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How expectations of reward influence spatial memories remains unclear. Here, the authors reveal a dopamine pathway to the hippocampus that increases activity with proximity to expected rewards, thus stabilizing spatial representations of trajectories that lead to rewards.

Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the 1-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTDs). GIF and FUT2 are 2 genes associated with the uptake and blood level of vitamin B12. We evaluated GIF and FUT2 as predictors of severe birth defects, in 183 aborted fetuses compared with 375 healthy newborns. The GIF290C allele frequency was estimated to 0.4% in healthy newborns and to 8.1% in NTD fetuses (odds ratio 17.8 [95% confidence interval CI: 4.0-77.6]). The frequency of FUT2 rs601338 secretor variant was not different among groups. The GIF 290C heterozygous/ FUT2 rs601338 secretor variant combined genotype was reported in 6 of the 37 NTD fetuses, but not in other fetuses and healthy newborns ( P < .0001). This GIF/ FUT2 combined genotype has been previously reported in children with congenital gastric intrinsic factor (GIF) deficiency, with respective consequences on B12 binding activity and GIF secretion. In conclusion, a genotype reported in congenital GIF deficiency produces also severe forms of NTD. This suggests that vitamin B12 delivery to neural tissue by the CUBN/GIF pathway could play a role in the neural tube closure mechanisms. [ABSTRACT FROM AUTHOR]

Plant fibers have been used for over 2,000 years to make paper. When the process of hand papermaking paled, I set out to find a way to use cellulosic fibers as paint. A decade of experimenting led to the choice of 3 main fibers that worked best. Methods of cooking, preparing, coloring, and drying were tested and refined. Using pulp as paint brought me the innovative techniques I developed in this new craft medium and led to recognition as a Tennessee Master Craft Artist. I continue to experiment with new ways to use pulp as paint.

Contextual fear conditioning is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. There are few paradigms that test contextual fear conditioning in head-fixed mice, and none where the behavioral outcome following fear conditioning is freezing, the most common measure of fear in freely moving animals. To address this gap, we developed a contextual fear conditioning paradigm in head-fixed mice using virtual reality (VR) environments. We designed an apparatus to deliver tail shocks (unconditioned stimulus, US) while mice navigated a VR environment (conditioned stimulus, CS). The acquisition of contextual fear was tested when the mice were reintroduced to the shock-paired VR environment the following day. We tested three different variations of this paradigm and, in all of them, observed an increased conditioned fear response characterized by increased freezing behavior. This was especially prominent during the first trial in the shock-paired VR environment, compared to a neutral environment where the mice received no shocks. Our results demonstrate that head-fixed mice can be fear conditioned in VR, discriminate between a feared and neutral VR context, and display freezing as a conditioned response, similar to freely behaving animals. Furthermore, using a two-photon microscope, we imaged from large populations of hippocampal CA1 neurons before, during, and following contextual fear conditioning. Our findings reconfirmed those from the literature on freely moving animals, showing that CA1 place cells undergo remapping and show narrower place fields following fear conditioning. Our approach offers new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories. As the head-fixed preparation is compatible with multi-photon microscopy and holographic stimulation, it enables long-term tracking and manipulation of cells throughout distinct memory stages and provides subcellular resolution for investigating axonal, dendritic, and synaptic dynamics in real-time.

War-related psychological disorders have a major impact on family relationships. There are tools and methods for dealing with families affected by war trauma, which can be insidiously transmitted. An account of the therapeutic work carried out with a family affected by psychotrauma reveals the particularities of this systemic intervention., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The most common gram-negative, Escherichia coli , and gram-positive bacteria, Bacillus spp., have evolved different mechanisms that have caused the emergence of multi-drug resistance. As a result, drugs that block the bacterial growth cycle are needed. Here, in silico and in vitro studies were performed to assess compounds in the Pluchea indica leaf extract, a medicinal plant, that can inhibit bacterial proteins. Briefly, P. indica leaves were extracted using ethanol. The crude extract was then subjected to gas chromatography-mass spectrometry for metabolite screening. Molecular docking simulations with rhomboid protease (R pro ) (Protein data bank ID number: 3ZMI from E. coli and filamenting temperature-sensitive mutant Z (FtsZ) protein data bank ID number: 2VAM from Bacillus subtilis were performed. Moreover, the well diffusion method was used to confirm the antibacterial activity of P. indica leaf extract. A total of 10 compounds were identified in the P. indica extract and used for computational analysis. Based on drug-likeness prediction, P. indica compounds may be drug-like molecules. Binding affinity tests indicated that 10,10-Dimethyl-2,6-dimethylenebicyclo(7.2.0)undecan-5.β.-ol and 11,11-Dimethyl-4,8-dimethylenebicyclo(7.2.0)undecan-3-ol had the most negative values. Accordingly, these compounds may be potential ligands that bind to bacterial proteins. The root mean square fluctuation values was <2 Å, indicating stable fluctuation binding for the ligand-protein complex. According to in vitro antibacterial assays, a high concentration (50%) of the P. indica extract markedly inhibited E. coli and B. subtilis , with inhibitory zone diameters of 31.86±1.63 and 21.09±0.09 mm, respectively. Overall, the compounds in the P. indica leaf extract were identified as functional inhibitors of E. coli and B. subtilis proteins via in silico analysis. This may facilitate development of antibacterial agents., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Wahyuni et al.)

