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BackgroundDiabetes is a serious public health concern worldwide. Despite public health efforts encouraging early screening and improving knowledge of effective interventions for those at increased risk of type 2 diabetes (T2D), the incorporation of preventative behaviors into an individual’s daily life remains suboptimal. Successfully and accurately increasing risk perception has been demonstrated to increase behavioral intention. ObjectiveThe study aims to codesign a T2D risk communication tool by engaging public participants to (1) identify key characteristics that contribute to an effective risk communication tool and (2) test and iterate to develop a culturally sensitive and meaningful risk communication tool that can motivate T2D preventative behaviors. MethodsWe adopted a novel methodology, “Patient and Public Involvement (PPI) Hawkers,” where we approached patrons at hawker centers and public eateries frequented by all local residents to evaluate and test 3 prototypes for the tool. The three prototypes were (1) “Diabetes Onset”—estimated age of diabetes onset of T2D based on one’s risk factors, (2) “Relative Risk”—the relative risk of T2D is presented in a 1-10 scale indicating where one’s risk score lie in relation to others, and (3) “Metabolic Age”—the median age of the risk category based on one’s risk factors, presented to be compared against their chronological age. We gathered reactions and feedback through rapid testing and iteration to understand which risk result presentation would be received the best. All the collected data were revisited and analyzed using an inductive thematic analysis to identify the key characteristics contributing to an effective risk communication tool. ResultsWe engaged with 112 participants (female: n=59, 56%) across 6 hawker centers. The key characteristics that were important to participants emerged in four main themes: (1) appeal and user experience, in terms of format and readability; (2) trust and validity of the institution providing the tool and the accuracy of the risk result; (3) threat appraisal: salience of risk information, which influenced their risk perception; and (4) coping appraisal: facilitators for behavior change, which impacted their intention for implementing T2D preventative behaviors. The predictive nature of the prototype entitled “Diabetes Onset” was poorly received and removed after the first iteration. The Relative Risk prototype was valued for being straightforward but feared to be boring. The Metabolic Age prototype was anticipated to be more motivating for behavior change, but there were some concerns that the terminology may not be understood by everyone. ConclusionsParticipants were divided on which of the 2 prototypes, “Metabolic Age” or “Relative Risk,” they would favor adopting. Further testing is now required to determine which prototype will be more effective in motivating behavior change. This study’s insights on the design process and valued characteristics of a risk communication tool will inform future development of such interventions.

Glioma is a common primary malignant brain tumor with low survival rate. Immunotherapy with immune checkpoints inhibitors (ICI) can be a choice for glioma management, and extracellular vesicles (EVs) are recognized as a potential drug delivery system for various disease management due to their enhanced barrier permeation ability and immunomodulatory effect. The aim of this study is to develop ICI-loaded EVs (ICI/EV) that have sufficient efficacy in managing glioma. Calcium phosphate particles (CaP) were used to stimulate the secretion of EVs from murine macrophage cells. CaP conditioning of cells showed an enhanced amount of EVs secretion and macrophage polarization toward a proinflammatory phenotype. The CaP-induced EVs were shown to polarize macrophages into proinflammatory phenotype in vitro, as correlated with the conditioning method. ICI/EVs were successfully prepared with high loading efficiency using the sonication method. The EVs can be distributed throughout the entire brain upon intranasal administration and facilitate ICIs distribution into glioma lesion. Combinatory treatment with ICI/EVs showed benefit in glioma-bearing mice by reducing their tumor volume and prolonging their survival. Cytotoxic T cell infiltration, polarization of tumor-associated macrophage, and lower tumor proliferation were observed in ICI/EVs-treated mice. The developed ICI/EVs showed promise in immunotherapeutic management of glioma.

