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TRAF3, a versatile adaptor protein within the TRAF family, participates in various signaling pathways involving the tumor necrosis factor receptor, toll-like receptor, and retinoic acid-inducible gene I-like receptor families. In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production. Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia. In this study, we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity. Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3Hl within two different families. These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia. Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy. In addition, a TRAF3 start-loss variant (c.3G > A) was identified in a fourth patient, but after familial and molecular studies, it was not considered disease-causing, excluding TRAF3Hl in this patient. This study illustrates the usefulness of targeted reanalysis of genes with reported novel phenotypes. We rescued three patients with TRAF3Hl, presenting similarities and differences with the previously reported patients. The most significant differences were hypogammaglobulinemia and a CVID-like presentation. These data expand the clinical phenotype of TRAF3Hl and pave the way for further investigation into loss-of-function variants in patients with CVID. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prevalence of dysphagia in survivors of head and neck cancer (sHNC) and to identify the predictors contributing to the development of dysphagia. Methods: We enrolled 62 sHNC in a cross-sectional study to check the prevalence of dysphagia in sHNC and to evaluate which factors were influencing the presence of this side effect. Besides dysphagia, sociodemographic and clinical characteristics, oral symptoms, maximal mouth opening (MMO), sleep quality and physical condition were evaluated, and a linear regression analysis was performed to verify which of these outcomes impact dysphagia. Results: Among all the sHNC, 85.5% presented dysphagia. The linear regression analysis confirmed that 44.9% of the variance in dysphagia was determined by coughing, MMO and sleep quality, being MMO the most powerful predictor, followed by coughing and sleep quality. Conclusion: Dysphagia affected the great majority of sHNC. Moreover, symptoms as coughing, reduced MMO and sleep disorders may act as predictors contributing to the development of dysphagia. Our results emphasize the importance of an early and proper identification of the symptoms as well as an adequate treatment strategy to address the cluster of symptoms that sHNC undergo. [ABSTRACT FROM AUTHOR]

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics. [ABSTRACT FROM AUTHOR]

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.Integrated data, including 100 human genomes from the Mesolithic, Neolithic and Early Bronze Age periods show that two major population turnovers occurred over just 1,000 years in Neolithic Denmark, resulting in dramatic changes in the genes, diet and physical appearance of the local people, as well as the landscape in which they lived. [ABSTRACT FROM AUTHOR]

Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary. [ABSTRACT FROM AUTHOR]

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer’s disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.Analyses of imputed ancient genomes and of samples from the UK Biobank indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans. [ABSTRACT FROM AUTHOR]

Background: Overexposure to sunlight and sunburn are the main preventable causes of skin cancer. Outdoor sports are associated with significant levels of sunlight exposure. Aims: We sought to quantify the sun radiation exposure received by outdoor rock climbers and assess their sun exposure habits, sun protection behaviors, attitudes, and knowledge regarding skin cancer. Methods: From April to June 2021, outdoor rock climbers contacted via email completed an online validated self-reported questionnaire on sun related habits, behaviors, attitudes and knowledge. As a pilot trial, ten participants wore a personal dosimeter during two outdoor climbing weekends in May and November 2021. Ambient ultraviolet radiation (UVR) was also recorded. Results: A total of 217 outdoor rock climbers (103 women), mean age 36.8 ± 8.8 years (range 20–70 years) and median climbing practice per week of 8 h (IQR 7.5) were studied. Two in three (65.9%) participants reported at least one sunburn event during the previous rock climbing season. Of the survey respondents, 49.3% reported using sunscreen with SPF ≥ 15, 47% wore sunglasses, and 14.3% indicated they reapplied sunscreen every two hours. The median personal UVR dose measured during the two outdoor climbing weekends analyzed was 5.2 (IQR 1.8) and 8.8 (IQR 1.1) standard erythemal doses, respectively. Conclusions: The high rates of sunburn, the elevated personal UVR measured and the clearly insufficient sun protection practices followed during rock climbing together with unsatisfactory attitudes towards tanning reveal the need to develop explicit sun protection campaigns and educational strategies to reduce the risk of skin cancer among the athletes studied. [ABSTRACT FROM AUTHOR]

Chronic granulomatous disease (CGD) is a prototypical inborn error of immunity affecting phagocytes, in which these cells are unable to produce reactive oxygen species. CGD is caused by defects in genes encoding subunits of the NADPH oxidase enzyme complex (CYBA, CYBB, CYBC1, NCF1, NCF2, NCF4); inflammatory responses are dysregulated, and patients are highly susceptible to recurrent severe bacterial and fungal infections. X-linked CGD (XL-CGD), caused by mutations in the CYBB gene, is the most common and severe form of CGD. In this study, we describe the analytical processes undertaken in 3 families affected with XL-CGD to illustrate several molecular challenges in the genetic diagnosis of this condition: in family 1, a girl with a heterozygous deletion of CYBB exon 13 and skewed X-chromosome inactivation (XCI); in family 2, a boy with a hemizygous deletion of CYBB exon 7, defining its consequences at the mRNA level; and in family 3, 2 boys with the same novel intronic variant in CYBB (c.1151 + 6 T > A). The variant affected the splicing process, although a small fraction of wild-type mRNA was produced. Their mother was a heterozygous carrier, while their maternal grandmother was a carrier in form of gonosomal mosaicism. In summary, using a variety of techniques, including an NGS-based targeted gene panel and deep amplicon sequencing, copy number variation calling strategies, microarray-based comparative genomic hybridization, and cDNA analysis to define splicing defects and skewed XCI, we show how to face and solve some uncommon genetic mechanisms in the diagnosis of XL-CGD. [ABSTRACT FROM AUTHOR]

