scan. Cox proportional hazards regression modeling was used to identify factors independently associated with the primary outcome of death or myocardial infarction (MI). Formal risk reclassification analyses were conducted to assess whether the addition of ischemia change to traditional predictors resulted in improved risk classification for death or MI. Results More MT patients (15.6%) developed ≥5% ischemia worsening compared with those undergoing percutaneous coronary intervention (6.2%) or coronary artery bypass grafting (6.7%) (p < 0.001). After adjustment for established predictors, ≥5% ischemia worsening remained a significant independent predictor of death or MI (hazard ratio: 1.634; p = 0.0019) irrespective of treatment arm. Inclusion of ≥5% ischemia worsening in this model resulted in significant improvement in risk classification (net reclassification improvement: 4.6%, p = 0.0056) and model discrimination (integrated discrimination improvement: 0.0062, p = 0.0057). Conclusions In stable CAD, ischemia worsening is an independent predictor of death or MI, resulting in significantly improved risk reclassification when added to previously known predictors.
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