Real-World Effectiveness of Biologics in Patients With Severe Asthma: Analysis of the KoSAR.

PURPOSE: Severe asthma is associated with high morbidity and healthcare utilization; however, treatment options for these patients are limited. This study aimed to determine the therapeutic effects of biologics in clinical practice. METHODS: This multicenter, retrospective cohort study included 136 patients who received biologics for at least 4 months between September 2017 and July 2022 at 25 medical centers affiliated with the Korean Severe Asthma Registry (KoSAR). The study evaluated the treatment effects, including acute exacerbation rates, maintenance of oral corticosteroid dosages, lung function, quality of life, blood eosinophil count, and fractional exhaled nitric oxide (FeNO) levels, by comparing measurements before and after 4 months of biologic treatment. Responses for each medication was evaluated based on the Global Evaluation of Treatment Effectiveness score, and any adverse reactions were summarized. RESULTS: With the administration of biologics over the course of 4 months, there was a reduction in asthma acute exacerbations, a significant improvement in lung function, and a significant decrease in daily maintenance dose of oral steroid. Blood eosinophil counts decreased in the mepolizumab and reslizumab groups, while FeNO levels decreased only in the dupilumab group. The Asthma Control Test, Quality of Life Questionnaire for Adult Korean Asthmatics, and the EuroQol-visual analogue scale scores showed a significant improvement. Most patients (80.15%) responded to the biologic treatment. Meanwhile, non-responders often had chronic rhinosinusitis as a comorbidity, exhibited lower lung function, and required higher doses of oral steroids. No severe adverse events were reported. CONCLUSIONS: Biologics are highly effective in Korean patients with Type 2 severe asthma, significantly reducing acute exacerbation rates and doses of oral corticosteroids, while also improving lung function. Therefore, it seems beneficial to administer biologics without any restrictions to patients exhibiting Type 2 severe asthma.

Characteristics of Severe Asthma in the Elderly: Observations From the Korean Severe Asthma Registry (KoSAR).

PURPOSE: Few studies have compared the clinical characteristics of severe asthma (SA) in elderly patients compared to that in nonelderly patients. METHODS: We analyzed data from the Korean SA Registry, a nationwide, real-world observational study of SA in Korea. The baseline clinical characteristics, disease control status, and medication use of the patients were compared between elderly (≥ 65 years) and nonelderly groups. RESULTS: Of the 864 patients with SA, 260 (30.1%) were in the elderly group. The elderly group had lower atopy rate, but had higher prevalence of chronic obstructive pulmonary disease (COPD), hypertension, and osteoporosis than did the nonelderly group. The elderly group had a lower rate of type 2 inflammation and lower levels of forced expiratory volume in 1 second (FEV1) (% predicted) and FEV1/forced vital capacity ratio than did the nonelderly group (P < 0.05 for all). However, asthma symptom scores and the frequency of asthma exacerbation were not significantly different between the 2 groups. Of controller medications, biologics were less frequently used in the elderly group (P < 0.05 for all). CONCLUSIONS: SA in the elderly is characterized by lower lung function, less type 2-low airway inflammation, and comorbidity with COPD. These findings are being taken into consideration in the management of elderly patients with SA in real-world clinical practice.

Glycemic Control and Oral Health Outcomes in Patients With Diabetes: Insights From a Nationwide Korean Survey.

