Helper T cell immunity in humans with inherited CD4 deficiency.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Planning with a gender lens: A gender analysis of pandemic preparedness plans from eight countries in Africa.

Background: Health planning and priority setting with a gender lens can help to anticipate and mitigate vulnerabilities that women and girls may experience in health systems, which is especially relevant during health emergencies. This study examined how gender considerations were accounted for in COVID-19 pandemic response planning in a subset of countries in Africa. Methods: Multi-country document review of national pandemic response plans (published before July 2020 and as of March 2022) from Ethiopia, Ghana, Kenya, Nigeria, Rwanda, South Africa, Uganda, and Zambia, supplemented with secondary data on gender representation on planning committees. A gender analysis framework informed the study design and the Morgan et al. matrix guided data extraction and analysis. Results: All plans reflected implicit and explicit considerations of the impacts of the pandemic responses on women and girls. Through a gender lens, the implicit considerations focused on ensuring safety and protections (e.g., training, access to personal protective equipment) for community and facility-based health care workers and broad engagement of the community in risk communication. The explicit gender considerations, reflected in a minority of plans, focused on addressing gender-based violence and providing access to essential services (e.g., sexual and reproductive health care, psychosocial supports), products (e.g., menstrual hygiene products) and social protection measures. Women were underrepresented on the COVID-19 planning committees in all countries. Conclusions: The plans reflected varying national efforts to develop pandemic responses that anticipated and reflected unique vulnerabilities faced by women, though subsequent plans reflected further consideration of gender-relevant impacts compared to initial plans. Embedding a gender lens in emergency preparedness planning furthers equity and could support anticipation and timely mitigation of negative outcomes for women and girls who are often further marginalized during health emergencies.

Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.

Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene SPPL2A in a patient with mycobacterial disease. AGAIN also predicts a retention of six intronic nucleotides that encode an in-frame stop codon, turning AG-gain into stop-gain. This allele was then confirmed experimentally to lead to loss of function by disrupting splicing. We further showed that AG-gain variants inside the high-risk region led to misspliced products, while those outside the region did not, by two case studies in genes STAT1 and IRF7. We finally evaluated AGAIN on our 14 paired exome-RNAseq samples and found that 82% of AG-gain variants in high-risk regions showed evidence of missplicing. AGAIN is publicly available from https://hgidsoft.rockefeller.edu/AGAIN and https://github.com/casanova-lab/AGAIN.

Impact of strategies to mitigate misinformation in diverse settings and populations: a protocol for a living evidence synthesis.

INTRODUCTION: Misinformation refers to inadvertent misleading information that the public may be exposed and share without intent to cause harm, and can delay or prevent effective care, affect mental health, lead to misallocation of health resources and/or create or exacerbate public-health crises. There are many strategies to address misinformation, but there is a need to evaluate their effects. Our objective is to synthesise and routinely update evidence to assess the impact of strategies to mitigate health-related misinformation in diverse settings, and populations. METHODS AND ANALYSIS: We will search seven databases in May 2023 with planned updates at 6 and 9 months, which will be supplemented with searches for grey literature and reference lists of included studies and contacting experts. Two reviewers will independently screen all search results for studies that evaluate one or more approaches to addressing health-related misinformation. One researcher will conduct data extraction and risk of bias assessments, which will be reviewed by a second reviewer for accuracy. We will include experimental, quasi-experimental and observational studies for any populations, settings and diseases without language or publication restrictions. We will conduct quantitative analysis if meta-analytical pooling is possible. If pooling is not possible, we will synthesise quantitative data according to outcomes and interventions addressed, and present a narrative summary of findings disaggregated by sex and/or gender, irrespective of whether differences were found. ETHICS AND DISSEMINATION: There are no individuals or protected health information involved and no safety issues identified. Results will be published through the Global Commission on Evidence and COVID-END websites, in a peer-reviewed journal, as well as through plain-language materials. PROSPERO REGISTRATION NUMBER: CRD42023421149.

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.

Factors that influence the provision of home-based rehabilitation services for people needing rehabilitation: a qualitative evidence synthesis.

