A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis

<p>Abstract</p> <p>Background</p> <p>Hereditary Hemochromatosis(HH) is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the <it>HFE </it>gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables.</p> <p>Methods</p> <p>Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers). An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters.</p> <p>Results</p> <p>A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T) was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G) was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese patients were also observed in the geographically different population of Canadian patients, also predicting CD8+ T-lymphocyte numbers and the severity of disease.</p> <p>Conclusion</p> <p>These results may have important implications not only for approaching the question of the penetrance of the hemochromatosis gene in different world populations but also to further narrow the region of interest to find a candidate gene involved in the setting of CD8+ T-lymphocyte numbers in humans.</p

A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload

BACKGROUND: It has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described. METHODS: The study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region. RESULTS: Eighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 ± 0.14 × 10(6)/ml), in comparison with subjects carrying only one copy of those alleles (0.46 ± 0.19 × 10(6)/ml) and subjects without any copy of those alleles (0.79 ± 0.15 × 10(6)/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 ± 0.14; 0.45 ± 0.21 and 0.41 ± 0.17 × 10(6)/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009). CONCLUSION: The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed

COVID-19 stressors and health behaviors:A multilevel longitudinal study across 86 countries

Anxiety associated with the COVID-19 pandemic and home confinement has been associated with adverse health behaviors, such as unhealthy eating, smoking, and drinking. However, most studies have been limited by regional sampling, which precludes the examination of behavioral consequences associated with the pandemic at a global level. Further, few studies operationalized pandemic-related stressors to enable the investigation of the impact of different types of stressors on health outcomes. This study examined the association between perceived risk of COVID-19 infection and economic burden of COVID-19 with health-promoting and health-damaging behaviors using data from the PsyCorona Study: an international, longitudinal online study of psychological and behavioral correlates of COVID-19. Analyses utilized data from 7,402 participants from 86 countries across three waves of assessment between May 16 and June 13, 2020. Participants completed self-report measures of COVID-19 infection risk, COVID-19-related economic burden, physical exercise, diet quality, cigarette smoking, sleep quality, and binge drinking. Multilevel structural equation modeling analyses showed that across three time points, perceived economic burden was associated with reduced diet quality and sleep quality, as well as increased smoking. Diet quality and sleep quality were lowest among respondents who perceived high COVID-19 infection risk combined with high economic burden. Neither binge drinking nor exercise were associated with perceived COVID-19 infection risk, economic burden, or their interaction. Findings point to the value of developing interventions to address COVID-related stressors, which have an impact on health behaviors that, in turn, may influence vulnerability to COVID-19 and other health outcomes

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

COVID-19 stressors and health behaviors. A multilevel longitudinal study across 86 countries

Anxiety associated with the COVID-19 pandemic and home confinement has been associated with adverse health behaviors, such as unhealthy eating, smoking, and drinking. However, most studies have been limited by regional sampling, which precludes the examination of behavioral consequences associated with the pandemic at a global level. Further, few studies operationalized pandemic-related stressors to enable the investigation of the impact of different types of stressors on health outcomes. This study examined the association between perceived risk of COVID-19 infection and economic burden of COVID-19 with health-promoting and health-damaging behaviors using data from the PsyCorona Study: an international, longitudinal online study of psychological and behavioral correlates of COVID-19. Analyses utilized data from 7,402 participants from 86 countries across three waves of assessment between May 16 and June 13, 2020. Participants completed self-report measures of COVID-19 infection risk, COVID-19-related economic burden, physical exercise, diet quality, cigarette smoking, sleep quality, and binge drinking. Multilevel structural equation modeling analyses showed that across three time points, perceived economic burden was associated with reduced diet quality and sleep quality, as well as increased smoking. Diet quality and sleep quality were lowest among respondents who perceived high COVID-19 infection risk combined with high economic burden. Neither binge drinking nor exercise were associated with perceived COVID-19 infection risk, economic burden, or their interaction. Findings point to the value of developing interventions to address COVID-related stressors, which have an impact on health behaviors that, in turn, may 111 influence vulnerability to COVID-19 and other health outcomes