Background: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways., Methods: We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts., Findings: CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated., Interpretation: The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations., Funding: French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Monitoring of host cell proteins (HCPs) during the manufacturing of monoclonal antibodies (mAb) has become a critical requirement to provide effective and safe drug products. Enzyme-linked immunosorbent assays are still the gold standard methods for the quantification of protein impurities. However, this technique has several limitations and does, among others, not enable the precise identification of proteins. In this context, mass spectrometry (MS) became an alternative and orthogonal method that delivers qualitative and quantitative information on all identified HCPs. However, in order to be routinely implemented in biopharmaceutical companies, liquid chromatography-MS based methods still need to be standardized to provide highest sensitivity and robust and accurate quantification. Here, we present a promising MS-based analytical workflow coupling the use of an innovative quantification standard, the HCP Profiler solution, with a spectral library-based data-independent acquisition (DIA) method and strict data validation criteria. The performances of the HCP Profiler solution were compared to more conventional standard protein spikes and the DIA approach was benchmarked against a classical data-dependent acquisition on a series of samples produced at various stages of the manufacturing process. While we also explored spectral library-free DIA interpretation, the spectral library-based approach still showed highest accuracy and reproducibility (coefficients of variation < 10%) with a sensitivity down to the sub-ng/mg mAb level. Thus, this workflow is today mature to be used as a robust and straightforward method to support mAb manufacturing process developments and drug products quality control., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Author(s).)

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary "RS-type DLBCL" with unfavorable prognosis., (© 2023. The Author(s).)

Hippocampal place cells support reward-related spatial memories by forming a cognitive map that over-represents reward locations. The strength of these memories is modulated by the extent of reward expectation during encoding. However, the circuit mechanisms underlying this modulation are unclear. Here we find that when reward expectation is extinguished in mice, they remain engaged with their environment, yet place cell over-representation of rewards vanishes, place field remapping throughout the environment increases, and place field trial-to-trial reliability decreases. Interestingly, Ventral Tegmental Area (VTA) dopaminergic axons in CA1 exhibit a ramping reward-proximity signal that depends on reward expectation and inhibiting VTA dopaminergic neurons largely replicates the effects of extinguishing reward expectation. We conclude that changing reward expectation restructures CA1 cognitive maps and determines map reliability by modulating the dopaminergic VTA-CA1 reward-proximity signal. Thus, internal states of high reward expectation enhance encoding of spatial memories by reinforcing hippocampal cognitive maps associated with reward., (© 2022. The Author(s).)

