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Abstract Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Objectives With the sudden global shift to online learning modalities, this study aimed to understand the unique challenges and experiences of emergency remote teaching (ERT) in nursing education. Methods We conducted a comprehensive online international cross-sectional survey to capture the current state and firsthand experiences of ERT in the nursing discipline. Our analytical methods included a combination of traditional statistical analysis, advanced natural language processing techniques, latent Dirichlet allocation using Python, and a thorough qualitative assessment of feedback from open-ended questions. Results We received responses from 328 nursing educators from 18 different countries. The data revealed generally positive satisfaction levels, strong technological self-efficacy, and significant support from their institutions. Notably, the characteristics of professors, such as age (p = 0.02) and position (p = 0.03), influenced satisfaction levels. The ERT experience varied significantly by country, as evidenced by satisfaction (p = 0.05), delivery (p = 0.001), teacher-student interaction (p = 0.04), and willingness to use ERT in the future (p = 0.04). However, concerns were raised about the depth of content, the transition to online delivery, teacher-student interaction, and the technology gap. Conclusions Our findings can help advance nursing education. Nevertheless, collaborative efforts from all stakeholders are essential to address current challenges, achieve digital equity, and develop a standardized curriculum for nursing education.

Abstract Renin-angiotensin system inhibitors (RASi), particularly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are commonly used in the treatment of hypertension and are recommended for kidney protection. Uncertainty remains about the effectiveness of RASi being used as first-line antihypertensive therapy on eGFR maintenance compared to its alternatives, especially for those with no or early-stage chronic kidney disease (CKD). We conducted a retrospective cohort study of 19,499 individuals (mean age 64.1, 43.5% males) from primary care in Singapore with 4.5 median follow-up years. The study cohort included newly diagnosed individuals with hypertension (whose eGFR was mainly in CKD stages G1-G2) and initiated on ACEIs, ARBs, beta-blockers (BBs), calcium channel blockers (CCBs) or diuretics (Ds) as first-line antihypertensive monotherapy. We compared the estimated glomerular filtration rate (eGFR) curve before/after the drug initiation over time of patients under different drug classes and analyzed the time to declining to a more advanced stage CKD. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline confounding factors. Two key findings were observed. First, after initiating antihypertensive drugs, the eGFR almost maintained the same as the baseline in the first follow-up year, compared with dropping 3 mL/min/1.73 m2 per year before drug initiation. Second, ARBs were observed to be slightly inferior to ACEIs (HR = 1.14, 95% CI = (1.04, 1.23)) and other antihypertensive agents (HR = 1.10, 95% CI = (1.01, 1.20)) in delaying eGFR decline to a more advanced CKD stage in the study population. Our results showed that initiating antihypertensive agents can significantly maintain eGFR for those newly diagnosed patients with hypertension. However, RASi may not be superior to other antihypertensive agents in maintaining eGFR levels for non-CKD or early stages CKD patients.

Abstract Evidence on the influence of patient characteristics on HbA1c treatment response for add-on medications in patients with type 2 diabetes (T2D) is unclear. This study aims to investigate the predictors of HbA1c treatment response for three add-on medications (sulfonylureas (SU), dipeptidyl peptidase-4 (DPP-4) and sodium–glucose cotransporter-2 (SGLT-2) inhibitor) in metformin monotherapy treated patients with T2D. This retrospective cohort study was conducted using the electronic health record data from six primary care clinics in Singapore. A total of 9748 adult patients with T2D on metformin monotherapy receiving SU, DPP-4 or SGLT-2 add-on were 1:1 propensity score matched to patients receiving other add-on medications. Patient demographics, laboratory results, diabetes related complications, comedications, and treatment response at two endpoints (HbA1c reduction ≥ 1% at 6th month, HbA1c goal attainment

Background Cardiovascular disease is a leading cause of global death. Prospective population-based studies have found that changes in retinal microvasculature are associated with the development of coronary artery disease. Recently, artificial intelligence deep learning (DL) algorithms have been developed for the fully automated assessment of retinal vessel calibres.Methods In this study, we validate the association between retinal vessel calibres measured by a DL system (Singapore I Vessel Assessment) and incident myocardial infarction (MI) and assess its incremental performance in discriminating patients with and without MI when added to risk prediction models, using a large UK Biobank cohort.Results Retinal arteriolar narrowing was significantly associated with incident MI in both the age, gender and fellow calibre-adjusted (HR=1.67 (95% CI: 1.19 to 2.36)) and multivariable models (HR=1.64 (95% CI: 1.16 to 2.32)) adjusted for age, gender and other cardiovascular risk factors such as blood pressure, diabetes mellitus (DM) and cholesterol status. The area under the receiver operating characteristic curve increased from 0.738 to 0.745 (p=0.018) in the age–gender-adjusted model and from 0.782 to 0.787 (p=0.010) in the multivariable model. The continuous net reclassification improvements (NRIs) were significant in the age and gender-adjusted (NRI=21.56 (95% CI: 3.33 to 33.42)) and the multivariable models (NRI=18.35 (95% CI: 6.27 to 32.61)). In the subgroup analysis, similar associations between retinal arteriolar narrowing and incident MI were observed, particularly for men (HR=1.62 (95% CI: 1.07 to 2.46)), non-smokers (HR=1.65 (95% CI: 1.13 to 2.42)), patients without DM (HR=1.73 (95% CI: 1.19 to 2.51)) and hypertensive patients (HR=1.95 (95% CI: 1.30 to 2.93)) in the multivariable models.Conclusion Our results support DL-based retinal vessel measurements as markers of incident MI in a predominantly Caucasian population.