Background: The clinical presentations of abusive head trauma can abruptly worsen, so the occurrence of seizures and changes of EEG can be variable according to patients’ conditions. Since the changes of EEG background waves reflect the cortical function of children, we aimed to find out whether the timing of EEG background, epileptiform discharges and seizure patterns were associated with the outcomes of patients with AHT. Material and methods: Using seizure type and acute stage electroencephalographic (EEG) characteristics to assess adverse neurological outcomes in children with seizures secondary to abusive head trauma (AHT). Children who were hospitalized with AHT at a tertiary referral hospital from October 2000 to April 2010 were evaluated retrospectively. A total of 50 children below 6 years of age admitted due to AHT were included. KOSCHI outcome scale was used to evaluate the primary outcome and neurological impairment was used as secondary outcome after 6 months discharge. Results: Children with apnea, cardiac arrest, reverse blood flow and skull fracture in clinic had a higher mortality rate even in the no-seizure group (3/5 [60%] vs. 3/45 [6.7%], odds ratio [OR] = 11; 95% CI = 2.3–52; p = 0.025). Seizure occurrence reduced mostly at the second day after admission in seizure groups; but children with persistent seizures for 1 week showed poor neurological outcomes. The occurrence of initial seizure was frequency associated with younger age; focal seizure, diffuse cortical dysfunction in acute-stage EEG, and low Glasgow Coma Scale (GCS) score were significantly related to poor outcomes after 6 months. Diffuse cortical dysfunction was also associated with motor, speech, and cognitive dysfunction. Conclusions: Diffuse cortical dysfunction in acute-stage EEG combined with low GCS score and focal seizure may related to poor outcomes and neurological dysfunctions in children with AHT.

Objective Patients with type 2 diabetes require patient-centred care as guided by the Chronic Care Model (CCM). Many diabetes patients in Singapore are managed by the Primary Care Networks (PCNs) which organised healthcare professionals (HCPs) comprising general practitioners, nurses and care coordinators into teams to provide diabetes care. Little is known about how the PCNs deliver care to people with type 2 diabetes. This study evaluated the consistency of diabetes care delivery in the PCNs with the CCM.Design This was a mixed-method study. The Assessment of Chronic Illness Care (ACIC version 3.5) survey was self-administered by the HCPs in the quantitative study (ACIC scores range 0–11, the latter indicating care delivery most consistent with CCM). Descriptive statistics were obtained, and linear mixed-effects regression model was used to test for association between independent variables and ACIC total scores. The qualitative study comprised semi-structured focus group discussions and used thematic analysis.Setting The study was conducted on virtual platforms involving the PCNs.Participants 179 HCPs for quantitative study and 65 HCPs for qualitative study.Results Integrated analysis of quantitative and qualitative results found that there was support for diabetes care consistent with the CCM in the PCNs. The mean ACIC total score was 5.62 (SD 1.93). The mean element scores ranged from 6.69 (SD 2.18) (Health System Organisation) to 4.91 (SD 2.37) (Community Linkages). The qualitative themes described how the PCNs provided much needed diabetes services, their characteristics such as continuity of care, patient-centred care; collaborating with community partners, financial aspects of care, enablers for and challenges in performing care, and areas for enhancement.Conclusion This mixed-methods study informs that diabetes care delivery in the Singapore PCNs is consistent with the CCM. Future research should consider using independent observers in the quantitative study and collecting objective data such as patient outcomes.

Abstract Background Type 2 diabetes (T2D) remains an important chronic condition worldwide requiring integrated patient-centred care as advocated by the Chronic Care Model (CCM). The Primary Care Networks (PCNs) in Singapore organise general practitioners (GPs) with nurses and care coordinators to deliver team-based care for patients with chronic conditions. This study examined the quality of care in the PCNs as defined by the CCM from the patients’ perspective. Methods This study followed a cross-sectional convergent mixed-method design with T2D patients across three PCN types (GP-led, Group, and Cluster). The Patient Assessment of Chronic Illness Care (PACIC, range 1-5) was completed by a convenience sample of 343 patients. Multivariate linear regression was performed to estimate the associations between patient and service characteristics and PACIC summary score. Twenty-four participants were purposively recruited for interviews on the experienced care until thematic saturation was reached. Quantitative and qualitative data were collected concurrently and independently. Integration occurred during study design and data analysis using the CCM as guidance. Quantitative and qualitative results were compared side-by-side in a joint comparison table to develop key concepts supported by themes, subthemes, and patients’ quotes. Results The PACIC mean summary score of 3.21 for 343 patients evidenced that some have received CCM consistent care in the PCNs. Being younger and spending more time with the GP were associated with higher PACIC summary scores. PACIC summary scores did not differ across PCN types. The 24 patients interviewed in the qualitative study reported receiving team-based care, nurse services, good continuity of care, as well as patient-centred care, convenient access, and affordable care. Key concepts showed that integrated care consistent with the CCM was sometimes received by patients in the PCNs. Patient activation, delivery system design/decision support, goal setting/tailoring, and problem-solving/contextual counselling were sometimes received by patients, while follow-up/coordination was generally not received. Conclusions Patients with T2D from the Singapore Primary Care Networks received integrated care consistent with the Chronic Care Model, particularly in patient activation, delivery system design/decision support, goal setting/tailoring, and problem-solving/contextual counselling. Follow-up/coordination needed improvement to ensure higher quality of diabetes care.

