Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy

Background: Despite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of 'namely' atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation. Methods: We studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity. Results: Phenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: Í4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and Í4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035). Conclusion: We identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Hybrid laparoscopic versus fully robot-assisted minimally invasive esophagectomy:an international propensity-score matched analysis of perioperative outcome

Background: Currently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE). Methods: This retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers. Results: After propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p &lt; 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p &lt; 0.0001) were longer for the hybrid laparoscopic RAMIE group. Conclusions: Hybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE.</p

How the microbiome reshapes obesity research : from altered gut microbial composition to important co-factor in weight loss strategies

Abstract: INTRODUCTION: Obesity has become one of the most common chronic conditions, causing a large number of comorbidities. During the last decades, a growing number of studies have associated obesity with altered microbiome composition. Moreover, numerous studies reported the effects of diet- and surgery-induced weight loss on the microbiome. This narrative review aims to give an overview of studies published between 2021 and early 2022 about the microbiome in obesity. MATERIAL AND METHODS: A literature search using the search term \u2018Obesity AND (Microbiota OR Microbiome)\u2019 was conducted in Medline. Only research studies in humans published between March 2021 and March 2022 were eligible for inclusion. RESULTS: Out of 1877 studies, 69 discussed the microbiome composition in obesity or reported how weight loss by a diet or bariatric surgery influenced the microbiome. In general, obesity is associated with the upregulation of the Firmicutes phylum compared to the Bacteroidetes phylum. However, the microbiome is also modified due to changes at all levels of the microbiome. No studies were able to unravel a causal link between certain microbial patterns and the development of obesity. The intestinal microbiome in obesity was affected by genetic, environmental, and phenotypic factors. Similarly, weight loss was also associated with extensive modifications of the gut microbiome. More changes in the microbiome were seen after bariatric surgery compared to diet-induced weight loss. CONCLUSIONS: Although a large number of studies have demonstrated that obesity and weight loss modify the intestinal microbiome, it is unclear how these changes occur. Future studies should focus on the mechanisms by which the microbiome interacts with the metabolism in obesity

An empirical assessment of the consistency of taxonomic identifications

Plankton counting and analysis is essential in ecological study, yet scant literature exists as to the reliability of those counts and the consistency of the experts who make the counts. To assess how variable expert taxonomic identifications are, a set of six archived mesozooplankton samples from a series of Longhurst Hardy Plankton Recorder net hauls were counted by expert zooplankton analysts located at six marine laboratories. Sample identifications were repeated on two separate days with over 700 target specimens counted and identified on each day across the samples. Twenty percent of the analysts returned counts that varied by more than 10%. Thirty-three percent of analysts exhibited low identification consistencies, returning Intraclass Correlation Coefficient scores of less than 0.80. Statistical analyses of these data suggest that over 83% of the observed categorical count variance can be attributed to inconsistencies within analysts. We suggest this is the root cause of variation in expert specimen labelling consistency