This research examined the relationship between social network site (SNS) intensity, SNS addiction, and the severity of obsessive-compulsive disorder (OCD), alongside its factors of obsession and compulsion. The overlap of SNS intensity and SNS addiction was controlled in the study to predict the measured severity of OCD. In this study, 204 Malaysian undergraduate students were recruited to complete the revised Facebook Intensity Scale, the revised Bergen Facebook Addiction Scale, and the self-report version of the Yale-Brown Obsessive-Compulsive Scale. The overlap of SNS intensity and SNS addiction was supported by their significant positive correlation. Furthermore, SNS addiction significantly correlated with the measured OCD and its corresponding factors. The hierarchical regression analysis revealed that the entry of SNS intensity enhanced the facilitative effect of SNS addiction on OCD and its factors. Therefore, the role of SNS intensity as a suppressor was supported. In the same regression model, SNS intensity predicted the severity of OCD and its compulsion subscale negatively. Implications and directions for future research were also discussed in this manuscript.

BackgroundAntimicrobial stewardship programs attempting to optimize antibiotic therapy and clinical outcomes mainly focus on inpatient and outpatient settings. The lack of antimicrobial stewardship program studies in the emergency department (ED) represents a gap in tackling the problem of antimicrobial resistance as EDs treat a substantial number of upper respiratory tract infection cases throughout the year. ObjectiveWe intend to implement two evidence-based interventions: (1) patient education and (2) providing physician feedback on their prescribing rates. We will incorporate evidence from a literature review and contextualizing the interventions based on findings from a local qualitative study. MethodsOur study uses a quasi-experimental design to evaluate the effects of interventions over time in the EDs of 4 public hospitals in Singapore. We will include an initial control period of 18 months. In the next 6 months, we will randomize 2 EDs to receive 1 intervention (ie, patient education) and the other 2 EDs to receive the alternative intervention (ie, physician feedback). All EDs will receive the second intervention in the subsequent 6 months on top of the ongoing intervention. Data will be collected for another 6 months to assess the persistence of the intervention effects. The information leaflets will be handed to patients at the EDs before they consult with the physician, while feedback to individual physicians by senior doctors is in the form of electronic text messages. The feedback will contain the physicians’ antibiotic prescribing rate compared with the departments’ overall antibiotic prescribing rate and a bite-size message on good antibiotic prescribing practices. ResultsWe will analyze the data using segmented regression with difference-in-difference estimation to account for concurrent cluster comparisons. ConclusionsOur proposed study assesses the effectiveness of evidence-based, context-specific interventions to optimize antibiotic prescribing in EDs. These interventions are aligned with Singapore’s national effort to tackle antimicrobial resistance and can be scaled up if successful. Trial RegistrationClinicalTrials.gov NCT05451863; https://clinicaltrials.gov/study/NCT05451836 International Registered Report Identifier (IRRID)DERR1-10.2196/50417

Abstract Background A recent prospective demonstrated that cardiovascular risk factors in early childhood were associated with later cardiovascular events. However, the impact of secondhand smoke (SHS) on children is unclear. The aims of this study is to determine the effects of SHS exposure on the retinal vasculature of children. Methods This is a population-based cross-sectional study of children aged 6 to 8 years. All participants received comprehensive ophthalmic examinations and retinal photography. Data on SHS exposure was derived from a validated questionnaire. A validated deep-learning system was used to automatically estimate retinal arteriolar and venular calibers from retinal photographs. Associations of quantitative retinal vessel caliber values with SHS exposure, number of smokers in the household, and total number of cigarettes smoked were determined by analyses of covariance (ANCOVA) after adjusting for potential confounders. Test of trend was determined by treating categorical risk factors as continuous ordinal variables. Results Here we show children exposed to SHS have wider retinal arteriolar (CRAE 152.1 µm vs. 151.3 µm, p

Summary: Background: During pandemics, avoiding time delay in diagnosing infection is crucial. We evaluated factors associated with delayed diagnosis of symptomatic SARS-CoV-2 infection in a national cohort of adult Singaporeans, during which emergence of the more transmissible Omicron variant shifted pandemic management towards endemicity. Methods: Retrospective cross-sectional study amongst all adult Singaporeans diagnosed with symptomatic SARS-CoV-2 infection during the transition from Delta to Omicron BA.1 (September 2021–February 2022). SARS-CoV-2 testing was fully subsidised and compulsory for all symptomatic individuals presenting at primary care. Results and demographic information were extracted from national databases. Time to diagnosis was defined as days from symptom-onset to diagnosis (date of first positive SARS-CoV-2 test); dichotomising into no delay (≤24 h from symptom-onset) and delay >24 h. Multivariable logistic regression was utilised to assess factors associated with delay >24 h, and association of delay >24 h with progression to severe COVID-19. Findings: Of 149,063 Singaporean adults presenting with symptomatic SARS-CoV-2 infection, 75.9% (113,195/149,063) were diagnosed within 24 h of symptom-onset. On multivariable analysis, female gender, older age (>60 years), Chinese (vs. Malay) ethnicity, socioeconomic status (housing type), primary care characteristics, presentation during Omicron BA.1 (vs. Delta), symptom-onset on Friday/Saturday (vs. Monday), and not having completed a primary vaccination series were independently associated with higher odds of delay >24 h. Delay >24 h was independently associated with severe COVID-19 (adjusted odds-ratio, aOR = 1.45, 95% CI = 1.27–1.65, p 60 years) had higher odds of delay in diagnosis. Delay >24 h in diagnosis was independently associated with severe COVID-19. Funding: This study was not grant-funded.

