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Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P‐glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2‐specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5‐dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate‐sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5‐dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors., Tetrahydroquinoline/4,5‐dihydroisoxazole hybrids can inhibit the ABCG2 transporter activity and increase the ATP hydrolysis in cells overexpressing ABCG2. Molecular docking and molecular dynamics simulation results suggest that molecular hybrids inhibit ABCG2 activity by binding at the inhibitor binding region, as well as the substrate binding regions.

Anticancer drug conjugates may benefit from simultaneous action at two targets potentially overcoming the drawbacks of current cancer treatment, such as insufficient efficacy, high toxicity, and development of resistance. Compared to a combination of two single-target drugs, they may offer an advantage of pharmacokinetic simplicity and fewer drug-drug interactions. Here, we report a series of compounds connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib via a covalent linkage. These hybrid ligands retain both ER antagonist activity and EGFR inhibition. The most potent analogues exhibited single-digit nanomolar activities at both targets. The amide-linked endoxifen-gefitinib drug conjugates

Purpose Parenting stress has been studied as a potential predictor of developmental outcomes in children with normal hearing and children who are deaf and hard of hearing. However, it is unclear how parenting stress might underlie at-risk spoken language and neurocognitive outcomes in this clinical pediatric population. We investigated parenting stress levels and the shared relations between parenting stress, language comprehension, and inhibitory control skills in children with and without hearing loss (HL) using a cross-sectional design. Method Families of children with HL ( n = 39) and with normal hearing ( n = 41) were tested. Children completed an age-appropriate version of the Concepts & Following Directions subtest of the Clinical Evaluation of Language Fundamentals and the NIH Toolbox Flanker Test of Attention and Inhibitory control. Caregivers completed the Parenting Stress Index–Short Form 4. Results Parenting stress levels were not significantly different between parents of children with and without HL. A significant negative association was observed between parenting stress and our measure of language comprehension in children with HL. A negative association between parenting stress and inhibitory control skills was also found in families of children with HL, but not hearing children. The parenting stress–inhibitory control relationship was indirectly accounted for by delayed language comprehension skills in children with HL. Conclusion Even at moderate levels of parenting stress similar to parents of children with normal hearing, increases in parenting stress were associated with lower scores on our measures of language comprehension and inhibitory control in children with HL. Thus, parenting stress may underlie some of the variability in at-risk pediatric HL outcomes.

Purpose The purpose of this study was to describe and explain individual differences in complex/higher order language processing in long-term cochlear implant (CI) users relative to normal-hearing (NH) peers. Method Measures of complex/higher order language processing indexed by the Clinical Evaluation of Language Fundamentals–Fourth Edition (CELF-4) Core Language subtests were obtained from 53 long-term (≥ 7 years) CI users aged 9–29 years and 60 NH controls who did not differ in age, gender, or nonverbal IQ. Vocabulary knowledge and fast, automatic language processing (rapid phonological coding, verbal rehearsal speed, and speech intelligibility) were also assessed. Results CI users showed weaker performance than NH controls on all CELF-4 Core Language subtests. These differences remained for Formulated Sentences and Recalling Sentences even when vocabulary knowledge was statistically controlled. About 50% of the CI sample scored within the range of the NH sample on Formulated Sentences and Recalling Sentences, while the remaining 50% scored well below the NH sample on these subtests. Vocabulary knowledge, rapid phonological coding, verbal rehearsal speed, and speech intelligibility were more strongly correlated with CELF-4 subtest scores in the CI sample than in the NH sample. Conclusions Weaknesses in complex, higher order language processing shown by a subgroup of CI users compared to NH peers may result from delays in fast, automatic processing of language. These at-risk domains of language functioning could serve as targets for novel interventions for deaf children who experience suboptimal spoken language outcomes following cochlear implantation.

Standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC), nab-paclitaxel (NPT) plus gemcitabine (Gem), has led to an average survival of 8.5 months. Presently, no therapeutics exist that effectively target the KRAS oncogene, activated in 95% of PDACs, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling. Through combined inhibition of PI3K and MAPK signaling with MK-2206 (MK) and trametinib (Tra), enhancement of NPT + Gem response was evaluated. Median animal survival was significantly improved by the NPT + Gem combination (67% increase). Addition of MK-2206 or trametinib further increased median survival: NPT + Gem + MK (86%), NPT + Gem + Tra (105%), and NPT + Gem + MK + Tra (129%). In cell line-derived xenografts, the net tumor growth (in mm3) compared to controls (878.5) was significantly reduced by NPT + Gem (191.2), NPT + Gem + MK (150.7), NPT + Gem + Tra (62.2) and NPT + Gem + MK + Tra (49.9) therapies. In patient-derived xenografts, the combination of MK-2206 and trametinib with chemotherapy had an additive response in reducing tumor growth. Effects of therapy on tumor cell proliferation and apoptosis corresponded with tumor growth inhibition. These findings suggest that the standard chemotherapy response of PDAC can be enhanced through dual targeting of PI3K and MAPK signaling, which could lead to improved PDAC therapy.

Purpose The purpose of this study was to investigate the information-processing strategies of early-implanted, prelingually deaf cochlear implant (CI) users with the California Verbal Learning Test–Second Edition (CVLT-II; Delis, Kramer, Kaplan, & Ober, 2000 ), a well-established normed measure of verbal learning and memory used in neuropsychological assessments of memory loss. Method Verbal learning and memory skills were compared in 20 older adolescent and young adult prelingually deaf long-term early-implanted CI users and their 24 normal hearing (NH) peers using the CVLT-II, a widely used multitrial free recall test of verbal learning and memory. Results On average, CI users recalled fewer words than their NH peers across the immediate, delayed, and cued recall trials of the CVLT-II but were comparable to their NH peers on yes/no recognition memory. CI users showed little evidence of semantic clustering of words during free recall but greater serial clustering compared to their NH peers, suggesting fundamental disturbances in automatic semantic activation of words from long-term memory. No differences were found in verbal memory between CI users and their NH peers on measures of retroactive interference and encoding/retrieval interactions. Performance on the 2nd word list of the CVLT-II (List B) and amount of semantic clustering of words during recall were correlated with sentence recognition in the CI group. Conclusion Study findings demonstrate significant differences in free recall performance and information-processing strategies that early-implanted, prelingually deaf CI users use to encode, organize, store, and retrieve spoken words in conventional verbal list learning paradigms, compared to their NH peers. Because verbal learning and memory are core foundational processes routinely used in daily functioning for a wide range of neurocognitive and language processing operations, these findings suggest potential domains for assessment and novel interventions to promote the development of optimal outcomes in prelingually deaf early-implanted long-term CI users.

