IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been ...almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs kb) on carriers’ educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio OR, 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.
...the definite diagnosis of COVID-19 mostly relies on positive RT-PCR on respiratory samples, although discriminant features have been reported on thoracic CT scan.1 However, access to these ...diagnostic tests is limited in the context of this large-scale pandemic. ...the sample size was small and the response rate suboptimal. ...as the diagnosis relied on detection of SARS-CoV-2 by RT-PCR on nasopharyngeal samples, suboptimal sensitivity of this test (as low as 60% in some reports) might have led to misclassification and diagnostic bias.7 However, this preliminary report of an association between hypogeusia or hyposmia and COVID-19 diagnosis in patients with ILI suggests that these symptoms might be a useful tool for initial diagnostic work-up in patients with suspected COVID-19.
At the beginning of the COVID-19 pandemic, several contamination clusters were reported in food-processing plants in France and several countries worldwide. Therefore, a need arose to better ...understand viral transmission in such occupational environments from multiple perspectives: the protection of workers in hotspots of viral circulation; the prevention of supply disruption due to the closure of plants; and the prevention of cluster expansion due to exports of food products contaminated by the virus to other locations. This paper outlines a simulation-based approach (using agent-based models) to study the effects of measures taken to prevent the contamination of workers, surfaces, and food products. The model includes user-defined parameters to integrate characteristics relating to SARS-CoV-2 (variant of concern to be considered, symptom onset…), food-processing plants (dimensions, ventilation…), and other sociodemographic transmission factors based on laboratory experiments as well as industrial and epidemiological investigations. Simulations were performed for a typical meat-processing plant in different scenarios for illustration purposes. The results suggested that increasing the mask-wearing ratio led to great reductions in the probability of observing clusters of more than 25 infections. In the case of clusters, masks being worn by all workers limited the presence of contamination (defined as levels of at least 5 log10 viral RNA copies) on meat cuts at less than 0.05 % and maintained the production capacity of the plant at optimal levels. Increasing the average distance between two workers from less than 1 m to more than 2 m decreased the cluster-occurrence probability by up to 15 % as well as contamination of food products during cluster situations. The developed approach can open up several perspectives in terms of potential communication-support tools for the agri-food sector and further reuses or adaptations for other hazards and occupational environments.
•Mask-wearing reduces the contamination of surfaces and meat cuts by SARS-CoV-2.•Production losses can be important if no COVID-19 preventive measures are taken.•Mask-wearing has strong influence on COVID-19 cluster occurrence in food facilities.
Molecular biology amplification enables sensitive detection of most respiratory viruses through nasopharyngeal swabbing. We developed an innovative approach to detect viral genomes on used facial ...tissues. In 2 communities of children, used tissues were collected once weekly for 1 year. Pooled analysis of tissues enabled detection of successive virus circulation in 4 age groups over time and forecasted by several weeks the circulation of influenza in the general population. At the individual level, in a proof-of-concept study of 30 volunteers with influenza-like signs/symptoms, we identified common respiratory viruses. The signals for SARS-CoV-2 obtained in parallel from 15 facial tissues and swab samples were similar and often higher for the tissues (11/15). Individual analysis of tissues offers a noninvasive, sensitive, and affordable alternative to self-sampling without a medical care requirement. Pooled analyses may be used to detect virus spread in specific communities, predict seasonal epidemics, and alert the population to viral infections.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective:Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of ...autism is underpinned by specific genotype-phenotype relationships.Methods:This international study included 547 individuals (mean age, 12.3 years SD=4.2, 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years SD=4.9, 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview–Revised and IQ testing.Results:The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%–97% of the variance, depending on the trait), whereas variability between groups was low (1%–21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.Conclusions:Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
Human mineral malnutrition or hidden hunger is considered a global challenge, affecting a large proportion of the world’s population. The reduction in the mineral content of edible plant products is ...frequently found in cultivars bred for higher yields, and is probably increased by intensive agricultural practices. The filling of grain with macro and micronutrients is partly the result of a direct allocation from root uptake and remobilization from vegetative tissues. The aim of this bibliographic review is to focus on recent knowledge obtained from ionomic analysis of plant tissues in order to build a global appraisal of the potential remobilization of all macro and micronutrients, and especially those from leaves. Nitrogen is always remobilized from leaves of all plant species, although with different efficiencies, while nutrients such as K, S, P, Mg, Cu, Mo, Fe and Zn can be mobilized to a certain extent when plants are facing deficiencies. On the opposite, there is few evidence for leaf mobilization of Ca, Mn, Ni and B. Mechanisms related to the remobilization process (remobilization of mineral forms from vacuolar and organic compounds associated with senescence, respectively) are also discussed in the context of drought, an abiotic stress that is thought to increase and known to modulate the ionic composition of grain in crops.