BACKGROUND: Diabetes is recognized as a risk factor for various inflammatory conditions, including periodontitis. There exists a bidirectional relationship between glycemic control and oral health in individuals with diabetes. This study aimed to analyze the link between glycemic control and oral health status among Korean patients with diabetes. METHODS: Using data from a population-based nationwide survey conducted between 2007 and 2019, we identified 70,554 adults with diabetes-related information. The study population included 9,090 individuals diagnosed with diabetes and 61,164 healthy controls. The association between glycemic control, defined by mean glycated hemoglobin (HbA1c) values, and various oral health measures, such as tooth brushing frequency, periodontitis, denture wearing, Decayed, Missing, and Filled Teeth (DMFT) index, number of remaining teeth, and past-year dental clinic visits, was evaluated using multivariate logistic regression analyses. RESULTS: Compared to the control group, patients with diabetes exhibited a higher prevalence of periodontitis (88.6% vs. 73.3%), complete dentures (5.0% vs. 1.5%), and elevated DMFT index (33.2% vs. 26.7%) (all P < 0.001). Multivariate analyses revealed significant associations between diabetes and several oral health factors: denture status (No denture: adjusted odds ratio [aOR], 0.784; 95% confidence interval [CI], 0.627-0.979), and having fewer permanent teeth (0-19) (aOR, 1.474; 95% CI, 1.085-2.003). Additionally, a positive correlation was found between higher HbA1c levels and the risk of having fewer remaining teeth (0-19) (HbA1c < 6.5%: aOR, 1.129; 95% CI, 0.766-1.663; 6.5% ≤ HbA1c < 8.0%: aOR, 1.590; 95% CI, 1.117-2.262; HbA1c ≥ 8%: aOR, 1.910; 95% CI, 1.145-3.186) (P for trends = 0.041). CONCLUSION: We found a positive association between diabetes and poor oral health, as well as a noteworthy relationship between reduced permanent teeth (≤ 19) and glycemic control. These insights emphasize the critical role of oral health management in diabetic care and underscore the importance of maintaining effective glycemic control strategies for overall health and well-being in patients with diabetes.

Work-related asthma in adults with severe asthma from the Korean Severe Asthma Registry (KoSAR).

Background: Exposure to allergens or irritants in the workplace may affect asthma control and the quality of life (QoL) of patients with asthma. Objective: To examine the prevalence and characteristics of work-related asthma (WRA) in adult patients with severe asthma. Methods: We analyzed data from the Korean Severe Asthma Registry (KoSAR), which is a nationwide multicenter observational study on severe asthma in Korea. Severe asthma was defined according to the American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines. WRA was identified on the basis of asthma symptom aggravation at the workplace, as indicated by responses to a structured questionnaire. We compared the demographic and clinical characteristics and QoL between adult patients with severe asthma and WRA and those without WRA. Results: Among 364 patients with severe asthma who were employed at the time of enrollment, 65 (17.9%) had WRA. There were no significant differences in age, sex, obesity, or smoking history between the WRA and non-WRA groups. However, individuals with WRA exhibited a higher prevalence of anxiety (7.7% vs 2.4%, P = 0.046) and depression (12.3% vs 3.7%, P = 0.010) than those without. The levels of asthma control, lung function, and frequency of asthma exacerbations were similar between the two groups, but patients with WRA reported lower QoL, as determined by the Quality of Life Questionnaire for Adult Korean Asthmatics (56.6 ± 14.6 vs. 63.5 ± 13.9, P < 0.001). Conclusion: Patients with severe asthma and WRA are more likely to experience anxiety and depression and have lower QoL than those without WRA.

Uncovering risk factors for adverse events and infections in rheumatoid arthritis and rheumatoid arthritis with interstitial lung disease under treatment with biologics or targeted synthetic DMARDs: insights from the KOBIO Registry.

OBJECTIVES: This study aimed to identify the risk factors associated with overall adverse events (AEs) and infections in patients with rheumatoid arthritis (RA) and comorbid interstitial lung disease (ILD), receiving biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), using data from the Korean College of Rheumatology Biologics registry. METHODS: We analysed data from a cohort of 2,266 adult patients with RA who received b/tsDMARDs, including 169 patients with comorbid ILD. We identified the risk factors for overall AEs and infections in both the all RA group and the subgroup of patients with RA-ILD and investigated the impact of infections on mortality in patients with RA-ILD. RESULTS: Among all patients with RA, 45.7% withdrew b/tsDMARDs, whereas among those with RA-ILD, a higher proportion of 57.4% withdrew their treatment regimen. The main reason for withdrawing b/tsDMARDs in the RA-ILD group was AEs, with infections accounting for the largest proportion of reported AEs. In multivariable analysis of the risk factors for overall AEs and infections in the RA-ILD group, older age was identified as a risk factor for overall AEs (odds ratio [OR], 3.01; p=0.014), and only a current smoking status was identified as a risk factor for infections (OR, 2.11; p=0.035). CONCLUSIONS: Patients with RA-ILD exhibited a higher rate of b/tsDMARDs withdrawal due to overall AEs and infections than those with RA without ILD. In the RA-ILD group, older age was identified as a risk factor for overall AEs, whereas a current smoking status was identified as a risk factor for infections.