BACKGROUND: To increase people's access to rehabilitation services, particularly in the context of the COVID-19 pandemic, we need to explore how the delivery of these services can be adapted. This includes the use of home-based rehabilitation and telerehabilitation. Home-based rehabilitation services may become frequently used options in the recovery process of patients, not only as a solution to accessibility barriers, but as a complement to the usual in-person inpatient rehabilitation provision. Telerehabilitation is also becoming more viable as the usability and availability of communication technologies improve. OBJECTIVES: To identify factors that influence the organisation and delivery of in-person home-based rehabilitation and home-based telerehabilitation for people needing rehabilitation. SEARCH METHODS: We searched PubMed, Global Health, the VHL Regional Portal, Epistemonikos, Health Systems Evidence, and EBM Reviews as well as preprints, regional repositories, and rehabilitation organisations websites for eligible studies, from database inception to search date in June 2022.  SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis; and that explored patients, caregivers, healthcare providers and other stakeholders' experiences, perceptions and behaviours about the provision of in-person home-based rehabilitation and home-based telerehabilitation services responding to patients' needs in different phases of their health conditions.   DATA COLLECTION AND ANALYSIS: We used a purposive sampling approach and applied maximum variation sampling in a four-step sampling frame. We conducted a framework thematic analysis using the CFIR (Consolidated Framework for Implementation Research) framework as our starting point. We assessed our confidence in the findings using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach.  MAIN RESULTS: We included 223 studies in the review and sampled 53 of these for our analysis. Forty-five studies were conducted in high-income countries, and eight in low-and middle-income countries. Twenty studies addressed in-person home-based rehabilitation, 28 studies addressed home-based telerehabilitation services, and five studies addressed both modes of delivery. The studies mainly explored the perspectives of healthcare providers, patients with a range of different health conditions, and their informal caregivers and family members.  Based on our GRADE-CERQual assessments, we had high confidence in eight of the findings, and moderate confidence in five, indicating that it is highly likely or likely respectively that these findings are a reasonable representation of the phenomenon of interest. There were two findings with low confidence. High and moderate confidence findings Home-based rehabilitation services delivered in-person or through telerehabilitation  Patients experience home-based services as convenient and less disruptive of their everyday activities. Patients and providers also suggest that these services can encourage patients' self-management and can make them feel empowered about the rehabilitation process. But patients, family members, and providers describe privacy and confidentiality issues when services are provided at home. These include the increased privacy of being able to exercise at home but also the loss of privacy when one's home life is visible to others.  Patients and providers also describe other factors that can affect the success of home-based rehabilitation services. These include support from providers and family members, good communication with providers, the requirements made of patients and their surroundings, and the transition from hospital to home-based services. Telerehabilitation specifically Patients, family members and providers see telerehabilitation as an opportunity to make services more available. But providers point to practical problems when assessing whether patients are performing their exercises correctly. Providers and patients also describe interruptions from family members.  In addition, providers complain of a lack of equipment, infrastructure and maintenance and patients refer to usability issues and frustration with digital technology. Providers have different opinions about whether telerehabilitation is cost-efficient for them. But many patients see telerehabilitation as affordable and cost-saving if the equipment and infrastructure have been provided. Patients and providers suggest that telerehabilitation can change the nature of their relationship. For instance, some patients describe how telerehabilitation leads to easier and more relaxed communication. Other patients describe feeling abandoned when receiving telerehabilitation services.  Patients, family members and providers call for easy-to-use technologies and more training and support. They also suggest that at least some in-person sessions with the provider are necessary. They feel that telerehabilitation services alone can make it difficult to make meaningful connections. They also explain that some services need the provider's hands. Providers highlight the importance of personalising the services to each person's needs and circumstances. AUTHORS' CONCLUSIONS: This synthesis identified several factors that can influence the successful implementation of in-person home-based rehabilitation and telerehabilitation services. These included factors that facilitate implementation, but also factors that can challenge this process. Healthcare providers, program planners and policymakers might benefit from considering these factors when designing and implementing programmes.

