Neural substrates of L2-L1 transfer effects on phonological awareness in young Chinese-English bilingual children.

The growing trend of bilingual education between Chinese and English has contributed to a rise in the number of early bilingual children, who were exposed to L2 prior to formal language instruction of L1. The L2-L1 transfer effect in an L1-dominant environment has been well established. However, the threshold of L2 proficiency at which such transfer manifests remains unclear. This study investigated the behavioral and neural processes involved when manipulating phonemes in an auditory phonological task to uncover the transfer effect in young bilingual children. Sixty-two first graders from elementary schools in Taiwan were recruited in this study (29 Chinese monolinguals, 33 Chinese-English bilinguals). The brain activity was measured using fNIRS (functional near-infrared spectroscopy). Bilingual children showed right lateralization to process Chinese and left lateralization to process English, which supports more on the accommodation effect within the framework of the assimilation-accommodation hypothesis. Also, compared to monolinguals, bilingual children showed more bilateral frontal activation in Chinese, potentially reflecting a mixed influence from L2-L1 transfer effects and increased cognitive load of bilingual exposure. These results elucidate the developmental adjustments in the neural substrates associated with early bilingual exposure in phonological processing, offering valuable insights into the bilingual learning process.

Associations of Atopic Dermatitis with Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Atopic dermatitis (AD) shares similarities with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) regarding pathogenesis involving neuroinflammation and genetics. Nevertheless, evidence on the associations of AD with ADHD and/or ASD is inconclusive. This study aimed to systematically examine the existing evidence on the associations between AD, ADHD, and ASD. METHODS: The Meta-Analysis of Observational Studies in Epidemiology guideline was followed. We searched MEDLINE, Embase, Cochrane Library, and Web of Science databases from their respective inceptions to March 4, 2022. Observational studies providing adjusted estimates and/or prevalences for ADHD and ASD in patients with AD were enrolled. A random-effects model meta-analysis was conducted to calculate pooled odds ratios (ORs) and confidence intervals (CIs). Subgroup analyses according to AD severity, age, geographic location, and study design were performed. RESULTS: Overall, a total of 24 studies with 71,373,639 subjects were enrolled. Our meta-analysis demonstrated significant associations of AD with ADHD (pooled OR: 1.28; 95% CI: 1.18-1.40) and ASD (pooled OR: 1.87; 95% CI: 1.30-2.68). Subgroup analyses revealed that the associations for ADHD were the most prominent in studies evaluating severe AD patients as well as in studies focusing on school-age children and adolescents. Among patients with AD, the pooled prevalence of ADHD was 6.6%, and the respective prevalence of ASD was 1.6%. CONCLUSION: The evidence to date suggests significant associations of AD with ADHD and ASD. Psychiatric consultation and an interdisciplinary approach would benefit patients with AD presented with behavioral symptoms suggestive of ADHD or ASD.

Depressive symptoms and daily living dependence in older adults with type 2 diabetes mellitus: the mediating role of positive and negative perceived stress.

BACKGROUND: Higher stress is associated with higher levels of depression and instrumental-activities-of-daily-living (IADL) dependence, and depression is strongly associated with specific IADL disabilities. Accordingly, the aim of this study was to investigate the mediating effect of perceived stress on the association between depression and IADL dependence among older adults with diabetes mellitus (DM). METHODS: We examined baseline data collected from a longitudinal study that recruited 110 patients with DM aged ≥ 65 years from the endocrinology outpatient clinic of a district hospital. The instruments used for our measurement processes comprised a demographic data sheet and Chinese versions of the Perceived Stress Scale (PSS), the short form of the Geriatric Depression Scale (GDS-S), and the Lawton IADL Scale. We assessed the mediating effects of positive perceived stress (PPS) and negative perceived stress (NPS) after controlling for five covariates by using a regression-based model run through the SPSS macro PROCESS. RESULTS: We observed negative correlations between GDS-S scores and PPS and between PPS and IADL dependence; we noted positive correlations between GDS-S scores and NPS and between NPS and IADL dependence (all P < 0.01). The indirect effect is coefficient = 0.12, [95% confidence interval = (0.0, 0.33)], suggesting that PPS achieves a mediating effect between depressive symptoms and IADL dependence. However, the NPS does not achieve a mediating effect in the relationship between depressive symptoms and IADL dependence (coefficient = 0.06, 95% CI = - 0.03, 0.15). CONCLUSIONS: Personal PPS mediates the association between depression and IADL dependence in older adults with DM. This finding suggests that providing patients with psychological education to promote their PPS may help prevent their functional decline.

Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.

Phonological and morphological literacy skills in English and Chinese: A cross-linguistic neuroimaging comparison of Chinese-English bilingual and monolingual English children.

Over the course of literacy development, children learn to recognize word sounds and meanings in print. Yet, they do so differently across alphabetic and character-based orthographies such as English and Chinese. To uncover cross-linguistic influences on children's literacy, we asked young Chinese-English simultaneous bilinguals and English monolinguals (N = 119, ages 5-10) to complete phonological and morphological awareness (MA) literacy tasks. Children completed the tasks in the auditory modality in each of their languages during functional near-infrared spectroscopy neuroimaging. Cross-linguistically, comparisons between bilinguals' two languages revealed that the task that was more central to reading in a given orthography, such as phonological awareness (PA) in English and MA in Chinese, elicited less activation in the left inferior frontal and parietal regions. Group comparisons between bilinguals and monolinguals in English, their shared language of academic instruction, revealed that the left inferior frontal was less active during phonology but more active during morphology in bilinguals relative to monolinguals. MA skills are generally considered to have greater language specificity than PA skills. Bilingual literacy training in a skill that is maximally similar across languages, such as PA, may therefore yield greater automaticity for this skill, as reflected in the lower activation in bilinguals relative to monolinguals. This interpretation is supported by negative correlations between proficiency and brain activation. Together, these findings suggest that both the structural characteristics and literacy experiences with a given language can exert specific influences on bilingual and monolingual children's emerging brain networks for learning to read.

Brain bases of English morphological processing: A comparison between Chinese-English, Spanish-English bilingual, and English monolingual children.

How do early bilingual experiences influence children's neural architecture for word processing? Dual language acquisition can yield common influences that may be shared across different bilingual groups, as well as language-specific influences stemming from a given language pairing. To investigate these effects, we examined bilingual English speakers of Chinese or Spanish, and English monolinguals, all raised in the US (N = 152, ages 5-10). Children completed an English morphological word processing task during fNIRS neuroimaging. The findings revealed both language-specific and shared bilingual effects. The language-specific effects were that Chinese and Spanish bilinguals showed principled differences in their neural organization for English lexical morphology. The common bilingual effects shared by the two groups were that in both bilingual groups, increased home language proficiency was associated with stronger left superior temporal gyrus (STG) activation when processing the English word structures that are most dissimilar from the home language. The findings inform theories of language and brain development during the key periods of neural reorganization for learning to read by illuminating experience-based plasticity in linguistically diverse learners.

Relation of environmental factors with activity limitations and participation restrictions in older adults with diabetes mellitus over time: an international classification of functioning framework perspective.

BACKGROUND: Activity limitations and participation restrictions were observed in patients with diabetes, which may impact their quality of life. Environmental factors such as seasonal effects, resources and perceived stress may play important role in activity limitations and participation restrictions. In this study, a variant of International Classification of Functioning (ICF) model was used to clarify the associations of function/structure factors, personal factors and environmental factors with activity limitations and participation restrictions. METHODS: This was a longitudinal design with 1 year follow-up. The Mini-Mental State Examination (MMSE), Geriatric Depression Scale- short form, Perceived Stress Scale, and Instrumental Activities of Daily Living assessments were measured at 3-month intervals for long-term follow-up in 110 patients with diabetes aged ≥ 65 years. RESULTS: Hierarchical linear regression models revealed that age (p = 0.001), perceived health status, MMSE scores (p < 0.01), and positive perceived stress (p < 0.001) were predictors of activity limitations (adjusted R2 = 53%). GDS-S (p < 0.05) and positive perceived stress (p < 0.01) were predictors of participation restrictions (adjusted R2 = 30%). Generalized estimating equation analysis indicated that seasonal effects, age, perceived health status, MMSE predicted the changes of slopes in activity limitations. Seasonal effects and GDS-S were predictors of the changes of slopes for participation restrictions (all p < 0.001). CONCLUSIONS: The ICF can be used to identify the risk factors for activity limitations and participation restrictions in older adults with diabetes. Practitioners should provide individualized interventions with consideration of these risk factors.

