Miracle-dz/UniFAR-FTUs huggingface dataset:
Language Development and Impairment in Children With Mild to Moderate Sensorineural Hearing Loss.

Purpose The goal of this study was to examine language development and factors related to language impairments in children with mild to moderate sensorineural hearing loss (MMHL). Method Ninety children, aged 8-16 years (46 children with MMHL; 44 aged-matched controls), were administered a battery of standardized language assessments, including measures of phonological processing, receptive and expressive vocabulary and grammar, word and nonword reading, and parental report of communication skills. Group differences were examined after controlling for nonverbal ability. Results Children with MMHL performed as well as controls on receptive vocabulary and word and nonword reading. They also performed within normal limits, albeit significantly worse than controls, on expressive vocabulary, and on receptive and expressive grammar, and worse than both controls and standardized norms on phonological processing and parental report of communication skills. However, there was considerable variation in performance, with 26% showing evidence of clinically significant oral or written language impairments. Poor performance was not linked to severity of hearing loss nor age of diagnosis. Rather, outcomes were related to nonverbal ability, maternal education, and presence/absence of family history of language problems. Conclusions Clinically significant language impairments are not an inevitable consequence of MMHL. Risk factors appear to include lower maternal education and family history of language problems, whereas nonverbal ability may constitute a protective factor.
Caco-2 intestinal cell differentiation is associated with G1 arrest and suppression of CDK2 and CDK4.

The cellular mechanisms regulating intestinal proliferation and differentiation remain largely undefined. Previously, we showed an early induction of the cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1 in Caco-2 cells, a human colon cancer line that spontaneously differentiates into a small bowel phenotype. The purpose of our present study was to assess the timing of cell cycle arrest in relation to differentiation in Caco-2 cells and to examine the mechanisms responsible for CDK inactivation. Caco-2 cells undergo a relative G1/S block and cease to proliferate at day 3 postconfluency; an increase in the activity of terminally differentiated brush-border enzymes (sucrase and alkaline phosphatase) was noted at day 6 postconfluency. Cell cycle block was associated with suppression of both CDK2 and CDK4 activities, which are important for G1/S progression. Treatment of the CDK immune complexes with the detergent deoxycholate (DOC) resulted in restoration of CDK2, but not CDK4, activity at day 3postconfluency, suggesting the presence of inhibitory protein(s) binding to the cyclin/CDK2 complex at this time point. An increased binding of p21Waf1/Cip1 to CDK2 complexes at day 3 postconfluency was noted, suggesting a potential role for p21Waf1/Cip1in CDK2 inactivation; however, immunodepletion of p21Waf1/Cip1 from Caco-2 protein extracts demonstrated that p21Waf1/Cip1 is only partially responsible for CDK2 suppression at day 3postconfluency. A decrease in the cyclin E/CDK2 complex appears to contribute to the CDK2 inactivation noted at days 6 and 12 postconfluency. Taken together, our results suggest that multiple mechanisms contribute to CDK suppression during Caco-2 cell differentiation. Inhibition of CDK2 and CDK4 leads to G1 arrest and inhibition of proliferation that precede Caco-2 cell differentiation.
Reptile Extinctions on Land‐Bridge Islands: Life‐History Attributes and Vulnerability to Extinction

One of the central questions of conservation biology is what life‐history traits render a species prone to extinction. We addressed this problem by calculating extinction rates for 35 species of turtles and squamates (lizards and snakes) occurring on 87 land‐bridge islands in the Mediterranean Sea. We calculated extinction rates in two ways: first, by incorporating the known sequence of historical island separations and second by ignoring history and assuming that the islands became isolated simultaneously. The second procedure is simpler and more frequently used in the literature and produces estimates of extinction rates that are similar to the first, more complex procedure. We then determined the relationship between extinction rates (calculated using both methods) and body mass, longevity, habitat specialization, and population abundance using two methods: first, by accounting for the phylogenetic relationships among species and, second, by ignoring them. Only population abundance and habitat specialization explained a significant amount of the observed variation in species extinction rates. Body mass itself did not explain variation in extinction rates, although it was strongly correlated with abundance. These conclusions were obtained using both procedures for calculating extinction rates and both procedures for correlating extinction rates with life‐history traits.
Pain catastrophizing, neuroticism, fear of pain, and anxiety: Defining the genetic and environmental factors in a sample of female twins

