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Abstract Background The value of abdominal echography in primary care is great because it is innocuous, inexpensive, easy to perform and provides a great deal of information making this the first examination to be requested in cases of probable abdominal disease. However, too many abdominal echographies are probably requested overcrowding the Departments of Radiodiagnosis with not always justified petitions or with repetition of tests based on little clinical criteria. Methods/Design The aim of the study is to evaluate the adequacy and quality of abdominal echographies requested by primary care physicians in the Maresme County (North of Barcelona), develop guidelines for indicating echographies and reevaluate this adequacy after implementing these guidelines. We will perform a two-phase study: the first descriptive, and retrospective evaluating the adequacy and quality of petitions for abdominal echographies, and in the second phase we will evaluate the impact of recommendations for indicating abdominal echographies for PC physicians on the adequacy and quality of echography petitions thereafter. This study will be carried out in 10 primary care centres in the Maresme (Barcelona). 1067 abdominal echographies requested by primary care physicians from the above mentioned centres from January 2007 to April 2010 and referred to the Department of Radiology and the same number of applications after the intervention. All the petitions for abdominal echographies requested will be analysed and the clinical histories will be obtained to determine demographic variables, the reason for the visit and for the echography petition and diagnostic orientation, clinical and echographic data, evaluation of the echographies according to the quality and variables characterising the professionals requesting the echographies including: age, sex, laboral situation, length of time in work post, formation, etc. To achieve a consensus of the adequacy of abdominal echography, a work group including gastroenterologists, radiologists and general practitioners will be created following the nominal group. This will allow the design of guidelines for the indication of abdominal echography and posterior evaluation of their impact among physicians by diffusion and posterior reevaluation of the adequacy of the petitions.

Abstract Background Non alcoholic fatty liver disease (NAFL) consists in the accumulation of fat vacuoles in the cytoplasm of hepatocytes. Many etiologic factors are associated with NAFL, such as, the metabolic syndrome factors, medications, bariatric surgery, nutritional disorders. However, very little information is available on the clinical relevance of this disorder as a health problem in the general population. Methods and design The aim of the study is establish the risk factors most frequently associated with NAFL in a general adult population assigned to the primary care units and to investigate the relationship between each component of the metabolic syndrome and the risk of having a NAFL. A population based case-control, observational and multicenter study will be carried out in 18 primary care units from the "Area de Gestión del Barcelonés Nord y Maresme" (Barcelona) attending a population of 360,000 inhabitants and will include 326 cases and 370 controls. Cases are defined as all subjects fulfilling the inclusion criteria and with evidence of fatty liver in an abdominal ultrasonography performed for any reason. One control will be randomly selected for each case from the population, matched for age, gender and primary care center. Controls with fatty liver or other liver diseases will be excluded. All cases and controls will be asked about previous hepatic diseases, consumption of alcohol, smoking and drugs, and a physical examination, biochemical analyses including liver function tests, the different components of the metabolic syndrome and the HAIR score will also be performed. Paired controls will also undergo an abdominal ultrasonography. Discussion This study will attempt to determine the factors most frequently associated with the presence of NAFL investigate the relationship between the metabolic syndrome and the risk of fatty liver and study the influence of the different primary care professionals in avoiding the evolution of the disease.