Purpose Youth with cochlear implants (CIs) are at risk for delays in verbal short-term memory (STM)/working memory (WM), which adversely affect language, neurocognitive, and behavioral outcomes. Assessment of verbal STM/WM is critical for identifying and addressing these delays, but standard assessment procedures require face-to-face (FTF) administration. The purpose of this study was to determine the feasibility and validity of remote testing methods (teleassessment) of verbal STM/WM in youth with CIs as a method of addressing COVID-19–related restrictions on FTF test administration. Method Tests of verbal STM/WM for nonwords, digit spans, letter–number sequences, sentences, and stories were individually administered by speech-language pathologists over a teleassessment platform to 28 youth (aged 9–22 years) with CIs and 36 same-aged normal-hearing peers. Examiners, parents, and participants completed quality and satisfaction ratings with the teleassessment procedure. Teleassessment scores were compared to results of tests obtained at FTF visits an average of 1.6 years earlier. Results Quality and satisfaction ratings for teleassessment were high and in almost all cases did not differ between the CI and normal-hearing samples. Youth with CIs scored lower than normal-hearing peers on measures of verbal STM/WM, and scores for digit span and letter–number sequencing did not differbetween teleassessment and FTF methods. Correlations across teleassessment and FTF visits were strong for digit span, letter–number sequencing, and sentence memory, but were more modest for nonword repetition. Conclusion With some caveats, teleassessment of verbal STM/WM was feasible and valid for youth with CIs.

Human activities that fragment fish habitat have isolated inland salmonid populations. This isolation is associated with loss of migratory life histories and declines in population density and abundance. Isolated populations exhibiting only resident life histories may be more likely to persist if individuals can increase lifetime reproductive success by maturing at smaller sizes or earlier ages. Therefore, accurate estimates of age and size at maturity across resident salmonid populations would improve estimates of population viability. Commonly used methods for assessing maturity such as dissection, endoscopy and hormone analysis are invasive and may disturb vulnerable populations. Ultrasound imaging is a non-invasive method that has been used to measure reproductive status across fish taxa. However, little research has assessed the accuracy of ultrasound for determining maturation status of small-bodied fish, or reproductive potential early in a species’ reproductive cycle. To address these knowledge gaps, we tested whether ultrasound imaging could be used to identify maturing female Westslope Cutthroat Trout (Oncorhynchus clarkii lewisi). Our methods were accurate at identifying maturing females reared in a hatchery setting up to eight months prior to spawning, with error rates ≤ 4.0%; accuracy was greater for larger fish. We also imaged fish in a field setting to examine variation in the size of maturing females among six wild, resident populations of Westslope Cutthroat Trout in western Montana. The median size of maturing females varied significantly across populations. We observed oocyte development in females as small as 109 mm, which is smaller than previously documented for this species. Methods tested in this study will allow researchers and managers to collect information on reproductive status of small-bodied salmonids without disrupting fish during the breeding season. This information can help elucidate life history traits that promote persistence of isolated salmonid populations.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Objectives To examine differences in family environment and associations between family environment and key speech, language, and cognitive outcomes in samples of children with normal hearing and deaf and hard-of-hearing (DHH) children who use hearing aids and cochlear implants. Design Thirty families of children with normal hearing (n = 10), hearing aids (n = 10), or cochlear implants (n = 10) completed questionnaires evaluating executive function, social skills, and problem behaviors. Children's language and receptive vocabulary were evaluated using standardized measures in the children's homes. In addition, families were administered a standardized in-home questionnaire and observational assessment regarding the home environment. Results Family environment overall was similar across hearing level and sensory aid, although some differences were found on parental responsivity and physical environment. The level of supportiveness and enrichment within family relationships accounted for much of the relations between family environment and the psychosocial and neurocognitive development of DHH children. In contrast, the availability of objects and experiences to stimulate learning in the home was related to the development of spoken language. Conclusions Whereas broad characteristics of the family environments of DHH children may not differ from those of hearing children, variability in family functioning is related to DHH children's at-risk speech, language, and cognitive outcomes. Results support the importance of further research to clarify and explain these relations, which might suggest novel methods and targets of family-based interventions to improve developmental outcomes.

OBJECTIVE: Verbal working memory (WM) is more strongly correlated with spoken language skills in prelingually deaf, early-implanted cochlear implant (CI) users than in normal-hearing peers, suggesting that CI users access WM in order to support and compensate for their slower, more effortful spoken language processing. This pilot study tested the feasibility and validity of a dual-task method for establishing the causal role of WM in basic language processing (lexical access speed) in samples of 9 CI users (ages 8-26 years) and 9 normal-hearing peers. METHODS: Participants completed tests of lexical access speed (rapid automatized picture naming test and lexical decision test) under two administration conditions: a standard condition and a dual-task WM condition requiring participants to hold numerals in working memory during completion of the lexical access speed tests. RESULTS: CI users showed more dual-task interference (decline in speed during the WM condition compared to the standard condition) than normal-hearing peers, indicating that their lexical access speed was more dependent on engagement of WM resources. Furthermore, dual-task interference scores were significantly correlated with several measures of speed-based executive functioning, consistent with the hypothesis that the dual-task method reflects the involvement of executive functioning in language processing. CONCLUSION: These pilot study results support the feasibility and validity of the dual-task WM method for investigating the influence of WM in the basic language processing of CI users. Preliminary findings indicate that CI users are more dependent on use of WM as a compensatory strategy during slow-effortful basic language processing than normal-hearing peers.

OBJECTIVE: Deaf children with cochlear implants (CIs) show poorer verbal working memory compared to normal-hearing (NH) peers, but little is known about their verbal learning and memory (VLM) processes involving multi-trial free recall. DESIGN: Children with CIs were compared to NH peers using the California Verbal Learning Test for Children (CVLT-C). STUDY SAMPLE: Participants were 21 deaf (before age 6 months) children (6–16 years old) implanted prior to age 3 years, and 21 age-IQ matched NH peers. RESULTS: Results revealed no differences between groups in number of words recalled. However, CI users showed a pattern of increasing use of serial clustering strategies across learning trials, whereas NH peers decreased their use of serial clustering strategies. In the CI sample (but not in the NH sample), verbal working memory test scores were related to resistance to the build-up of proactive interference, and sentence recognition was associated with performance on the first exposure to the word list and to the use of recency recall strategies. CONCLUSIONS: Children with CIs showed robust evidence of VLM comparable to NH peers. However, their VLM processing (especially recency and proactive interference) was related to speech perception outcomes and verbal WM in different ways from NH peers.

Deaf children with cochlear implants (CIs) are at risk for psychosocial adjustment problems, possibly due to delayed speech-language skills. This study investigated associations between a core component of spoken-language ability-speech intelligibility-and the psychosocial development of prelingually deaf CI users. Audio-transcription measures of speech intelligibility and parent reports of psychosocial behaviors were obtained for two age groups (preschool, school-age/teen). CI users in both age groups scored more poorly than typically hearing peers on speech intelligibility and several psychosocial scales. Among preschool CI users, five scales were correlated with speech intelligibility: functional communication, attention problems, atypicality, withdrawal, and adaptability. These scales and four additional scales were correlated with speech intelligibility among school-age/teen CI users: leadership, activities of daily living, anxiety, and depression. Results suggest that speech intelligibility may be an important contributing factor underlying several domains of psychosocial functioning in children and teens with CIs, particularly involving socialization, communication, and emotional adjustment.