Neural substrates of theory of mind in adults with autism spectrum disorder: An fMRI study of the social animation task.

BACKGROUND: Although the neural mechanisms of the theory of mind (ToM) in children with autism spectrum disorder (ASD) through fMRI using the social animation task have been investigated, little is known in adults with ASD. Therefore, the present study aimed to explore the neural substrates of ToM in adults with ASD. Moreover, we aimed to elucidate the relationship between brain activation and behavior of social interaction in adults with ASD. METHODS: Twenty-four healthy controls and 24 adults with the clinical diagnosis of ASD were recruited. Participants were asked to complete the social animation task in functional magnetic resonance imaging. The imaging analyses of within (whole brain analysis) and between (5 regions of interest) group comparisons were conducted to explore the process of ToM. The correlation analyses were further conducted to explore the relationship between neural activations associated with ToM and social interaction abilities assessed by ADI-R. RESULTS: The ASD group showed greater activation in the left precuneus and right superior temporal gyrus (STG) than the control group. For correlation analyses, greater right STG activation was positively correlated with autistic symptoms assessed by the ADI-R in the ASD group. CONCLUSION: ASD adults might spend a lot of effort on identification processing, thereby influencing social communication skills. Also, the neural deficits of ToM in ASD adults might be associated with their social interaction difficulties.

Deep Learning-Based Link Quality Estimation for RIS-Assisted UAV-Enabled Wireless Communications System.

In recent years, unmanned aerial vehicles (UAVs) have become a valuable platform for many applications, including communication networks. UAV-enabled wireless communication faces challenges in complex urban and dynamic environments. UAVs can suffer from power limitations and path losses caused by non-line-of-sight connections, which may hamper communication performance. To address these issues, reconfigurable intelligent surfaces (RIS) have been proposed as helpful technologies to enhance UAV communication networks. However, due to the high mobility of UAVs, complex channel environments, and dynamic RIS configurations, it is challenging to estimate the link quality of ground users. In this paper, we propose a link quality estimation model using a gated recurrent unit (GRU) to assess the link quality of ground users for a multi-user RIS-assisted UAV-enabled wireless communication system. Our proposed framework uses a time series of user channel data and RIS phase shift information to estimate the quality of the link for each ground user. The simulation results showed that the proposed GRU model can effectively and accurately estimate the link quality of ground users in the RIS-assisted UAV-enabled wireless communication network.

Exploring social emotion processing in autism: evaluating the reading the mind in the eyes test using network analysis.

BACKGROUND: Features of autism spectrum disorder (ASD) include difficulties in processing and interpreting socioemotional information. The "Reading the Mind in the Eyes" test (RMET) is a validated measurement for processing socioemotional ability. However, previous RMET studies did not explore patterns of incorrect answers and the emotional valence of the test items. This study used the Taiwanese version of the RMET and the network analysis methods to examine the differences in underlying mechanisms of socioemotional processes between 30 males with autism spectrum disorder (ASD) (mean age = 18 years) and 30 healthy control males (mean age = 17 years). For each test item, a picture of a person's eyes and partial face was shown with four words describing the emotional status on picture corners. Participants were instructed to choose one of the four words that best matched the person's thinking or feeling. We further classified the words into three valences of emotional categories to examine socioemotional processes. RESULTS: Our results showed that ASD males performed poorer on the RMET than the controls. ASD males had higher network density and in-degree scores, especially in negative words, than control males. CONCLUSIONS: The findings suggest that males with ASD might have deficits in mapping the best emotional concept words to the target item, especially for processing negative emotion.