The objective of the present study was to establish the heritability of pain catastrophizing and its subdomains of helplessness, magnification, and rumination and to further explore the genetic and environmental sources that may contribute to pain catastrophizing as well as to its commonly reported psycho-affective correlates, including neuroticism, anxiety sensitivity, and fear of pain. N = 2,401 female twin individuals from the TwinsUK registry were subject to univariate and multivariate twin analyses. Well validated questionnaires including the Pain Catastrophizing Scale, the Pain Anxiety Symptom Scale, the Ten Item Personality Index, and the Anxiety Sensitivity Index were used to assess the study variables. Moderate estimates of heritability for pain catastrophizing (36%) and the three subdomains of helplessness (35%), rumination (27%), and magnification (36%) were detected. The high correlations observed between the three subdomains were explained mainly by overlapping genetic factors, with a single factor loading on all three phenotypes. High genetic correlations between pain catastrophizing and its psycho-affective correlates of fear of pain and anxiety sensitivity were found, while the genetic overlap between neuroticism and pain catastrophizing was low. Each measure of negative affect demonstrated relatively distinct environmental contributing factors, with very little overlap. This is the first study to show shared genetic factors in the observed association between pain catastrophizing and other measures of negative affect. Our findings provide deeper insight into the aetiology of pain catastrophizing and confirm that it is at least partially distinct from other measures of negative affect and personality that may influence the development and treatment of chronic pain conditions. Further research in males is warranted to check the comparability of the findings.
Association of Hypoglycemia With Subsequent Dementia in Older Patients With Type 2 Diabetes Mellitus

Background Studies have found conflicting evidence regarding the association of hypoglycemia with dementia. We evaluated an association of hypoglycemia with subsequent dementia in patients with type 2 diabetes. Methods This retrospective longitudinal cohort study used the Clinical Practice Research Datalink, an electronic medical records data from the United Kingdom, from 2003 to 2012. We included patients aged >65 years diagnosed with type 2 diabetes, with no prior diagnosis of dementia. Dementia was defined using diagnosis codes from medical records. All patients were followed from the date of initial diabetes diagnosis. To account for competing risk of death, we used Fine and Gray's competing risk model to determine the association of hypoglycemia with dementia while adjusting for potential confounders. Hypoglycemia was modeled as a time-dependent covariate. Results Of 53,055 patients, 5.7% (n = 3,018) had at least one hypoglycemia episodes. The overall incidence rate of dementia was 12.7 per 1,000 person-years. In the fully adjusted model that controlled for all confounders, the occurrence of at least one hypoglycemia episode was associated with 27% higher odds of subsequent dementia (hazard ratio = 1.27; 95% confidence interval = 1.06-1.51). The risk increased with the number of hypoglycemia episodes: one episode (hazard ratio = 1.26; 95% confidence interval = 1.03-1.54); two or more episodes (hazard ratio = 1.50; 95% confidence interval = 1.09-2.08). Conclusions Hypoglycemia is associated with a higher risk of dementia and may be responsible in part for the higher risk of dementia in patients with diabetes. Alternatively, hypoglycemia may be a marker for undiagnosed cognitive impairment, and we cannot rule out the possibility of reverse causation between hypoglycemia and dementia.
Influence of Bovine Serum Lipids and Fetal Bovine Serum on the Expression of Cell Surface Markers in Cultured Bovine Preadipocytes

