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IntroductionStatus epilepticus (SE) is a seizure lasting more than 5 min that can have lethal consequences or lead to various neurological disorders, including epilepsy. Using a pilocarpine-induced SE model in mice we investigated temporal changes in the hippocampal transcriptome.MethodsWe performed mRNA-seq and microRNA-seq analyses at various times after drug treatment.ResultsAt 1 h after the start of seizures, hippocampal cells upregulated transcription of immediate early genes and genes involved in the IGF-1, ERK/MAPK and RNA-PolII/transcription pathways. At 8 h, we observed changes in the expression of genes associated with oxidative stress, overall transcription downregulation, particularly for genes related to mitochondrial structure and function, initiation of a stress response through regulation of ribosome and translation/EIF2 signaling, and upregulation of an inflammatory response. During the middle of the latent period, 36 h, we identified upregulation of membrane components, cholesterol synthesis enzymes, channels, and extracellular matrix (ECM), as well as an increased inflammatory response. At the end of the latent period, 120 h, most changes in expression were in genes involved in ion transport, membrane channels, and synapses. Notably, we also elucidated the involvement of novel pathways, such as cholesterol biosynthesis pathways, iron/BMP/ferroptosis pathways, and circadian rhythms signaling in SE and epileptogenesis.DiscussionThese temporal changes in metabolic reactions indicate an immediate response to injury followed by recovery and regeneration. CREB was identified as the main upstream regulator. Overall, our data provide new insights into molecular functions and cellular processes involved at different stages of seizures and offer potential avenues for effective therapeutic strategies.

Abstract Maturation of the 3′ end of almost all eukaryotic messenger RNAs (mRNAs) requires cleavage and polyadenylation. Most mammalian mRNAs are polyadenylated at different sites within the last exon, generating alternative polyadenylation (APA) isoforms that have the same coding region but distinct 3′ untranslated regions (UTRs). The 3′UTR contains motifs that regulate mRNA metabolism; thus, changing the 3′UTR length via APA can significantly affect gene expression. Endochondral ossification is a central process in bone healing, but the impact of APA on gene expression during this process is unknown. Here, we report the widespread occurrence of APA, which impacts multiple pathways that are known to participate in bone healing. Importantly, the progression of endochondral ossification involves global 3′UTR shortening, which is coupled with an increased abundance of shortened transcripts relative to other transcripts; these results highlight the role of APA in promoting gene expression during endochondral bone formation. Our mechanistic studies of transcripts that undergo APA in the fracture callus revealed an intricate regulatory network in which APA enhances the expression of the collagen, type I, alpha 1 (Col1a1) and Col1a2 genes, which encode the 2 subunits of the abundantly expressed protein collagen 1. APA exerts this effect by shortening the 3′UTRs of the Col1a1 and Col1a2 mRNAs, thus removing the binding sites of miR-29a-3p, which would otherwise strongly promote the degradation of both transcripts. Taken together, our study is the first to characterize the crucial roles of APA in regulating the 3′UTR landscape and modulating gene expression during fracture healing.

Abstract Myocardial infarction patients had decreased methylation at four growth differentiating factor-15 (GDF-15) related CpG sites (cg13033858, cg16936953, cg17150809, and cg18608055). These sites had not been studied for their association with cardiovascular disease (CVD) deaths. Thus, we aimed to assess the associations independent of genes, shared environment, and traditional CVD risk factors. Nineteen white, male, monozygotic twin pairs discordant for CVD deaths were included from the National Heart, Lung and Blood Institute Twin Study (NHLBI) initiated in 1969. Data on vital status was collected through December 31, 2014. Methylation of buffy coat DNA at exam 3 (1986–87) was measured using the Illumina HumanMethylation450 BeadChip. Principal component analysis was used to generate a score representing blood leukocyte composition and baseline CVD risk factors and predominated with natural killer cells, CD4+ T cells, and Framingham risk score. Conditional logistic regression demonstrated that methylation at the four CpG sites was not associated with CVD deaths before (all p > 0.05, bootstrapped p > 0.05) and after adjustment for the score (all p > 0.05). Joint influences of cg16936953 and the score were statistically significant (p