What's in a word? Cross-linguistic influences on Spanish-English and Chinese-English bilingual children's word reading development.

This study investigates the cross-linguistic transfer of literacy skills in Spanish-English, Chinese-English bilingual, and English monolingual children (N = 283, 5-10 years). Research question 1 examines English literacy and asks how phonological and morpho-semantic skills contribute to word reading as a function of children's language background. Structural equation modeling revealed contrasting bilingual effects: compared to English monolinguals, Spanish-English bilinguals relied more on phonological awareness in word reading, whereas Chinese-English bilinguals relied more on lexical knowledge. Research question 2 examines relations between bilinguals' heritage language proficiency and English literacy. Results revealed direct and indirect effects of heritage language meta-linguistic skills on English word reading. The study yields implications for reading theories and instructional practices in optimizing literacy in linguistically diverse children.

Efficacy of atropine, orthokeratology, and combined atropine with orthokeratology for childhood myopia: A systematic review and network meta-analysis.

BACKGROUND/PURPOSE: Orthokeratology (Ortho-K), atropine eye drops and combined atropine with Ortho-K are proven to be effective ways to prevent myopic progression in many studies, but there is scarce evidence regarding the comparative efficacy of different dosages of atropine,Ortho-K, and combined atropine with Ortho-K for childhood myopia. METHODS: We performed a network meta-analysis (NMA) to assess the relative efficacy of the aforementioned interventions for myopic progression; moreover, we calculated the surface under cumulative ranking area (SUCRA) to determine the relative ranking of treatments. RESULTS: We identified 19 randomized controlled trials (3435 patients). NMA revealed that 0.01%-1% atropine, Ortho-K, and 0.01% atropine combined with Ortho-K inhibited axial elongation (AL) over one year. For refractive change, SUCRA analysis revealed that the hierarchy was high-dose (0.5%-1%), moderate-dose (0.1%-0.25%), and low-dose (0.01%-0.05%) atropine. Regarding AL, SUCRA analysis revealed the following hierarchy: Ortho-K combined with 0.01% atropine, high-dose atropine, moderate-dose atropine, Ortho-K, and low-dose atropine. CONCLUSION: In conclusion, we found that atropine (0.01%-1%), Ortho-K, and 0.01% atropine combined with Ortho-K could significantly slow down myopia progression. The atropine efficacy followed a dose-related pattern; moreover, Ortho-K and low-dose atropine showed similar efficacy. There was a synergistic effect of using 0.01% atropine combined with Ortho-K, and it showed comparable efficacy to that of high-dose atropine.

Effects of Biological/Targeted Therapies on Bone Mineral Density in Inflammatory Arthritis.

Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Progress in both animal and clinical studies has provided a better understanding of the osteoclastogenesis-related pathways regarding the receptor activator of nuclear factor-κB ligand (RANKL), anti-citrullinated protein antibodies (ACPAs), and Wnt signaling and Dickkopf-related protein 1 (Dkk-1). The complex interplay between inflammatory cytokines and bone destruction has been elucidated, especially that in the interleukin-17/23 (IL-17/23) axis and Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling. Moreover, advances in biological and targeted therapies have achieved essential modifications to the bone metabolism of these inflammatory arthritis types. In this narrative review, we discuss recent findings on the pathogenic effects on bone in RA and SpA. Proinflammatory cytokines, autoantibodies, and multiple signaling pathways play an essential role in bone destruction in RA and SpA patients. We also reviewed the underlying pathomechanisms of bone structure in biological and targeted therapies of RA and SpA. The clinical implications of tumor necrosis factor inhibitors, abatacept, rituximab, tocilizumab, Janus kinase inhibitors, and inhibitors of the IL-17/23 axis are discussed. Since these novel therapeutics provide new options for disease improvement and symptom control in patients with RA and SpA, further rigorous evidence is warranted to provide a clinical reference for physicians and patients.