Introduction Relationships between secondhand smoke exposure (SHSE) in various temporal and physical settings are not fully studied despite its adverse impacts on human health, especially in multi-ethnic Asian populations. We investigated associations of childhood and current SHSE at home (SHSE home ) with current SHSE at work (SHSE work ) in Singapore and its relation to sources of daily smokers at home. Methods This cross-sectional study identified 925 healthy, never smoker working adults from the Singapore Multi-Ethnic Cohort (2004–2010). Firstly, the multiple logistic regression model estimated the adjusted odds ratios (AORs) of SHSE home . Subsequently, sources of daily smokers entered through an additional model building process using the former as a base. Results Current adults (AOR=2.05; 95% CI: 1.28–3.29) and childhood SHSE home (AOR=1.43; 95% CI: 0.93–2.19) had a positive and no association with current SHSE work , respectively. These findings persisted when smoker identity-related variables entered the model: child (AOR=3.56; 95% CI: 1.19–10.64) for current daily smokers; father (AOR=2.30; 95% CI: 0.94–5.64) and sibling (AOR=2.97; 95% CI: 1.55–5.68) for childhood. Compared to no childhood SHSE home , only those living with their fathers and siblings who smoked daily at home had significantly higher odds of reporting current SHSE work (AOR=3.70; 95% CI: 1.88–7.30). Conclusions Current SHSE home was a risk factor for current SHSE work , with risks elevated among those who smoke daily at home and living with their children. Childhood SHSE home becomes a risk factor when daily household smokers include fathers and siblings. Deformalizing smoking could consider interpersonal dynamics of daily smokers at home with family members in different temporal settings, to reduce SHSE work .

The emergence of endometriosis-associated clear cell carcinoma (CCC) within the abdominal wall is a notably rare phenomenon. This condition predominantly impacts females who have previously undergone surgical interventions, including hysterectomy or caesarean section (C-section), with the malignant transformation of endometriosis within the post-surgical abdominal scar posited as a likely mechanism. Herein, we delineate a distinctive case of endometriosis-associated CCC emanating from the abdominal wall. The therapeutic approach for the patient encompassed surgical resection, complemented by a regimen of adjuvant chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Despite these measures, the patient experienced disease progression, manifested by bilateral inguinal lymph node involvement and metastasis to the left femoral bone. Advanced molecular diagnostics, specifically next-generation sequencing (NGS) of the resected specimen, identified a targetable PIK3CA E726K mutation. Subsequent treatment with alpelisib and everolimus was initiated, culminating in a sustained complete response.

Abstract Anthocyanin (ACN) fortification of commonly consumed foods is significant as a dietary strategy against the development of metabolic complications by delivering ACNs at high doses. However, its bioactivity and translated metabolic effects in the presence of varying food matrices and macro-constituents is particularly unclear. This end-to-end study investigates the metabolic effects of black rice ACN extract (BRAE) fortification—from in-vitro enzyme inhibitory activities and digestibility, to downstream in vivo impacts on GI, postprandial glycemia and lipidemia. The in vivo effects were investigated in two separate crossover randomised controlled trials (RCT) of 24 healthy participants each—the first RCT determined the postprandial blood glucose, insulin, and ACN bioavailability to a starch-rich single food over 2 h, while the second RCT determined the postprandial blood glucose, insulin, lipid panel, and lipoprotein particles and subfractions to a starch- and fat-rich composite meal over 4 h. In-vitro findings confirmed the inhibitory activities of major black rice ACNs on carbohydrases (p = 0.0004), lipases (p = 0.0002), and starch digestibility (p