Polysorbate (PS) 20 and 80 are the main surfactants used to stabilize biopharmaceutical products. Industry practices on various aspects of PS based on a confidential survey and following discussions by 16 globally acting major biotechnology companies is presented in two publications. Part 1 summarizes the current practice and use of PS during manufacture in addition to aspects like current understanding of the (in)stability of PS, the routine QC testing and control of PS, and selected regulatory aspects of PS. 1 The current part 2 of the survey focusses on understanding, monitoring, prediction, and mitigation of PS degradation pathways in order to propose an effective control strategy. The results of the survey and extensive cross-company discussions are put into relation with currently available scientific literature., Competing Interests: Conflict of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0-12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1-47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4-7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: In food animals, Salmonella can exist as multiserovar populations, and the goal of this study was to determine whether Salmonella-positive animal feed samples also consist of multiserovar populations., Methods and Results: In all, 50 Salmonella-positive samples, collected from 10 countries, were cultured using three different media for Salmonella isolation: universal pre-enrichment broth, Rappaport-Vassiliadis (RV) broth and tetrathionate (TT) broth. The samples included 25 samples from feed ingredients, 13 from complete feed and 12 feed mill dust samples. Samples from pelleted overnight cultures were analysed by CRISPR-SeroSeq to examine serovar populations in individual samples. Serovars Anatum and Mbandaka were the most commonly identified and were found in feed, feed ingredients and feed environments. Serovars commonly associated with human illness were also identified, and included serovars Enteritidis, Typhimurium and Infantis. Overall, we detected 12 different serogroups (37 different serovars), with eight serovars belonging to the O:7 serogroup (C 1 ). Over half (56%) of the samples contained two or more serovars, with 11 serovars found in one sample. Feed ingredients exhibited higher serovar diversity, with an average of three serovars. Across paired samples of pre-enriched and enriched populations, the Bray-Curtis dissimilarity metric showed that 83% of serovar populations were a strong match., Conclusions: The data presented show that serovars belonging to the O:7 serogroup are commonly found in feed, and that feed can contain multiple serovars. The serovar populations across different Salmonella media were largely concordant., Significance and Impact of Study: The presence of Salmonella in animal feed is considered a transmission route into meat and poultry products and this study demonstrates that animal feed can contain multiple Salmonella serovars., (© 2022 The Society for Applied Microbiology.)

Background: Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci., Methods: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls., Results: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37-23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06-1.92; p = .001), but not immediate hypersensitivity., Conclusion: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Polysorbates (PS) are widely used as a stabilizer in biopharmaceutical products. Industry practices on various aspects of PS are presented in this part 1 survey report based on a confidential survey and following discussions by 16 globally acting major biotechnology companies. The current practice and use of PS during manufacture across their global manufacturing sites are covered in addition to aspects like current understanding of the (in)stability of PS, the routine QC testing and control of PS, and selected regulatory aspects of PS. The results of the survey and extensive cross-company discussions are put into relation with currently available scientific literature. Part 2 of the survey report (upcoming) will focus on understanding, monitoring, prediction, and mitigation of PS degradation pathways to develop an effective control strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Context: A recent study identified 14 low-frequency coding variants associated with body mass index (BMI) in 718 734 individuals predominantly of European ancestry., Objective: We investigated the association of 2 genetic scores (GS) with i) the risk of severe/morbid obesity, ii) BMI variation before weight-loss intervention, iii) BMI change in response to an 18-month lifestyle/behavioral intervention program, and iv) BMI change up to 24 months after bariatric surgery., Methods: The 14 low-frequency coding variants were genotyped or sequenced in 342 French adults with severe/morbid obesity and 574 French adult controls from the general population. We built risk and protective GS based on 6 BMI-increasing and 5 BMI-decreasing low-frequency coding variants that were polymorphic in our study., Results: While the risk GS was not associated with severe/morbid obesity status, BMI-decreasing low-frequency coding variants were significantly less frequent in patients with severe/morbid obesity than in French adults from the general population. Neither the risk nor the protective GS was associated with BMI before intervention in patients with severe/morbid obesity, nor did they affect BMI change in response to a lifestyle/behavioral modification program. The protective GS was associated with a greater BMI decrease following bariatric surgery. The risk and protective GS were associated with a higher and lower risk of BMI regain after bariatric surgery., Conclusion: Our data indicate that in populations of European descent, low-frequency coding variants associated with BMI in the general population also affect the outcomes of bariatric surgery in patients with severe/morbid obesity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nasal intestinal-type adenocarcinomas (ITAC) are strongly related to chronic wood dust exposure: The intestinal phenotype relies on CDX2 overexpression but underlying molecular mechanisms remain unknown. Our objectives were to investigate transcriptomic and methylation differences between healthy non-exposed and tumor olfactory cleft mucosae and to compare transcriptomic profiles between non-exposed, wood dust-exposed and ITAC mucosa cells., Methods: We conducted a prospective monocentric study (NCT0281823) including 16 woodworkers with ITAC, 16 healthy exposed woodworkers and 13 healthy, non-exposed, controls. We compared tumor samples with healthy non-exposed samples, both in transcriptome and in methylome analyses. We also investigated wood dust-induced transcriptome modifications of exposed (without tumor) male woodworkers' samples and of contralateral sides of woodworkers with tumors. We conducted in parallel transcriptome and methylome analysis, and then, the transcriptome analysis was focused on the genes highlighted in methylome analysis. We replicated our results on dataset GSE17433., Results: Several clusters of genes enabled the distinction between healthy and ITAC samples. Transcriptomic and IHC analysis confirmed a constant overexpression of CDX2 in ITAC samples, without any specific DNA methylation profile regarding the CDX2 locus. ITAC woodworkers also exhibited a specific transcriptomic profile in their contralateral (non-tumor) olfactory cleft, different from that of other exposed woodworkers, suggesting that they had a different exposure or a different susceptibility. Two top-loci (CACNA1C/CACNA1C-AS1 and SLC26A10) were identified with a hemimethylated profile, but only CACNA1C appeared to be overexpressed both in transcriptomic analysis and in immunohistochemistry., Conclusions: Several clusters of genes enable the distinction between healthy mucosa and ITAC samples even in contralateral nasal fossa thus paving the way for a simple diagnostic tool for ITAC in male woodworkers. CACNA1C might be considered as a master gene of ITAC and should be further investigated., Trial Registration: NIH ClinicalTrials, NCT0281823, registered May 23 d 2016, https://www.clinicaltrials.gov/NCT0281823 ., (© 2021. The Author(s).)

