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Objectives The aim of the study was to estimate the rate of adverse reactions to live BCG Moreau vaccine, manufactured by Biomed in Poland, in severe combined immunodeficiency (SCID) patients. Material The profiles of 52 SCID patients vaccinated at birth with BCG, hospitalized in Children's Memorial Health Institute, Warsaw (CMHI), in the years 1980-2015 were compared with those of 349 BCG-vaccinated SCID patients from other countries analyzed by Beatriz E. Marciano et al. in a retrospective study (Marciano et al. J Allergy Clin Immunol. 2014;133(4):1134-1141). Results Significantly less disseminated BCG infections (10 out of 52 SCID, 19%) occurred in comparison with Marciano study-119 out of 349, 34% (p = 0.0028), with no death in patients treated with SCID anti-TB drug, except one in lethal condition. In our study, disseminated BCG infection was observed only in SCID with T-B+NK- phenotype and significantly lower NK cell counts (p = 0.0161). NK cells do not influence on the frequency of local BCG reaction. A significantly higher number of hematopoietic stem cells transplantations (HSCT) were performed in CMHI study (p = 0.0001). Anti-TB treatment with at least two medicines was provided. Conclusion The BCG Moreau vaccine produced in Poland, with well-documented genetic characteristics, seems to be safer than other BCG substrains used in other regions of the world. Importantly, NK cells seem to play a role in protecting SCID patients against disseminated BCG complications, which NK- SCID patients are more prone to. HSCT and TB therapy could be relevant due to the patients' survival and the fact that they protect against BCG infection.

Purpose: The study aimed to compare morphological and anatomic plaque markers derived from coronary computed tomography angiography (cCTA) for the detection of lesion specific ischemia with invasive instantaneous wave free ratio (iFR (R)) as the reference standard. Methods: In our prospective study, we enrolled patients with suspected coronary artery disease (CAD), who had undergone cCTA, using a low-dose third-generation dual-source CT and invasive coronary angiography (ICA) with iFR (R) measurement. Various plaque markers were assessed on cCTA. Discriminatory power of these markers for the detection of ischemia-inducing coronary artery disease was evaluated against invasive iFR (R). Results: Our study cohort included 39 patients (66.6 +/- 12.0 years, 72 % male). Among 54 vessel-specific lesions, 15 lesions (28 %) were characterized as hemodynamically significant by iFR (R) <= 0.89. The area under the curve (AUC) of lesion length/ minimal luminal diameter(4) (LL/MLD4) (0.84) was greater than the AUC of minimal luminal area (MLA) (0.82), MLD (0.81), the degree of luminal diameter stenosis (0.81), corrected coronary opacification (CCO) (0.79), remodeling index (RI) (0.75), and percentage aggregate plaque volume (%APV) (0.72). LL, vessel volume (VV), total plaque volume (TPV), calcified and non-calcified plaque volume (CPV and NCPV) did not reach statistical significance and were unable to discriminate between vessels with and without ischemia-inducing coronary stenosis. Conclusion: LL/MLD4, MLA, MLD, the degree of luminal diameter stenosis, CCO, RI, and %APV derived from cCTA can support the detection of hemodynamically significant coronary stenosis as compared with iFR (R), with LL/MLD4 showing the greatest discriminatory power.

"Intralitter likeness," the possibility that the shared genetics and/or maternal environment in multiparous species causes strong similarity for outcome variables in littermates, violates a core statistical assumption, that of observation independence, when littermate outcomes are analyzed. Intralitter likeness has been of major concern to investigators for several decades. Despite consensus and guidance, many research reports in the rodent literature continue to ignore intralitter likeness. A historical review of the literature revealed that the long-preferred solution was to include litter as an effect in statistical models. Limitations in software development and computing capacity prior to 1990, however, appear to have led researchers and guidance authorities to endorse instead the method of using one value per litter. Here, the history of discussions regarding intralitter likeness in developmental neurotoxicological research is reviewed; growing knowledge regarding the biological bases and significance of intralitter likeness is discussed; principles underlying the use of litter as a random effect in mixed models are presented; statistical examples are provided illustrating the advantages and critical importance of including litter as a random effect in mixed models; and results using all data points (all pups from all litters) with litter as a random effect, are compared to results based on random selections of representative littermates. Mixed models with litter included as a random effect have distinct advantages for the analysis of clustered data. Modern computing capacity provides ready accessibility to mixed models for all researchers. Accessibility however does not preclude the need for appropriate expertise and consultation in the use of mixed (hierarchical) models.

The advances made in bioorthogonal chemistry and the development of chemical reporters have afforded new strategies to explore the targets and functions of specific metabolites in biology. These metabolite chemical reporters have been applied to diverse classes of bacteria including Gram-negative, Gram-positive, mycobacteria, and more complex microbiota communities. Herein we summarize the development and application of metabolite chemical reporters to study fundamental pathways in bacteria as well as microbiota mechanisms in health and disease.

Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These involve reengagement of memory B cell (MBC) clones, the diversity and specificity of which determine the breadth and effectiveness of the ensuing antibody response. Using prime-boost models in mice, we find that secondary responses are characterized by a clonality bottleneck that restricts the engagement of the large diversity of MBC clones generated by priming. Rediversification of mutated MBCs is infrequent within secondary germinal centers (GCs), which instead consist predominantly of B cells without prior GC experience or detectable clonal expansion. Few MBC clones, generally derived from higher-affinity germline precursors, account for the majority of secondary antibody responses, while most primary-derived clonal diversity is not reengaged detectably by boosting. Understanding how to counter this bottleneck may improve our ability to elicit antibodies to non-immunodominant epitopes by vaccination.

Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.

Question What is the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled atopic dermatitis? Findings In this randomized phase 3 clinical trial including 251 adolescents with moderate to severe atopic dermatitis, dupilumab 200 or 300 mg every 2 weeks and 300 mg every 4 weeks resulted in a significant treatment response vs placebo following 16-week treatment, with an acceptable safety profile. Meaning The findings appear to support the use of dupilumab for the treatment of adolescents with moderate to severe atopic dermatitis. Importance Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population. Objective To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD. Design, Setting, and Participants A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included. Interventions Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight >= 60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85). Main Outcomes and Measures Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16. Results A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%). Conclusions and Relevance In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults. This phase 3 randomized clinical trial evaluates the efficacy and safety of 2 dose regimens of dupilumab for treatment of moderate to severe atopic dermatitis in adolescents.

Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic. Author summary Parvoviruses are small, genetically simple single-strand DNA viruses that remain viable outside their hosts for very long periods of time. They cause disease in several domesticated species and in humans. Mouse kidney parvovirus (MKPV) is a causative agent of kidney failure in immune-compromised mice and is the only member of the provisional Chapparvovirus genus for which the complete genome including telomeres is known. Here, we show that MKPV propagates almost exclusively in the kidneys of mice infected naturally, wherein it produces novel accessory proteins whose coding regions are conserved in amniote-associated chapparvovirus sequences. We assemble a closely related complete viral genome present in DNA extracted from the kidney of a wild Cebus imitator monkey, and show that another related chapparvovirus is preferentially found in kidneys of the vampire bat Desmodus rotundus. We conclude that many mammal-hosted chapparvovirus are adapted to the kidney niche and may therefore cause disease following kidney stress in multiple species.

The original version of this article unfortunately contained mistakes in reference numbers. The in-text citations and the references were mismatched. The original article has been corrected.