To establish the influence of fetal bovine serum (FBS) and bovine serum lipids (BSL) on cell differentiation marker expression, bovine adipose-derived stem cells from subcutaneous tissue were incubated for 14 days in 4 types of differentiation media containing 10% FBS and 10 µL/mL BSL (TRT-1), no FBS and 10 µL/mL of BSL (TRT-2), 10% FBS and no BSL (TRT-3), or no supplements (TRT-4). Cells were subjected to Nile red staining, immunocytochemistry (CD73, CD90, CD105, DLK1, FabP4), and quantitative real-time PCR (CD73, CD90, CD105, FabP4). The number of cells presenting FabP4 and the percentage of mature adipocytes with large lipid droplets were increased in TRT-2, accompanied by a robust increase in FabP4 mRNA abundance and a decrease in DLK1-positive cells. In preadipocytes, CD73 was present around the nucleus and translocated towards cell membranes during differentiation. Although the percentage of CD73-positive cells was not different among treatments, its mRNA abundance, immunocytochemical staining intensity, and translocation towards cell membranes were decreased when the medium contained no FBS (TRT-2 and TRT-4). All cells showed a diffuse distribution of CD90 and CD105 and remained positive for these markers irrespective of the treatment. However, the CD90 and CD105 mRNA abundance was decreased in TRT-2 and TRT-4; i.e., in media containing no FBS. The presence of FBS increased the absolute number of cell nuclei as assessed by DAPI fluorescence. Our results suggest that bovine subcutaneous preadipocytes display typical stem cell markers. The differentiation into mature adipocytes is promoted by BSL, whereas FBS endorses cell proliferation.
Data-driven models of dominantly-inherited Alzheimer’s disease progression

Dominantly-inherited Alzheimer’s disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer’s disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163 PSEN1; 17 PSEN2; and 31 APP) and a baseline visit (age 19–66; up to four visits each, 1·1 ± 1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer’s disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.
Facilitators of Physical Activity: Voices of Adolescents in a Disadvantaged Community

Despite increasing socioeconomic inequalities in the health and well-being of adolescents, the voices of adolescents in disadvantaged communities regarding facilitators of physical activity (PA) have received relatively little attention. In response, the purpose of this study was to illuminate what adolescents in a multicultural community of low socioeconomic status (SES) in Sweden convey concerning facilitators of PA. Adolescents (n = 53, aged 12–13 years) were recruited from a school in a multicultural community of low SES in Sweden. Following an interpretive approach, 10 focus group interviews were conducted to produce data for a qualitative content analysis. When the adolescents mentioned PA, they mostly referred to spontaneous PA rather than organized PA, and expressed that they enjoyed their PA engagement, which they stated was promoted by the variation of PA, available options for PA, their physical skills, and the presence of peers. They reported that social support from family and friends facilitated their PA, and they offered several suggestions regarding how the school environment could better support their PA. From the perspective of self-determination theory (SDT), the results stress the importance of facilitating intrinsic motivation with a supportive PA environment in which adolescents can satisfy their needs for autonomy, competence, and relatedness.
The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer

Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT-regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells. When AKT was transfected into nucleus of cisplatin-resistant ovarian cancer cells, DNA-PK was phosphorylated at S473. The activated AKT (pAKT-S473) in these cells inhibited the death signal induced by cisplatin thereby inhibiting cisplatin-mediated apoptosis. Results from this study showed that the combination of cisplatin, DNA-PK inhibitor NU7441, and AKT inhibitor TCN can overcome drug resistance, increase apoptosis, and re-sensitize PEO4 cells to cisplatin treatment. A decrease in apoptotic activity was seen in PEO4 cells when Bad was downregulated by siRNA, which indicated that Bad promotes apoptosis in PEO4 cells. Use of the Bcl-2 inhibitor ABT-737 showed that ABT-737 binds to Bcl-2 but not Mcl-1 and releases Bax/Bak which leads to cell apoptosis. The combination of ABT-737 and cisplatin leads to a significant increase in the death of PEO1 and PEO4 cells. All together, these results indicate that Bcl-2 family proteins are regulators of drug resistance. The combination of cisplatin and Bcl-2 family protein inhibitor could be a strategy for the treatment of cisplatin-resistant ovarian cancer.
Intimate partner violence: a predictor of worse HIV outcomes and engagement in care.