The lack of predictivity of animal's models has increased the failure rate of drug candidates. Thus, the reversion of this scenario using preliminary in vitro assays and metabolism prediction can reduce the unnecessary use of animals, as well as predict toxic effects at preclinical and clinical stages. The present study aimed to evaluate safety of four biologically active molecules (RN104, RI78, ICH, PCH) with potential therapeutic applications synthesized in our laboratory. Initially, we used MTT cytotoxicity against A549, H9C2, HepG2, LLC-PK1 and NEURO-2 cell lines. RN104 showed the lowest cytotoxicity and further studies were conducted with it. The neutral red (NR) test was performed according to OECD-129 and then acute toxicity test (OECD-423). According to NR results we administered at 300 mg/kg on animals; however, no toxic effect was observed, while 2,000 mg/kg resulted in the death of one animal per group. After, metabolism prediction studies, performed using both ligand-based and structure-based, suggests three potential metabolites. In silico results suggested that potential metabolites could be fast eliminated and, then, this could be an explanation for lower observed toxicity in in vivo experiments. The results showed limitations of the NR as a predictor of the initial dose for the acute toxicity study, which may be related to metabolism. Therefore, the combination of theoretical and experimental studies is relevant to a general understanding of new molecule's toxicity.

Purpose The current study adopts a systematic approach to the examination of working memory components in pediatric cochlear implant (CI) users by separately assessing contributions of encoding, storage, and retrieval. Method Forty-nine long-term CI users and 56 typically hearing controls completed forward and backward span tasks with 3 stimulus sets: visually presented digits, pictures of concrete nouns, and novel symbols. In addition, measures associated with each memory stage were collected: Rapid digit naming provided an estimate of phonological recoding speed, nonword repetition assessed the robustness of representations within phonological storage, and vocabulary knowledge (as measured by the Peabody Picture Vocabulary Test; Dunn & Dunn, 1997 ) estimated redintegration abilities during retrieval. Results Linear mixed modeling revealed that digit naming speed and vocabulary knowledge were consistently related to short-term and working memory span in both CI users and typically hearing controls. However, nonword repetition only contributed to the model for short-term memory. Conclusions Nonword repetition, an index of phonological storage, explained little of the individual variability inworking memory differences between CI users and typically hearing peers. On the other hand, individual differences in encoding and retrieval explained a significant amount of outcome variability in both short-term and working memory tasks. Differences between CI users and typically hearing peers in working memory therefore appear to reflect process components of encoding and retrieval and not simply differences in memory storage. Supplemental Material https://doi.org/10.23641/asha.7849394

Objectives The objective of the present study was to determine whether long-term cochlear implant (CI) users would show greater variability in rapid phonological coding skills and greater reliance on slow-effortful compensatory executive functioning (EF) skills than normal-hearing (NH) peers on perceptually challenging high-variability sentence recognition tasks. We tested the following three hypotheses: First, CI users would show lower scores on sentence recognition tests involving high speaker and dialect variability than NH controls, even after adjusting for poorer sentence recognition performance by CI users on a conventional low-variability sentence recognition test. Second, variability in fast-automatic rapid phonological coding skills would be more strongly associated with performance on high-variability sentence recognition tasks for CI users than NH peers. Third, compensatory EF strategies would be more strongly associated with performance on high-variability sentence recognition tasks for CI users than NH peers. Design Two groups of children, adolescents, and young adults aged 9 to 29 years participated in this cross-sectional study: 49 long-term CI users (≥7 years) and 56 NH controls. All participants were tested on measures of rapid phonological coding (Children's Test of Nonword Repetition), conventional sentence recognition (Harvard Sentence Recognition Test), and two novel high-variability sentence recognition tests that varied the indexical attributes of speech (Perceptually Robust English Sentence Test Open-set test and Perceptually Robust English Sentence Test Open-set test-Foreign Accented English test). Measures of EF included verbal working memory (WM), spatial WM, controlled cognitive fluency, and inhibition concentration. Results CI users scored lower than NH peers on both tests of high-variability sentence recognition even after conventional sentence recognition skills were statistically controlled. Correlations between rapid phonological coding and high-variability sentence recognition scores were stronger for the CI sample than for the NH sample even after basic sentence perception skills were statistically controlled. Scatterplots revealed different ranges and slopes for the relationship between rapid phonological coding skills and high-variability sentence recognition performance in CI users and NH peers. Although no statistically significant correlations between EF strategies and sentence recognition were found in the CI or NH sample after use of a conservative Bonferroni-type correction, medium to high effect sizes for correlations between verbal WM and sentence recognition in the CI sample suggest that further investigation of this relationship is needed. Conclusions These findings provide converging support for neurocognitive models that propose two channels for speech-language processing: a fast-automatic channel that predominates whenever possible and a compensatory slow-effortful processing channel that is activated during perceptually-challenging speech processing tasks that are not fully managed by the fast-automatic channel (ease of language understanding, framework for understanding effortful listening, and auditory neurocognitive model). CI users showed significantly poorer performance on measures of high-variability sentence recognition than NH peers, even after simple sentence recognition was controlled. Nonword repetition scores showed almost no overlap between CI and NH samples, and correlations between nonword repetition scores and high-variability sentence recognition were consistent with greater reliance on engagement of fast-automatic phonological coding for high-variability sentence recognition in the CI sample than in the NH sample. Further investigation of the verbal WM-sentence recognition relationship in CI users is recommended. Assessment of fast-automatic phonological processing and slow-effortful EF skills may provide a better understanding of speech perception outcomes in CI users in the clinical setting.

BACKGROUND & AIMS Hepatocyte death is an important factor in development and progression of cirrhosis. Cytokeratin 18-based serum markers reflecting apoptotic (M30) and overall epithelial cell death (M65 and M65EpiDeath) have been used as prognostic parameters for survival in patients with acute liver failure. However, there has been no trial investigating M30, M65 and M65EpiDeath as survival parameters in patients with cirrhosis and acute-on-chronic liver failure. METHODS Patients with cirrhosis were enrolled and followed until death, liver transplantation or last contact. M30, M65 and M65EpiDeath serum levels were quantified in patient's sera. RESULTS Three hundred and thirty-one patients were screened and 211 patients could be included in this study. The median duration of follow-up was 322 days with a range of 1-1382 days. All three cell death parameters correlated with the extent of the severity of the disease. However, M65EpiDeath was the only of the three parameters which was associated with the severe complications of cirrhosis including ascites, spontaneous bacterial peritonitis and hepatorenal syndrome. Additionally, M65EpiDeath was the only cell death parameter which was independently from liver function and its surrogate parameter such as Child-Pugh score and the model of end-stage liver disease associated with overall survival. CONCLUSIONS Epithelial cell death reflected by M65EpiDeath serum levels is an indicator for the severity of cirrhosis and a prognostic survival parameter in cirrhotic patients.