Abstract Background Fatty liver disease is characterized by the accumulation of fat vacuoles inside of the hepatocytes. Non alcoholic fatty liver is associated with obesity, type 2 diabetes, dyslipemia, the intake of certain drugs and with the so-called metabolic syndrome. However, there is little information on the clinical relevance of this disorder as a healthcare problem in the general population, since the studies published generally include a limited number of patients and the diagnosis is established on the basis of clear biochemical alterations and liver biopsy. Methods/Design The aim of the study is the prevalence of non-alcoholic fatty liver disease in a general adult population by hepatic ultrasonography. A population-based, descriptive, transversal, multicentre study. Eighteen primary care centres of the north of Barcelona and the Maresme Areas of Healthcare Management attending an urban and semi-urban population of 360.000 inhabitants. A randomized sample of 786 subjects of 15 years or older were selected from the population and assigned to the participating centres according to the Primary Care Information System (SIAP): This population is practically the same as the general population of the area. The following determinations will be carried out in all the participants: hepatic ultrasonography to detect fatty liver, a questionnaire concerning liver diseases, alcohol intake, smoking and drug use, physical examination including abdominal perimeter and body mass index and biochemical analysis including liver function tests and parameters related to the metabolic syndrome and the HAIR score. Ultrasonographic diagnosis of fatty liver will be made according to established criteria (American Gastroenterology Association) and diagnosis of metabolic syndrome according to the criteria of the European Group for the Study of Insulin Resistance. Discussion This study will attempt to determine the prevalence of non alcoholic fatty liver disease, as well as, the factors most frequently associated with the presence of this disease to thereby achieve the most appropriate treatment and avoid the evolution of the disease.

Objectives: Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients., Methods: We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls., Results: Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21 lo CD27 + influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains., Conclusions: Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups., Competing Interests: MK has acted as a consultant for Sanofi group of companies but not at the time the research was conducted. All other authors have declared that no conflict of interest exists., (© 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Age can profoundly affect susceptibility to a broad range of human diseases. Children are more susceptible to some infectious diseases such as diphtheria and pertussis, while in others, such as coronavirus disease 2019 and hepatitis A, they are more protected compared with adults. One explanation is that the composition of the immune system is a major contributing factor to disease susceptibility and severity. While most studies of the human immune system have focused on adults, how the immune system changes after birth remains poorly understood. Here, using high-dimensional spectral flow cytometry and computational methods for data integration, we analyzed more than 50 populations of immune cells in the peripheral blood, generating an immune cell atlas that defines the healthy human immune system from birth up to 75 years of age. We focused our efforts on children under 18 years old, revealing major changes in immune cell populations after birth and in children of schooling age. Specifically, CD4 + T effector memory cells, Vδ2 + gamma delta (γδ)T cells, memory B cells, plasmablasts, CD11c + B cells and CD16 + CD56 bright natural killer (NK) cells peaked in children aged 5-9 years old, whereas frequencies of T helper 1, T helper 17, dendritic cells and CD16 + CD57 + CD56 dim NK cells were highest in older children (10-18 years old). The frequency of mucosal-associated invariant T cells was low in the first several years of life and highest in adults between 19 and 30 years old. Late adulthood was associated with fewer mucosal-associated invariant T cells and Vδ2 + γδ T cells but with increased frequencies of memory subsets of B cells, CD4 + and CD8 + T cells and CD57 + NK cells. This human immune cell atlas provides a critical resource to understand changes to the immune system during life and provides a reference for investigating the immune system in the context of human disease. This work may also help guide future therapies that target specific populations of immune cells to protect at-risk populations., (© 2022 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Prior vaccination can alternately enhance or attenuate influenza vaccine immunogenicity and effectiveness. Analogously, we found that vaccine immunogenicity was enhanced by prior A(H3N2) virus infection among participants of the Ha Nam Cohort, Viet Nam, but was attenuated by prior vaccination among Australian Health Care Workers (HCWs) vaccinated in the same year. Here, we combined these studies to directly compare antibody titers against 35 A(H3N2) viruses spanning 1968-2018. Participants received licensed inactivated vaccines containing A/HongKong/4801/2014 (H3N2). The analysis was limited to participants aged 18-65 Y, and compared those exposed to A(H3N2) viruses circulating since 2009 by infection (Ha Nam) or vaccination (HCWs) to a reference group who had no recent A(H3N2) infection or vaccination (Ha Nam). Antibody responses were compared by fitting titer/titer-rise landscapes across strains, and by estimating titer ratios to the reference group of 2009-2018 viruses. Pre-vaccination, titers were lowest against 2009-2014 viruses among the reference (no recent exposure) group. Post-vaccination, titers were, on average, two-fold higher among participants with prior infection and two-fold lower among participants with 3-5 prior vaccinations compared to the reference group. Titer rise was negligible among participants with 3-5 prior vaccinations, poor among participants with 1-2 prior vaccinations, and equivalent or better among those with prior infection compared to the reference group. The enhancing effect of prior infection versus the incrementally attenuating effect of prior vaccinations suggests that these exposures may alternately promote and constrain the generation of memory that can be recalled by a new vaccine strain.