Impact of adjuvant chemotherapy on patients with stage IB non-small cell lung cancer with visceral pleural invasion.

Background: Adjuvant chemotherapy has reduced the risk of recurrence and death in stage IB non-small cell lung cancer (NSCLC) with high-risk factors; however, the impact of visceral pleural invasion (VPI) on outcomes in stage IB NSCLC treated with adjuvant chemotherapy remains controversial. The aim of this study was to explore the clinical and prognostic significance of adjuvant chemotherapy for stage IB (1-4 cm) NSCLC with VPI. Methods: This retrospective study included 251 patients admitted between January 2008 and May 2018 from four hospitals who underwent complete resection for Tumor-Node-Metastasis (TNM) 8th edition stage IB NSCLC with VPI. The relationship between adjuvant chemotherapy and overall survival (OS) or recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards model. Results: Of 251 patients with stage IB NSCLC with VPI, 122 (48.6%) received adjuvant chemotherapy after surgical resection and 129 (51.4%) were placed under observation. Multivariable analysis showed that adjuvant chemotherapy was an independent predictor of RFS [adjusted hazard ratio (aHR), 0.57; 95% confidence interval (CI): 0.33-0.96; P=0.036]. A micropapillary pattern (aHR, 2.46; 95% CI: 1.33-4.55; P=0.004) and lymphovascular invasion (aHR, 2.86; 95% CI: 1.49-5.48; P=0.002) were associated with a higher risk of recurrence. Multivariable analysis also showed that adjuvant chemotherapy was an independent predictor of OS (aHR, 0.22; 95% CI: 0.09-0.58; P=0.002). In a subgroup analysis of patients with a tumor size of 1-3 cm, adjuvant chemotherapy was associated with improved RFS and OS, and this association was maintained even when patients with VPI had additional risk factors. Conclusions: Our study shows that adjuvant chemotherapy is appropriate for patients with stage IB (1-4 cm) NSCLC with VPI, and even those with smaller tumors (1-3 cm).

Impact of air pollution on healthcare utilization in patients with bronchiectasis.

Introduction: Air pollutants are increasingly recognized to affect long-term outcomes in patients with bronchiectasis. We aimed to figure out the association between air pollutants and the risk of healthcare utilization in patients with bronchiectasis. Methods: Data for 1,029 subjects with bronchiectasis in Seoul were extracted. The air pollutants included particulate matter of 10 µm or less in diameter (PM10), particulate matter of 2.5 µm or less in diameter (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO), ozone (O3), and nitrogen dioxide (NO2). The outcome was all-cause healthcare uses, defined as outpatient visit, emergency department visit, or hospitalization. The concentration-response curves between each air pollutant and relative risks for healthcare utilization were obtained. Results: There were significant correlations between air pollutant concentrations and the risk of healthcare utilization, particularly for PM10, NO2, SO2, and CO. This risk was observed even at concentrations below the recommended safe thresholds for the general population. The slopes for the association between PM10 and NO2 and the risk of healthcare use showed a logarithmic growth pattern, with the steepest increase up to 30 µg/m3 and 0.030 parts per million (ppm), respectively. The curves for SO2 and CO showed an inverted U-shaped pattern, with a peak at 0.0045 ppm and a slow upward curve, respectively. No specific trends were observed for PM2.5 and O3 and the risk of healthcare use. Discussion: Increased concentrations of PM10, NO2, SO2, and CO were associated with increased healthcare utilization in patients with bronchiectasis. For patients with bronchiectasis, there were no safety thresholds for those air pollutants, and even low levels of air pollutant exposure can negatively impact bronchiectasis outcomes.

Treatment Sequence After Initiating Biologic Therapy for Patients With Rheumatoid Arthritis in Korea: A Nationwide Retrospective Cohort Study.