BackgroundThe uncertainties surrounding the COVID-19 pandemic led to a surge in non-urgent emergency department (ED) attendance among people presenting with upper respiratory tract infection (URTI) symptoms. These non-urgent visits, often manageable in primary care, exacerbated ED overcrowding, which could compromise the quality of ED services. Understanding patients' expectations and the reasons for these ED visits is imperative to mitigate the problem of ED overcrowding. Hence, we assessed the factors influencing patients' expectations for diagnostic tests during their ED visits for uncomplicated URTI during different phases of the pandemic.MethodsWe conducted a cross-sectional study on adults with URTI symptoms seeking care at four public EDs in Singapore between March 2021 and March 2022. We segmented the study period into three COVID-19 pandemic phases—containment, transition, and mitigation. The outcome variables are whether patients expected (1) a COVID-19-specific diagnostic test, (2) a non-COVID-19-specific diagnostic test, (3) both COVID-19-specific and non-COVID-19-specific diagnostic tests, or (4) no diagnostic test. We built a multinomial regression model with backward stepwise selection and classified the findings according to Andersen's healthcare utilization model.ResultsThe mean age of participants was 34.5 (12.7) years. Factors (adjusted odds ratio [95% confidence interval]) influencing expectations for a COVID-19-specific diagnostic test in the ED include younger age {21–40 years: (2.98 [1.04–8.55])}, no prior clinical consultation (2.10 [1.13–3.89]), adherence to employer's health policy (3.70 [1.79–7.67]), perceived non-severity of illness (2.50 [1.39–4.55]), being worried about contracting COVID-19 (2.29 [1.11–4.69]), and during the transition phase of the pandemic (2.29 [1.15–4.56]). Being non-employed influenced the expectation for non-COVID-19-specific diagnostic tests (3.83 [1.26–11.66]). Factors influencing expectations for both COVID-19-specific and non-COVID-19-specific tests include younger age {21–40 years: (3.61 [1.26–10.38]); 41–60 years: (4.49 [1.43–14.13])}, adherence to employer's health policy (2.94 [1.41–6.14]), being worried about contracting COVID-19 (2.95 [1.45– 5.99]), and during the transition (2.03 [1.02–4.06]) and mitigation (2.02 [1.03–3.97]) phases of the pandemic.ConclusionPatients' expectations for diagnostic tests during ED visits for uncomplicated URTI were dynamic across the COVID-19 pandemic phases. Expectations for COVID-19-specific diagnostic tests for ED visits for uncomplicated URTI were higher among younger individuals and those worried about contracting COVID-19 during the COVID-19 pandemic. Future studies are required to enhance public communications on the availability of diagnostic services in primary care and public education on self-management of emerging infectious diseases such as COVID-19.

ABSTRACT: Objectives: Pre-COVID-19 pandemic, patients who attended the emergency department (ED) for upper respiratory tract infection (URTI) were more likely to receive antibiotics if they expected them. These expectations could have changed with the change in health-seeking behaviour during the pandemic. We assessed the factors associated with antibiotics expectation and receipt for uncomplicated URTI patients in four Singapore EDs during the COVID-19 pandemic. Methods: We conducted a cross-sectional study on adult patients with URTI from March 2021 to March 2022 in four Singapore EDs and assessed the determinants of antibiotics expectation and receipt using multivariable logistic regression models. We also assessed the reasons patients expect antibiotics during their ED visit. Results: Among 681 patients, 31.0% expected antibiotics while 8.7% received antibiotics during their ED visit. Factors (adjusted odds ratio [95% confidence interval]) that significantly influenced expectation for antibiotics include: 1) prior consultation for current illness with (6.56 [3.30–13.11]) or without (1.50 [1.01–2.23]) antibiotics prescribed; 2) anticipation for COVID-19 test (1.56 [1.01–2.41]); and 3) poor (2.16 [1.26–3.68]) to moderate (2.26 [1.33–3.84]) knowledge on antibiotics use and resistance. Patients expecting antibiotics were 10.6 times (10.64 [5.34–21.17]) more likely to receive antibiotics. Those with tertiary education were twice (2.20 [1.09–4.43]) as likely to receive antibiotics. Conclusion: In conclusion, patients with URTI who expected antibiotics to be prescribed remained more likely to receive it during the COVID-19 pandemic. This highlights the need for more public education on the non-necessity for antibiotics for URTI and COVID-19 to address the problem of antibiotic resistance.

Objectives: This study aimed to establish reference values for fetal aortic isthmus blood flow velocity and associated indices during the first trimester, utilizing a novel ultrasonographic technique known as high-definition flow imaging (HDFI). Additionally, the correlation between Doppler profiles of aortic blood flow and key fetal parameters, including nuchal thickness (NT), crown-rump length (CRL), and fetal heartbeat (FHB), was investigated. Methods: A total of 262 fetuses were included in the analysis between December 2022 and December 2023. Utilizing 2D power Doppler ultrasound images, aortic blood flow parameters were assessed, including aortic peak systolic velocity (PS), aortic end-diastolic velocity (ED), aortic time average maximal velocity (TAMV), and various indices such as aortic systolic velocity/diastolic velocity (S/D), aortic pulsatile index (PI), aortic resistance index (RI), aortic isthmus flow velocity index (IFI), and aortic isthmic systolic index (ISI). Concurrently, fetal FHB, NT, and CRL were evaluated during early trimester Down syndrome screening. Results: Significant findings include a positive correlation between gestational age (GA) and PS (PS = 3.75 × (GA) − 15.4, r2 = 0.13, p < 0.01), ED (ED = 0.42 × (GA) − 0.61, r2 = 0.04, p < 0.01), PI (PI = 0.07 × (GA) + 1.03, r2 = 0.04, p < 0.01), and TAMV (TAMV = 1.23 × (GA) − 1.66, r2 = 0.08, p < 0.01). In contrast, aortic ISI demonstrated a significant decrease (ISI = −0.03 × (GA) + 0.57, r2 = 0.05, p < 0.05) with gestational age. No significant correlation was observed for aortic RI (p = 0.33), S/D (p = 0.39), and IFI (p = 0.29) with gestational age. Aortic PS exhibited positive correlations with NT (0.217, p = 0.001) and CRL (0.360, p = 0.000) but a negative correlation with FHB (−0.214, p = 0.001). Aortic PI demonstrated positive correlations with CRL (0.208, p = 0.001) and negative correlations with FHB (−0.176, p = 0.005). Aortic TAMV showed positive correlations with NT (0.233, p = 0.000) and CRL (0.290, p = 0.000) while exhibiting a negative correlation with FHB (−0.141, p = 0.026). Aortic ISI demonstrated negative correlations with NT (−0.128, p = 0.045) and CRL (−0.218, p = 0.001) but a positive correlation with FHB (0.163, p = 0.010). Conclusions: Power Doppler angiography with Doppler ultrasound demonstrates the ability to establish accurate reference values for fetal aortic blood flow during the first trimester of pregnancy. Notably, aortic PS, TAMV, and ISI exhibit significant correlations with NT, CRL, and FHB, with ISI appearing more relevant than IFI, PS, TAMV, and FHB. The utilization of HDFI technology proves advantageous in efficiently detecting the site of the aortic isthmus compared to traditional color Doppler mode in early second trimesters.