Abstract Growth mindsets and self-efficacy beliefs have been known to predict and promote resilience, challenge seeking, and improved outcomes in areas such as education and intelligence. However, little is known about the role of these two potentially influential beliefs in the context of type 2 diabetes (T2D), specifically in terms of whether and in which domains (i.e., beliefs toward general life, general health, or condition-specific domains) these beliefs—or lack thereof—is prevalent among individuals with T2D. Given the lifelong challenges that individuals with diabetes often encounter with managing their disease, many may slip into a conceding negative belief that their diabetes is “too difficult to control” or simply “out of their hands,” inhibiting proactive self-management efforts. Results from our study (n = 893) revealed that individuals with T2D had a significantly lower growth mindset towards their blood glucose level and lower self-efficacy towards their general health, blood glucose, and cholesterol levels compared to those without T2D. Among participants with T2D, further analyses showed a pattern of higher HbA1c among those with lower growth mindsets and self-efficacy toward their general health or blood glucose level. These findings identify the belief-domains that may pose barriers to necessary self-care behaviors, informing future interventions to promote improved diabetes care and management.

Abstract Background Two polyclinics in Singapore modified systems and trained health professionals to provide person-centred Care and Support Planning (CSP) for people with diabetes within a clinical trial. We aimed to investigate health professionals’ perspectives on CSP to inform future developments. Methods Qualitative research including 23 semi-structured interviews with 13 health professionals and 3 co-ordinators. Interpretive analysis, including considerations of how different understandings, enactments, experiences and evaluative judgements of CSP clustered across health professionals, and potential causal links between them. Results Both polyclinic teams introduced CSP and sustained it through COVID-19 disruptions. The first examples health professionals gave of CSP ‘going well’ all involved patients who came prepared, motivated and able to modify behaviours to improve their biomedical markers, but health professionals also said that they only occasionally saw such patients in practice. Health professionals’ accounts of how they conducted CSP conversations varied: some interpretations and reported enactments were less clearly aligned with the developers’ person-centred aspirations than others. Health professionals brought different communication skill repertoires to their encounters and responded variably to challenges to CSP that arose from: the linguistic and educational diversity of patients in this polyclinic context; the cultural shift that CSP involved; workload pressures; organisational factors that limited relational and informational continuity of care; and policies promoting biomedical measures as key indicators of healthcare quality. While all participants saw potential in CSP, they differed in the extent to which they recognised relational and experiential benefits of CSP (beyond biomedical benefits), and their recommendations for continuing its use beyond the clinical trial were contingent on several considerations. Our analysis shows how narrower and broader interpretive emphases and initial skill repertoires can interact with situational challenges and respectively constrain or extend health professionals’ ability to refine their skills with experiential learning, reduce or enhance the potential benefits of CSP, and erode or strengthen motivation to use CSP. Conclusion Health professionals’ interpretations of CSP, along with their communication skills, interact in complex ways with other features of healthcare systems and diverse patient-circumstance scenarios. They warrant careful attention in efforts to implement and evaluate person-centred support for people with long-term conditions.