Objective: To evaluate treatment patterns and healthcare resource utilization (HCRU) after initiating biologic disease-modifying antirheumatic drugs (bDMARDs) in Korean patients with rheumatoid arthritis (RA). Methods: Patients newly diagnosed with RA in 2014 were identified and followed up on using the Korean National Health Insurance Database until 2018. The initial line of therapy (LOT) or LOT1 included patients treated with conventional DMARDs (cDMARD). Patients who started a bDMARD were assigned to LOT2 bDMARD. Those who moved from a bDMARD to a Janus kinase inhibitor were assigned to LOT3. Analyzed outcomes were treatment patterns and HCRU in LOT2 bDMARD. Results: The most prescribed initial bDMARD was a tumor necrosis factor inhibitor. Seventy-five percent of patients had changes in treatment after starting a bDMARD, such as addition/removal or switch of a DMARD, and transition to LOT3. For the first and second changes in LOT2 bDMARD, adding a cDMARD to a bDMARD was more common than switching to another bDMARD (7.98% vs. 2.93% for the first change, and 17.10% vs. 6.51% for the second change). Tocilizumab was the most common bDMARD that was switched to. Forty-eight percent of patients had at least one hospitalization after initiating bDMARDs. Of these patients, 64.3% were admitted due to RA-related reasons. Conclusion: This real-world study provides information on treatment characteristics of RA patients in Korea after starting a bDMARD. In contrary to guidelines, cDMARD addition was more often than bDMARD switches in daily clinical practice.

Retention Rate and Safety of Biologic and Targeted Synthetic DMARDs in Patients with RA-Associated Interstitial Lung Disease: A KOBIO Registry Study.

OBJECTIVES: This study aimed to evaluate the long-term retention and safety of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) and identify the factors associated with drug withdrawal in patients with rheumatoid arthritis (RA) with interstitial lung disease (ILD) enrolled in the Korean College of Rheumatology Biologics and Targeted Therapy registry. METHODS: We investigated adults with RA (n = 2266) administered with bDMARDs or tsDMARDs between 2012 and 2021. Propensity score matching (1:3) was performed between patients with RA with ILD (RA-ILD) and without ILD (RA-no ILD). The Kaplan-Meier method was used to analyse drug survival and a logistic regression model to identify withdrawal-related factors in RA-ILD. RESULTS: One hundred and fifty-nine patients with RA-ILD were matched with 477 patients with RA-no ILD. The 5-year drug retention rate was lower in RA-ILD than in RA-no ILD (log-rank p = 0.020), and both the ILD and no-ILD groups had statistical differences of drug retention rate among agents (log-rank p = 0.019 and 0.020, respectively). In the RA-ILD group, Janus kinase inhibitors had the highest drug retention rate (64.3%), and tumour necrosis factor-α inhibitors showed the lowest retention rate (30.6%). Approximately 58.5% and 48.4% of the patients with RA-ILD and RA-no ILD, respectively, withdrew from their regimen, and the main cause of withdrawal in RA-ILD was adverse events, followed by inefficacy. In the logistic regression analysis, current smoking had a negative effect on drug retention (odds ratio [OR]: 9.938, 95% confidence interval [CI]: 2.550-38.733; p < 0.001), while concomitant corticosteroid use had a protective effect against withdrawal (OR: 0.284, 95% CI: 0.008-0.917; p = 0.035) in RA-ILD. CONCLUSION: The patients with RA-ILD had lower bDMARD and tsDMARD retention rates than those with RA-no ILD. In the RA-ILD group, current smoking and concomitant corticosteroid use were associated factors affecting drug withdrawal.

Longitudinal Patterns of Strengths Among Youth with Psychiatric Disorders: A Latent Profile Transition Analysis.

A better understanding of variability in the strengths of youth with psychiatric disorders is critical as a strength-based approach can lead to recovery. This study aimed to identify subgroups of strengths among youth with mental disorders and determine whether subgroups changes were associated with mental health recovery. Youth with mental disorders (N = 2228) from a statewide database were identified in the state fiscal year of 2019. Using the latent profile analysis and latent transition analysis, we identified three strength profiles (i.e., essential, usable, and buildable). Over 90% of youth sustained or developed strengths over time. Positive transitions were associated with mental health recovery, symptom reduction, and personal recovery. Buildable strengths supported youth's personal recovery independent of improving mental health needs. The findings suggest that subgroups of strengths may be a promising source for planning and tracking youth's progress and guiding clinicians to more efficiently allocate community-based resources.