BackgroundInjury is an increasingly pressing global health issue. An effective surveillance system is required to monitor the trends and burden of injuries. ObjectiveThis study aimed to identify a set of valid and context-specific injury indicators to facilitate the establishment of an injury surveillance program in Hong Kong. MethodsThis development of indicators adopted a multiphased modified Delphi research design. A literature search was conducted on academic databases using injury-related search terms in various combinations. A list of potential indicators was sent to a panel of experts from various backgrounds to rate the validity and context-specificity of these indicators. Local hospital data on the selected core indicators were used to examine their applicability in the context of Hong Kong. ResultsWe reviewed 142 articles and identified 55 indicators, which were classified into 4 domains. On the basis of the ratings by the expert panel, 13 indicators were selected as core indicators because of their good validity and high relevance to the local context. Among these indicators, 10 were from the construct of health care service use, and 3 were from the construct of postdischarge outcomes. Regression analyses of local hospitalization data showed that the Hong Kong Safe Community certification status had no association with 5 core indicators (admission to intensive care unit, mortality rate, length of intensive care unit stay, need for a rehabilitation facility, and long-term behavioral and emotional outcomes), negative associations with 4 core indicators (operative intervention, infection rate, length of hospitalization, and disability-adjusted life years), and positive associations with the remaining 4 core indicators (attendance to accident and emergency department, discharge rate, suicide rate, and hospitalization rate after attending the accident and emergency department). These results confirmed the validity of the selected core indicators for the quantification of injury burden and evaluation of injury-related services, although some indicators may better measure the consequences of severe injuries. ConclusionsThis study developed a set of injury outcome indicators that would be useful for monitoring injury trends and burdens in Hong Kong.

Individuals with a high school education represent the largest subset of the U.S. workforce. However, little is known about the employer expectations of these individuals, particularly in the area of soft skills--also known as 21st-century skills. Online job advertisements offer useful data for examining these expectations, as they may supplement employer survey data and reflect actual recruitment practices. Our analysis of 68,505 online job advertisements suggests that employers hold generally lower expectations for the soft skills of high school-educated individuals than they do for postsecondary-educated individuals. However, employer expectations for two soft skills--professionalism and customer service skills--appear to be substantially higher for high school-educated individuals than for postsecondary-educated individuals. Additional results highlight similarities and differences within the high school-educated workforce across nine workplace industries. We discuss the implications of these results not only for high school-educated individuals and the organizations that employ them but also for practitioners and educators charged with assessing and providing training for these skills.

Objective: This study aimed at exploring the attempters’ perception of community social services included any barriers to seeking help and services. Method: The participants were patients with self-harming behavior aged 15 years or above. A set of guiding questions were designed to explore the general barriers and accessibility to community social services. A voice recording was made, which was later converted into a text transcript and then preceded for content analysis with co-occurrence and similarity matrix interpretation. Two males and nine females with a history of self-harm aged between 24 and 58 years were recruited for the interviews. Result: The participants had diverse experiences and backgrounds, and attitudes toward community social services. However, there was a shared perception of the need to enhance community social services. There were four main themes and 12 sub themes identified. The main theme included the service availability, service accessibility, affordability and acceptability. For details, participants were unaware of the available types of care/social services in the community, and were unaware about the nearby social services. They also suggested extending service hours and focused services should be offered to help people with different backgrounds and needs. Actually, those with experience of service utilization had both positive and negative perspectives and they gave suggestions for service delivery, mainly extending service hours and offering focused services such as for gambling control and financial planning. In view of interaction with service providers, counseling skills and trust were highly appreciated by the participants. Conclusion: The results identified common circumstances of falling into financial hardship (gambling) and social fragmentation (divorce, poor family relationships, and poor marital relationships), which also suggested to enhance services on center location, service arrangement, and skill of caregivers. Keywords: Cognition, Community health services, Patients, Self mutilation

Introduction: The In-patient Medication Order Entry System (IPMOE) was first implemented in the medical ward of Princess Margaret Hospital, Hong Kong. It was a local developed close-loop system including prescription, dispensing and administration modules. Evaluation on its impact on nursing tasks would be important for practice improvement and subsequent system enhancement. Objective: The study was conducted to quantify the nursing times across medication-associated tasks for paper-based MAR and computer-based IPMOE, including change in the tasks and time patterns before and after IPMOE implementation. Methods: This was a prospective observation study in medical wards before (Jan 2014–Jun 2014) and after (Mar 2015–Jun 2015) the implementation of IPMOE. We conducted 8-hr observation studies of individual nurses with a customized application to time various pre-categorized nursing tasks. Statistical inferences and interrupted time series analysis was performed to identify the change in the intercept and trends over time after implementation. Result: The average number of medication-related tasks was significantly reduced from 61.07 to 29.81, a reduction of 31.26 episodes per duty (P

Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969–1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986–1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini–Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log2-fold changes and p < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.