Background: The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported., Methods: We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients., Results: All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients., Conclusions: We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

Background: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19., Methods: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls., Results: Blood neutrophil elastase, histone-DNA, myeloperoxidase-DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10-fold, compared with controls. Neutrophil elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin-6 (IL-6), IL-8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL-8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity., Conclusion: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

Problematic eating behaviors such as overeating and loss of control over consumption can lead to obesity. Problematic eating behaviors among women of differing body mass indexes were explored through focus group methodology, the Palatable Eating Motives Scale (PEMS), and a taste test in a sample of low-income African American women (n = 45). Women who were overweight or obese (W-O/O) reported more problematic eating behaviors including eating in the absence of hunger, frequent overeating, and increased food thoughts than women who were lean or normal weight (W-L/N). The W-O/O appear to possess more problematic eating behaviors than W-L/N.

Objectives: This study explored the accuracy of self-reported heights and weights and factors associated with self-reported bias in a diverse American sample., Methods: Demographic, self-reported, and measured height and weight data from different studies with the same PI were compiled into one SPSS file and analyzed with paired t-tests to detect differences between self-reported and actual values. Kruskal-Wallis tests followed by pairwise t-tests detected differences among age, ethnicity, sex, income, and education. Stepwise regression analyses were done using anthropometric differences as the dependent variable and age category, sex, and ethnicity as independent variables to explore which variable was most predictive of anthropometric differences., Results: Individuals over-reported height and under-reported weight leading to an under-calculated BMI from self-reported height and weight by 0.6-1 kg/m 2 . These under-calculations of BMI led to misclassifications of obesity by 3, 6, 8, and 4% for African American, Euro-American, Native American women, and total women, and by 5, 6, 8, and 8% by African American, Euro-American, Native American men, and total men. Older individuals and males over-reported height more than younger individuals and females. African American females over-reported height to a lesser extent than other ethnicities. Asian males over-reported height to a lesser extent than other ethnicities., Conclusions: Self-reported heights and weights lead to invalid results. Most individuals over-report height and under-report weight, resulting in an inaccurate underweight and obesity prevalence. Being misclassified into the incorrect BMI category could result in inappropriate healthcare treatment. Age, ethnicity, and sex appear to influence the misreporting of height and weight., (© 2018 Wiley Periodicals, Inc.)

Objectives Pediatric obesity is complicated by many factors including psychological issues, such as body dissatisfaction. Body image assessment tools are used with children to measure their acceptance of their body shape or image. Limited research has been conducted with African American and American Indian children to understand their opinions on assessment tools created. This study investigated: (a) children's perception about body image and (b) differences between two body image instruments among low-income, multi-ethnic children. Methods This study uses mixed methodology including focus groups (qualitative) and body image assessment instruments (quantitative). Fifty-one children participated (25 girls, 26 boys); 53% of children identified as African American and 47% as American Indian. The average age was 10.4 years. Open coding methods were used by identify themes from focus group data. SPSS was used for quantitative analysis. Results Children preferred the Figure Rating Scale (FRS/silhouette) instrument over the Children's Body Image Scale (CBIS/photo) because their body parts and facial features were more detailed. Children formed their body image perception with influence from their parents and the media. Children verbalized that they have experienced negative consequences related to poor body image including disordered eating habits, depression, and bullying. Healthy weight children are also aware of weight-related bullying that obese and overweight children face. Conclusions for Practice Children prefer that the images on a body image assessment tool have detailed facial features and are clothed. Further research into body image assessment tools for use with African American and American Indian children is needed.