We have recently shown that major alterations of serum sphingolipid metabolites in chronic liver disease associate significantly with the stage of liver fibrosis in corresponding patients. In the current study we assessed via mass spectrometry serum concentrations of sphingolipid metabolites in a series of 122 patients with hepatocellular carcinoma (HCC) compared to an age- and sex-matched series of 127 patients with cirrhosis. We observed a highly significant upregulation of long and very long chain ceramides (C16-C24) in the serum of patients with HCC as compared to patients with cirrhosis (P < 0.001). Accordingly, dihydro-ceramides, synthetic precursors of ceramides and notably sphingosine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) were upregulated in patients with HCC (P < 0.001). Especially the diagnostic accuracy of C16-ceramide and S1P, assessed by receiver operating curve (ROC) analysis, showed a higher area under the curve (AUC) value as compared to alpha fetoprotein (AFP) (0.999 and 0.985 versus 0.823, P < 0.001 respectively). In conclusion, serum levels of sphingolipid metabolites show a significant upregulation in patients with HCC as compared to patients with cirrhosis. Particularly C16-ceramide and S1P may serve as novel diagnostic markers for the identification of HCC in patients with liver diseases. Our data justify further investigations on the role of sphingolipids in HCC.

Genetic rescue is a potentially effective management tool to offset the effects of reduced genetic diversity in imperiled populations. However, implementation requires complex choices. Here we address the consequences of introducing males versus females, highlighting the possibility that introduced females might lead to maladapted mitonuclear genomes and reduced offspring fitness.

Purpose Statistical learning—the ability to learn patterns in environmental input—is increasingly recognized as a foundational mechanism necessary for the successful acquisition of spoken language. Spoken language is a complex, serially presented signal that contains embedded statistical relations among linguistic units, such as phonemes, morphemes, and words, which represent the phonotactic and syntactic rules of language. In this review article, we first review recent work that demonstrates that, in typical language development, individuals who display better nonlinguistic statistical learning abilities also show better performance on different measures of language. We next review research findings that suggest that children who are deaf and use cochlear implants may have difficulties learning sequential input patterns, possibly due to auditory and/or linguistic deprivation early in development, and that the children who show better sequence learning abilities also display improved spoken language outcomes. Finally, we present recent findings suggesting that it may be possible to improve core statistical learning abilities with specialized training and interventions and that such improvements can potentially impact and facilitate the acquisition and processing of spoken language. Method We conducted a literature search through various online databases including PsychINFO and PubMed, as well as including relevant review articles gleaned from the reference sections of other review articles used in this review. Search terms included various combinations of the following: sequential learning, sequence learning, statistical learning, sequence processing, procedural learning, procedural memory, implicit learning, language, computerized training, working memory training, statistical learning training, deaf, deafness, hearing impairment, hearing impaired, DHH, hard of hearing, cochlear implant(s), hearing aid(s), and auditory deprivation. To keep this review concise and clear, we limited inclusion to the foundational and most recent (2005–2018) relevant studies that explicitly included research or theoretical perspectives on statistical or sequential learning. We here summarize and synthesize the most recent and relevant literature to understanding and treating language delays in children using cochlear implants through the lens of statistical learning. Conclusions We suggest that understanding how statistical learning contributes to spoken language development is important for understanding some of the difficulties that children who are deaf and use cochlear implants might face and argue that it may be beneficial to develop novel language interventions that focus specifically on improving core foundational statistical learning skills.

Purpose The purpose of this study was to report how verbal rehearsal spee d (VRS), a form of covert speech used to maintain verbal information in working memory, and another verbal processing speed measure, perceptual encoding speed, are related to 3 domains of executive function (EF) at risk in cochlear implant (CI) users: verbal working memory, fluency-speed, and inhibition-concentration. Method EF, speech perception, and language outcome measures were obtained from 55 prelingually deaf, long-term CI users and matched controls with normal hearing (NH controls). Correlational analyses were used to assess relations between VRS (articulation rate), perceptual encoding speed (digit and color naming), and the outcomes in each sample. Results CI users displayed slower verbal processing speeds than NH controls. Verbal rehearsal speed was related to 2 EF domains in the NH sample but was unrelated to EF outcomes in CI users. Perceptual encoding speed was related to all EF domains in both groups. Conclusions Verbal rehearsal speed may be less influential for EF quality in CI users than for NH controls, whereas rapid automatized labeling skills and EF are closely related in both groups. CI users may develop processing strategies in EF tasks that differ from the covert speech strategies routinely employed by NH individuals. Supplemental Material https://doi.org/10.23641/asha.6170501

PurposeWe sought to determine whether speech perception and language skills measured early after cochlear implantation in children who are deaf, and early postimplant growth in speech perception and language skills, predict long-term speech perception, language, and neurocognitive outcomes.MethodThirty-six long-term users of cochlear implants, implanted at an average age of 3.4 years, completed measures of speech perception, language, and executive functioning an average of 14.4 years postimplantation. Speech perception and language skills measured in the 1st and 2nd years postimplantation and open-set word recognition measured in the 3rd and 4th years postimplantation were obtained from a research database in order to assess predictive relations with long-term outcomes.ResultsSpeech perception and language skills at 6 and 18 months postimplantation were correlated with long-term outcomes for language, verbal working memory, and parent-reported executive functioning. Open-set word recognition was correlated with early speech perception and language skills and long-term speech perception and language outcomes. Hierarchical regressions showed that early speech perception and language skills at 6 months postimplantation and growth in these skills from 6 to 18 months both accounted for substantial variance in long-term outcomes for language and verbal working memory that was not explained by conventional demographic and hearing factors.ConclusionSpeech perception and language skills measured very early postimplantation, and early postimplant growth in speech perception and language, may be clinically relevant markers of long-term language and neurocognitive outcomes in users of cochlear implants.Supplemental materialshttps://doi.org/10.23641/asha.5216200

