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Abstract Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions.

Abstract Background Noonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive. Methods Induced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D- and 3D-cultured systems in vitro. Results Here we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-β signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity. Conclusion Our findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.

Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations in Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Although diverse neurological manifestations are commonly diagnosed in NS patients, the mechanisms as to how SHP2 mutations induce the neurodevelopmental defects associated with NS remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs develop normally in their appearance, single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS.

An amendment to this paper has been published and can be accessed via the original article.

Background: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. Methods: The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. Results: The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. Discussion: ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to investigate the measurable impact of Buddhist liberal arts courses on college students’ ability to engage in self-reflection. This study uses the data gathered to establish, through statistical analysis, any correlations between two variables—Buddhist liberal arts as courses as the independent variable and self-reflection intelligence as the continuous dependent variable. First, the following results of the study show that the mean of the four self-reflection sub-categories for the students who found that the courses were helpful was higher than that of the students who found that they were not helpful: self-awareness (4.10 ± 0.49 > 3.90 ± 0.87), self-design (3.84 ± 0.66 > 3.40 ± 0.97), self-regulation (4.01 ± 0.04 > 3.48 ± 0.18), and self-examination (4.21 ± 0.03 > 3.94 ± 0.15), respectively. Second, the mean of the four self-reflection sub-categories for students who experienced a positive change of their perception in the courses was higher than that of students who experienced a negative change, as follows: self-awareness (4.08 ± 0.50 > 3.75 ± 0.82), self-design (3.84 ± 0.68 > 3.51 ± 0.93), self-regulation (4.00 ± 0.59 > 3.56 ± 0.67), and self-examination (4.17 ± 0.49 > 4.04 ± 0.73), respectively. This study illuminates the role of Buddhist-related liberal arts courses in higher education, specifically in fostering students’ self-reflection skills. It offers valuable insights into educational practices aimed at enhancing self-reflection levels.

ABSTRACT: Objectives: The socioeconomic and clinical burden of multidrug-resistant organisms (MDRO), including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant Acinetobacter baumannii (MRAB), multidrug-resistant Pseudomonas aeruginosa (MRPA), and carbapenem-resistant Enterobacteriaceae (CRE) have not yet been adequately addressed. Methods: We prospectively searched for MDRO bacteremia cases with matched controls from 10 hospitals across Korea during a 6-month period in 2017. Patients were classified into the MDRO, susceptible organism, and no-infection groups. The corresponding susceptible or no-infection controls had been selected according to predefined criteria. We collected clinical information and estimated the total additional medical cost due to MDRO infections using the multistate model. Results: During the 6-month period, a total of 486 MDRO bacteremia cases (260, 87, 18, 20, and 101 cases of MRSA, MRAB, MRPA, CRE, and VRE, respectively) were identified. The 90-d mortality rates were 30.4%, 63.2%, 16.7%, 55.0%, and 47.5%, respectively. The additional costs caused by bacteremia were $15 768, $35 682, $39 908, $72 051, and $33 662 per MDRO type, respectively. Based on these 6-month data, the estimated annual number of bacteremia cases due to these five MDRO in Korea were 7979 (4070, 1396, 218, 461, and 1834 cases, respectively). Overall, this caused an estimated 3280 (1237, 882, 36, 254, and 871, respectively) deaths and cost $294 505 002 ($84 707 359, $74 387 364, $10 344 370, $45 850 215, and $79 215 694, respectively) (range $170,627,020–$416,094,679) in socioeconomic loss. Conclusions: A tremendous clinical and economic burden is caused by MDRO bacteremia compared with antibiotic-susceptible and no-infection groups. Substantial investment and efforts by related government agencies and medical staffs are needed.