Abstract Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

Abstract The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

BackgroundGlycine is an integral component of the human detoxification system as it reacts with potentially toxic exogenous and endogenously produced compounds and metabolites via the glycine conjugation pathway for urinary excretion. Because individuals with obesity have reduced glycine availability, this detoxification pathway may be compromised. However, it should be restored after bariatric surgery because of increased glycine production.ObjectiveTo examine the impact of obesity-associated glycine deficiency on the glycine conjugation pathway. We hypothesize that the synthesis rates of acylglycines from endogenous and exogenous sources are significantly reduced in individuals with obesity but increase after bariatric surgery.MethodsWe recruited 21 participants with class III obesity and 21 with healthy weight as controls. At baseline, [1,2-13C2] glycine was infused to study the glycine conjugation pathway by quantifying the synthesis rates of several acylglycines. The same measurements were repeated in participants with obesity six months after bariatric surgery. Data are presented as mean ± standard deviation, and p-value< 0.05 is considered statistically significant.ResultsBaseline data of 20 participants with obesity were first compared to controls. Participants with obesity were significantly heavier than controls (mean BMI 40.5 ± 7.1 vs. 20.8 ± 2.1 kg/m2). They had significantly lower plasma glycine concentration (168 ± 30 vs. 209 ± 50 μmol/L) and slower absolute synthesis rates of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Pre- and post-surgery data were available for 16 participants with obesity. Post-surgery BMI decreased from 40.9 ± 7.3 to 31.6 ± 6.0 kg/m2. Plasma glycine concentration increased from 164 ± 26 to 212 ± 38 μmol/L) and was associated with significantly higher rates of excretion of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Benzoic acid (a xenobiotic dicarboxylic acid) is excreted as benzoylglycine; its synthesis rate was significantly slower in participants with obesity but increased after bariatric surgery.ConclusionObesity-associated glycine deficiency impairs the human body’s ability to eliminate endogenous and exogenous metabolites/compounds via the glycine conjugation pathway. This impairment is ameliorated when glycine supply is restored after bariatric surgery. These findings imply that dietary glycine supplementation could treat obesity-associated metabolic complications due to the accumulation of intramitochondrial toxic metabolites.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04660513, identifier NCT04660513.

Background: Personalised care and support planning (CSP) is a person-centred approach for the care of people living with long-term conditions. Patient Activation through Community Empowerment/Engagement for Diabetes Management (PACE-D) adapts the Year of Care Partnerships (YOCP) approach to CSP in the UK for people living with diabetes at Singapore polyclinics. Polyclinics are multi-storey primary care hubs that provide affordable, multidisciplinary, comprehensive, and high-throughput public health care for the multi-ethnic, multilingual Singapore population. Aim: To explore the experience of PACE-D-enrolled people living with diabetes with personalised CSP at Singapore polyclinics. Design & setting: Qualitative interviews of people living with diabetes who experienced personalised CSP at National University Polyclinics (NUP) in Singapore between July 2020 and November 2021. Method: PACE-D-enrolled people living with diabetes who experienced personalised CSP were purposively sampled. In-depth semi-structured interviews were recorded, transcribed, and analysed using Braun and Clarke’s reflexive thematic analysis. Results: Fifty-two patients participated in the study. Four main themes were identified. Theme 1 was the importance of the care-planning letter. Patients reported that the CPL prompted reflection and patient preparation for CSP conversations. Theme 2 was the role of the programme coordinator. PACE-D programme coordinators amplified self-management by playing advocate and confidant beyond administrative duties. Theme 3 was the value of the personalised CSP conversation. CSP providers were perceived as partners in care, with more time to listen compared with usual consultations. Patient engagement was affected by language confidence. Theme 4 was agency in self-management. With adequate time and support, patients increased in confidence and agency both in CSP engagement and diabetes self-management. Conclusion: While language confidence may affect patient engagement, personalised CSP shows promise for strengthening patient engagement and self-management among people living with diabetes at Singapore polyclinics.