High-Intensity Post-Stroke Rehabilitation Is Associated with Lower Risk of Pressure Ulcer Development in Patients with Stroke: Real-World Evidence from a Nationwide, Population-Based Cohort Study.

Background and Objectives: Multiple factors are associated with pressure ulcer (PU) development, including limited mobility following stroke. We performed a nationwide cohort study to investigate the impact of rehabilitation intensity on the incidence of post-stroke PU. Materials and Methods: Data of patients diagnosed with stroke between 2000 and 2012 were collected from the 2000 Longitudinal Health Insurance Database (Taiwan). Based on the number of rehabilitation sessions attended within 90 days of discharge, the rehabilitation intensity was classified as low, medium, or high. After adjusting for sociodemographic factors and comorbidities, the Cox proportional hazards model evaluated the risk of PU development during the 12-year follow-up period. Kaplan−Meier curves were used to estimate the cumulative incidence of PUs. Results: Our study included 18,971 patients who had their first episode of stroke. Of these, 9829 (51.8%) underwent rehabilitation therapy after discharge. Female patients and patients with a National Institutes of Health Stroke Scale (NIHSS) score >13 points, who commenced high-intensity post-stroke rehabilitation after discharge had a significantly lower risk of PU development than those who underwent low-intensity post-stroke rehabilitation after discharge. Cumulative survival analysis showed a significantly lower cumulative incidence of PU during the 12-year follow-up period in the high-intensity rehabilitation group. Conclusion: Compared with low-intensity post-stroke rehabilitation, high-intensity post-stroke rehabilitation after discharge from hospital is associated with a lower risk of post-stroke PU development, especially in female stroke patients and patients with a NIHSS score >13 points. High-intensity rehabilitation is also associated with a significantly lower cumulative incidence of PU events during the 12-year follow-up period.

Pre-harvest sprouting in cereals: genetic and biochemical mechanisms.

With the growth of the global population and the increasing frequency of natural disasters, crop yields must be steadily increased to enhance human adaptability to risks. Pre-harvest sprouting (PHS), a term mainly used to describe the phenomenon in which grains germinate on the mother plant directly before harvest, is a serious global problem for agricultural production. After domestication, the dormancy level of cultivated crops was generally lower than that of their wild ancestors. Although the shortened dormancy period likely improved the industrial performance of cereals such as wheat, barley, rice, and maize, the excessive germination rate has caused frequent PHS in areas with higher rainfall, resulting in great economic losses. Here, we systematically review the causes of PHS and its consequences, the major indicators and methods for PHS assessment, and emphasize the biological significance of PHS in crop production. Wheat quantitative trait loci functioning in the control of PHS are also comprehensively summarized in a meta-analysis. Finally, we use Arabidopsis as a model plant to develop more complete PHS regulatory networks for wheat. The integration of this information is conducive to the development of custom-made cultivated lines suitable for different demands and regions, and is of great significance for improving crop yields and economic benefits.

Developmental differences in neural connectivity for semantic processing in youths with autism.

BACKGROUND: Youths with autism spectrum disorder (ASD) rely more on lower-level visual processing as revealed by greater occipital activation, yet less effectively engage higher-level processing of modality-independent semantic knowledge as indicated by reduced frontal activation, compared to typically developing (TD) youths. However, little is known about age-dependent differences in neural connectivity during semantic processing in youths with ASD as compared to TD youths. METHODS: Four groups were recruited: 31 ASD children (mean age = 10.5 years old), 33 TD children (mean age = 10.4), 30 ASD adolescents (mean age = 14.9), and 34 TD adolescents (mean age = 15.1). We explored their differences in neural connectivity by using functional magnetic resonance imaging (fMRI) with psychophysiological interaction (PPI) during semantic judgments. RESULTS: In comparison with TD children, children with ASD showed greater activation in the left cuneus and weaker connectivity between the left cuneus and left middle temporal gyrus (MTG). In comparison with TD adolescents, adolescents with ASD showed less activation in the left inferior frontal gyrus (IFG) and weaker functional connectivity between the left IFG and left MTG. CONCLUSIONS: Children with ASD may rely more on visual processes in the occipital cortex that are disconnected from modality-independent semantics in the temporal cortex. However, adolescents with ASD may less effectively engage frontal mechanisms involved in the top-down control of modality-independent semantic knowledge in the temporal cortex. Our findings provide evidence of developmental differences in the neural substrates of the alterations in semantic processing in youths with ASD compared to TD youths.