Engagement in a Preventive Intervention for Preadolescent Children in Foster Care: Considerations for Intervention Design.

Engagement in mental health-focused preventive interventions is understudied. Demographic, child, and system-level predictors of engagement were explored in a study with children in foster care (N = 222, Mage = 10.3) who participated in a 30-week intervention. Attendance and engagement in mentor visits and skills groups were rated weekly. Only 4 of 21 predictors showed bivariate associations with attendance/engagement: child sex, IQ, behavior problems, and trauma symptoms. SEM models with these three variables and a measure of adverse childhood experience (ACEs), were used to develop a model of engagement. Males had poorer mentor visit and group engagement. Group attendance was positively associated with trauma symptoms and negatively associated with ACEs. Group engagement was associated with higher IQ and fewer behavior problems. A contextually-sensitive intervention can result in high engagement for a vulnerable and diverse population, yet a few child factors still impacted engagement, and when identified could be ameliorated.Trial Registration ClinicalTrials.gov, Identifiers: NCT00809315 & NCT00810056.

Intensity of Grandparent Caregiving, Health, and Well-Being in Cultural Context: A Systematic Review.

BACKGROUND AND OBJECTIVES: Grandparents are key resources in grandchildren care globally. However, mixed findings indicated that multiple role engagement may enhance well-being and bring demands on grandparent caregivers in different contexts. This systematic review examines the association between the intensity of grandparent caregiving and their health and well-being (i.e., physical, mental, cognitive, and life satisfaction) by continent and country/region. RESEARCH DESIGN AND METHODS: Systematic searches were conducted in 4 databases. Peer-reviewed articles with quantitative designs published between 1990 and November 2021 were identified. A rigorous selection process was followed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The studies were critically appraised, and their results were narratively synthesized. RESULTS: Sixty-five articles from 29 countries/regions were included. Findings suggested a concave curvilinear relationship between the intensity of grandparent caregiving and their health and well-being, with the optimal caregiving intensity varying across sociocultural contexts. In Europe, Oceania, the Middle East, and South America, providing supplementary or occasional care seems beneficial for grandparents' health and well-being, especially supporting dual-earner families. In East Asia, economic resources appear to buffer the adverse effect of primary care on grandparents' well-being. In the United States, findings vary across ethnicity/race. DISCUSSION AND IMPLICATIONS: Collectively, the intensity of grandparent caregiving, health, and well-being is complicated by grandparents' roles in the family and cultural differences. Acknowledging the bidirectional relationship between well-being and grandparents' capacity for providing care, the well-being as outcome is a limitation. Despite so, this systematic review calls for culturally-tailored family programs to support grandparent caregiving.

Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway.

Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.

Oocyte Development and Quality in Young and Old Mice following Exposure to Atrazine.

