Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation.

Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. High-affinity cells are proposed to preferentially select into this compartment, potentiating the immune response. We used single-cell RNA-seq to track the germinal center (GC) development of Ighg2A10 B cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites, we identified 3 populations of cells in the GC light zone (LZ). One LZ population expressed a gene signature associated with the initiation of PC differentiation and readily formed PCs in vitro. The estimated affinity of these pre-PC B cells was indistinguishable from that of LZ cells that remained in the GC. This remained true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. These findings suggest that the initiation of PC development occurs via an affinity-independent process.

Does losing reduce the tendency to engage with rivals to reach mates? An experimental test.

Male-male contests for access to females or breeding resources are critical in determining male reproductive success. Larger males and those with more effective weaponry are more likely to win fights. However, even after controlling for such predictors of fighting ability, studies have reported a winner-loser effect: previous winners are more likely to win subsequent contests, while losers often suffer repeated defeats. While the effect of winning-losing is well-documented for the outcome of future fights, its effect on other behaviors (e.g. mating) remains poorly investigated. Here, we test whether a winning versus losing experience influenced subsequent behaviors of male mosquitofish (Gambusia holbrooki) toward rivals and potential mates. We housed focal males with either a smaller or larger opponent for 24 h to manipulate their fighting experience to become winners or losers, respectively. The focal males then underwent tests that required them to enter and swim through a narrow corridor to reach females, bypassing a cylinder that contained either a larger rival male (competitive scenario), a juvenile or was empty (non-competitive scenarios). The tests were repeated after 1 wk. Winners were more likely to leave the start area and to reach the females, but only when a larger rival was presented, indicating higher levels of risk-taking behavior in aggressive interactions. This winner-loser effect persisted for at least 1 wk. We suggest that male mosquitofish adjust their assessment of their own and/or their rival's fighting ability following contests in ways whose detection by researchers depends on the social context.

Psychological symptoms and health-related quality of life in intubated and non-intubated intensive care survivors: A multicentre, prospective observational cohort study.

Objective: To compare long-term psychological symptoms and health-related quality of life (HRQOL) in intubated versus non-intubated ICU survivors. Design: Prospective, multicentre observational cohort study. Setting: Four tertiary medical-surgical ICUs in Australia. Participants: Intubated and non-intubated adult ICU survivors. Main outcome measures: Primary outcomes: clinically significant psychological symptoms at 3- and 12-month follow-up using Post-Traumatic Stress Syndrome-14 for post-traumatic stress disorder; Depression, Anxiety Stress Scales-21 for depression, anxiety, and stress. Secondary outcomes: HRQOL, using EuroQol-5D-5L questionnaire. Results: Of the 133 ICU survivors, 54/116 (47 %) had at least one clinically significant psychological symptom (i.e., post-traumatic stress disorder, anxiety, depression, stress) at follow-up. Clinically significant scores for psychological symptoms were observed in 26 (39 %) versus 16 (32 %) at 3-months [odds ratio 1.4, 95 % confidence interval (0.66-3.13), p = 0.38]; 23 (37 %) versus 10 (31 %) at 12-months [odds ratio 1.3, 95 % confidence interval (0.53-3.31), p = 0.57] of intubated versus non-intubated survivors, respectively. Usual activities and mobility were the most commonly affected HRQOL dimension, with >30 % at 3 versus months and >20 % at 12-months of overall survivors reporting ≥ moderate problems. There was no difference between the groups in any of the EQ5D dimensions. Conclusions: Nearly one-in-two (47 %) of the intubated and non-intubated ICU survivors reported clinically significant psychological symptoms at 3 and 12-month follow-ups. Overall, more than 30 % at 3-months and over 20 % at 12-months of the survivors in both groups had moderate or worse problems with their usual activities and mobility. The presence of psychological symptoms and HRQOL impairments was similar between the groups.

Response to COVID-19 vaccination in patients on cancer therapy: Analysis in a SARS-CoV-2-naïve population.

BACKGROUND: Cancer patients have increased morbidity and mortality from COVID-19, but may respond poorly to vaccination. The Evaluation of COVID-19 Vaccination Efficacy and Rare Events in Solid Tumors (EVEREST) study, comparing seropositivity between cancer patients and healthy controls in a low SARS-CoV-2 community-transmission setting, allows determination of vaccine response with minimal interference from infection. METHODS: Solid tumor patients from The Canberra Hospital, Canberra, Australia, and healthy controls who received COVID-19 vaccination between March 2021 and January 2022 were included. Blood samples were collected at baseline, pre-second vaccine dose and at 1, 3 (primary endpoint), and 6 months post-second dose. SARS-CoV-2 anti-spike-RBD (S-RBD) and anti-nucleocapsid IgG antibodies were measured. RESULTS: Ninety-six solid tumor patients and 20 healthy controls were enrolled, with median age 62 years, and 60% were female. Participants received either AZD1222 (65%) or BNT162b2 (35%) COVID-19 vaccines. Seropositivity 3 months post vaccination was 87% (76/87) in patients and 100% (20/20) in controls (p = .12). Seropositivity was observed in 84% of patients on chemotherapy, 80% on immunotherapy, and 96% on targeted therapy (differences not satistically significant). Seropositivity in cancer patients increased from 40% (6/15) after first dose, to 95% (35/37) 1 month after second dose, then dropped to 87% (76/87) 3 months after second dose. CONCLUSION: Most patients and all controls became seropositive after two vaccine doses. Antibody concentrations and seropositivity showed a decrease between 1 and 3 months post vaccination, highlighting need for booster vaccinations. SARS-CoV-2 infection amplifies S-RBD antibody responses; however, cannot be adequately identified using nucleocapsid serology. This underlines the value of our COVID-naïve population in studying vaccine immunogenicity.

