In studies of child psychopathology, phenotypes of interest are often obtained by parental ratings. When behavioral ratings are obtained in the context of a twin study, this allows for the ...decomposition of the phenotypic variance, into a genetic and a non-genetic part. If a phenotype is assessed by a single rater, heritability is based on the child’s behavior as expressed in the presence of that particular rater, whereas heritability based on assessments by multiple raters allows for the estimation of the heritability of the phenotype based on rater agreement, as well as the heritability of the rater specific view of the behavior. The aim of this twin study was to quantify the rater common and rater specific contributions to the variation in children’s behavioral problems. We estimated the heritability of maternal and paternal ratings of the Child Behavior Checklist (CBCL) 6–18 empirical emotional and behavioral problem scales in a large sample of 12,310 7-year old Dutch twin pairs. Between 30 and 59% of variation in the part of the phenotype parents agree upon was explained by genetic effects. Common environmental effects that make children in the same family similar explained less variance, ranging between 0 and 32%. For unique views of their children’s behavioral problems, heritability ranged between 0 and 20% for maternal and between 0 and 22% for paternal views. Between 7 and 24% of the variance was accounted for by common environmental factors specific to mother and father’s views. The proportion of rater shared and rater specific heritability can be translated into genetic correlations between parental views and inform the design and interpretation of results of molecular genetic studies. Genetic correlations were nearly or above 0.7 for all CBCL based psychopathology scales. Such large genetic correlations suggest two practical guidelines for genome-wide association studies (GWAS): when studies have collected data from either fathers or mothers, the shared genetic aetiology in parental ratings indicates that is possible to analyze paternal and maternal assessments in a single GWAS or meta-analysis. Secondly, if a study has collected information from both parents, a gain in statistical power may be realized in GWAS by the simultaneous analysis of the data.
Provision of HIV prevention services by primary care (PCP) healthcare providers is critical to reduce the number of new HIV infections. We examined the performance of HIV risk assessments and ...provision of HIV prevention services by PCPs. In our cohort, less than one-half of respondents asked about sex and drug use all or most of the time, and among those that did not routinely ask about sex and drug use only 66% and 59%, respectively, would ask given more time. Less than a quarter of respondents noted that HIV prevention services were part of their clinical practice. These findings demonstrate gaps in the provision of HIV prevention services by a key population of healthcare providers.
Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-κB inhibitor ...BAY 11-7085, through inactivation of PPAR-γ, induces apoptosis in human synovial fibroblasts. In this work we showed that BAY 11-7085 induced autophagy that preceded BAY 11-7085-induced apoptosis. Of interest, BAY 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. BAY 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both BAY 11-7085-induced autophagy and GR activation were down regulated with PPAR-γ agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and BAY 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-γ1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-γ1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-γ inactivation mediated BAY 11-7085-induced autophagy.
We have developed a rapid and robust technological solution including a membrane filtration and dissolution method followed by a molecular enrichment and a real-time PCR assay, for detecting the ...presence of
Enterococcus sp. or
Enterococcus faecalis/
faecium per 100 mL of water in less than 5 h and we compared it to Method 1600 on mEI agar in terms of specificity, sensitivity, and limit of detection. The mEI and the
Enterococcus sp.-specific assay detected respectively 73 (64.0%) and 114 (100%) of the 114 enterococcal strains tested. None of the 150 non-enterococcal strains tested was detected by both methods with the exception of
Tetragenococcus solitarius for the
Enterococcus sp. assay. The multiplexed
E. faecalis/
faecium assay efficiently amplified DNA from 47 of 47 (100%)
E. faecalis and 27 of 27 (100%)
E. faecium strains tested respectively, whereas none of the 191 non-
E. faecalis/
faecium strains tested was detected. By simultaneously detecting the predominant fecal enterococcal species, the
E. faecalis/
faecium-specific assay allows a better distinction between enterococcal strains of fecal origin and those provided by the environment than Method 1600. Our procedure allows the detection of 4.5 enterococcal colony forming units (CFU) per 100 mL in less than 5 h, whereas the mEI method detected 2.3 CFU/100 mL in 24 h (95% confidence). Thus, our innovative and highly effective method provides a rapid and easy approach to concentrate very low numbers of enterococcal cells present in a 100 mL water sample and allows a better distinction between fecal and environmental enterococcal cells than Method 1600.
► We have developed a rapid and robust technological solution for detecting the presence of
Enterococcus sp. or
Enterococcus faecalis/
faecium in water. ► Our new procedure allows the detection of 4.5 enterococcal colony forming units (CFU) per 100 mL in less than 5 h. ► The
Enterococcus sp.-specific assay detected 100% of the 114 enterococcal strains tested. ► The multiplexed
E. faecalis/
faecium assay efficiently amplified DNA from 100% of
E. faecalis and
E. faecium strains tested. ► The
E. faecalis/
faecium-specific assay allows a better distinction between enterococcal strains of fecal origin and those provided by the environment than Method 1600.