The identification of distinct charge transport features, deriving from nontrivial bulk band and surface states, has been a challenging subject in the field of topological systems. In topological Dirac and Weyl semimetals, nontrivial conical bands with Fermi-arc surface states give rise to negative longitudinal magnetoresistance due to chiral anomaly effect and unusual thickness dependent quantum oscillation from Weyl-orbit effect, which were demonstrated recently in experiments. In this work, we report the experimental observations of large nonlinear and nonreciprocal transport effects for both longitudinal and transverse channels in an untwinned Weyl metal of SrRuO_{3} thin film grown on a SrTiO_{3} substrate. From rigorous measurements with bias current applied along various directions with respect to the crystalline principal axes, the magnitude of nonlinear Hall signals from the transverse channel exhibits a simple sinα dependence at low temperatures, where α is the angle between bias current direction and orthorhombic [001]_{o}, reaching a maximum when current is along orthorhombic [11[over ¯]0]_{o}. On the contrary, the magnitude of nonlinear and nonreciprocal signals in the longitudinal channel attains a maximum for bias current along [001]_{o}, and it vanishes for bias current along [11[over ¯]0]_{o}. The observed α-dependent nonlinear and nonreciprocal signals in longitudinal and transverse channels reveal a magnetic Weyl phase with an effective Berry curvature dipole along [11[over ¯]0]_{o} from surface states, accompanied by 1D chiral edge modes along [001]_{o}.

Abstract Background The COVID-19 pandemic has changed the epidemiology of upper respiratory tract infections (URTI) and the disease profile of patients attending the emergency department (ED). Hence, we sought to explore the changes in ED physicians’ attitudes and behaviours in four EDs in Singapore. Methods We employed a sequential mixed-methods approach (quantitative survey followed by in-depth interviews). Principal component analysis was performed to derive latent factors, followed by multivariable logistic regression to explore the independent factors associated with high antibiotic prescribing. Interviews were analysed using the deductive-inductive-deductive framework. We derive five meta-inferences by integrating the quantitative and qualitative findings with an explanatory bidirectional framework. Results We obtained 560 (65.9%) valid responses from the survey and interviewed 50 physicians from various work experiences. ED physicians were twice as likely to report high antibiotic prescribing rates pre-COVID-19 pandemic than during the pandemic (AOR = 2.12, 95% CI 1.32 to 3.41, p = 0.002). Five meta-inferences were made by integrating the data: (1) Less pressure to prescribe antibiotics due to reduced patient demand and more patient education opportunities; (2) A higher proportion of ED physicians self-reported lower antibiotic prescribing rates during the COVID-19 pandemic but their perception of the overall outlook on antibiotic prescribing rates varied; (3) Physicians who were high antibiotic prescribers during the COVID-19 pandemic made less effort for prudent antibiotic prescribing as they were less concerned about antimicrobial resistance; (4) the COVID-19 pandemic did not change the factors that lowered the threshold for antibiotic prescribing; (5) the COVID-19 pandemic did not change the perception that the public's knowledge of antibiotics is poor. Conclusions Self-reported antibiotic prescribing rates decreased in the ED during the COVID-19 pandemic due to less pressure to prescribe antibiotics. The lessons and experiences learnt from the COVID-19 pandemic can be incorporated into public and medical education in the war against antimicrobial resistance going forward. Antibiotic use should also be monitored post-pandemic to assess if the changes are sustained.

Granular activated carbon (GAC) and powdered activated carbon (PAC) are the two most common forms of activated carbon with varying particle size range. The goal of this study was to analyze the key factors (particle size and activation temperature) affecting the surface characteristics of GAC and PAC derived from palm kernel shell (PKS). The surface morphology suggested that the pore network in PKS-PAC is more developed than that in PKS-GAC owing to the presence of a micropore structure when prepared at lower activation temperatures. This study also demonstrated that activation performed on different PKS particle size range influenced the mesopore domain of the activated carbon produced. The PKS-GAC was found to have more mesopores than PKS-PAC, which made it more reliable for dye adsorption in water treatment. Overall, this study demonstrated that applying different particle size range of PKS during the activation process can have a significant influence on the surface characteristics, thus having a direct impact on the application of activated carbon. An accurate particle size range will ensure that the most cost-effective activated carbon is selected to achieve the desired performance objectives.

Abstract In a thin Weyl semimetal, a thickness dependent Weyl-orbit quantum oscillation was proposed to exist, originating from a nonlocal cyclotron orbit via electron tunnelings between top and bottom Fermi-arc surface states. Here, magneto-transport measurements were carried out on untwinned Weyl metal SrRuO3 thin films. In particular, quantum oscillations with a frequency F s1 ≈ 30 T were identified, corresponding to a small Fermi pocket with a light effective mass. Its oscillation amplitude appears to be at maximum for thicknesses in a range of 10 to 20 nm, and the phase of oscillation exhibits a systematic change with film thickness. The constructed Landau fan diagram shows an unusual concave downward curvature in the 1/μ 0 H n -n curve, where n is the Landau level index. From thickness and field-orientation dependence, the F s1 oscillation is attributed to be of surface origin. Those findings can be understood within the framework of the Weyl-orbit quantum oscillation effect with non-adiabatic corrections.