The organization of tissues in appendages often affects their mechanical properties and function. In the fish family Labridae, swimming behavior is associated with pectoral fin flexural stiffness and morphology, where fins range on a continuum from stiff to relatively flexible fins. Across this diversity, pectoral fin flexural stiffness decreases exponentially along the length of any given fin ray, and ray stiffness decreases along the chord of the fin from the leading to trailing edge. In this study, we examine the morphological properties of fin rays, including the effective modulus in bending (E), second moment of area (I), segmentation, and branching patterns, and their impact on fin ray stiffness. We quantify intrinsic pectoral fin ray stiffness in similarly sized fins of two closely related species that employ fins of divergent mechanics, the flapping Gomphosus varius and the rowing Halichoeres bivittatus. While segmentation patterns and E were similar between species, measurements of I and the number of fin ray branch nodes were greater in G. varius than in H. bivittatus. A multiple regression model found that of these variables, I was always significantly correlated with fin ray flexural stiffness and that variation in I always explained the majority of the variation in flexural stiffness. Thus, while most of the morphological variables quantified in this study correlate with fin ray flexural stiffness, second moment of area is the greatest factor contributing to variation in flexural stiffness. Further, interspecific variation in fin ray branching pattern could be used as a means of tuning the effective stiffness of the fin webbing to differences in swimming behavior and hydrodynamics. The comparison of these results to other systems begins to unveil fundamental morphological features of biological beams and yields insight into the role of mechanical properties in fin deformation for aquatic locomotion., (© 2018 Wiley Periodicals, Inc.)

Importance: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated., Objective: To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab-associated disease., Design, Setting, and Participants: This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols., Main Outcomes and Measures: Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs)., Results: A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P < .001). Fifty-two children (51.0%) received DMDs: 28 (53.8%) were treated with 1 DMD, 17 (32.7%) with 2, and 7 (13.5%) with 3 or more sequential DMDs. Patients relapsed during all treatments, with a total of 127 relapses on treatment reported. No changes in median ARR and EDSS score were observed between the preinitiation and postinitiation phases of interferon beta and glatiramer acetate treatment (n = 11). The median ARR was reduced from 1.84 to 1.0 with azathioprine (n = 20, P < .001), 1.79 to 0.52 with mycophenolate mofetil (n = 15, P = .003), and 2.12 to 0.67 with rituximab (n = 9, P < .001), although the median EDSS score remained unchanged. An improvement in ARR (from 2.16 to 0.51, P < .001) and EDSS score (from 2.2 to 1.2, P = .01) was observed in the 12 patients treated with regular intravenous immunoglobulins., Conclusions and Relevance: Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab-associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab-associated disorders is therefore important to optimize immune treatment.