Inhibition of acetylcholinesterase (AChE) by certain organophosphates (OPs) can be life-threatening and requires reactivating antidote accessibility to the peripheral and central nervous systems to reverse symptoms and enhance survival parameters. In considering dosing requirements for oxime antidotes in OP exposures that inactivate AChE, clearance of proton ionizable, zwitterionic antidotes is rapid and proceeds with largely the parent antidotal compound being cleared by renal transporters. Such transporters may also control disposition between target tissues and plasma as well as overall elimination from the body. An ideal small-molecule antidote should access and be retained in primary target tissues-central nervous system (brain), skeletal muscle, and peripheral autonomic sites-for sufficient periods to reactivate AChE and prevent acute toxicity. We show here that we can markedly prolong the antidotal activity of zwitterionic antidotes by inhibiting P-glycoprotein (P-gp) transporters in the brain capillary and renal systems. We employ the P-gp inhibitor tariquidar as a reference compound and show that tissue and plasma levels of RS194B, a hydroxyl-imino acetamido alkylamine reactivator, are elevated and that plasma clearances are reduced. To examine the mechanism, identify the transporter, and establish the actions of a transport inhibitor, we compare the pharmacokinetic parameters in a P-glycoprotein knockout mouse strain and see dramatic enhancements of short-term plasma and tissue levels. Hence, repurposed transport inhibitors that are candidate or Food and Drug Administration-approved drugs, should enhance target tissue concentrations of the zwitterionic antidote through inhibition of both renal elimination and brain capillary extrusion. SIGNIFICANCE STATEMENT: We examine renal and brain capillary transporter inhibition as means for lowering dose and frequency of dosing of a blood-brain barrier permanent reactivating antidote, RS194B, an ionizable zwitterion. Through a small molecule, tariquidar, and gene knockout mice, CNS antidote concentrations are enhanced, and total body clearances are concomitantly diminished. RS194B with repurposed transport inhibitors should enhance reactivation of central and peripheral OP-inhibited acetylcholinesterase. Activities at both disposition sites are a desired features for replacing the antidote, pralidoxime, for acute OP exposure.

Glycine is deficient in individuals with obesity but improves following bariatric surgery. Glycine deficiency could impair glutathione (GSH) synthesis and worsen oxidative stress. We examined the impact of obesity-associated glycine deficiency and bariatric surgery on GSH synthesis. Twenty-one participants with severe obesity and twenty-one healthy weight controls were recruited. [1,2-13C2] glycine was infused to measure the erythrocyte (RBC) GSH synthesis rate. Participants with obesity underwent bariatric surgery, and 19 were restudied six months post-surgery. Compared to healthy weight controls, individuals with obesity had significantly lower concentrations of RBC GSH (2.43 ± 0.23 vs. 2.63 ± 0.26 mmol/L, p < 0.01). However, there were no differences in GSH fractional synthesis rate [78.0 (51.4–123.7) vs. 76.9 (49.3–110.1) % pool/day, p = 0.58] or absolute synthesis rate [1.85 (1.25–3.32) vs. 1.92 (1.43–3.03) mmol/L RBC/day, p = 0.97]. Despite a post-surgery increase in glycine concentration, no statistically significant changes in RBC GSH concentration or synthesis rates were detected. Further, the significant correlation between plasma glycine and RBC GSH concentration at baseline (r = 0.46, p < 0.01) was also lost following bariatric surgery. GSH concentration was significantly lower in participants with obesity, but bariatric surgery did not significantly increase GSH concentrations or synthesis rates.

Herlyn–Werner–Wunderlich (HWW) syndrome is characterized by obstructed hemivagina and ipsilateral renal anomaly, a rare congenital anomaly of the genitourinary tract, resulting from malformations of the renal tract associated with Müllerian duct anomalies. The initial symptoms of HWW frequently present after menarche and may be nonspecific, leading to a delayed diagnosis. We presented a 19-year-old female with 3-year hematuria and abdominal pain. The final diagnosis of HWW syndrome with a rare vesicovaginal fistula was made. The treatment of HWW syndrome typically involves surgical intervention. The primary treatment is resection or removal of the obstructed vaginal septum. The patient underwent excision of vaginal septum and vaginal reconstruction via hysteroscopy, as well as repair of the vesicovaginal fistula. The patient improved well after surgery and fully recovered without sequelae after 3 months. In addition, unilateral renal agenesis is one of congenital abnormalities of the kidney and urinary tract, which are the most frequent cause of chronic kidney disease (CKD) in children. This report describes a patient of HWW syndrome with rarely combined vesicovaginal fistula, and highlights the importance of early recognition and management to prevent associated complications.