ABSTRACT: Objectives: Although many deaths due to carbapenem-resistant Acinetobacter baumannii (CRAB) bacteraemia occur within a few days after the onset of bacteraemia, risk factors for early mortality (EM) have not been deeply investigated. We aimed to determine the risk factors for EM and the difference between risk factors associated with EM and late mortality (LM) in CRAB bacteraemia. Methods: Clinical information on all patients with CRAB bacteraemia in 10 hospitals during a 1-year period was collected. Among the cases with mortality within 30 days, EM and LM were defined as death within 3 and more than 5 calendar days from the first positive blood culture, respectively. Results: In total, 212 CRAB bacteraemia cases were included in the analysis. Of 122 (57.5%) patients with 30-day mortality, EM was observed in 75 (61.5%) patients and LM in 39 (32.0%) patients. The proportion of severe sepsis or septic shock, Pitt score, and Sequential Organ Failure Assessment (SOFA) score was significantly higher in patients with EM than those with LM. Although urinary tract infection as the site of infection and the severity of illness were independent predictors of LM, only factors representing the severity of illness were independent risk factors for EM. Conclusion: Our results suggest that a large proportion of CRAB bacteraemia with high severity progresses to a rapidly fatal course, regardless of the underlying diseases or source of infection. Further studies might be needed to investigate the microbiological factors associated with CRAB and pathogen-host interaction in patients with EM.

Abstract We aimed to estimate the socioeconomic burden of pneumonia due to multidrug-resistant Acinetobacter baumannii (MRAB) and Pseudomonas aeruginosa (MRPA). We prospectively searched for MRAB and MRPA pneumonia cases and matched them with susceptible-organism pneumonia and non-infected patients from 10 hospitals. The matching criteria were: same principal diagnosis, same surgery or intervention during hospitalisation, age, sex, and admission date within 60 days. We calculated the economic burden by using the difference in hospital costs, the difference in caregiver costs, and the sum of productivity loss from an unexpected death. We identified 108 MRAB pneumonia [MRAB-P] and 28 MRPA pneumonia [MRPA-P] cases. The estimated number of annual MRAB-P and MRPA-P cases in South Korea were 1309–2483 and 339–644, with 485–920 and 133–253 deaths, respectively. The annual socioeconomic burden of MRAB-P and MRPA-P in South Korea was $64,549,723–122,533,585 and $15,241,883–28,994,008, respectively. The results revealed that MRAB-P and MRPA-P occurred in 1648–3127 patients, resulted in 618–1173 deaths, and caused a nationwide socioeconomic burden of $79,791,606–151,527,593. Multidrug-resistant organisms (MDRO) impose a great clinical and economic burden at a national level. Therefore, controlling the spread of MDRO will be an effective measure to reduce this burden.

Abstract This study aimed to evaluate the differences in clinical characteristics and impact of carbapenem resistance (CR) on outcomes between Acinetobacter baumannii (Ab) and Pseudomonas aeruginosa (Pa) bacteraemia. We prospectively identified all patients with Ab and Pa bacteraemia in 10 hospitals over 1 year. Treatment failure was defined as all-cause 30-day mortality, persistent bacteraemia, or recurrent bacteraemia within 30 days. We included 304 Ab and 241 Pa bacteraemia cases. CR was detected in 216 patients (71%) with Ab bacteraemia and 55 patients (23%) with Pa bacteraemia. Treatment failure was significantly higher in CR-Ab than in CR-Pa (60.6% vs. 34.5%, P = 0.001). In Ab, severe sepsis or septic shock and high Pitt bacteraemia score were independent risk factors for treatment failure in the inappropriate empirical antibiotics group. In Pa, hospital-acquired infection and high Pitt bacteraemia score were independent risk factors for treatment failure in both groups. CR was an independent risk factor in Ab for treatment failure in both groups, but not in Pa bacteraemia. We demonstrated significant differences in clinical characteristics and impact of CR on clinical outcomes between Ab and Pa bacteraemia, suggesting that different treatment approaches may be needed.