BACKGROUND: Egg development has unique features that render it vulnerable to environmental perturbation. The herbicide atrazine is an endocrine disruptor shown to have detrimental effects on reproduction across several vertebrate species. OBJECTIVES: This study was designed to determine whether exposure to low levels of atrazine impairs meiosis in female mammals, using a mouse model; in particular, the study's researchers sought to determine whether and how the fidelity of oocyte chromosome segregation may be affected and whether aging-related aneuploidy is exacerbated. METHODS: Female C57BL/6J mice were exposed to two levels of atrazine in drinking water: The higher level equaled aqueous saturation, and the lower level corresponded to detected environmental contamination. To model developmental exposure, atrazine was ingested by pregnant females at 0.5 d post coitum and continued until pups were weaned at 21 d postpartum. For adult exposure, 2-month-old females ingested atrazine for 3 months. Following exposure, various indicators of oocyte development and quality were determined, including: a) chromosome synapsis and crossing over in fetal oocytes using immunofluorescence staining of prophase-I chromosome preparations; b) sizes of follicle pools in sectioned ovaries; c) efficiencies of in vitro fertilization and early embryogenesis; d) chromosome alignment and segregation in cultured oocytes; e) chromosomal errors in metaphase-I and -II (MI and MII) preparations; and f) sister-chromatid cohesion via immunofluorescence intensity of cohesin subunit REC8 on MI-chromosome preparations, and measurement of interkinetochore distances in MII preparations. RESULTS: Mice exposed to atrazine during development showed slightly higher levels of defects in chromosome synapsis, but sizes of initial follicle pools were indistinguishable from controls. However, although more eggs were ovulated, oocyte quality was lower. At the chromosome level, frequencies of spindle misalignment and numerical and structural abnormalities were greater at both meiotic divisions. In vitro fertilization was less efficient, and there were more apoptotic cells in blastocysts derived from eggs of atrazine-exposed females. Similar levels of chromosomal defects were seen in oocytes following both developmental and adult exposure regimens, suggesting quiescent primordial follicles may be a consequential target of atrazine. An important finding was that defects were observed long after exposure was terminated. Moreover, chromosomally abnormal eggs were very frequent in older mice, implying that atrazine exposure during development exacerbates effects of maternal aging on oocyte quality. Indeed, analogous to the effects of maternal age, weaker cohesion between sister chromatids was observed in oocytes from atrazine-exposed animals. CONCLUSION: Low-level atrazine exposure caused persistent changes to the female mammalian germline in mice, with potential consequences for reproductive lifespan and congenital disease. https://doi.org/10.1289/EHP11343.

Dicarbonyl/L-xylulose reductase (DCXR) producing xylitol regulates egg retention through osmolality control in Caenorhabditis elegans.

To support life, the osmolality of the cellular fluid is tightly regulated by various means, including osmolyte control. Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved enzyme reducing L-xylulose to xylitol, which serves as an effective osmolyte in various mammalian and human tissues such as lung epithelium, sperm, and lens. DHS-21 is the only DCXR ortholog in Caenorhabditis elegans, and DCXR null mutant worms accumulate eggs in the uterus. However, it has been unknown how and why the mutant worms impair egg retention. In this study, we tested whether the egg-retention in dhs-21 (jh129), the DCXR null mutant worm, is sensitive to changes in osmolarity. Low osmolality reverted the egg retention phenotype of dhs-21(jh129), while high osmolarity aggravated it. Also, knock-down of either one of osr-1, osm-7, or osm-11, osmoregulatory genes, also rescued egg-retention phenotypes of the null mutants. The study indicates that DCXR functions in fluid homeostasis by regulating cellular osmolality in C. elegans and provides insights into DCXR-involved clinical conditions, such as congenital cataracts and malfunctioning lung and kidney.

Effectiveness of GenerationPMTO to Promote Parenting and Child Adjustment: A Meta-Analytic Review.

GenerationPMTO is a theory- and evidence-based behavioral parenting program widely implemented in the past three decades. This systematic review and meta-analysis examined the effectiveness of twenty GenerationPMTO studies on parenting and child adjustment among 3893 families in six countries. Hedges' g from studies with pretest-posttest-controlled designs were computed and robust variance estimation (RVE) was used to deal with the effect size dependency. Results showed that GenerationPMTO significantly promoted parenting and child adjustment with moderate to high levels of heterogeneity. Specifically, GenerationPMTO improved parental discipline, parenting monitoring, skill encouragement, child externalizing problems, and child internalizing problems. Subgroup analyses revealed several important moderators, including type of comparison group, measurement, informant, risk of bias, etc. Intervention effects were quite robust across countries and multiple demographic characteristics. No publication bias across studies for parenting and child adjustment was detected. The revised Cochrane risk of bias for randomized trials (RoB 2) procedure was used to assess risk of bias within the included studies. Some studies showed a higher level of risk due to problems with the randomization process, missing data, low measurement quality, and reporting bias. Due to lack of data, we did not examine intervention effects on parental mental health or couple relationship quality. Future studies should test mediation models to understand the mechanisms of change and to identify moderators in order to understand the high levels of heterogeneity in GenerationPMTO studies.

Discovery of GSK3ß Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation.

Direct inhibitors of glycogen synthase kinase 3ß (GSK3ß) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3ß enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3ß enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.