Noise-vocoded speech is a valuable research tool for testing experimental hypotheses about the effects of spectral degradation on speech recognition in adults with normal hearing (NH). However, very little research has utilized noise-vocoded speech with children with NH. Earlier studies with children with NH focused primarily on the amount of spectral information needed for speech recognition without assessing the contribution of neurocognitive processes to speech perception and spoken word recognition. In this study, we first replicated the seminal findings reported by ) who investigated effects of lexical density and word frequency on noise-vocoded speech perception in a small group of children with NH. We then extended the research to investigate relations between noise-vocoded speech recognition abilities and five neurocognitive measures: auditory attention (AA) and response set, talker discrimination, and verbal and nonverbal short-term working memory.Thirty-one children with NH between 5 and 13 years of age were assessed on their ability to perceive lexically controlled words in isolation and in sentences that were noise-vocoded to four spectral channels. Children were also administered vocabulary assessments (Peabody Picture Vocabulary test-4th Edition and Expressive Vocabulary test-2nd Edition) and measures of AA (NEPSY AA and response set and a talker discrimination task) and short-term memory (visual digit and symbol spans).Consistent with the findings reported in the original ) study, we found that children perceived noise-vocoded lexically easy words better than lexically hard words. Words in sentences were also recognized better than the same words presented in isolation. No significant correlations were observed between noise-vocoded speech recognition scores and the Peabody Picture Vocabulary test-4th Edition using language quotients to control for age effects. However, children who scored higher on the Expressive Vocabulary test-2nd Edition recognized lexically easy words better than lexically hard words in sentences. Older children perceived noise-vocoded speech better than younger children. Finally, we found that measures of AA and short-term memory capacity were significantly correlated with a child's ability to perceive noise-vocoded isolated words and sentences.First, we successfully replicated the major findings from the ) study. Because familiarity, phonological distinctiveness and lexical competition affect word recognition, these findings provide additional support for the proposal that several foundational elementary neurocognitive processes underlie the perception of spectrally degraded speech. Second, we found strong and significant correlations between performance on neurocognitive measures and children's ability to recognize words and sentences noise-vocoded to four spectral channels. These findings extend earlier research suggesting that perception of spectrally degraded speech reflects early peripheral auditory processes, as well as additional contributions of executive function, specifically, selective attention and short-term memory processes in spoken word recognition. The present findings suggest that AA and short-term memory support robust spoken word recognition in children with NH even under compromised and challenging listening conditions. These results are relevant to research carried out with listeners who have hearing loss, because they are routinely required to encode, process, and understand spectrally degraded acoustic signals.

Objectives: Evaluated the effects of atomoxetine on the reading abilities of children with dyslexia only or attention-deficit/hyperactivity disorder (ADHD) and comorbid dyslexia. Methods: Children aged 10–16 years (N = 209) met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for dyslexia only (n = 58), ADHD and comorbid dyslexia (n = 124), or ADHD only (n = 27) and were of normal intelligence. Patients were treated with atomoxetine (1.0–1.4 mg/kg/day) or placebo in a 16-week, randomized, placebo-controlled, double-blind trial. The dyslexia-only and ADHD and comorbid dyslexia groups were randomized 1:1; the ADHD-only group received atomoxetine in a blinded manner. Reading abilities were measured with the Woodcock Johnson III (WJIII), Comprehensive Test of Phonological Processing (CTOPP), Gray Oral Reading Tests-4, and Test of Word Reading Efficiency. Results: Atomoxetine-treated dyslexia-only patients compared with placebo patients had significantly greater improvement (p

This study investigated if a period of auditory sensory deprivation followed by degraded auditory input and related language delays affects visual concept formation skills in long-term prelingually deaf cochlear implant (CI) users. We also examined if concept formation skills are mediated or moderated by other neurocognitive domains (i.e., language, working memory, and executive control). Relative to normally hearing (NH) peers, CI users displayed significantly poorer performance in several specific areas of concept formation, especially when multiple comparisons and relational concepts were components of the task. Differences in concept formation between CI users and NH peers were fully explained by differences in language and inhibition–concentration skills. Language skills were also found to be more strongly related to concept formation in CI users than in NH peers. The present findings suggest that complex relational concepts may be adversely affected by a period of early prelingual deafness followed by access to underspecified and degraded sound patterns and spoken language transmitted by a CI. Investigating a unique clinical population such as early-implanted prelingually deaf children with CIs can provide new insights into foundational brain–behavior relations and developmental processes.

During endoscopic retrograde cholangiopancreatography (ERCP), a guidewire is used to cannulate biliary strictures and allow for therapeutic interventions. The aim of this study was to assess the success of stricture cannulation using a combination of a flexible guidewire and a stable nitinol wire vs. a novel, single, stiff-shaft, flexible-tip guidewire.Consecutive patients who were scheduled for ERCP for biliary obstruction were randomized to undergo the procedure with either a 260-cm long, angled-tip hydrophilic wire in combination with a nitinol wire as required (standard group), or a novel, 270-cm guidewire featuring a hyperflexible, hydrophilic tip with a stiff shaft (novel group). At unsuccessful negotiation of the stricture, patients in the standard group were switched to the novel guidewire and vice versa ("crossover"). Successful cannulation (primary success: as assigned; final success: after "crossover"), procedure time, and total number of wires needed per procedure were compared.A total of 222 patients were randomized and 197 were included in the study (97 in the standard group and 100 in the novel group). The primary success rate was significantly higher in the novel group (94/100, 94 %) compared with the standard group (77/97, 79 %; P = 0.00041), and final success was similar. Mean time (median, interquartile range) to stricture cannulation was 11.2 minutes (6.3, 3.7 - 14.6) in the standard group and 8.1 minutes (2.5, 0.9 - 7.7) in the novel group (P 0.0001). The mean total procedure time was 31.2 minutes (24.6, 16.5 - 40.8) vs. 24.3 minutes (16.9, 10.0 - 31.5), respectively (P = 0.0011). There were no complications observed with either of the guidewires.A guidewire that features a flexible tip with a stable shaft could replace the use of a combination of flexible and stable guidewires and increase the success rate of stricture cannulation while decreasing the procedure time.ClinicalTrials.gov Identifier: NCT 01382680.

Soluble CD163 (sCD163), a marker for macrophage activation, was found to be associated with the severity of liver cirrhosis. The aim of the current study was to investigate whether serum sCD163 levels correlate with liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection. In a retrospective cohort study, serum sCD163 levels were assessed by ELISA together with clinical and laboratory data in 186 patients with chronic HBV infection and 15 healthy controls. The relation between parameters for liver fibrosis and necroinflammation and sCD163 levels was analysed. Additionally, sCD163 was quantified in a subset of follow-up serum samples after initiation of antiviral treatment. sCD163 levels differed among phases of chronic HBV infection (P < 0.0001), and sCD163 concentrations were associated with inflammatory activity and fibrosis in the liver. sCD163 levels ≥ 1961 ng/l had a high specificity in the identification of subjects with substantial fibrosis (F ≥ 2). sCD163 concentrations decreased significantly after initiation of antiviral treatment. The correlation of sCD163 levels with necroinflammation and fibrosis and the sCD163 decline under treatment indicates that macrophage activation plays a role in HBV-related liver pathogenesis.