Abstract We aimed to investigate the associations of previous influenza/URI with the susceptibility of COVID-19 patients compared to that of non-COVID-19 participants. A nationwide COVID-19 cohort database was collected by the Korea National Health Insurance Corporation. A total of 8,070 COVID-19 patients (1 January 2020 through 4 June 2020) were matched with 32,280 control participants. Severe COVID-19 morbidity was defined based on the treatment histories of the intensive care unit, invasive ventilation, and extracorporeal membrane oxygenation and death. The susceptibility/morbidity/mortality associated with prior histories of 1–14, 1–30, 1–90, 15–45, 15–90, and 31–90 days before COVID-19 onset were analyzed using conditional/unconditional logistic regression. Prior influenza infection was related to increased susceptibility to COVID-19 (adjusted odds ratio [95% confidence interval] = 3.07 [1.61–5.85] for 1–14 days and 1.91 [1.54–2.37] for 1–90 days). Prior URI was also associated with increased susceptibility to COVID-19 (6.95 [6.38–7.58] for 1–14 days, 4.99 [4.64–5.37] for 1–30 days, and 2.70 [2.55–2.86] for 1–90 days). COVID-19 morbidity was positively associated with influenza (3.64 [1.55–9.21] and 3.59 [1.42–9.05]) and URI (1.40 [1.11–1.78] and 1.28 [1.02–1.61]) at 1–14 days and 1–30 days, respectively. Overall, previous influenza/URI did not show an association with COVID-19 mortality. Previous influenza/URI histories were associated with increased COVID-19 susceptibility and morbidity. Our findings indicate why controlling influenza/URI is important during the COVID-19 pandemic.

Abstract Background Skilled attendance at delivery is a key marker for reducing maternal mortality. Effective community engagement strategies complemented by community health worker (CHW) services can improve access to maternal health services in areas with limited health infrastructure or workforce. Methods A quasi-experimental study with matched comparison groups was conducted in Cambodia, Kenya and Zambia to determine the effect of integrated community investments on skilled birth attendance (SBA). In each country, communities in two districts/sub-districts received a package of community-oriented interventions comprised of timed CHW household health promotion for maternal, newborn and child health complemented by social accountability mechanisms using community scorecards. Two matched comparison districts/sub-districts received ongoing routine interventions. Data from the final evaluation were examined to determine the effect of timed CHW services and community-oriented interventions on SBA. Results Over 80% of the 3037 women in Cambodia, 2805 women in Kenya and 1171 women in Zambia reported SBA. Women in intervention sites who received timely CHW health promotion and social accountability mechanisms in Cambodia showed significantly higher odds of SBA (aOR = 7.48; 95% CI: 3.87, 14.5). The findings also indicated that women over the age of 24 in Cambodia, women with primary or secondary education in Cambodia and secondary education in Kenya, women from higher wealth quintiles in Cambodia, and women with four or more antenatal care (ANC) visits in all countries reported significantly higher odds of SBA. Inclusion of family members in pregnancy-related discussions in Kenya (aOR = 2.12; 95% CI: 1.06, 4.26) and Zambia (aOR = 6.78; 95% CI: 1.15, 13.9) and follow up CHW visits after a referral or health facility visit (aOR = 2.44; 95% CI: 1.30, 4.60 in Cambodia; aOR = 2.17; 95% CI 1.25, 3.75 in Kenya; aOR = 1.89; 95% CI: 1.05, 2.02 in Zambia) also showed significantly greater odds of SBA. Conclusions Enhancing people-centered care through culturally appropriate community-oriented strategies integrating timely CHW health promotion and social accountability mechanisms shows some evidence for improving SBA during delivery. These strategies can accelerate the achievement of the sustainable development goals for maternal child and newborn health.