Chagas disease is a very important vector-borne disease in México, and Triatoma dimidiata sensu stricto (Latreille) is one of the most important vectors of Trypanosoma cruzi Chagas, mainly in ...southern and central states. In the Pacific Coast states with the highest prevalence of human T. cruzi infection, T. dimidiata s. s. is considered as a secondary vector. However, the vectorial capacity of those populations has not been studied. Therefore, the vector characteristics of three populations of T. dimidiata s. s. in western México were evaluated in this study. The populations were maintained in the laboratory at 27 ± 1°C and 75% ± 5% RH with a 12:12 h (light:dark) regime, fed on rabbits in a fortnight basis. The development times were short (172–238 d), and the number of bloodmeals to molt was low (11). Mortality was moderate (36–45%), the onset of feeding was relatively rapid (0.5–1.7 min), and feedings were extended (>15 min). More than 40% of individuals in most instars defecated in one of three categories: <1 min when feeding (5–37.9%), immediately after feeding (9–28.6%), or in <1 min post feeding (7–25.8%). The median number of laid eggs was high (over 2.5) in the three populations, as were the egg eclosion rates (>86%). Thus, the T. dimidiata s. s. in the three populations are potentially efficient vectors of T. cruzi and could contribute to the high prevalence of infection in human populations in western México. Graphical Abstract
What Might Machines Mean? Green, Mitchell; Michel, Jan G.
Minds and machines,
2022/6, Letnik:
32, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This essay addresses the question whether artificial speakers can perform speech acts in the technical sense of that term common in the philosophy of language. We here argue that under certain ...conditions artificial speakers can perform speech acts so understood. After (§1) explaining some of the issues at stake in these questions, we (§2) elucidate a relatively uncontroversial way in which machines can communicate, namely through what we call verbal signaling. But verbal signaling is not sufficient for the performance of a speech act. To explain the difference, we (§3) elucidate the notion of a speech act developed by Austin (
How to Do Things with Words
, 1962) in the mid-twentieth century and then discuss Strawson’s ("Intention and Convention in Speech Acts", 1964) influential proposal for how that notion may be related to Grice’s ("Meaning", 1957) conception of speaker meaning. We then refine Strawson’s synthesis in light of Armstrong’s ("Meaning and Communication", 1971) reconceptualization of speaker meaning in terms of objectives rather than intentions. We next (§4) extend this conception of speech acts to the cases of recorded, proxy, and conditional speech acts. On this basis, we propose (§5) that a characteristic role for artificial speakers is as proxies in the performance of speech acts on behalf of their human creators. We (§6) also consider two objections to our position, and compare our approach with others: while other authors appeal to notions such as “quasi-assertion,” we offer a sharp characterization of what artificial speakers can do that does not impute intentions or similarly controversial powers to them. We conclude (§7) by raising doubts that our strategy can be applied to speech acts generally.
To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children ...transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR)=0.4, P=0.01) and for those transplanted in CR1 and CR2 (HR=0.3, P=0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P=0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR=2, P=0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes.
T cell epitopes derived from polymorphic proteins or from proteins encoded by alternative reading frames (ARFs) play an important role in (tumor) immunology. Identification of these peptides is ...successfully performed with mass spectrometry. In a mass spectrometry-based approach, the recorded tandem mass spectra are matched against hypothetical spectra generated from known protein sequence databases. Commonly used protein databases contain a minimal level of redundancy, and thus, are not suitable data sources for searching polymorphic T cell epitopes, either in normal or ARFs. At the same time, however, these databases contain much non-polymorphic sequence information, thereby complicating the matching of recorded and theoretical spectra, and increasing the potential for finding false positives. Therefore, we created a database with peptides from ARFs and peptide variation arising from single nucleotide polymorphisms (SNPs). It is based on the human mRNA sequences from the well-annotated reference sequence (RefSeq) database and associated variation information derived from the Single Nucleotide Polymorphism Database (dbSNP). In this process, we removed all non-polymorphic information. Investigation of the frequency of SNPs in the dbSNP revealed that many SNPs are non-polymorphic “SNPs”. Therefore, we removed those from our dedicated database, and this resulted in a comprehensive high quality database, which we coined the Human Short Peptide Variation Database (HSPVdb). The value of our HSPVdb is shown by identification of the majority of published polymorphic SNP- and/or ARF-derived epitopes from a mass spectrometry-based proteomics workflow, and by a large variety of polymorphic peptides identified as potential T cell epitopes in the HLA-ligandome presented by the Epstein-Barr virus cells.
To describe the level of obligation conveyed by deontic terms (words such as "should", "may", "must" and "is indicated") commonly found in clinical practice guidelines.
Cross-sectional electronic ...survey.
A clinical scenario was developed by the researchers, and recommendations containing 12 deontic terms and phrases were presented to the participants.
All 1332 registrants of the 2008 annual conference of the US Agency for Healthcare Research and Quality.
Participants indicated the level of obligation they believed guideline authors intended by using a slider mechanism ranging from "No obligation" (leftmost position recorded as 0) to "Full obligation" (rightmost position recorded as 100.)
445/1332 registrants (36%) submitted the on-line survey; 254/445 (57%) reported that they have experience in developing clinical practice guidelines; 133/445 (30%) indicated that they provide healthcare. "Must" conveyed the highest level of obligation (median = 100) and least amount of variability (interquartile range = 5.) "May" (median = 37) and "may consider" (median = 33) conveyed the lowest levels of obligation. All other terms conveyed intermediate levels of obligation characterised by wide and overlapping interquartile ranges.
Members of the health services community believe guideline authors intend variable levels of obligation when using different deontic terms within practice recommendations. Ranking of a subset of terms by intended level of obligation is possible. Matching deontic terminology to the intended recommendation strength can help standardise the use of deontic terminology by guideline developers.
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