Objective Pathological spontaneous activity (PSA) in electromyography (EMG) has not yet been systematically analysed in various types of myopathies. Methods 136 Patients with well-defined myopathies were retrospectively analysed for the presence of PSA in distal, proximal, and paravertebral muscles. PSA comprised fibrillations (fib)/positive sharp waves (PSW) and high frequency discharges (HFD; i.e., myotonic and complex repetitive discharges). Results fib/PSW occurred more frequently than HFD. HFD were rarely myotonic in nature. 50% and more patients presented with HFD in PROMM (80%), Pompe’s disease (70%), matrin-3 myopathy (60%), sIBM (50%), CNM (50%), while far less than 50% of the patients showed RD in LGMD2I (21%), LGMD2A (17%), LGMD2B (17%), LGMD2L (14%), FSHD (4%), BMD (0%). Four different HFD patterns were proposed. Conclusion The segregation of myopathies relative to the occurrence of PSA and especially HFD in a high prevalence group and in a low prevalence group may be diagnostically valuable. Significance The screening for HFD by means of EMG is also valuable in the diagnosis of non-myotonic myopathies.

Summary Background Vitamin D is involved in many biological processes. The role of vitamin D in patients with hepatocellular carcinoma (HCC) remains inconclusive, although there is evolving evidence that vitamin D may modulate cancer development and progression. Aim To evaluate serum vitamin D as prognostic parameter in HCC, we performed a prospective cohort study. Methods HCC patients were prospectively recruited and 25-hydroxyvitamin D3 (25(OH)D3) levels were determined. 25(OH)D3 levels were compared to stages of cirrhosis and HCC stages with nonparametric Kruskal–Wallis tests and Spearman correlations in 200 HCC patients. The association of the 25(OH)D3 levels and overall survival (OS) was assessed in uni- and multivariate Cox regression models. Results Two-hundred patients with HCC were included. The mean follow-up time was 322 ± 342 days with a range of 1–1508 days. Nineteen patients underwent liver transplantation and 60 patients died within the observation time. The mean serum 25(OH)D3 concentration was 17 ± 13 ng/mL with a range of 1–72 ng/mL. 25(OH)D3 serum levels negatively correlated with the stage of cirrhosis as well as with stages of HCC. Patients with severe 25(OH)D3 deficiency had the highest mortality risk (hazard ratio 2.225, 95% confidence interval 1.331–3.719, P = 0.002). Furthermore, very low 25(OH)D3 levels were associated with mortality independently from the MELD score and high alpha-Fetoprotein levels (>400 ng/mL) in a multivariate Cox regression model. Conclusions We conclude that 25(OH)D3 deficiency is associated with advanced stages of hepatocellular carcinoma and it is a prognostic indicator for a poor outcome.

High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the grey matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising, 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9–0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.

Speech and language measures during grade school predict adolescent speech-language outcomes in children who receive cochlear implants, but no research has examined whether speech and language functioning at even younger ages is predictive of long-term outcomes in this population. The purpose of this study was to examine if early preschool measures of speech and language performance predict speech-language functioning in long-term users of cochlear implants. Early measures of speech intelligibility and receptive vocabulary (obtained during preschool ages of 3 – 6 years) in a sample of 35 prelingually deaf, early-implanted children predicted speech perception, language, and verbal working memory skills up to 18 years later. Age of onset of deafness and age at implantation added additional variance to preschool speech intelligibility in predicting some long-term outcome scores, but the relationship between preschool speech-language skills and later speech-language outcomes was not significantly attenuated by the addition of these hearing history variables. These findings suggest that speech and language development during the preschool years is predictive of long-term speech and language functioning in early-implanted, prelingually deaf children. As a result, measures of speech-language functioning at preschool ages can be used to identify and adjust interventions for very young CI users who may be at long-term risk for suboptimal speech and language outcomes.

Purpose Verbal short-term memory (STM) and working memory (WM) skills predict speech and language outcomes in children with cochlear implants (CIs) even after conventional demographic, device, and medical factors are taken into account. However, prior research has focused on single end point outcomes as opposed to the longitudinal process of development of verbal STM/WM and speech-language skills. In this study, the authors investigated relations between profiles of verbal STM/WM development and speech-language development over time. Method Profiles of verbal STM/WM development were identified through the use of group-based trajectory analysis of repeated digit span measures over at least a 2-year time period in a sample of 66 children (ages 6–16 years) with CIs. Subjects also completed repeated assessments of speech and language skills during the same time period. Results Clusters representing different patterns of development of verbal STM (digit span forward scores) were related to the growth rate of vocabulary and language comprehension skills over time. Clusters representing different patterns of development of verbal WM (digit span backward scores) were related to the growth rate of vocabulary and spoken word recognition skills over time. Conclusion Different patterns of development of verbal STM/WM capacity predict the dynamic process of development of speech and language skills in this clinical population.

Background & Aims: Soluble CD163 (sCD163) is shed in the blood circulation by activated macrophages, correlates strongly with the hepatic venous pressure gradient (HVPG) and is thereby a good indicator of portal hypertension. It is unknown whether sCD163 correlates with the risk of variceal bleeding and overall survival (OS) in patients with liver cirrhosis. We performed a prospective study to investigate if sCD163 serum levels correlate with the risk of variceal bleeding and OS in cirrhotic patients. Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death or last contact. At the day of inclusion in the study, blood samples were taken and sCD163 serum levels were assessed by ELISA (enzyme-linked immunosorbent assay). The time until the end points death and variceal bleeding was assessed and the risks of death or variceal bleeding were calculated with uni- and multivariate Cox regression analyses. Results: High sCD163 levels (>4100 ng/L) were associated with death independently of the MELD (model of end stage liver disease) score, CRP (C-reactive protein), age and gender. Furthermore, high sCD163 levels were associated with gastrointestinal bleeding independently of the variceal stage and red spots. Conclusions: The sCD163 serum level is a new independent noninvasive risk factor for death and variceal bleeding in cirrhotic patients. 2013 European Association for the Study of the Liver. Published

To examine and compare the family environment of preschool- and school-age children with cochlear implants and assess its influence on children's executive function and spoken language skills.Retrospective between-subjects design.Outpatient research laboratory.Prelingually deaf children with cochlear implants and no additional disabilities and their families.Cochlear implantation and speech-language therapy.Parents completed the Family Environment Scale and the Behavior Rating Inventory of Executive Function (or the preschool version). Children were tested using the Peabody Picture Vocabulary Test-4 and either the Preschool Language Scales-4 or the Clinical Evaluation of Language Fundamentals-4.The family environments of children with cochlear implants differed from normative data obtained from hearing children, but average scores were within 1 standard deviation of norms on all subscales. Families of school-age children reported higher levels of control than those of preschool-age children. Preschool-age children had fewer problems with emotional control when families reported higher levels of support and lower levels of conflict. School-age children had fewer problems with inhibition but more problems with shifting of attention when families reported lower levels of conflict. School-age children's receptive vocabularies were enhanced by families with lower levels of control and higher levels of organization.Family environment and its relation to language skills and executive function development differed across the age groups in this sample of children with cochlear implants. Because family dynamics is one developmental/environmental factor that can be altered with therapy and education, the present results have important clinical implications for family-based interventions for deaf children with cochlear implants.