IntroductionPrimary biliary cholangitis (PBC) is a rare and chronic autoimmune liver disease characterized by the progressive destruction of small intrahepatic bile ducts that may eventually lead to cirrhosis. PBC with features of autoimmune hepatitis (AIH) has rarely been reported in pediatric patients with genetic defects. We present the case of an adolescent with chromosome 14q24.1q24.2 deletion who was given the diagnosis of stage IV PBC with features of AIH.Case presentationA 19-year-old male adolescent with multiple congenital abnormalities and an intellectual disability presented with abnormal liver enzymes levels and pruritus for more than 5 years. Laboratory examinations revealed elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase. After the exclusion of viral hepatitis, alpha-1 antitrypsin deficiency, Wilson's disease, and other genetic cholestatic liver diseases by laboratory tests and whole exome sequencing, a liver biopsy was performed and stage IV PBC was diagnosed. Notably, features of AIH were also noted in the histopathological report, indicating the presence of PBC with AIH features. The patient responded well to a combination therapy of ursodeoxycholic acid and steroids. Array comparative genomic hybridization analysis performed to study the congenital abnormalities revealed a 3.89 Mb 14q24.1q24.2 deletion.ConclusionPBC with AIH features has rarely been reported in an adolescent with a chromosomal abnormality. The present case can increase awareness for early-onset PBC and its possible correlation with chromosomal defects.

Abstract Purpose Our objective was to assess the adverse outcomes during pregnancy, as well as for the fetus and neonates, in women with epilepsy, both with and without the use of antiseizure medications (ASMs). Methods A cohort of singleton pregnancies between January 1, 2004 and December 31, 2014 was identified using the Taiwan National Health Database. The pregnancies were categorized into ASM exposure, ASM nonexposure, and control (consisting of women without an epilepsy diagnosis) groups. We recorded adverse outcomes in neonates and documented pregnancy complications. The generalized estimating equation with logit link was used to estimate adjusted odds ratios. Results There were 629 singleton pregnancies in the group exposed to ASMs, 771 in the epilepsy group without ASM exposure, and 2,004,479 in the control group. Women with epilepsy had a significantly higher risk of puerperal cerebrovascular diseases (adjusted odds ratios in the exposure and nonexposure groups = 54.46 and 20.37, respectively), respiratory distress syndrome (5.1 and 2.99), mortality (3.15 and 3.22), sepsis (2.67 and 2.54), pregnancy‐related hypertension (1.71 and 1.8), preeclampsia (1.87 and 1.79), cesarean delivery (1.72 and 2.15), and preterm labor (1.38 and 1.56). The use of ASMs may increase the risk of eclampsia (adjusted odds ratio = 12.27). Compared to controls, fetuses/neonates born to women with epilepsy had a higher risk of unexplained stillbirth (adjusted odds ratios in the exposure and nonexposure groups = 2.51 and 2.37, respectively), congenital anomaly (1.37 and 1.33), central nervous system malformation (3.57 and 2.25), low birth weight (1.90 and 1.97), and a low Apgar score at 5 min (2.63 and 1.3). The use of ASMs may introduce an additional risk of small for gestational age; the adjusted odds ratio was 1.51. Conclusion Women with epilepsy, irrespective of their exposure to ASMs, had a slightly elevated risk of pregnancy and perinatal complications. Puerperal cerebrovascular diseases may be a hidden risk for women with epilepsy.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value

Abstract Renal defects in maturity onset diabetes of the young 3 (MODY3) patients and Hnf1a -/- mice suggest an involvement of HNF1A in kidney development and/or its function. Although numerous studies have leveraged on Hnf1α -/- mice to infer some transcriptional targets and function of HNF1A in mouse kidneys, species-specific differences obviate a straightforward extrapolation of findings to the human kidney. Additionally, genome-wide targets of HNF1A in human kidney cells have yet to be identified. Here, we leveraged on human in vitro kidney cell models to characterize the expression profile of HNF1A during renal differentiation and in adult kidney cells. We found HNF1A to be increasingly expressed during renal differentiation, with peak expression on day 28 in the proximal tubule cells. HNF1A ChIP-Sequencing (ChIP-Seq) performed on human pluripotent stem cell (hPSC)-derived kidney organoids identified its genome-wide putative targets. Together with a qPCR screen, we found HNF1A to activate the expression of SLC51B, CD24, and RNF186 genes. Importantly, HNF1A-depleted human renal proximal tubule epithelial cells (RPTECs) and MODY3 human induced pluripotent stem cell (hiPSC)-derived kidney organoids expressed lower levels of SLC51B. SLC51B-mediated estrone sulfate (E1S) uptake in proximal tubule cells was abrogated in these HNF1A-deficient cells. MODY3 patients also exhibit significantly higher excretion of urinary E1S. Overall, we report that SLC51B is a target of HNF1A responsible for E1S uptake in human proximal tubule cells. As E1S serves as the main storage form of nephroprotective estradiol in the human body, lowered E1S uptake and increased E1S excretion may reduce the availability of nephroprotective estradiol in the kidneys, contributing to the development of renal disease in MODY3 patients.