The functional capabilities of flexible, propulsive appendages are directly influenced by their mechanical properties. The fins of fishes have undergone extraordinary evolutionary diversification in structure and function, which raises questions of how fin mechanics relate to swimming behavior. In the fish family Labridae, pectoral fin swimming behavior ranges from rowing to flapping. Rowers are more maneuverable than flappers, but flappers generate greater thrust at high speeds and achieve greater mechanical efficiency at all speeds. Interspecific differences in hydrodynamic capability are largely dependent on fin kinematics and deformation, and are expected to correlate with fin stiffness. Here we examine fin ray stiffness in two closely related species that employ divergent swimming behaviors, the flapping Gomphosus varius and the rowing Halichoeres bivittatus To determine the spatial distribution of flexural stiffness across the fin, we performed three-point bending tests at the center of the proximal, middle and distal regions of four equally spaced fin rays. Pectoral fin ray flexural stiffness ranged from 0.0001 to 1.5109 µN m 2 , and the proximal regions of G. varius fin rays were nearly an order of magnitude stiffer than those of H. bivittatus In both species, fin ray flexural stiffness decreased exponentially along the proximodistal span of fin rays, and flexural stiffness decreased along the fin chord from the leading to the trailing edge. Furthermore, the proportion of fin area occupied by fin rays was significantly greater in G. varius than in H. bivittatus , suggesting that the proportion of fin ray to fin area contributes to differences in fin mechanics., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Purpose: This study uses participatory research methods with survivors of homicide and their service providers to explore the feasibility and acceptability of a culturally adapted mindfulness intervention for stress reduction and resilience in homicide survivors., Procedures: Our mixed methods approach included: (a) previewing a Mindfulness-Based Stress Reduction program with providers and survivors; (b) using their iterative feedback during focus groups to revise the curriculum; and (c) studying the acceptability of the adapted curriculum for survivors through focus group and standardized data collection., Findings: We learned that providers use mindfulness for self-care and both providers and survivors view the approach for survivors as promising. Based on attendance, participation, and focus group data, the adapted curriculum was both feasible and acceptable. Survivors' reports suggested most experienced improved emotion regulation, feelings of empowerment, and better coping., Conclusions: Culturally adapted mindfulness programs may support healing for homicide survivors and possibly other low-income people of color with significant trauma backgrounds. Further investigation is needed to rigorously assess outcomes and specific effects, both positive and negative, of mindfulness in this and other more diversified populations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Malignant peripheral nerve sheath tumors are rare tumors that originate from Schwann cells. Patients with neurofibromatosis type 1 are prone to develop these tumors. Due to their rarity and lack of established treatment, the prognosis of malignant peripheral nerve sheath tumors is poor. A retrospective study was conducted on children treated for malignant peripheral nerve sheath tumors at the Seoul National University Children's Hospital between 2007 and 2016. Eleven patients were diagnosed with malignant nerve sheath tumors at a median age of 12 years, eight of whom had neurofibromatosis type 1. All the patients underwent chemotherapy and received surgical resection, and 5 patients relapsed. The 2-year overall survival rate was 72.7%, and the 2-year event-free survival rate was 58.2%. Univariate analysis was performed to assess the correlations between the clinical factors. There was no statistically significant difference in the overall survival rate according to the patients' clinical factors. However, there was a decreasing trend in the relationship between the event-free survival rate and the prevalence of neurofibromatosis type 1. Regular follow up of neurofibromatosis type 1. Regular follow-up of neurofibromatosis type 1 patients may identify detection of early relapse of malignant peripheral nerve sheath tumors. Genetic studies of these patients and tumors may identify opportunities for targeted therapy.