This study investigated long-term speech and language outcomes in 51 prelingually deaf children, adolescents and young adults who received cochlear implants (CIs) prior to 7 years of age and had used their implants for at least 7 years. Average speech perception scores were similar to those found in prior research with other samples of experienced CI users. Mean language test scores were lower than norm-referenced scores from nationally representative normal-hearing, typically developing samples, although a majority of the CI users scored within 1 standard deviation of the normative mean or higher on the Peabody Picture Vocabulary Test, Fourth Edition (63%), and the Clinical Evaluation of Language Fundamentals, Fourth Edition (69%). Speech perception scores were negatively associated with a meningitic etiology of hearing loss, older age at implantation, poorer preimplant unaided pure-tone average thresholds, lower family income and the use of ‘total communication'. Subjects who had used CIs for 15 years or more were more likely to have these characteristics and were more likely to score lower on measures of speech perception compared to those who had used CIs for 14 years or less. The aggregation of these risk factors in the >15 years of CI use subgroup accounts for their lower speech perception scores and may stem from more conservative CI candidacy criteria in use at the beginning of pediatric cochlear implantation.

The psychometric properties of the Learning, Executive, and Attention Functioning (LEAF) scale were investigated in an outpatient clinical pediatric sample. As a part of clinical testing, the LEAF scale, which broadly measures neuropsychological abilities related to executive functioning and learning, was administered to parents of 118 children and adolescents referred for psychological testing at a pediatric psychology clinic; 85 teachers also completed LEAF scales to assess reliability across different raters and settings. Scores on neuropsychological tests of executive functioning and academic achievement were abstracted from charts. Psychometric analyses of the LEAF scale demonstrated satisfactory internal consistency, parent-teacher inter-rater reliability in the small to large effect size range, and test-retest reliability in the large effect size range, similar to values for other executive functioning checklists. Correlations between corresponding subscales on the LEAF and other behavior checklists were large, while most correlations with neuropsychological tests of executive functioning and achievement were significant but in the small to medium range. Results support the utility of the LEAF as a reliable and valid questionnaire-based assessment of delays and disturbances in executive functioning and learning. Applications and advantages of the LEAF and other questionnaire measures of executive functioning in clinical neuropsychology settings are discussed.

Delays in the development of executive functioning skills are frequently observed in pediatric neuropsychology populations and can have a broad and significant impact on quality of life. As a result, assessment of executive functioning is often relevant for the development of formulations and recommendations in pediatric neuropsychology clinical work. Questionnaire-based measures of executive functioning behaviors in everyday life have unique advantages and complement traditional neuropsychological measures of executive functioning. Two case studies of children with spina bifida are presented to illustrate the clinical use of a new questionnaire measure of executive and learning-related functioning, the Learning, Executive, and Attention Functioning Scale (LEAF). The LEAF emphasizes clinical utility in assessment by incorporating four characteristics: brevity in administration, breadth of additional relevant content, efficiency of scoring and interpretation, and ease of availability for use. LEAF results were consistent with another executive functioning checklist in documenting everyday behavior problems related to working memory, planning, and organization while offering additional breadth of assessment of domains such as attention, processing speed, and novel problem-solving. These case study results demonstrate the clinical utility of questionnaire-based measurement of executive functioning in pediatric neuropsychology and provide a new measure for accomplishing this goal.

Immunotherapy in cancer is a recent and very promising approach, namely the inhibition of the PD/programmed death-ligand 1 (PD-L1) axis. Here we aimed to investigate the prognostic value of a soluble form of PD-L1 in hepatocellular carcinoma (HCC) patients.HCC patients were prospectively recruited and soluble programmed death-ligand 1 (sPD-L1) levels were determined. sPD-L1 levels were compared to stages of cirrhosis and HCC. The association of the sPD-L1 levels and overall survival (OS) was assessed.Two hundred fifteen patients with HCC were prospectively included. The median serum sPD-L1 concentration in patients with HCC was 0.5 ng/ml (range 0.03-6.04). Soluble PD-L1 levels positively correlated with the stage of cirrhosis and with stages of HCC. Furthermore, sPD-L1 correlated positively with a marker of macrophage activation (sCD163) and inflammation (C-reactive protein). The cut-off for high-level sPD-L1 (0.8 ng/ml) was defined by sPD-L1 levels determined in a healthy control cohort. Patients with high serum sPD-L1 concentrations had an increased mortality risk (hazard ratio 3.340, 95 % confidence interval 1.609-6.934, P0.001), while very low PD-L1 levels seem to come along with better prognosis. High sPD-L1 levels were associated with mortality independently from cirrhosis stage, alpha-fetoprotein and sCD163 levels in a multivariate Cox regression model.We conclude that a high sPD-L1 level is a possible prognostic indicator for a poor outcome in HCC patients. The predictive value of sPD-L1 levels for a successful anti-PD1/PD-L1 therapy should be investigated in the future.

Purpose To evaluate the family environments of children with cochlear implants and to examine relationships between family environment and postimplant language development and executive function. Method Forty-five families of children with cochlear implants completed a self-report family environment questionnaire (Family Environment Scale—Fourth Edition; Moos & Moos, 2009) and an inventory of executive function (Behavior Rating Inventory of Executive Function [Gioia, Isquith, Guy, & Kenworthy, 2000] or Behavior Rating Inventory of Executive Function—Preschool Version [Gioia, Espy, & Isquith, 2003]). The authors also evaluated children's receptive vocabulary (Peabody Picture Vocabulary Test—Fourth Edition; Dunn & Dunn, 2007) and global language skills (Preschool Language Scale—Fourth Edition [Zimmerman, Steiner, & Pond, 2002] and Clinical Evaluation of Language Fundamentals—Fourth Edition [Semel, Wiig, & Secord, 2003]). Results The family environments of children with cochlear implants differed from those of normal-hearing children but not in clinically significant ways. Language development and executive function were found to be atypical but not uncharacteristic of this clinical population. Families with higher levels of self-reported control had children with smaller vocabularies. Families reporting a higher emphasis on achievement had children with fewer executive function and working memory problems. Finally, families reporting a higher emphasis on organization had children with fewer problems related to inhibition. Conclusion Some of the variability in cochlear implantation outcomes that have protracted periods of development is related to family environment. Because family environment can be modified and enhanced by therapy or education, these preliminary findings hold promise for future work in helping families to create robust language-learning environments that can maximize their child's potential with a cochlear implant.

