Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demon-strated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel anti-angiogenic therapy for endometriosis.

Purpose: This study aimed to compare cognitive, non-cognitive, and overall learning outcomes for sepsis and trauma resuscitation skills in novices with virtual patient simulation (VPS) versus in-person simulation (IPS). Methods: A randomized controlled trial was conducted on junior doctors in 1 emergency department from January to December 2022, comparing 70 minutes of VPS (n=19) versus IPS (n=21) in sepsis and trauma resuscitation. Using the nominal group technique, we created skills assessment checklists and determined Bloom’s taxonomy domains for each checklist item. Two blinded raters observed participants leading 1 sepsis and 1 trauma resuscitation simulation. Satisfaction was measured using the Student Satisfaction with Learning Scale (SSLS). The SSLS and checklist scores were analyzed using the Wilcoxon rank sum test and 2-tailed t-test respectively. Results: For sepsis, there was no significant difference between VPS and IPS in overall scores (2.0; 95% confidence interval [CI], -1.4 to 5.4; Cohen’s d=0.38), as well as in items that were cognitive (1.1; 95% CI, -1.5 to 3.7) and not only cognitive (0.9; 95% CI, -0.4 to 2.2). Likewise, for trauma, there was no significant difference in overall scores (-0.9; 95% CI, -4.1 to 2.3; Cohen’s d=0.19), as well as in items that were cognitive (-0.3; 95% CI, -2.8 to 2.1) and not only cognitive (-0.6; 95% CI, -2.4 to 1.3). The median SSLS scores were lower with VPS than with IPS (-3.0; 95% CI, -1.0 to -5.0). Conclusion For novices, there were no major differences in overall and non-cognitive learning outcomes for sepsis and trauma resuscitation between VPS and IPS. Learners were more satisfied with IPS than with VPS (clinicaltrials.gov identifier: NCT05201950).

Purpose: This study aimed to compare cognitive, non-cognitive, and overall learning outcomes for sepsis and trauma resuscitation skills in novices with virtual patient simulation (VPS) versus in-person simulation (IPS). Methods: A randomized controlled trial was conducted on junior doctors in 1 emergency department from January to December 2022, comparing 70 minutes of VPS (n=19) versus IPS (n=21) in sepsis and trauma resuscitation. Using the nominal group technique, we created skills assessment checklists and determined Bloom’s taxonomy domains for each checklist item. Two blinded raters observed participants leading 1 sepsis and 1 trauma resuscitation simulation. Satisfaction was measured using the Student Satisfaction with Learning Scale (SSLS). The SSLS and checklist scores were analyzed using the Wilcoxon rank sum test and 2-tailed t-test respectively. Results: For sepsis, there was no significant difference between VPS and IPS in overall scores (2.0; 95% confidence interval [CI], -1.4 to 5.4; Cohen’s d=0.38), as well as in items that were cognitive (1.1; 95% CI, -1.5 to 3.7) and not only cognitive (0.9; 95% CI, -0.4 to 2.2). Likewise, for trauma, there was no significant difference in overall scores (-0.9; 95% CI, -4.1 to 2.3; Cohen’s d=0.19), as well as in items that were cognitive (-0.3; 95% CI, -2.8 to 2.1) and not only cognitive (-0.6; 95% CI, -2.4 to 1.3). The median SSLS scores were lower with VPS than with IPS (-3.0; 95% CI, -1.0 to -5.0). Conclusion For novices, there were no major differences in overall and non-cognitive learning outcomes for sepsis and trauma resuscitation between VPS and IPS. Learners were more satisfied with IPS than with VPS (clinicaltrials.gov identifier: NCT05201950).

Purpose: This study aimed to compare cognitive, non-cognitive, and overall learning outcomes for sepsis and trauma resuscitation skills in novices with virtual patient simulation (VPS) versus in-person simulation (IPS). Methods: A randomized controlled trial was conducted on junior doctors in 1 emergency department from January to December 2022, comparing 70 minutes of VPS (n=19) versus IPS (n=21) in sepsis and trauma resuscitation. Using the nominal group technique, we created skills assessment checklists and determined Bloom’s taxonomy domains for each checklist item. Two blinded raters observed participants leading 1 sepsis and 1 trauma resuscitation simulation. Satisfaction was measured using the Student Satisfaction with Learning Scale (SSLS). The SSLS and checklist scores were analyzed using the Wilcoxon rank sum test and 2-tailed t-test respectively. Results: For sepsis, there was no significant difference between VPS and IPS in overall scores (2.0; 95% confidence interval [CI], -1.4 to 5.4; Cohen’s d=0.38), as well as in items that were cognitive (1.1; 95% CI, -1.5 to 3.7) and not only cognitive (0.9; 95% CI, -0.4 to 2.2). Likewise, for trauma, there was no significant difference in overall scores (-0.9; 95% CI, -4.1 to 2.3; Cohen’s d=0.19), as well as in items that were cognitive (-0.3; 95% CI, -2.8 to 2.1) and not only cognitive (-0.6; 95% CI, -2.4 to 1.3). The median SSLS scores were lower with VPS than with IPS (-3.0; 95% CI, -1.0 to -5.0). Conclusion For novices, there were no major differences in overall and non-cognitive learning outcomes for sepsis and trauma resuscitation between VPS and IPS. Learners were more satisfied with IPS than with VPS (clinicaltrials.gov identifier: NCT05201950).

Purpose: To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. Materials and Methods: READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. Results: A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876–1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I–III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70–90), indicating good overall health on average during ADT initiation. Conclusions The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

INTRODUCTION: In Europe and North America, the majority of children with high-risk neuroblastoma survive the disease. Elsewhere, the treatment outcomes are poor. METHODS: A retrospective review of children treated for high-risk neuroblastoma in a single institution in Singapore from 2007 to 2019 was carried out. Treatment consisted of intensive chemotherapy, surgery aimed at gross total resection of residual disease after chemotherapy, consolidation with high-dose therapy followed by autologous stem cell rescue, and radiotherapy to the primary and metastatic sites followed by maintenance treatment with either cis-retinoic acid or anti-disialoganglioside monoclonal antibody therapy. Survival data were examined on certain clinical and laboratory factors. RESULTS: There were 57 children (32 male) treated for high-risk neuroblastoma. Their mean age was 3.9 (range 0.7-14.9) years. The median follow-up time was 5.5 (range 1.8-13.0) years for the surviving patients. There were 31 survivors, with 27 patients surviving in first remission, and the five-year overall survival and event-free survival rates were 52.5% and 47.4%, respectively. On log-rank testing, only the group of 17 patients who were exclusively treated at our centre had a survival advantage. Their five-year overall survival rate compared to patients whose initial chemotherapy was done elsewhere was 81.6% versus 41.1% (P = 0.011), and that of event-free survival was 69.7% versus 36.1% (P = 0.032). Published treatment results were obtained from four countries in Southeast Asia with five-year overall survival rates from 13.5% to 28.2%. CONCLUSION Intensified medical and surgical treatment for high-risk neuroblastoma proved to be effective, with superior survival rates compared to previous data from Southeast Asia.
Child ; Humans ; Male ; Infant ; Child, Preschool ; Adolescent ; Disease-Free Survival ; Neuroblastoma/pathology* ; Hematopoietic Stem Cell Transplantation/methods* ; Treatment Outcome ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Asia, Southeastern/epidemiology* ; Combined Modality Therapy