Background: Sustainable agriculture encompasses economic, environmental, and social aspects of the food system. Members of the Academy of Nutrition and Dietetics (Academy) play an important role in promoting sustainable agriculture because they work in areas where they can influence the food purchasing decisions of foodservice operations and the public., Objective: To investigate behavior of registered dietitian nutritionists (RDNs) toward incorporating sustainable agriculture principles into professional practice using the Theory of Planned Behavior., Design: This cross-sectional study surveyed RDNs nationwide about their perspectives on incorporating sustainable agriculture issues into practice. The survey questions were based on a survey originally administered to Minnesota RDNs during 2002., Participants and Setting: The sample (N=626) was drawn from a randomly selected, national sample of Academy members., Statistical Analyses Performed: Data were analyzed using descriptive statistics, independent t tests, Pearson correlations, and stepwise regression., Results: The sample was mostly white, female, and the average age was 45.4±12.2 years. Almost half of Academy RDNs (47%) reported incorporating environmental issues into their practice. All four Theory of Planned Behavior variables (intention, attitude, perceived behavior control, and subjective norm) were predictive of behavior to include sustainable agriculture issues into practice. Barriers to incorporating this topic into practice included lack of knowledge, ability, time, and employer support., Conclusions: This study found that most of the RDN respondents had heard of sustainable agriculture and nearly half reported including this topic in their professional practice. To integrate this topic into practice more consistently, RDNs need more knowledge, time, and employer support., (Copyright © 2017 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B 12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways., Objective: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism., Methods: We performed a case-control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls)., Results: In the discovery study on 'mothers', the CBS locus reached array-wide significance (p=9.13×10 -6 ; Bonferroni p=4.77×10 -3 ; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10 -4 ; Bonferroni p=2.00×10 -2 ; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10 -5 ; Bonferroni p=7.80×10 -3 ; OR 0.40 (0.25 to 0.63)). In the 'children' group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele)., Conclusions: The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P =5.00×10 -4 ) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 ' AAA ' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)- P =1.31×10 -2 ]. In the Derivation#2 study, results were confirmed for the BRIP1 ' GGG ' haplotype [OR, 0.53 (0.36-0.79); FDR- P =3.90×10 -3 ]. In both Validation#1 and #2 studies, BRIP1 ' AAA ' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR- P =7.30×10 -2 ; and OR, 6.45 (4.17-9.99); FDR- P =2.33×10 -19 , respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease., Competing Interests: CONFLICTS OF INTEREST The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Focus groups (n = 7) were conducted with Chinese students (n = 43) studying in the USA to determine how acculturation and environmental factors influence dietary behavior and body mass index (BMI). This study used mixed methodology, collecting both qualitative (focus groups) and quantitative (24-h dietary recalls, food adoption scores, degree of acculturation, and height and weight measures) data. Themes emerging from focus group discussions were: a) dietary and social acculturation, b) factors influencing food intake, c) cultural importance of food, and d) changes in weight and BMI status. Environmental, behavioral, and cultural factors appear to have impacted the eating behaviors of the students. Because of the nature of the study, self-reported heights and weights were used to calculate BMI while living in China and actual heights and weights were taken for each student at the focus group to calculate current BMI after living in the USA. The majority of Chinese students (69% males; 85% females) experienced weight gain, resulting in an increased BMI based on weight/height data and as reported in focus group discussions. As a result, if students continue to gain weight, they may be at higher risk of developing chronic diseases in the future. Further, implemented dietary change may be transferred to other family members if students return to China. Results suggest that nutrition education should be provided to incoming foreign students during their orientation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives The purpose of this research was to have ethnically diverse, 9- to 13-year-olds who live in urban, low-income households use Photovoice to represent their physical activity practices and their perception of their physical activity environment. Methods Photovoice methodology was used to allow children to capture their physical activity habits and environment through photographs and interviews. The Social Cognitive Theory was used as the theoretical framework. Heights and weights were taken for all children and BMI was calculated. Photographs were analyzed by recording the content of usable photos in SPSS software. Qualitative analysis of the interview transcripts used the open coding method. Results Participants were 24 children (15 male, 9 female) living in inner city, low-income households. On average, children were 10.9 years old and the mean BMI-for-age percentile was 72 %. Children took a total of 377 pictures and 339 of these were usable. Three themes were identified across interviews and photographs, (a) types of activity, (b) social environment, and (c) physical environment where activity took place. Conclusions for Practice This study provides insight into low-income, urban children's physical activity habits and environment using a novel approach. Potential ways to increase moderate to high intensity activity among this population are to involve church-based organizations, create more safe places to play by increasing green space in urban areas, and to provide financial support for after-school programs and community centers.

Objective: Investigate food choice, food access, and food insecurity among seniors., Methods: Eight focus groups were conducted in 2 counties with high and low Supplemental Nutrition Assistance Program (SNAP) participation rates. A total of 62 seniors (aged ≥ 60 years) were recruited and each attended 1 focus group at a community center. The sample was 79% female and most were Caucasian (91%), similar to state demographics. The focus group themes of how seniors make food choices and access food, and food insecurity perceptions among this population were identified based on discussion commonalities. For quantitative data, P < .05 was significant., Results: Five themes emerged: (1) former experiences affecting eating behaviors; (2) financial and food security driving use of food assistance programs; (3) food access strategies: restaurants, retail markets, and alternative sources; (4) physical changes associated with aging influencing food access and intake; and (5) social influences that play a role in decision making., Conclusions and Implications: Both SNAP and congregate dining offer food assistance to seniors, but SNAP use was considered unacceptable by some seniors living in county 1 because of the negative stigma attached to the program or because they lacked program knowledge about income criteria. More effort needs to be made to educate seniors about SNAP. It is important to gain insight into how food insecurity affects their food choices., (Copyright © 2016 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite advances in the treatment of cancer in paediatric patients, 15% of children die from the illness progression in Chile, and pain is the most significant symptom in advanced stages. Although the World Health Organization guidelines demonstrate that opioids are fundamental in pain management, there is still resistance to their use. The main objective of this article was to describe the experience in the use of opioids for pain management in paediatric patients with advanced cancer in palliative care (PC)., Patients and Method: Retrospective study of patients admitted into the PC Program at the Hospital Roberto del Río between 2002 and 2013. Analysis was carried out on demographic data; oncological diagnosis; pain intensity on admission and discharge, according to validated scales; use of non-steroidal anti-inflammatory drugs; weak opioids; strong opioids; adjuvants drugs; the presence of secondary effects resulting from the use of morphine, and the need for palliative sedation., Results: Of the 99 medical records analysed, the median age was 8 years, 64.6% were male, and there was a similar distribution in three oncological diagnosis groups. Upon admission, 43.4% presented intense to severe pain, and upon discharge there were four patients, but with a maximum VAS score of 7 in only one case. Of the 66 patients taking strong opioids, 89% required less than 0.5mg/kg/hr. Constipation was the most frequently observed secondary effect., Conclusions: Two thirds of the patients studied required strong opioids, with which adequate pain management was achieved, with no serious complications observed. The use of opioids in this group of patients, following a protocol, is considered effective and safe., (Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: To pilot Photovoice methodology with low-income, urban 9- to 13-year-olds to gain insight about their food environment and to determine whether this methodology was engaging and acceptable to them., Methods: Photovoice methodology was used to allow children to represent their food environment. Twenty male and 9 female, low-income, 9- to 13-year-old children participated. Quantitative photograph analysis included quantity taken and usable internal/external and social environment and healthfulness categorizations. Qualitative analysis was conducted through open coding of interview transcripts., Results: A total of 345 usable photos were taken by the children (n = 29), depicting both healthy and unhealthy foods. Four themes were identified (1) food characteristics; (2) social environment; (3) kitchen, cooking, and dining environments; and (4) food insecurity. Unhealthy food was most readily available to children. Children reported a lack of functioning kitchen equipment and multiple physical and environmental challenges to consuming a healthy diet. Food insecurity was prevalent. Food stamps and food pantries were used to fill gaps in the home food supply., Conclusions and Implications: Photovoice can be effective in engaging children in conversation about their food environment and increases understanding of their experiences with food. Photovoice can provide insight into the household food environments. This information can be used to tailor interventions to better reflect the living environment and eating behaviors in low-income populations., (Copyright © 2015 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 × 10(-34), P = 7.02 × 10(-34), and P = 8.27 × 10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10(-26); rs2070959, p.Thr181Ala, P = 2.87 × 10(-27); and rs1105879, p.Arg184Ser, P = 3.27 × 10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P = 3.21 × 10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