Disruptive behavior disorders (DBD) are among the most commonly diagnosed mental disorders in children and adolescents. Some important characteristics of DBD vary based on the presence or absence of comorbid attention-deficit/hyperactivity disorder (ADHD), which may affect the understanding of and treatment decision-making related to the disorders. Thus, identifying neurobiological characteristics of DBD with comorbid ADHD (DBD+ADHD) can provide a basis to establish a better understanding of the condition. This study aimed to assess abnormal white matter microstructural alterations in DBD+ADHD as compared to DBD alone and healthy controls using diffusion tensor imaging (DTI). Thirty-three DBD (19 with comorbid ADHD) and 46 age-matched healthy adolescents were studied using DTI. Fractional anisotropy (FA), and mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were analyzed using tract-based spatial statistics (TBSS). Significantly lower FA and higher MD, RD and AD in many white matter fibers were found in adolescents with DBD+ADHD compared to controls. Moreover, lower FA and higher RD were also found in the DBD+ADHD versus the DBD alone group. Alterations of white matter integrity found in DBD patients were primarily associated with ADHD, suggesting that ADHD comorbidity in DBD is reflected in greater abnormality of microstructural connections.

Background MicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-α and ribavirin. Aim Assessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response. Methods RNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response. Results The levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response. Conclusion Serum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-α and ribavirin in patients with chronic hepatitis C virus infection.

The objective of this study was to evaluate the development of functional auditory skills, language, and adaptive behavior in deaf children with cochlear implants (CI) who also have additional disabilities (AD). Design: A two-group, pre-test versus post-test design was used. Study sample: Comparisons were made between 23 children with CIs and ADs, and an age-matched comparison group of 23 children with CIs without ADs (No-AD). Assessments were obtained pre-CI and within 12 months post-CI. Results: All but two deaf children with ADs improved in auditory skills using the IT-MAIS. Most deaf children in the AD group made progress in receptive but not expressive language using the Preschool Language Scale, but their language quotients were lower than the No-AD group. Five of eight children with ADs made progress in daily living skills and socialization skills; two made progress in motor skills. Children with ADs who did not make progress in language, did show progress in adaptive behavior. Conclusions: Children with deafness and ADs made progress in functional auditory skills, receptive language, and adaptive behavior. Expanded assessment that includes adaptive functioning and multi-center collaboration is recom- mended to best determine benefi ts of implantation in areas of expected growth in this clinical population.

a b s t r a c t Background: Reduction of necroinflammatory activity is a major goal of antiviral therapy of patients with chronic hepatitis B. Serum ALT does not detect all forms of cell death. Objectives: To analyze dynamics of novel serum cell death markers for apoptosis and necrosis in associ- ation with virologic response to nucleos(t)ide (Nuc) analogue treatment. Study design: Quantification of the M30-apoptosis neoepitope and the cytokeratin-18 (M65-necrosis) serum levels before and during treatment of patients with chronic hepatitis B with Nuc (n = 26). Results: Before treatment, M30-apoptotic activity was significantly correlated with M65-necrosis and fibrosis but not with serum ALT. During therapy with Nucs, cell death parameters M30-apoptosis, M65- necrosis, and ALT declined in association with virologic response. The most frequent cell death pattern was simultaneous decline of ALT and M30-apoptosis which occurred more frequently in patients with HBs- Antigen decline than in patients with HBs-Antigen increase during treatment (87.5% vs. 40.0%; p = 0.024). ALT decline in association with increase of M30 apoptosis was frequent in patients with HBs-Antigen increase during treatment (36.3%) but was not observed in patients with HBs-Antigen decline during treatment. Conclusion: Decline of cell death parameters in association with decline of HBV-DNA and HBs-Antigen indicates a reduction in overall cell death activity during Nuc treatment supporting the concept that response to Nuc therapy reduces necroinflammatory activity and progression of liver disease. © 2011 Elsevier B.V. All rights reserved.

The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection.RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis.Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA.The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.

Purpose This study investigated the feasibility and efficacy of a working memory training program for improving memory and language skills in a sample of 9 children who are deaf (age 7–15 years) with cochlear implants (CIs). Method All children completed the Cogmed Working Memory Training program on a home computer over a 5-week period. Feasibility and acceptability of the program were evaluated using parent report and measures of children’s performance on the training exercises. Efficacy measures of working memory and sentence repetition were obtained prior to training, immediately after training, and 1 month and 6 months after training. Results Children’s performance improved on most training exercises, and parents reported no problems with children’s hearing or understanding of the exercises. After completion of working memory training, children demonstrated significant improvement on measures of verbal and nonverbal working memory, parent-reported working memory behavior, and sentence-repetition skills. The magnitude of improvement in working memory decreased slightly at the 1-month follow-up and more substantially at 6-month follow-up. However, sentence repetition continued to show marked improvement at 6-month follow-up. Conclusions Working memory training may produce benefit for some memory and language skills for children with CIs, supporting the importance of conducting a large-scale, randomized clinical trial with this population.

Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. Results: During hospitalization, the platelet count was measured above 330,000/ll and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly. 2011 European Association for the Study of the Liver. Published

Only recently have investigations of the relationship between media violence exposure (MVE) and aggressive behavior focused on brain functioning. In this study, we examined the relationship between brain activation and history of media violence exposure in adolescents, using functional magnetic resonance imaging (fMRI). Samples of adolescents with no psychiatric diagnosis or with disruptive behavior disorder (DBD) with aggression were compared to investigate whether the association of MVE history and brain activation is moderated by aggressive behavior/personality. Twenty-two adolescents with a history of aggressive behavior and diagnosis of either conduct disorder or oppositional-defiant disorder (DBD sample) and 22 controls completed an emotional Stroop task during fMRI. Primary imaging results indicated that controls with a history of low MVE demonstrated greater activity in the right inferior frontal gyrus and rostral anterior cingulate during the violent word condition. In contrast, in adolescents with DBD, those with high MVE exhibited decreased activation in the right amygdala, compared with those with low MVE. These findings are consistent with research demonstrating the importance of fronto-limbic structures for processing emotional stimuli, and with research suggesting that media violence may affect individuals in different ways depending on the presence of aggressive traits.

Introduction Interferon alpha (IFN) down regulates CD81 expression on peripheral blood mononuclear cells (PBMC) in patients with chronic hepatitis C virus (HCV) infection. Aim of our study was to investigate whether amantadine alters IFN associated down regulation of CD81 expression on PBMC in patients with chronic hepatitis C. Methods Nineteen patients with chronic HCV infection received peginterferon alpha-2a/ribavirin (SOC) for 48 weeks. Patients were randomised to 12 weeks amantadine therapy ( n = 12) or no additional treatment ( n = 7). FACS analysis of CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was performed at baseline, week (TW) 4, TW12, and TW24 of antiviral therapy. Results A significant decline of CD81 expression was observed on CD4(+), CD8(+), and CD56(+) cells ( p = 0.011, p p = 0.015, respectively) but not on CD19(+) cells ( p > 0.2). CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was not different between patients treated with SOC plus amantadine and patients treated with SOC alone. Conclusion The current study confirms that CD81 expression is down regulated by SOC on CD4(+), CD8(+) and CD56(+) cells. Amantadine treatment was not associated with CD81 expression. Interaction between amantadine and CD81 is unlikely to be involved in potential antiviral activity of amantadine in chronic HCV infection.