Abstract Background While microbiomes in industrialized societies are well characterized, indigenous populations with traditional lifestyles have microbiomes that are more akin to those of ancient humans. However, metagenomic data in these populations remains scarce, and the association with soil-transmitted helminth infection status is unclear. Here, we sequenced 650 metagenomes of indigenous Malaysians from five villages with different prevalence of helminth infections. Results Individuals from villages with higher prevalences of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition were most strongly associated with different villages and the effects of helminth infection status on the microbiome varies by village. Longitudinal changes in the microbiome in response to albendazole anthelmintic treatment were observed in both helminth infected and uninfected individuals. Inference of bacterial population replication rates from origin of replication analysis identified specific replicating taxa associated with helminth infection. Conclusions Our results indicate that helminth effects on the microbiota were highly dependent on context, and effects of albendazole on the microbiota can be confounding for the interpretation of deworming studies. Furthermore, a substantial quantity of the microbiome remains unannotated, and this large dataset from an indigenous population associated with helminth infections is a valuable resource for future studies. Video Abstract

Abstract Type-2 diabetes mellitus (T2DM) is a medical condition in which oral medications avail to patients to curb their hyperglycaemia after failed dietary therapy. However, individual responses to the prescribed pharmacotherapy may differ due to their clinical profiles, comorbidities, lifestyles and medical adherence. One approach is to identify similar patients within the same community to predict their likely response to the prescribed diabetes medications. This study aims to present an evidence-based diabetes medication recommendation system (DMRS) underpinned by patient similarity analytics. The DMRS was developed using 10-year electronic health records of 54,933 adult patients with T2DM from six primary care clinics in Singapore. Multiple clinical variables including patient demographics, comorbidities, laboratory test results, existing medications, and trajectory patterns of haemoglobin A1c (HbA1c) were used to identify similar patients. The DMRS was evaluated on four groups of patients with comorbidities such as hyperlipidaemia (HLD) and hypertension (HTN). Recommendations were assessed using hit ratio which represents the percentage of patients with at least one recommended sets of medication matches exactly the diabetes prescriptions in both the type and dosage. Recall, precision, and mean reciprocal ranking of the recommendation against the diabetes prescriptions in the EHR records were also computed. Evaluation against the EHR prescriptions revealed that the DMRS recommendations can achieve hit ratio of 81% for diabetes patients with no comorbidity, 84% for those with HLD, 78% for those with HTN, and 75% for those with both HLD and HTN. By considering patients’ clinical profiles and their trajectory patterns of HbA1c, the DMRS can provide an individualized recommendation that resembles the actual prescribed medication and dosage. Such a system is useful as a shared decision-making tool to assist clinicians in selecting the appropriate medications for patients with T2DM.

Link prediction aims to predict the potential existence of links between two unconnected nodes within a network based on the known topological characteristics. Evaluation metrics are used to assess the effectiveness of algorithms in link prediction. The discriminating ability of these evaluation metrics is vitally important for accurately evaluating link prediction algorithms. In this study, we propose an artificial network model, based on which one can adjust a single parameter to monotonically and continuously turn the prediction accuracy of the specifically designed link prediction algorithm. Building upon this foundation, we show a framework to depict the effectiveness of evaluating metrics by focusing on their discriminating ability. Specifically, a quantitative comparison in the abilities of correctly discerning varying prediction accuracies was conducted encompassing nine evaluation metrics: Precision, Recall, F1-Measure, Matthews correlation coefficient, balanced precision, the area under the receiver operating characteristic curve (AUC), the area under the precision-recall curve (AUPR), normalized discounted cumulative gain (NDCG), and the area under the magnified receiver operating characteristic. The results indicate that the discriminating abilities of the three metrics, AUC, AUPR, and NDCG, are significantly higher than those of other metrics.

Activated carbon is the preferred adsorbent for gas and water treatment in various industry across the world due to its efficiency, reliability, and accessibility. Recently, in Malaysia, studies are mainly focused on the fabrication of activated carbon from lignocellulosic biomass-based precursors from agricultural waste such as coconut shell, rice husk, and palm kernel shell. Activated carbon fabrication is a two-step process; the precursor will first undergo carbonization, then, activation is carried out either physically or chemically to develop its porous surface for adsorption purposes. The main benefit of activated carbon is the customizable pore structure for different utilization, which can be easily achieved by the chemical activation process. The types and concentration of chemicals used for activation, pre-treatment of precursor, duration of the activation process, and the mass ratio of precursor to chemicals are proven to effectively influence the resulting pore structure. However, the chemicals used in the activation process can be harmful to the environment. Thus, the chemical recovery process is necessary after the activation process. Nonetheless, more in-depth research on producing activated carbon from abundant biomass materials with bio-based chemical agents for activation is needed to achieve an ecological and sustainable manufacturing process.

Adipose-derived stem cells (ASCs) have raised significant interest for their potential therapeutic applications in regenerative medicine. However, ASCs usually suffer from decreased pluripotency and functional plasticity during in vitro expansion. Herein, this study sought to develop a continuous cell production system that can mass-produce ASCs with sustained regenerative capacity. The strategy was blending pH-responsive chitosan (CS) with polyamide-66 (PA) to generate combined surface properties with controllable cell growth/detachment ability to achieve a repeated cell production process. From the collected data, all the polymer blends were capable of completing a minimum of four consecutive production cycles, wherein the PA17CS blend (PA:CS = 1:7) outperformed with respect to the working effectiveness (average cell detachment ratio= 88%) and the cell viability. Compared to the trypsin-based method, ASCs harvested from PA17CS exhibited superior stemness characteristics along with SDF-1-mediated CXCR4 chemotactic response for stem cell homing. Moreover, injection of ASCs generated from PA17CS blend could more effectively induce neovascularization and protect skin flaps during an ischemic injury in a rat model.