For HIV-infected patients, experiencing multiple traumas is associated with AIDS-related and all-cause mortality, increased opportunistic infections, progression to AIDS, and decreased adherence to therapy. The impact of intimate partner violence (IPV) on adherence and HIV outcomes is unknown. HIV-infected patients recruited from a public HIV clinic participated in this observational cohort study (n=251). Participants completed interviews evaluating IPV and covariates. CD4 count <200 (CD4<200), detectable HIV viral load (VL), and engagement in care ("no show rate" [NSR]) were the outcomes of interest. Medication adherence was not measured. Univariate and multivariate regression analyses were performed with covariates included if p<0.3 in the univariate phase. Seventy-four percent of the participants were male, 55% Caucasian, and 52.2% self-identified as "men who have sex with men. " IPV prevalence was 33.1% with no difference by gender or sexual orientation. In univariate analysis, IPV exposure predicted having a CD4<200 (p=0.005) and a detectable VL (p=0.04) but trended toward significance with a high NSR (p=0.077). Being threatened by a partner was associated with a CD4<200 (p=0.005), a detectable VL (p=0.011), and high NSR (p=0.019) in univariate analysis. In multivariate analysis, IPV predicted having a CD4<200 (p=0.005) and detectable VL (p=0.035). Being threatened by a partner predicted having a CD4<200 (p=0.020), a detectable VL (p=0.007), and a high NSR (p=0.020). Our results suggest IPV impacts biologic outcomes and engagement in care for HIV-infected patients. IPV alone predicts worse biologic outcomes, whereas the specific experience of being threatened by a partner was associated with all three outcomes in univariate and multivariate analyses.
Codon usage is less optimized in eukaryotic gene segments encoding intrinsically disordered regions than in those encoding structural domains

Codon usage tends to be optimized in highly expressed genes. A plausible explanation for this phenomenon is that translational accuracy is increased in highly expressed genes with infrequent use of rare codons. Besides structural domains (SDs), eukaryotic proteins generally have intrinsically disordered regions (IDRs) that by themselves do not assume unique three-dimensional structures. As IDRs are free from structural constraint, they can probably accommodate more translational errors than SDs can. Thus, codon usage in IDRs is likely to be less optimized than that in SDs. Codon usage in all the genes of seven eukaryotes was examined in terms of both tRNA adaptation index and codon adaptation index. Different amino acid compositions in different protein regions were taken into account in calculating expected adaptation indices, to which observed indices were compared. Codon usage is less optimized in gene regions encoding IDRs than in those corresponding to SDs. The finding does not depend on whether IDRs are located at the N-terminus, in the middle, or at the C-terminus of proteins. Furthermore, the observation remains unchanged in two different algorithms used to predict IDRs in proteins. The result is consistent with the idea that IDRs tolerate more translational errors than SDs.
Improved estimation of the cumulative incidence of rare outcomes

Studying the incidence of rare events is both scientifically important and statistically challenging. When few events are observed, standard survival analysis estimators behave erratically, particularly if covariate adjustment is necessary. In these settings, it is possible to improve upon existing estimators by considering estimation in a bounded statistical model. This bounded model incorporates existing scientific knowledge about the incidence of an event in the population. Estimators that are guaranteed to agree with existing scientific knowledge on event incidence may exhibit superior behavior relative to estimators that ignore this knowledge. Focusing on the setting of competing risks, we propose estimators of cumulative incidence that are guaranteed to respect a bounded model and show that when few events are observed, the proposed estimators offer improvements over existing estimators in bias and variance. We illustrate the proposed estimators using data from a recent preventive HIV vaccine efficacy trial. Copyright © 2017 John Wiley & Sons, Ltd.
Recurrent, low-frequency coding variants contributing to colorectal cancer in the Swedish population

Genome-wide association studies (GWAS) have identified dozens of common genetic variants associated with risk of colorectal cancer (CRC). However, the majority of CRC heritability remains unclear. In order to discover low-frequency, high-risk CRC susceptibility variants in Swedish population, we genotyped 1 515 CRC patients enriched for familial cases, and 12 108 controls. Case/control association analysis suggested eight novel variants associated with CRC risk (OR 2.0–17.6, p-value < 2.0E-07), comprised of seven coding variants in genes RAB11FIP5, POTEA, COL27A1, MUC5B, PSMA8, MYH7B, and PABPC1L as well as one variant downstream of NEU1 gene. We also confirmed 27 out of 30 risk variants previously reported from GWAS in CRC with a mixed European population background. This study identified rare, coding sequence variants associated with CRC risk through analysis in a relatively homogeneous population. The segregation data suggest a complex mode of inheritance in seemingly dominant pedigrees.