Introduction: Currently, there is no consensus regarding the management of intermittent exotropia (IXT), which includes both surgical and non-surgical treatment options. Nonsurgical management of IXT has been suggested and includes watchful observation, patching, overminus lenses, prism, and vision therapy/orthoptics. While a significant portion of IXT patients are treated by surgery, it is reported that there is a substantial tendency for reoperation or recurrence of IXT. This paper provides a comprehensive review of non-surgical and surgical treatment options for the IXT. Methods: Search strategies involving combination of keywords including intermittent exotropia, divergence excess, basic exotropia, refractive error, glasses, spectacles, natural history, untreated, observe, occlusion, patch, overminus, overcorrecting minus, prism, vision therapy, orthoptic, anti-suppression, fusion exercise, and surgery were used in Medline. All English articles from 01/01/1900 to 01/09/2020 were reviewed. The reference list of the identified articles was also checked for additional relevant articles. Studies focused on animal models or strabismus associated with neurologic disorders or injury were excluded. The following filters were used for surgical management due to the abundance of reports: full text, randomized controlled trial, review, in the last 5 years. Results: Appropriate optical correction of refractive error is generally the starting point for all management approaches, but there is a lack of randomized clinical trial data regarding this treatment modality. Randomized clinical trial data indicate that both observation and occlusion are reasonable management options for children 3–10 years old, and there were insufficient data to recommend occlusion for children 12–35 months old. While overminus lenses were found to improve the control of IXT when assessed wearing overminus spectacles, this improvement did not persist after the treatment ended. The result of the only randomized clinical trial on the effectiveness of base-in prism indicated that this treatment is no more effective than nonprism spectacles for improving control. A recent randomized clinical trial showed that vision therapy/orthoptics is effective in improving the control of IXT when compared to observation alone. Surgery was found to alter a number of clinical characteristics of IXT, including reducing the distance and near angle of deviation, reducing photophobia, improving health-related quality of life, stereopsis, and the Newcastle Control Score. However, there are no randomized clinical trial data comparing surgery with a control group such as placebo or a no treatment observation group. Discussion: Rigorously designed clinical trials to investigate the effectiveness of non-surgical and surgical treatments for intermittent exotropia are needed. [ABSTRACT FROM AUTHOR]

Introduction: Status epilepticus (SE) is a seizure lasting more than 5 min that can have lethal consequences or lead to various neurological disorders, including epilepsy. Using a pilocarpine-induced SE model in mice we investigated temporal changes in the hippocampal transcriptome. Methods: We performed mRNA-seq and microRNA-seq analyses at various times after drug treatment. Results: At 1 h after the start of seizures, hippocampal cells upregulated transcription of immediate early genes and genes involved in the IGF-1, ERK/MAPK and RNAPolII/transcription pathways. At 8 h, we observed changes in the expression of genes associated with oxidative stress, overall transcription downregulation, particularly for genes related to mitochondrial structure and function, initiation of a stress response through regulation of ribosome and translation/EIF2 signaling, and upregulation of an inflammatory response. During the middle of the latent period, 36 h, we identified upregulation of membrane components, cholesterol synthesis enzymes, channels, and extracellular matrix (ECM), as well as an increased inflammatory response. At the end of the latent period, 120 h, most changes in expression were in genes involved in ion transport, membrane channels, and synapses. Notably, we also elucidated the involvement of novel pathways, such as cholesterol biosynthesis pathways, iron/BMP/ferroptosis pathways, and circadian rhythms signaling in SE and epileptogenesis. Discussion: These temporal changes in metabolic reactions indicate an immediate response to injury followed by recovery and regeneration. CREB was identified as the main upstream regulator. Overall, our data provide new insights into molecular functions and cellular processes involved at different stages of seizures and offer potential avenues for effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the short‐term (1 week after completion of treatment) effect of office‐based vergence and anti‐suppression therapy (OBVAT) on the Office Control Score when compared to observation alone in children with small‐to‐moderate angle intermittent exotropia (IXT). Methods: In this single‐masked (examiner masked), two‐arm, single‐centre randomised clinical trial, 40 participants, 6 to <18 years of age with untreated IXT, were randomly assigned to OBVAT or observation alone. Participants assigned to therapy received 60 min of OBVAT with home reinforcement once per week for 16 weeks. Therapy included vergence, accommodation and anti‐suppression techniques. The primary outcome measure was the comparison of the distance Office Control Score between the two groups at the primary outcome visit (i.e., 17‐week follow‐up visit). Results: At the primary outcome visit, the OBVAT group (n = 20) had a significantly better distance Office Control Score (adjusted mean difference: −0.9; 95% CI: −0.2 to −1.5; p = 0.008; partial eta squared: 0.19) than the observation group (n = 16). Participants from the OBVAT group were more likely than those from the observation group to have ≥1 point of improvement at the 17‐week visit (OBVAT group: 75%; Observation group: 25%; p = 0.006). Conclusions: In this randomised clinical trial of participants aged 6 to <18 years with IXT, we found that the OBVAT group had a significantly better distance Office Control Score than the observation group at the 17‐week visit. This study provides the first data from a randomised clinical trial demonstrating the effectiveness of OBVAT for improving the control of IXT. Eye care practitioners should consider OBVAT as a viable, non‐surgical treatment option for IXT. A full‐scale randomised clinical trial investigating the long‐term effectiveness of OBVAT in treating IXT is warranted. [ABSTRACT FROM AUTHOR]