Blastocystis sp. has been considered as an opportunistic intestinal parasite particularly in immunocompromised patient. Recent findings of the predominance of Blastocystis subtypes infection in the clinical disease with its interaction with gut microbiota in the hosts will be discussed accordingly. A total of 57 eligible studies, published from 2010 to October 2020 from a broad search in electronic databases were accessed. The studies showed that bloating, abdominal pain and diarrhoea were among the common symptoms in Blastocystis sp. infection in the immunocompromised patients. However, asymptomatic and healthy individuals were also infected by the Blastocystis sp. with higher prevalence among healthy individuals. Specifically, Blastocystis sp. ST3 were most frequently discovered among immunocompromised patients (IBS, cancer, transplant, HIV/AIDS, dengue) followed by ST1 and ST2. Despite most studies suggesting that Blastocystis sp. promote a healthy gut, a few studies had suggested otherwise. Blastocystis sp. colonisation may modify the gut microbiota with the reduction of beneficial bacteria phyla such as Firmicutes and Bacteroides. Although there was a positive association between Blastocystis sp. subtypes and clinical diseases, more studies are needed. To understand the pathogenicity of Blastocystis sp., their interactions with the gut microbiota communities in humans are properly discussed.

IntroductionKawasaki disease (KD) is an acute idiopathic systemic vasculitis with a self- limiting course that predominantly affects children under 5 years old, particularly in the East Asian countries. Nevertheless, to date, the data on KD in Malaysia are limited. This study aimed to evaluate the epidemiology, clinical features, treatment, and outcomes of KD among the pediatric patients admitted to Hospital Canselor Tunku Muhriz (HCTM), Kuala Lumpur, Malaysia.MethodA retrospective cohort study of 66,500 pediatric patients presented at HCTM from the year 2004 to 2021 was conducted.Results62 KD cases out of 66,500 pediatric admissions were reported, with a male-to-female ratio of 1.58 to 1. Majority of KD patients (95.0%) were younger than 5 years old. Prior infection was reported in 5 KD patients (8.1%). Apart from the classical features, manifestations of various organ systems including cardiovascular (16.1%), gastrointestinal (43.5%), neurological (1.61%), musculoskeletal (1.61%), and genitourinary (17.7%) systems were observed. There was a significant association between sterile pyuria and coronary artery aneurysm (CAA) (p

Background and objectivesThe high transmissibility of SARS-CoV-2 has exposed weaknesses in our infection control and detection measures, particularly in healthcare settings. Aerial sampling has evolved from passive impact filters to active sampling using negative pressure to expose culture substrate for virus detection. We evaluated the effectiveness of an active air sampling device as a potential surveillance system in detecting hospital pathogens, for augmenting containment measures to prevent nosocomial transmission, using SARS-CoV-2 as a surrogate.MethodsWe conducted air sampling in a hospital environment using the AerosolSenseTM air sampling device and compared it with surface swabs for their capacity to detect SARS-CoV-2.ResultsWhen combined with RT-qPCR detection, we found the device provided consistent SARS-CoV-2 detection, compared to surface sampling, in as little as 2 h of sampling time. The device also showed that it can identify minute quantities of SARS-CoV-2 in designated “clean areas” and through a N95 mask, indicating good surveillance capacity and sensitivity of the device in hospital settings.ConclusionActive air sampling was shown to be a sensitive surveillance system in healthcare settings. Findings from this study can also be applied in an organism agnostic manner for surveillance in the hospital, improving our ability to contain and prevent nosocomial outbreaks.

BackgroundThis meta-analysis aimed at evaluating the efficacy of cognitive behavior therapy (CBT) against osteoarthritis-associated symptoms in patients with knee/hip osteoarthritis.MethodsMedline, PubMed, Cochrane Library, and EMBASE databases were searched from inception to July 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of CBT with other treatment approaches in adults with confirmed knee/hip osteoarthritis. The pain intensity (primary outcome) and the secondary outcomes including insomnia severity, sleep efficiency, physical function as well as the severity of depression and fatigue were assessed at two time points (i.e., immediately after treatment and during the follow-up period). The effect size is expressed as standardized mean difference (SMD) with SMDs of < 0.2, 0.2–0.5, and 0.5–0.8, and > 0.8 representing negligible, small, medium, and large effect sizes, respectively.ResultsFifteen RCTs were included for analysis. Immediately after CBT intervention, meta-analysis showed similar treatment effect in pain severity [SMD = –0.46, 95% confidence interval (CI): –0.95 to 0.04, 11 studies, 1557 participants] and other symptoms including depression (SMD = –0.26, 95% CI: –0.58 to 0.06, five studies, 735 participants), fatigue (SMD = –2.44, 95% CI:–6.53 to 1.65, two RCTs, 511 participants), and physical function (SMD = –0.11, 95% CI:–0.25 to 0.02, five RCTs, 720 participants) between CBT and control groups, while there was an improvement in insomnia severity (SMD = –0.65, 95% CI: –1.06 to –0.24, four RCTs, 639 participants, medium treatment effect) and sleep efficiency (SMD = 0.32, 95% CI: 0.04 to 0.59, three RCTs, 352 patients, small treatment effect). During follow-up, CBT improved pain severity (SMD = –0.52, 95% CI: –1.03 to –0.01, eight studies, 1447 participants, medium treatment effect), insomnia (SMD = –0.43, 95% CI: –0.85 to –0.01, three RCTs, 571 participants, small treatment effect), and depression (SMD = –0.39, 95% CI: –0.59 to –0.18, four RCTs, 791 participants, small treatment effect). Nevertheless, sleep efficiency, fatigue, and physical function were not improved in the follow-up period.ConclusionOur results may suggest the durability of CBT-associated treatment benefits, supporting its role as a potential promising alternative or complementary intervention for patients with knee/hip osteoarthritis, especially against pain and insomnia. Future large-scale investigations are warranted to verify our findings.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022331165].