BackgroundThe coverage for reproductive care continuum is a growing concern for communities in low- income economies. Adolescents (15-19 years) are often at higher odds of maternal morbidity and mortality due to other underlying factors including biological immaturity, social, and economic differences. The aim of the study was to examine a) differences in care-seeking and continuum of care (4 antenatal care (ANC4+), skilled birth attendance (SBA) and postnatal care (PNC) within 24h) between adult (20-49 Years) and adolescents and b) the effect of multilevel community-oriented interventions on adolescent and adult reproductive care-seeking in Cambodia, Guatemala, Kenya, and Zambia using a quasi-experimental study design.MethodsIn each country, communities in two districts/sub-districts received timed community health worker (CHW) household health promotion and social accountability interventions with community scorecards. Two matched districts/sub-districts were selected for comparison and received routine healthcare services.ResultsResults from the final evaluation showed that there were no significant differences in the care continuum for adolescents and adults except for Kenya (26.1% vs 18.8%, p

Objectives The prevalence of rheumatoid arthritis (RA) among patients with COVID-19 and the association between RA and the outcome of COVID-19 remain unclear. We aimed to compare the prevalence of RA between participants with and without COVID-19; we then analysed the association between the presence of RA and the severity of COVID-19.Design A cross-sectional study.Setting Data from a nationwide COVID-19 cohort database by the Korea National Health Insurance Corporation were used.Participants and interventions A total of 8070 patients with COVID-19 (1 January 2020 through 4 June 2020) were matched with 32 280 control participants with regard to age, sex and income. Patients with COVID-19 were confirmed by SARS-CoV-2 PCR and controls were collected from the database. RA was confirmed using the diagnostic code (International Classification of Disease, Tenth Revision) and medication claim codes. Conditional/unconditional logistic regression was applied to analyse the association between RA and COVID-19.Primary outcome and secondary outcome Laboratory confirmation of SARS-CoV-2 infection was defined as the primary outcome. The secondary outcome was severe COVID-19 defined as a history of intensive care unit admission, invasive ventilation or death.Results The prevalence of RA in the COVID-19 (0.4%, 35/8070) and control (0.4%, 121/32,280) groups did not differ (p=0.446). After adjusting for underlying diseases, no association between RA and COVID-19 was observed (adjusted OR=1.14, 95% CI: 0.78 to 1.67) and COVID-19 severity was not associated with RA (adjusted OR=0.62, 95% CI: 0.14 to 7.29). The overall mortality rate was 2.9% (237/8070) and RA was not significantly associated with mortality (adjusted OR=1.64, 95% CI: 0.33 to 8.15).Conclusion We did not find an association between the presence of RA and COVID-19. In addition, RA was not associated with the severity of COVID-19.

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is emerging in Asian 3 countries, China, Japan and Korea, which are scrub typhus endemic areas, and its incidence is increasing. As the two infections overlap epidemiologically and clinically and the accessibility or sensitivity of diagnostic tests is limited, early clinical prediction may be useful for diagnostic and therapeutic purposes. Methods Patients aged ≥16 years who were clinically suspected and laboratory-confirmed to be infected with Orientia tsutsugamushi or the SFTS virus in South Korea were enrolled. Clinical and laboratory parameters were compared. Scrub typhus was further subclassified according to the status of eschar and skin rash. An SFTS prediction scoring tool was generated based on a logistic regression analysis of SFTS compared with scrub typhus. Results The analysis was performed on 255 patients with scrub typhus and 107 patients with SFTS. At initial presentation, subjective symptoms except for gastrointestinal symptoms, were more prominent in scrub typhus patients. In addition to the characteristic eschar and skin rash, headache was significantly more prominent in scrub typhus, while laboratory abnormalities were more prominent in SFTS. Leukopenia (white blood cell count