Anti-GM-CSF Neutralizing Autoantibodies in Colombian Patients with Disseminated Cryptococcosis.

BACKGROUND: Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. METHODS: We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. RESULTS: Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. CONCLUSIONS: We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.

Prospective Multicenter Diagnostic Performance of Technologist-Performed Screening Breast Ultrasound After Tomosynthesis in Women With Dense Breasts (the DBTUST).

PURPOSE: To assess diagnostic performance of digital breast tomosynthesis (DBT) alone or combined with technologist-performed handheld screening ultrasound (US) in women with dense breasts. METHODS: In an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant multicenter protocol in western Pennsylvania, 6,179 women consented to three rounds of annual screening, interpreted by two radiologist observers, and had appropriate follow-up. Primary analysis was based on first observer results. RESULTS: Mean participant age was 54.8 years (range, 40-75 years). Across 17,552 screens, there were 126 cancer events in 125 women (7.2/1,000; 95% CI, 5.9 to 8.4). In year 1, DBT-alone cancer yield was 5.0/1,000, and of DBT+US, 6.3/1,000, difference 1.3/1,000 (95% CI, 0.3 to 2.1; P = .005). In years 2 + 3, DBT cancer yield was 4.9/1,000, and of DBT+US, 5.9/1,000, difference 1.0/1,000 (95% CI, 0.4 to 1.5; P < .001). False-positive rate increased from 7.0% for DBT in year 1 to 11.5% for DBT+US and from 5.9% for DBT in year 2 + 3 to 9.7% for DBT+US (P < .001 for both). Nine cancers were seen only by double reading DBT and one by double reading US. Ten interval cancers (0.6/1,000 [95% CI, 0.2 to 0.9]) were identified. Despite reduction in specificity, addition of US improved receiver operating characteristic curves, with area under receiver operating characteristic curve increasing from 0.83 for DBT alone to 0.92 for DBT+US in year 1 (P = .01), with smaller improvements in subsequent years. Of 6,179 women, across all 3 years, 172/6,179 (2.8%) unique women had a false-positive biopsy because of DBT as did another 230/6,179 (3.7%) women because of US (P < .001). CONCLUSION: Overall added cancer detection rate of US screening after DBT was modest at 19/17,552 (1.1/1,000; CI, 0.5- to 1.6) screens but potentially overcomes substantial increases in false-positive recalls and benign biopsies.

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency.

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-ß. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-ß and compensatory adaptive immunity.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia.

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

A Reporting Tool for Adapted Guidelines in Health Care: The RIGHT-Ad@pt Checklist.

BACKGROUND: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines. OBJECTIVE: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist. DESIGN: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group. SETTING: International collaboration. PARTICIPANTS: A total of 119 professionals participated in the development process. MEASUREMENTS: Participants' consensus on items in the checklist. RESULTS: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience. LIMITATION: The RIGHT-Ad@pt checklist requires further validation in real-life use. CONCLUSION: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations. PRIMARY FUNDING SOURCE: None.

Characterising COVID-19 empirical research production in Latin America and the Caribbean: A scoping review.