BackgroundThe accumulation of fatigue leads to reduced physical, emotional, psychological, and social functions.ObjectivesFermented Prunus mume vinegar (PV) improves fatigue in animals; however, studies in humans have not been conducted. We aimed to examine the effects and safety of consuming fermented PV for 8 weeks on fatigue indices in adults with unexplained fatigue while considering the placebo effect.MethodsA randomized, double-blind, placebo-controlled trial was conducted in adults of >19 years, who were diagnosed with unexplained fatigue for at least 1 month. Eighty participants were randomly assigned to receive daily 70 mL of fermented PV (2.56 mg/g, chlorogenic acid, and 15.3 mg/g, citric acid) or a placebo for 8 weeks. At baseline and 4 and 8 weeks after treatment, the participants were visited for blood tests (liver enzyme, glucose, creatinine, lactate, malondialdehyde [MDA], and creatine kinase [CK]) and questionnaires (Fatigue Severity Scale [FSS], fatigue visual analog scale [VAS], Beck Depression Inventory [BDI], the Korean version of the Brief Encounter Psychosocial Instrument [BEPSI-K], EQ-5D-3L, and EQ-VAS]).ResultsFermented PV supplementation for 8 weeks did not remarkably improve the fatigue indices when compared to placebo. Additionally, differences in fatigue VAS, BDI, BEPSI-K, EQ-5D-3L, EQ-VAS, lactate, CK, and MDA concentrations between the groups were not observed. However, FSS had positively correlated with fatigue VAS, BDI, and BEPSI-K, whereas it was negatively correlated with EQ-5D-3L and EQ-VAS at the baseline and 8 weeks. None of the participants reported adverse events.ConclusionThe efficacy of fermented PV did not exceed the efficacy of placebo in adults with unexplained fatigue.Clinical trial registration[ClinicalTrials.gov], identifier [NCT04319692].

IntroductionUlmus macrocarpa Hance extract (UME) has demonstrated an antilipidemic effect via upregulation of the adenosine monophosphate-activated protein kinase pathway and regulation of lipid metabolism in both laboratory and animal studies. Therefore, we examined the effects and safety of UME on plasma lipids in adults with untreated high, low-density lipoprotein cholesterol (LDL-C) concentrations.Materials and methodsIn the current double-blind placebo-controlled randomized clinical trial, 80 patients with untreated high LDL-C concentrations (130–190 mg/dl) were randomly allocated to either the “UME group” (received 500 mg UME as two capsules per day) or the “Placebo group” (received placebo containing cornstarch as two capsules per day) for 12 weeks. The primary outcome was the change in LDL-C concentration within the 12-week treatment period; secondary outcomes included changes in total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B (ApoB) concentrations.ResultsUME over 12 weeks led to a greater decrease in LDL-C, TC, and ApoB concentrations than did the placebo as follows: by 18.1 mg/dl (P < 0.001); 23.3 mg/dl (P < 0.001); 9.3 mg/dl (P = 0.018), respectively. When LDL-C, TC, and ApoB concentrations were expressed as a lsmeans percentage of the baseline concentration, they after 12 weeks of UME had greater % differences compared to the placebo as follows: by 11.9% (P < 0.001); 10.0% (P < 0.001); 8.6% (P < 0.05), respectively. However, no significant inter- and intra-group changes in liver enzyme, free fatty acid, anti-inflammatory marker, and fasting glucose concentrations were observed. None of the participants experienced notable adverse events.DiscussionUME causes a significant improvement in lipid profiles in adults with untreated high LDL-C concentrations.Clinical trial registration[www.clinicaltrials.gov/], identifier [NCT03773315].

Abstract Background Clinical trials have demonstrated that initiating oral anti-diabetic drugs (OADs) significantly reduce glycated hemoglobin (HbA1c) levels. However, variability in lifestyle modifications and OAD adherence impact on their actual effect on glycemic control. Furthermore, evidence on dose adjustments and discontinuation of OAD on HbA1c is lacking. This study aims to use real-world data to determine the effect of OAD initiation, up-titration, down-titration, and discontinuation on HbA1c levels, among Asian patients managed in primary care. Methods A retrospective cohort study over a 5-year period, from Jan 2015 to Dec 2019 was conducted on a cohort of multi-ethnic adult Asian patients with clinical diagnosis of type 2 diabetes mellitus (T2DM) managed by a network of primary care clinics in Singapore. Nine OADs from five different classes (biguanides, sulphonyurea, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter-2 [SGLT-2] inhibitors, and alpha-glucosidase inhibitors) were evaluated. Patients were grouped into “No OAD”, “Non-titrators,” and “Titrators” cohorts based on prescribing patterns. For the “Titrators” cohort, the various OAD titrations were identified. Subsequently, a descriptive analysis of HbA1c values before and after each titration was performed to compute a mean difference for each unique titration identified. Results Among the cohort of 57,910 patients, 43,338 of them had at least one OAD titration, with a total of 76,990 pairs of HbA1c values associated with an OAD titration. There were a total of 206 unique OAD titrations. Overall, initiation of OADs resulted in a reduction of HbA1c by 3 to 12 mmol/mol (0.3 to 1.1%), respectively. These results were slightly lower than those reported in clinical trials of 6 to 14 mmol/mol (0.5 to 1.25%). The change of HbA1c levels due to up-titration, down-titration, and discontinuation were −1 to −8 mmol/mol (−0.1 to −0.7%), +1 to 7 mmol/mol (+0.1 to +0.6%), and +2 to 11 mmol/mol (+0.2 to +1.0%), respectively. The HbA1c lowering effect of initiating newer OADs, namely DPP-4 inhibitors and SGLT-2 inhibitors was 8 to 11 mmol/mol (0.7 to 0.9%) and 7 to 11 mmol/mol (0.6 to 1.0%), respectively. Conclusion The real-world data on Asians with T2DM in this study show that the magnitudes of OAD initiation and dose titration are marginally lower than the results from clinical trials. During shared decision-making in selecting treatment options, the results enable physicians to communicate realistic expectation of the effect of oral medications on the glycemic control of their patients in primary care.