ObjectivesDespite the importance of the protection of patients' health information in clinical settings, little is known about the awareness of this concept in nursing students due to the lack of a suitable measurement tool. Hence, this study attempted to redevelop the Patients' Health Information Protection Awareness Scale, and evaluate its construct validity and reliability for nursing students.MethodsA cross-sectional descriptive study was conducted. Nursing students who were in their 3rd and 4th year were recruited from 10 universities in Korea to assess the construct validity, and 30 experts (27 nurses and 3 faculty members) participated in the content validation process.ResultsThe content validity assessment indicated that 23 items were ideal. The assessment of construct validity using exploratory factor analysis revealed three factors: communication, management, and referrals. They together accounted for 54.1% of the variance in scale scores. The three-factor scale had good fit in the confirmatory factor analysis. Scale reliability was confirmed, with a Cronbach's alpha of 0.94 for all items.ConclusionsThis study was the first attempt to redevelop the Patients' Health Information Protection Awareness Scale for student nurses. The 23-item scale was shown to be a reliable and valid tool. It facilitates the assessment of nursing students' awareness of patient information protection. Academic nursing programs and health organizations can use its scores to implement adequate education plans to safeguard information in nursing students.

INTRODUCTION:Emerging data suggest that early antiretroviral therapy (ART) could reduce serious AIDS and non-AIDS events and deaths but could also increase costs. In January 2016, the Spanish guidelines were updated to recommend ART at any CD4 count. However, the epidemiologic and economic impacts of early ART initiation in Spain remain unclear. METHODS:The Johns Hopkins HIV Economic-Epidemiologic Mathematical Model (JHEEM) was utilized to estimate costs, transmissions, and outcomes in Spain over 20 years. We compared implementation of guidelines for early ART initiation to a counterfactual scenario deferring ART until CD4-counts fall below 350 cells/mm3. We additionally studied the impact of early ART initiation in combination with improvements to HIV screening, care linkage and engagement. RESULTS:Early ART initiation (irrespective of CD4-count) is expected to avert 20,100 [95% Uncertainty Range (UR) 11,100-83,000] new HIV cases over the next two decades compared to delayed ART (28% reduction), at an incremental health system cost of €1.05 billion [€0.66 - €1.63] billion, and an incremental cost-effectiveness ratio (ICER) of €29,700 [€13,700 - €41,200] per QALY gained. Projected ICERs declined further over longer time horizon; e.g., an ICER of €12,691 over 30 years. Furthermore, the impact of early ART initiation was potentiated by improved HIV screening among high-risk individuals, averting an estimated 41,600 [23,200-172,200] HIV infections (a 58% decline) compared to delayed ART. CONCLUSIONS:Recommendations for ART initiation irrespective of CD4-counts are cost-effective and could avert > 30% of new cases in Spain. Improving HIV diagnosis can amplify this impact.

BACKGROUND:Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was recently identified in China, South Korea and Japan. The objective of the study was to evaluate the epidemiologic and clinical characteristics of SFTS in South Korea. METHODS/PRINCIPAL FINDINGS:SFTS is a reportable disease in South Korea. We included all SFTS cases reported to the Korea Centers for Disease Control and Prevention (KCDC) from January 2013 to December 2015. Clinical information was gathered by reviewing medical records, and epidemiologic characteristics were analyzed using both KCDC surveillance data and patient medical records. Risk factors for mortality in patients with SFTS were assessed. A total of 172 SFTS cases were reported during the study period. SFTS occurred throughout the country, except in urban areas. Hilly areas in the eastern and southeastern regions and Jeju island (incidence, 1.26 cases /105 person-years) were the main endemic areas. The yearly incidence increased from 36 cases in 2013 to 81 cases in 2015. Most cases occurred from May to October. The overall case fatality ratio was 32.6%. The clinical progression was similar to the 3 phases reported in China: fever, multi-organ dysfunction, and convalescence. Confusion, elevated C-reactive protein, and prolonged activated partial thromboplastin times were associated with mortality in patients with SFTS. Two outbreaks of nosocomial SFTS transmission were observed. CONCLUSIONS:SFTS is an endemic disease in South Korea, with a nationwide distribution and a high case-fatality ratio. Confusion, elevated levels of C-reactive protein, and prolonged activated partial thromboplastin times were associated with mortality in patients with SFTS.