Studies of successive vaccination suggest that immunological memory against past influenza viruses may limit responses to vaccines containing current strains. The impact of memory induced by prior infection is rarely considered and is difficult to ascertain, because infections are often subclinical. This study investigated influenza vaccination among adults from the Ha Nam cohort (Vietnam), who were purposefully selected to include 72 with and 28 without documented influenza A(H3N2) infection during the preceding 9 years (Australian New Zealand Clinical Trials Registry 12621000110886). The primary outcome was the effect of prior influenza A(H3N2) infection on hemagglutinin-inhibiting antibody responses induced by a locally available influenza vaccine administered in November 2016. Baseline and postvaccination sera were titrated against 40 influenza A(H3N2) strains spanning 1968-2018. At each time point (baseline, day 14 and day 280), geometric mean antibody titers against 2008-2018 strains were higher among participants with recent infection (34 (29-40), 187 (154-227) and 86 (72-103)) than among participants without recent infection (19 (17-22), 91 (64-130) and 38 (30-49)). On days 14 and 280, mean titer rises against 2014-2018 strains were 6.1-fold (5.0- to 7.4-fold) and 2.6-fold (2.2- to 3.1-fold) for participants with recent infection versus 4.8-fold (3.5- to 6.7-fold) and 1.9-fold (1.5- to 2.3-fold) for those without. One of 72 vaccinees with recent infection versus 4 of 28 without developed symptomatic A(H3N2) infection in the season after vaccination (P = 0.021). The range of A(H3N2) viruses recognized by vaccine-induced antibodies was associated with the prior infection strain. These results suggest that recall of immunological memory induced by prior infection enhances antibody responses to inactivated influenza vaccine and is important to attain protective antibody titers., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 + or CD4 + T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.

Objectives: A fundamental question in influenza research is whether antibody titre decline upon successive exposure to variant strains is consequent to recall of cross-reactive memory B cells that competitively inhibit naive B-cell responses. In connection, it is not clear whether naive and memory B cells remain phenotypically distinct acutely after activation such that they may be distinguished ex vivo ., Methods: Here, we first compared the capacity of anti-Ig and Toll-like-receptor (TLR) 7/8 and TLR9 agonists (R848 and CpG) to augment human B-cell differentiation induced by IL-21 and sCD40L. The conditions that induced optimal differentiation were then used to compare the post-activation phenotype of sort-purified naive and memory B-cell subsets by FACS and antibody-secreting cell (ASC) ELISPOT., Results: Sort-purified naive and memory B cells underwent robust plasmablast and ASC formation when stimulated with R848, but not CpG, and co-cultured with monocytes. This coincided with increased IL-1β and IL-6 production when B cells were co-cultured with monocytes and stimulated with R848, but not CpG. Naive B cells underwent equivalent ASC generation, but exhibited less class-switch and modulation of CD27, CD38 and CD20 expression than memory B cells after stimulation with R848 and monocytes for 6 days., Conclusion: Stimulation with R848, IL-21 and sCD40L in the presence of monocytes induces robust differentiation and ASC generation from both naive and memory B-cells. However, naive and memory B cells retain key phenotypic differences after activation that may facilitate ex vivo discrimination and better characterisation of acute responses to variant antigens., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.)

Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4 + T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against "drifted" (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 "swine" flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8 + T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such "memory" cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8 + CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 "Spanish flu," which killed more than 50 million people worldwide.