Over the past three decades, chemical and biological water contamination has become a major concern, particularly in the industrialized world. Heavy metals, aromatic compounds, and dyes are among the harmful substances that contribute to water pollution, which jeopardies the human health. For this reason, it is of the utmost importance to locate methods for the cleanup of wastewater that are not genuinely effective. Owing to its non-toxicity, biodegradability, and biocompatibility, starch is a naturally occurring polysaccharide that scientists are looking into as a possible environmentally friendly material for sustainable water remediation. Starch could exhibit significant adsorption capabilities towards pollutants with the substitution of amide, amino, carboxyl, and other functional groups for hydroxyl groups. Starch derivatives may effectively remove contaminants such as oil, organic solvents, pesticides, heavy metals, dyes, and pharmaceutical pollutants by employing adsorption techniques at a rate greater than 90%. The maximal adsorption capacities of starch-based adsorbents for oil and organic solvents, pesticides, heavy metal ions, dyes, and pharmaceuticals are 13,000, 66, 2000, 25,000, and 782 mg/g, respectively. Although starch-based adsorbents have demonstrated a promising future for environmental wastewater treatment, additional research is required to optimize the technique before the starch-based adsorbent can be used in large-scale in situ wastewater treatment.

Abstract The growth of SrRuO $$_3$$ 3 (SRO) thin film with high-crystallinity and low residual resistivity (RR) is essential to explore its intrinsic properties. Here, utilizing the adsorption-controlled growth technique, the growth condition of initial SrO layer on TiO $$_2$$ 2 -terminated SrTiO $$_3$$ 3 (STO) (001) substrate was found to be crucial for achieving a low RR in the resulting SRO film grown afterward. The optimized initial SrO layer shows a c(2 $$\times $$ × 2) superstructure that was characterized by electron diffraction, and a series of SRO films with different thicknesses (ts) were then grown. The resulting SRO films exhibit excellent crystallinity with orthorhombic-phase down to $$t \approx $$ t ≈ 4.3 nm, which was confirmed by high resolution X-ray measurements. From X-ray azimuthal scan across SRO orthorhombic (02 ± 1) reflections, we uncover four structural domains with a dominant domain of orthorhombic SRO [001] along cubic STO [010] direction. The dominant domain population depends on t, STO miscut angle ( $$\alpha $$ α ), and miscut direction ( $$\beta $$ β ), giving a volume fraction of about 92 $$\%$$ % for $$t \approx $$ t ≈ 26.6 nm and $$(\alpha , \beta ) \approx $$ ( α , β ) ≈ (0.14 $$^{\mathrm{o}}$$ o , 5 $$^{\mathrm{o}}$$ o ). On the other hand, metallic and ferromagnetic properties were well preserved down to t $$\approx $$ ≈ 1.2 nm. Residual resistivity ratio (RRR = $$\rho ({\mathrm{300 K}})$$ ρ ( 300 K ) / $$\rho ({\mathrm{5K}})$$ ρ ( 5 K ) ) reduces from 77.1 for t $$\approx $$ ≈ 28.5 nm to 2.5 for t $$\approx $$ ≈ 1.2 nm, while $$\rho ({\mathrm{5K}})$$ ρ ( 5 K ) increases from 2.5 $$\upmu \Omega $$ μ Ω cm for t $$\approx $$ ≈ 28.5 nm to 131.0 $$\upmu \Omega $$ μ Ω cm for t $$\approx $$ ≈ 1.2 nm. The ferromagnetic onset temperature ( $$T'_{\mathrm{c}}$$ T c ′ ) of around 151 K remains nearly unchanged down to t $$\approx $$ ≈ 9.0 nm and decreases to 90 K for t $$\approx $$ ≈ 1.2 nm. Our finding thus provides a practical guideline to achieve high crystallinity and low RR in ultra-thin SRO films by simply adjusting the growth of initial SrO layer.

IntroductionSarcopenia is a phenomenon in which skeletal muscle mass decreases with age, causing many health problems. Many studies have been conducted to improve sarcopenia nutritionally. Ishige okamura (IO) is a genus of brown algae and plays a role in anti-diabetes, anti-obesity, and myogenesis. However, the effect of IO extract (IOE) on human muscle strength and mass is unclear. Therefore, we will examine the impact and safety of consumption of IOE for 12 weeks on muscle strength and mass in middle-aged and old-aged adults with relatively low skeletal muscle mass.Materials and methodsA randomized controlled trial is conducted on 80 adults aged 50–80. A total of 80 participants will be enrolled in this study. Participants assign IOE-taking group (n = 40) and placebo taking group (n = 40). At a baseline and 12 weeks after treatment, the following parameters of the participants are checked: knee extension strength, handgrip strength, body composition, laboratory tests, dietary recall, physical activity, and EQ-5D-5L.DiscussionThe present study will be the first randomized, double-blind placebo-controlled trial to examine the efficacy and tolerability of IOE supplementation in adults with relatively low muscle mass. The nutritional intake and physical activity that might influence muscle strength and mass will be considered as covariates for transparency of results. The results of this study will provide clinical evidence for sarcopenia patients with nutrient treatment.Clinical Trial Registrationwww.clinicaltrials.gov/, Identifier: NCT04617951.

Abstract Optical response of crystalline solids is to a large extent driven by excitations that promote electrons among individual bands. This allows one to apply optical and magneto‐optical methods to determine experimentally the energy band gap —a fundamental property crucial to our understanding of any solid—with a great precision. Here it is shown that such conventional methods, applied with great success to many materials in the past, do not work in topological Dirac semimetals with a dispersive nodal line. There, the optically deduced band gap depends on how the magnetic field is oriented with respect to the crystal axes. Such highly unusual behavior is explained in terms of band‐gap renormalization driven by Lorentz boosts which results from the Lorentz‐covariant form of the Dirac Hamiltonian relevant for the nodal line at low energies.