Background: Whether or not patients with stage I epithelial ovarian cancer (EOC) benefit from postoperative chemotherapy in the Asian population remains unclear. This retrospective cohort study was aimed at investigating the use of adjuvant chemotherapy in clinical practice to treat patients with early-stage EOC considering clinical factors. Materials and Methods: A total of 414 patients with the International Federation of Gynecology and Obstetrics (FIGO) stage IA–IC and grade 1 EOC were enrolled from the Taiwan Cancer Registry. We used multivariable Cox proportional-hazards models to control for clinical factors. The overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan–Meier method. Results: DFS did not improve significantly for patients with FIGO stage IA/IB EOC receiving adjuvant chemotherapy, with a 10-year DFS rate of 98% and 88% for those with and without adjuvant chemotherapy, respectively (hazard ratio [HR] = 0.41, 95% confidence interval [CI]: 0.05–3.36). OS did not improve significantly for patients with FIGO stage IA/IB EOC with adjuvant chemotherapy (HR = 0.86, 95% CI: 0.18–4.22) or stage IC (HR = 0.50, 95% CI: 0.10–2.45). OS did not differ significantly for patients with optimal (10-year OS: 92% with chemotherapy and 86% without chemotherapy in the log-rank test, P = 0.629) or nonoptimal staging (10-year OS: 73% with chemotherapy and 90% without chemotherapy in the log-rank test, P = 0.959). Conclusion: Adjuvant chemotherapy did not improve the prognosis of patients with low to intermediate-risk EOC and optimal/nonoptimal surgery. This result should be considered in clinical practice.

The application of the Internet of Things has been greatly expanded; meanwhile, real-time and efficient communication has become an important feature of the Internet of Things. However, the centralized characteristics of cloud computing cannot meet the needs of low latency and high computing efficiency. To solve these issues, we utilized fog computing which is a new distributed computing paradigm that extends cloud services to the edge of the network, with mobility and low latency. Nevertheless, fog computing also brings new security issues, especially identity authentication. Authentication and key exchange are significant challenges that need to be taken into consideration in fog computing. Therefore, in this research, we proposed the architecture of the mutual authentication key establishment scheme based on elliptic curve cryptography for fog computing. After mutual authentication, the cloud server can transfer the remaining verification work to fog nodes, and fog nodes will be responsible for authenticating the device and distributing the established session key, thereby reducing the computational cost of the cloud server. Moreover, to evaluate the security of the proposed scheme, we not only used the random oracle model and the extended Canetti-Krawczyk (eCK) threat model to conduct a detailed analysis, but also proved that the security of the proposed scheme is strong enough against several attacks.

This review provides a thorough overview of contemporary treatment strategies for complex renal calculi, including large-volume stones, stones with increased hardness and greater number, or stones with abnormal anatomy. The development of tailored treatment plans for stone removal is essential for treatment success. A literature search was conducted on PubMed using the Keyword “complex renal calculi” along with “percutaneous nephrolithotomy (PCNL),” “retrograde intrarenal surgery (RIRS),” “endoscopic combined intrarenal surgery (ECIRS),” “stone free rate,” and “complications.” Based on the findings, the use of “minimally invasive PCNL,” “multiple-tract PCNL,” “staged RIRS,” and “ECIRS” is proposed in addition to the traditional PCNL suggested using the European Association of Urology guidelines. Renal calculi in patients with solitary kidneys or who underwent kidney transplants are considered to be complex, and treatment options that allow preservation of their remaining renal function should be considered.