A few cases of thyroid disease have been reported in tuberous sclerosis complex (TSC); however, studies on prevalence and characterization of lesions have not been done. Patients with TSC are routinely screened using chest CT for assessment of lung disease. Incidental thyroid findings on chest CT have been reported in large studies of the general population. The purpose of this study is to evaluate the frequency and type of thyroid anomalies in a cohort of TSC patients. We performed a retrospective review of 93 patients with a definite diagnosis of TSC, who had a chest CT. Images of the thyroid gland and final radiological report were reviewed. Reports of additional thyroid studies performed in some patients were also reviewed. Thyroid abnormalities were present in 19 of 93 (20.4%) patients. They consisted mainly of hypodense lesions categorized as nodules. Multiple nodules were found in 10 patients (52.6%). There was one papillary carcinoma. Thyroid gland lesions may be part of the clinical spectrum of TSC. They are usually asymptomatic. As some cases of thyroid carcinoma have been described in TSC, ultrasound exams are recommended, given that CT is not the gold standard technique for thyroid evaluation., (© 2015 Wiley Periodicals, Inc.)

Objective: To analyze the utility of three indices to predict hepatic fibrosis in the detection of non-alcoholic fatty liver disease (NAFLD) as a non-invasive method in primary care., Design: We performed a descriptive, cross-sectional, multicenter study with a populational base from 25 primary care centers in the province of Barcelona., Participants: Healthy individuals aged 17 to 83 years randomly selected from the Primary Care Computer System., Methods: Medical history, physical examination, and blood analyses were used to determine the following predictive indices of fibrosis; HAIR (hypertension, alanine-aminotransferase, insulin resistance); Fatty Liver Index (FLI) (body mass index, gammaglutamyl-transpeptidase, triglycerides, abdominal perimeter) and Lipid Accumulation Product (LAP) (triglycerides, abdominal perimeter), and abdominal echography., Results: We included 702 individuals; 58% were women and the mean age was 53±14 years. The FLI was positive in 30.8%, HAIR was positive in 6.7%, and LAP was positive in 15.5%. Agreement among the three indices ranged from 63.1% to 84.9%, with kappa indices between 0.18 and 0.50. A total of 184 individuals met the echographic criteria of NAFLD, representing a prevalence of 26.29%. The prevalence of NAFLD in patients with positive FLI, HAIR and LAP indices was 46.8%, 68.1% and 56%, respectively. The index with the greatest sensitivity for NAFLD was tFLI≥60 with 84%. Specificity was highest for HAIR and LAP with 97% and 91%, respectively., Conclusions: FLI, HAIR and LAP are highly prevalent and have been shown to be independent markers for the diagnosis of NAFLD. Because of the lack of concordance between the indices, different prevalences are obtained, thus requiring criteria to be unified in order to obtain a more useful index for the diagnosis of NAFLD., (Copyright © 2013 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.)

Objective: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC., Materials and Method: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts., Results: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2-PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines., Conclusion: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Arterial aneurysms, mostly aortic and intracranial, have been occasionally reported in patients with tuberous sclerosis complex. Brain magnetic resonance imaging reports of 404 patients with definite and 16 patients with either probable or possible tuberous sclerosis complex were revised for intracranial aneurysms. Among these patients, brain images of 220 patients with definite and 16 with probable or possible tuberous sclerosis complex were reviewed. Intracranial aneurysms were reported in 3 of 404 patients with a definite diagnosis (0.74%) (general population: 0.35%), including 2 children. A fourth intracranial aneurysm was found in a patient with probable tuberous sclerosis complex, who did not have tubers or subependymal nodules but had clinical manifestations related to neural crest derivatives, including lymphangioleiomyomatosis and extrarenal angiomyolipomas. The authors hypothesize that neural crest dysfunction can have a major role in intracranial arteriopathy in tuberous sclerosis complex, as smooth muscle cells in the forebrain vessels are of neural crest origin., (© The Author(s) 2013.)