Background: Immediate reactions to β-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation., Objective: We performed a fine-mapping genome-wide association study of the genetic predictors of β-lactam allergy to better understand the underlying mechanisms., Methods: We studied 387 patients with immediate allergic reactions to β-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy., Results: We found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c.64-471G>A, P = 9.9 × 10(-9)), rs17612 of C5 (c.4311A>C [p.Glu1437Asp], P = 7.5 × 10(-7)), rs7754768 and rs9268832 of the HLA-DRA | HLA-DRB5 interregion (P = 1.6 × 10(-6) and 4.9 × 10(-6)), and rs7192 of HLA-DRA (c.724T>G [p.Leu242Val], P = 7.4 × 10(-6)) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA | HLA-DRB5 interregion encompassed a motif involved in balanced expression of the α- and β-chains of MHC class II, whereas rs7192 was predicted to influence α-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P = 6.0 × 10(-4) and P = 4.0 × 10(-4), respectively) but not to cephalosporins in the replication study., Conclusions: Gene variants of HLA-DRA and the HLA-DRA | HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation plays a central role., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Problems in language processing have been associated with autism spectrum disorder (ASD), with some research attributing the problems to overall language skills rather than a diagnosis of ASD. Lexical access was assessed in a looking-while-listening task in three groups of 5- to 7-year-old children; two had high-functioning ASD (HFA), an ASD severe (ASD-S) group (n = 16) and an ASD moderate (ASD-M) group (n = 21). The third group were typically developing (TD) (n = 48). Participants heard sentences of the form "Where's the x?" and their eye movements to targets (e.g., train), phonological competitors (e.g., tree), and distractors were recorded. Proportions of looking time at target were analyzed within 200 ms intervals. Significant group differences were found between the ASD-S and TD groups only, at time intervals 1000-1200 and 1200-1400 ms postonset. The TD group was more likely to be fixated on target. These differences were maintained after adjusting for language, verbal and nonverbal IQ, and attention scores. An analysis using parent report of autistic-like behaviors showed higher scores to be associated with lower proportions of looking time at target, regardless of group. Further analysis showed fixation for the TD group to be significantly faster than for the ASD-S. In addition, incremental processing was found for all groups. The study findings suggest that severity of autistic behaviors will impact significantly on children's language processing in real life situations when exposed to syntactically complex material. They also show the value of using online methods for understanding how young children with ASD process language., (© 2014 International Society for Autism Research, Wiley Periodicals, Inc.)