•By age 7, children show adult-like task-set contingent attentional capture in behavior (top-down visual attentional control).•Children showed no behavioral evidence for multisensory enhancement of ...attention capture by visual objects paired with sounds.•But 9-year-olds adult-like EEG topographic patterns, differing when elicited by multisensory vs. purely visual distractors.•Traditional N2pc analyses showed no N2pc component in any of the children groups, and no multisensory modulations in adults.•Electrical neuroimaging of well-known ERP components is more sensitive to developmental change in neurocognitive processes.
Outside the laboratory, people need to pay attention to relevant objects that are typically multisensory, but it remains poorly understood how the underlying neurocognitive mechanisms develop. We investigated when adult-like mechanisms controlling one’s attentional selection of visual and multisensory objects emerge across childhood. Five-, 7-, and 9-year-olds were compared with adults in their performance on a computer game-like multisensory spatial cueing task, while 129-channel EEG was simultaneously recorded. Markers of attentional control were behavioural spatial cueing effects and the N2pc ERP component (analysed traditionally and using a multivariate electrical neuroimaging framework). In behaviour, adult-like visual attentional control was present from age 7 onwards, whereas multisensory control was absent in all children groups. In EEG, multivariate analyses of the activity over the N2pc time-window revealed stable brain activity patterns in children. Adult-like visual-attentional control EEG patterns were present age 7 onwards, while multisensory control activity patterns were found in 9-year-olds (albeit behavioural measures showed no effects). By combining rigorous yet naturalistic paradigms with multivariate signal analyses, we demonstrated that visual attentional control seems to reach an adult-like state at ∼7 years, before adult-like multisensory control, emerging at ∼9 years. These results enrich our understanding of how attention in naturalistic settings develops.
Deletion and duplication of 16p11.2 (BP4-BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a ...broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p < 0.001), attention deficit hyperactivity disorder (ADHD) (OR = 4.0, p = 0.01), and autism spectrum disorder (ASD) (OR = 39.9, p = 0.01) than controls. Duplication carriers had a higher frequency of any psychiatric diagnosis (OR = 5.3, p = 0.01) and ADHD (OR = 7.0, p = 0.02) than controls. The prevalence of ASD in child carriers of deletions and duplications was similar (22% versus 26%). Comparison of the two CNV groups indicated a higher frequency of ADHD in children with the duplication than deletion (OR = 2.7, p = 0.04) as well as a higher frequency of overall psychiatric disorders (OR = 2.8, p = 0.02) and psychotic symptoms (OR = 4.7, p = 0.02). However, no differences between deletion and duplications carriers in the prevalence of ASD were found. Both deletion and duplication are associated with an increased risk of psychiatric disorder, supporting the importance of early recognition, diagnosis, and intervention in these groups.
Background and Objectives: Long-term hydroxychloroquine (HCQ) therapy can lead to retinal toxicity. Typically, it is characterized by a bull’s eye maculopathy. More recently, a “pericentral” form of ...HCQ retinopathy that predominantly affects patients of Asian descent has been described. To our knowledge, this is the first reported case where such an asymmetry between the right and the left eye in the toxicity profile is observed. Case presentation: The patient presented with a 12-year exposure to HCQ at a daily dose of 4.35 mg/kg. She presented an inferior pericentral-only phenotype of HCQ toxicity on the right eye and a perifoveal-only toxicity on the left eye. Modest progression of toxicity was observed on both eyes over the seven years of follow-up, despite drug discontinuation. Conclusions: To our knowledge, this is the first time that two different phenotypes of HCQ-related retinopathy are found in the same patient, challenging our understanding of the pathophysiology of HCQ retinal toxicity.
To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor ...(INI)-based regimen.
This was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay.
Prevalence of the E157Q polymorphism was 2.7% among 8528 IN sequences from INI-naive patients and its distribution was 1.7%, 5.6% and 2.2% in B, CRF02_AG and various non-B subtypes, respectively. Thirty-nine INI-naive patients with E157Q-mutated virus initiated an INI-based regimen. Among them, 15 had a viral load (VL) <50 copies/mL at initiation and virological suppression was maintained during the first year of follow-up in all but two exhibiting a viral blip. Twenty-four patients had a VL > 50 copies/mL at the time of INI-based regimen initiation. Among them eight were receiving a first-line regimen and the only two patients who did not reach VL < 50 copies/mL at week 24 were receiving elvitegravir. The 16 remaining patients were ART experienced in virological failure with drug-resistant viruses displaying several virological outcomes independently of the genotypic susceptibility score. Phenotypic analyses showed a fold change in EC50 of 0.6, 0.9 and 1.9 for raltegravir, dolutegravir and elvitegravir, respectively, in a subtype B context, and 1.1, 1.9 and 2.4 for raltegravir, dolutegravir and elvitegravir, respectively, in a CRF02_AG context.
Assessment of virological response in 39 patients initiating an INI-based regimen with E157Q-mutated virus, in combination with phenotypic analysis, suggests that particular attention should be paid to antiretroviral-naive patients and dolutegravir should be preferentially used in these patients.
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