Chart validation of inpatient International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) administrative diagnosis codes for venous thromboembolism (VTE) among intravenous immune globulin (IGIV) users in the Sentinel Distributed Database

Abstract The Sentinel Distributed Database (SDD) is a database of patient administrative healthcare records, derived from insurance claims and electronic health records, sponsored by the US Food and Drug Administration for evaluation of medical product outcomes. There is limited information on the validity of diagnosis codes for acute venous thromboembolism (VTE) in the SDD and administrative healthcare data more generally. In this chart validation study, we report on the positive predictive value (PPV) of inpatient administrative diagnosis codes for acute VTE—pulmonary embolism (PE) or lower-extremity or site-unspecified deep vein thrombosis (DVT)—within the SDD. As part of an assessment of thromboembolic adverse event risk following treatment with intravenous immune globulin (IGIV), charts were obtained for 75 potential VTE cases, abstracted, and physician-adjudicated. VTE status was determined for 62 potential cases. PPVs for lower-extremity DVT and/or PE were 90% (95% CI: 73–98%) for principal-position diagnoses, 80% (95% CI: 28–99%) for secondary diagnoses, and 26% (95% CI: 11–46%) for position-unspecified diagnoses (originating from physician claims associated with an inpatient stay). Average symptom onset was 1.5 days prior to hospital admission (range: 19 days prior to 4 days after admission). PPVs for principal and secondary VTE discharge diagnoses were similar to prior study estimates. Position-unspecified diagnoses were less likely to represent true acute VTE cases

Time-layered cultural map of Australia

This paper reports on an Australian project that is developing an online system to deliver researcher-driven national-scale infrastructure for the humanities, focused on mapping, time series, and data integration. Australian scholars and scholars of Australia worldwide are well served with digital resources and tools to deepen the understanding of Australia and its historical and cultural heritage. There are, however, significant barriers to use. The Time Layered Cultural Map of Australia (TLCMap) will provide an umbrella infrastructure related to time and space, helping to activate and draw together existing high-quality resources. TLCMap expands the use of Australian cultural and historical data for research through sharply defined and powerful discovery mechanisms. See https://tlcmap.newcastle.edu.au/

Diagnosis and treatment of appendicitis: Systematic review and meta-analysis

Background:The optimal diagnosis and treatment of appendicitis remains controversial. This systematic review details the evidence and current best practices for the evaluation and management of uncomplicated and complicated appendicitis in adults and children. Methods:Eight questions regarding the diagnosis and management of appendicitis were formulated. PubMed, Embase, CINAHL, Cochrane and clinicaltrials.gov/NLM were queried for articles published from 2010 to 2022 with key words related to at least one question. Randomized and non-randomized studies were included. Two reviewers screened each publication for eligibility and then extracted data from eligible studies. Random effects meta-analyses were performed on all quantitative data. The quality of randomized and non-randomized studies was assessed using the Cochrane Risk of Bias 2.0 or Newcastle Ottawa Scale, respectively. Results:2792 studies were screened and 261 were included. Most had a high risk of bias. Computerized tomography scan yielded the highest sensitivity (\u3e 80%) and specificity (\u3e 93%) in the adult population, although high variability existed. In adults with uncomplicated appendicitis, non-operative management resulted in higher odds of readmission (OR 6.10) and need for operation (OR 20.09), but less time to return to work/school (SMD - 1.78). In pediatric patients with uncomplicated appendicitis, non-operative management also resulted in higher odds of need for operation (OR 38.31). In adult patients with complicated appendicitis, there were higher odds of need for operation following antibiotic treatment only (OR 29.00), while pediatric patients had higher odds of abscess formation (OR 2.23). In pediatric patients undergoing appendectomy for complicated appendicitis, higher risk of reoperation at any time point was observed in patients who had drains placed at the time of operation (RR 2.04). Conclusions:This review demonstrates the diagnosis and treatment of appendicitis remains nuanced. A personalized approach and appropriate patient selection remain key to treatment success. Further research on controversies in treatment would be useful for optimal management