Comprehensive systematic review and pooled analysis of real-world studies evaluating immunomodulator and biologic therapies for chronic pouchitis treatment.

Background and Aim: Pouchitis is a common complication after restorative ileal pouch-anal anastomosis following proctocolectomy for ulcerative colitis. Antibiotic-dependent or antibiotic-refractory chronic pouchitis (CP), which is a common cause of pouch failure affecting 15-20% of patients, is challenging to treat. The efficacy of second-line immunomodulator and biologic therapy remains poorly defined. We present a pooled analysis of real-world efficacy data from peer-reviewed full-text manuscripts, focusing on immunomodulator and biologic therapies in CP. Methods: Embase and PubMed databases were searched for full-text articles describing the treatment of CP. We performed a systematic review and pooled analysis of published studies to assess the efficacy of immunomodulators, including thiopurines and methotrexate, and biologics including antitumor necrosis factor, anti-integrin, and interleukin-12/23 antagonists. Clinical and endoscopic response and remission rates were combined for pooled analyses. Rates of treatment discontinuation and safety were also assessed. Results: Pooled analysis comprised 20 full-text articles (485 patients). Overall clinical response rate was 46% (95% CI: 35-59%) and clinical remission rate was 35% (95% CI: 21-52%). Overall endoscopic response and remission rates were 41% (95% CI: 18-68%) and 15% (95% CI: 5-39%), respectively. Individual agents' safety profile was reassuring, with vedolizumab being the most favorable. Conclusion: The real-world efficacy data of immunomodulators in the treatment of CP is insufficient. Vedolizumab and ustekinumab appeared effective and safe for CP, whereas anti-TNFs showed higher rates of adverse events. The high heterogeneity within the studies is attributed to the real-world study design, obfuscating drug efficacy comparisons across the studies. Further studies are required to define the comparative effectiveness of available treatments of CP.

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints / Terapia de reposição de leptina para o tratamento de síndromes lipodistróficas não associadas ao uso de antirretrovirais: uma metanálise dos efeitos da leptina em parâmetros metabólicos e hepáticos

The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36‐1.13), p=0.0001], HbA1c [0.49 (0.17‐0.81), p=0.003], triglycerides [1.00 (0.69‐1.31), p<0.00001], total cholesterol [0.62 (0.21‐1.02), p=0.003], liver volume [1.06 (0.51‐1.61), p=0.0002] and AST [0.41 (0.10‐0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.

As manifestações clínicas das síndromes lipodistróficas (SL) incluem hipoleptinemia, hiperglicemia, resistência insulínica, dislipidemia e esteatose hepática. A terapia de reposição de leptina (TRL) melhora tais parâmetros, mas atualmente não há dados compilados demonstrando tal efeito. Uma revisão sistemática dos bancos de dados MEDLINE e Cochrane Library identificou estudos avaliando os efeitos da TRL sobre parâmetros metabólicos e hepáticos em pacientes com SL não associadas ao uso de antirretrovirais. Diferenças médias padronizadas (DMP) e intervalos de confiança de 95% foram calculados a partir dos resultados, para os efeitos da TRL sobre a homeostase da glicose, perfil lipídico, e morfologia/função hepática, usando um modelo de variação inversa e efeitos randômicos. Após a triagem, 12 estudos foram incluídos para revisão. A metanálise dos resultados de 226 pacientes mostrou que a TRL reduziu a glicemia de jejum [0,75 DMP (amplitude 0,36‐1,13), p=0,0001], HbA1c [0,49 (0,17‐0,81), p=0,003], triglicerídeos [1,00 (0,69‐1,31), p<0,00001], colesterol total [0,62 (0,21‐1,02), p=0,003], volume hepático [1,06 (0,51‐1,61), p=0,0002] e AST [0,41 (0,10‐0,73), p=0,001]. Em pacientes com SL não associada ao uso de antirretrovirais, a TRL melhora vários parâmetros metabólicos e hepáticos. Os estudos avaliados foram limitados pelo pequeno número de pacientes. Maiores estudos clínicos prospectivos são necessários para validar tais achados.