INTRODUCTION: The Coronavirus Disease 2019 (COVID19) pandemic has struck Latin America and the Caribbean (LAC) particularly hard. One of the crucial areas in the international community's response relates to accelerating research and knowledge sharing. The aim of this article is to map and characterise the existing empirical research related to COVID-19 in LAC countries and contribute to identify opportunities for strengthening future research. METHODS: In this scoping review, articles published between December 2019 and 11 November 2020 were selected if they included an empirical component (explicit scientific methods to collect and analyse primary data), LAC population was researched, and the research was about the COVID-19 pandemic, regardless of publication status or language. MEDLINE, EMBASE, LILACS, Scielo, CENTRAL and Epistemonikos were searched. All titles and abstracts, and full texts were screened by two independent reviewers. Data from included studies was extracted by one reviewer and checked by a second independent reviewer. RESULTS: 14,406 records were found. After removing duplicates, 5,458 titles and abstracts were screened, of which 2,323 full texts were revised to finally include 1,626 empirical studies. The largest portion of research came from people/population of Brazil (54.6%), Mexico (19.1%), Colombia (11.2%), Argentina (10.4%), Peru (10.3%) and Chile (10%), while Caribbean countries concentrated 15.3%. The methodologies most used were cross-sectional studies (34.7%), simulation models (17.5%) and randomized controlled trials (RCTs) (13.6%). Using a modified version of WHO's COVID-19 Coordinated Global Research Roadmap classification, 54.2% were epidemiological studies, followed by clinical management (22.3%) and candidate therapeutics (12.2%). Government and public funds support were reported in 19.2% of studies, followed by universities or research centres (9%), but 47.5% did not include any funding statement. CONCLUSION: During the first part of the COVID-19 pandemic, LAC countries have contributed to the global research effort primarily with epidemiological studies, with little participation on vaccines research, meaning that this type of knowledge would be imported from elsewhere. Research agendas could be further coordinated aiming to enhance shared self-sufficiency regarding knowledge needs in the region.

Examining and Contextualizing Approaches to Establish Policy Support Organizations - A Critical Interpretive Synthesis.

BACKGROUND: In response to worldwide calls for the need to support evidence-informed policy-making (EIPM), more countries are increasingly interested in enhancing their efforts to use research to inform policy-making. In order to inform the efforts of those asked to lead the support of EIPM, our aim is to develop a conceptual framework to guide the process of establishing a policy support organization (PSO). METHODS: We conducted a critical interpretive synthesis (CIS). We conducted a two steps literature review. In the second step, we systematically searched OVID EMBASE, PsychInfo, HealthStar, CINAHL, Web of Science, Social Science Abstract, Health Systems Evidence, and ProQuest Dissertations and Theses Global databases for documents reporting the establishment of PSOs and the contextual factors influencing the process of establishing these organizations. We assessed the eligibility of the retrieved articles and synthesized the findings iteratively. RESULTS: We included 52 documents in the synthesis. Our findings suggest that a PSO establishment process has four interconnected stages: awareness, development, assessment, and maturation. The process of establishing a PSO is iterative and influenced by political, research and health systems contextual factors, which determine the availability of the resources and the trust between researchers and policy-makers. The contextual factors have an impact on each other, and the challenges that arise from one factor can be mitigated by other factors. CONCLUSION: For those interested in establishing a PSO, our framework provides a road map for identifying the most appropriate starting point and the factors that might influence the establishment process. Leaders of such PSOs can use our findings to expand or refine their scope of work. Given that this framework focuses only on PSOs in the health sector, an important next step for research would be to include other sectors from social systems and identify any additional insight that can enhance our framework.

Factor structure, measurement invariance and psychometric properties of the Quality of Life Scale WHOQOL-BREF in the Ecuadorian context.

BACKGROUND: The short version of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) is a popular instrument used to assess quality of life. The objective of this study was to evaluate the following psychometric properties: structural validity, convergent validity, internal consistency, and measurement invariance across sex of the WHOQOL-BREF in a sample of Ecuadorian adults. METHODS: We used a sample of undergraduates (n = 987) to assess the WHOQOL-BREF original four-factor structure, a model with correlated factors, a hierarchical model, and two models resulting from the exploratory factor analysis and exploratory graph analysis. All the models were evaluated using confirmatory factor analysis. RESULTS: The results of the exploratory factor analysis and exploratory graph analysis suggest that the items are organized into four factors, although differently from the original version and the orthogonality assumption is not maintained. The confirmatory factor analysis shows that the original WHOQOL-BREF structure with correlated factors presents adequate psychometric properties. However, we propose a four-factor structure that has the best psychometric properties and adequate internal consistency. The results of the measurement invariance show that strict and strong invariance is achieved between men and women. Convergent validity analysis reveals moderate correlations with self-esteem, resilience, and social support. CONCLUSIONS: Despite the original version of the WHOQOL-BREF with correlated factors has acceptable psychometric properties in the Ecuadorian context, we propose a version with a different organization of its items, which is consistent with the findings of other investigations.

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.