Seborrheic dermatitis and risk of incident peptic ulcer disease: A nationwide population-based cohort study.

BACKGROUND: Emerging evidence supports a strong association between the skin and the gut. The association between seborrheic dermatitis (SD) and peptic ulcer disease (PUD) was largely unknown. This study aimed to investigate the association of SD and PUD. METHODS: This nationwide population-based cohort study was conducted using the Taiwan's National Health Insurance Research Database. A total of 19 445 participants was recruited. Each patient with a diagnosis of incident SD was matched to four patients without SD using propensity scores based on age, gender, index year, insurance amount, urbanisation level, Charlson comorbidity index (CCI), the presence of comorbidities and medication use. The primary endpoint was the development of incident PUD. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for PUD occurrence in relation to the presence of SD were calculated. RESULTS: Overall, patients with SD had a significantly higher risk for incident PUD than those without SD in both univariable (crude HR = 1.60, 95% CI 1.38-1.86, P < 0.001) and multivariable (adjusted HR = 1.58, 95% CI 1.36-1.83, P < 0.001) Cox proportional hazard regression models. Kaplan-Meier analysis indicated that the cumulative incidence of PUD was consistently higher in individuals with SD than those without SD (log-rank test, P < 0.001). A higher risk of PUD was also found in individuals with SD than those without SD in all stratified analyses by age, gender, CCI and follow-up time. CONCLUSION: Patients with SD may have a higher risk for incident PUD. Further studies are warranted to validate our findings.

Medulla oblongata germinoma with Klinefelter syndrome.

Intracranial germinomas mostly occur in teenagers and young adults. The common sites are pineal and suprasellar regions. Males with Klinefelter syndrome, compared with males without chromosomal abnormalities, are known to have a higher incidence of developing pineal or suprasellar germinomas. As for germinoma in the medulla oblongata, this is rare, with only 21 previous cases reported. Due to the rarities, any relationship between people with Klinefelter syndrome and medulla oblongata germinomas remains undetermined. We present a rare case of medulla oblongata germinoma in a 25-year-old man. It is the second case of medulla oblongata germinoma in association with Klinefelter syndrome. We emphasize the importance of karyotyping in every case of germinoma, especially those with intracranial germinomas at atypical locations.

Digitally Controlled Oscillator with High Timing Resolution and Low Complexity for Clock Generation.

This paper presents a digitally controlled oscillator (DCO) with a low-complexity circuit structure that combines multiple delay circuits to achieve a high timing resolution and wide output frequency range simultaneously while also significantly reducing the overall power consumption. A 0.18 µm complementary metal-oxide-semiconductor standard process was used for the design, and measurements showed that the chip had a minimum controllable timing resolution of 4.81 ps and power consumption of 142 µW with an output signal of 364 MHz. When compared with other designs using advanced processes, the proposed DCO demonstrated the best power-to-frequency ratio. Therefore, it can output a signal at the required frequency more efficiently in terms of power consumption. Additionally, because the proposed DCO uses digital logic gates only, a cell-based design flow can be implemented. Hence, the proposed DCO is not only easy to implement in different processes but also easy to integrate with other digital circuits.

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

BACKGROUND: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. METHODS: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. RESULTS: The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. CONCLUSIONS: Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).