Chronic sun exposure and sunburns are the main preventable causes of skin cancer. Due to the nature of their work, physical education teachers are at high risk for occupational skin cancer. This descriptive, cross-sectional study analyzes primary and secondary physical education teachers in Andalusia, Spain. All participants were invited to monitor their ultraviolet (UV) radiation exposure using individual biologic dosimeters and record their photoprotection practices over 3 workdays. The teachers spent an average of 2.7 h outdoors and the mean personal UV radiation exposure was 309.9 J/m2 per day, a value three times higher than international recommendations. Based on the photoprotection diary, it was determined that classes held outdoors were not scheduled outside the hours with the highest UV index and that the percentage of participants who followed the photoprotective practices of remaining in the shade or wearing a hat during outdoor lessons were less than 20% and 60%, respectively. The results on sun exposure and photoprotection practices show a need for organizational and educational intervention strategies to mitigate sun exposure and increase compliance with photoprotection measures to reduce skin cancer risk among these workers and promote early diagnosis of the disease. [ABSTRACT FROM AUTHOR]

We aimed to assess if exercise applied after bariatric surgery (BS) improves bone mineral density (BMD) compared to usual care. Systematic search was conducted up to January 2021. Effect measures were determined using standardized mean difference (SMD) with 95% confidence interval (CI). Certainty evidence was assessed according to GRADE. Four clinical trials encompassing 340 patients were included. Exercise induced a positive BMD effect at total hip (SMD = 0.37 [95% CI 0.02, 0.71]; very low certainty evidence), femoral neck (SMD = 0.63 [95% CI 0.19, 1.06]; low certainty evidence), lumbar spine (SMD = 0.41 [95% CI 0.19, 0.62]; low certainty evidence), and 1/3 radius (SMD = 0.58 [95% CI 0.19, 0.97]; low certainty evidence). Exercise undertaken after BS seems to induce a positive effect on BMD. [ABSTRACT FROM AUTHOR]

Background: It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. Objectives: We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. Methods: Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. Results: A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. Conclusion: Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases. [ABSTRACT FROM AUTHOR]

Background: Previous studies have investigated weight loss caused by exercise following bariatric surgery. However, in most cases, the training program is poorly reported; the exercise type, volume, and intensity are briefly mentioned; and the sample size, selection criteria, and follow-up time vary greatly across studies. Purpose: The EFIBAR study aims to investigate over 1 year the effects of a 16-week supervised exercise program, initiated immediately after bariatric surgery, on weight loss (primary outcome), body composition, cardiometabolic risk, physical fitness, and quality of life in patients with severe/extreme obesity. Material and Methods: The EFIBAR study is a parallel-group, superiority, randomized controlled trial (RCT), comprising 80 surgery patients. Half of the participants, randomly selected, perform a 16-week supervised exercise program, including both strength and aerobic training, starting immediately after the surgery (7–14 days). For each participant, all primary and secondary outcomes are measured at three different time points: (i) before the surgery, (ii) after the intervention (≈4 months), and (iii) 1 year after the surgery. Conclusion: The EFIBAR study will provide new insights into the multidimensional benefits of exercise in adults with severe/extreme obesity following bariatric surgery. Trial Registration: EFIBAR randomized controlled trial was prospectively registered at Clinicaltrials.gov (NCT03497546) on April 13, 2018. [ABSTRACT FROM AUTHOR]

Summary: Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells. First, our results showed heterogeneous TLR expression by GBM cells from human tumors and, for the first time, by human GSCs defined by their CD133+ and CD44+ phenotypes. Next, the effect of TLR ligands was studied in in vitro cell cultures of neurospheres and CD44+ cells obtained from two GBM cell lines (U-87 and U-118). The expression of GSC markers diminished in the presence of Pam3CSK4 or LPS (TLR2 and TLR4 ligands, respectively), thus indicating TLR-dependent differentiation. Interestingly, simultaneous treatment with Pam3CSK4 plus temozolomide (TMZ), the reference drug in GBM treatment, significantly increased cell death compared to the effect of the ligand alone, which showed no toxicity, or TMZ alone. These results suggest a synergistic effect between Pam3CSK4 and TMZ based on the induction of TLR-dependent GSC differentiation towards mature GBM cells, which exhibited increased sensitivity to chemotherapy, and provide new perspectives in GBM therapy. [ABSTRACT FROM AUTHOR]

B Correction to b B : b B Obesity Surgery b https://doi.org/10.1007/s11695-021-05873-1 In the original article the word "Loss" was omitted from the article title - the title is correct here. The study was developed in the Research Center in Physical Activity, Health and Leisure (CIAFEL)-Faculty of Sports-University of Porto (FADEUP) (grant UID/DTP/00617/2020), and the Laboratory for Integrative and Translational Research in Population Health (ITR) (grant LA/P/0064/2020). Also, the funding details were inadvertently omitted: Florêncio Diniz-Sousa was supported by the FCT (grant SFRH/BD/117622/2016), Giorjines Boppre was supported by the FCT (grant SFRH/BD/146976/2019), Lucas Veras was supported by the FCT (grant UI/BD/150673/2020), and Alba Hernández-Martínez was supported by the Plan Propio, Gerty Cori program from the University of Almería, Spain. [Extracted from the article]