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Sumaiyah Mat,1 Chin Teck Ng,1–3 Farhana Fadzil,4 Faizatul Izza Rozalli,4 Maw Pin Tan1,5 1Ageing and Age-Associated Disorders Research Group, University of Malaya, Kuala Lumpur, Malaysia; 2Department of Rheumatology and Immunology, Singapore General Hospital, 3Duke-NUS Medical School, National University Singapore, Singapore; 4Department of Radiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 5Geriatric Division, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Abstract: The purpose of this study was to investigate the role of fear of falling (FoF) and psychological symptoms in explaining the relationship between osteoarthritis (OA) symptom severity and falls. Individuals aged ≥65 years with ≥2 falls or ≥1 injurious fall over the past 12 months were included in the falls group, while volunteers aged ≥65 years with no history of falls over 12 months were recruited as controls. The presence of lower extremity OA was determined radiologically and clinically. Severity of symptoms was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. FoF and psychological status were measured with the shortened version of the Falls Efficacy Scale-International and the 21-item Depression, Anxiety and Stress Scale (DASS-21), respectively. Of 389 (229 fallers, 160 non-fallers) potential participants, mean (SD) age: 73.74 (6.60) years, 141 had clinical OA and 171 had radiological OA. Fallers with both radiological OA and clinical OA had significantly higher FoF and DASS-21 scores than non-fallers. FoF was significantly positively correlated with symptom severity in fallers and non-fallers with radiological and clinical OA. Depression, anxiety, and stress scores were only significantly correlated with symptom severity among fallers but not non-fallers in both clinical and radiological OA. The relationship between mild symptoms and reduced risk of falls compared to no symptoms in those with radiological OA was attenuated by increased anxiety. The increased falls risk associated with severe symptoms compared to mild symptoms in clinical OA was attenuated by FoF. FoF may, therefore, be a potentially modifiable risk factor for OA-associated falls which could be considered in future intervention studies. Keywords: falls, fear of falling, osteoarthritis, psychological status, aged

Cheng Teng Ng,1,2,* Liang Qing Yong,1,* Manoor Prakash Hande,3 Choon Nam Ong,2 Liya E Yu,4 Boon Huat Bay,1 Gyeong Hun Baeg1 1Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Environmental Research Institute, National University of Singapore, Singapore; 3Department of Physiology, Yong Loo Lin School of Medicine, 4Department of Civil and Environmental Engineering, National University of Singapore, Singapore, Singapore *These authors contributed equally to this work Background: Although zinc oxide nanoparticles (ZnO NPs) have been widely used, there has been an increasing number of reports on the toxicity of ZnO NPs. However, study on the underlying mechanisms under in vivo conditions is insufficient.Methods: In this study, we investigated the toxicological profiles of ZnO NPs in MRC5 human lung fibroblasts in vitro and in an in vivo model using the fruit fly Drosophila melanogaster. A comprehensive study was conducted to evaluate the uptake, cytotoxicity, reactive oxygen species (ROS) formation, gene expression profiling and genotoxicity induced by ZnO NPs.Results: For in vitro toxicity, the results showed that there was a significant release of extracellular lactate dehydrogenase and decreased cell viability in ZnO NP-treated MRC5 lung cells, indicating cellular damage and cytotoxicity. Generation of ROS was observed to be related to significant expression of DNA Damage Inducible Transcript (DDIT3) and endoplasmic reticulum (ER) to nucleus signaling 1 (ERN1) genes, which are ER stress-related genes. Oxidative stress induced DNA damage was further verified by a significant release of DNA oxidation product, 8-hydroxydeoxyguanosine (8-OHdG), as well as by the Comet assay. For the in vivo study using the fruit fly D. melanogaster as a model, significant toxicity was observed in F1 progenies upon ingestion of ZnO NPs. ZnO NPs induced significant decrease in the egg-to-adult viability of the flies. We further showed that the decreased viability is closely associated with ROS induction by ZnO NPs. Removal of one copy of the D. melanogaster Nrf2 alleles further decreased the ZnO NPs-induced lethality due to increased production of ROS, indicating that nuclear factor E2-related factor 2 (Nrf2) plays important role in ZnO NPs-mediated ROS production.Conclusion: The present study suggests that ZnO NPs induced significant oxidative stress-related cytotoxicity and genotoxicity in human lung fibroblasts in vitro and in D. melanogaster in vivo. More extensive studies would be needed to verify the safety issues related to increased usage of ZnO NPs by consumers. Keywords: zinc oxide nanoparticles, ROS, oxidative stress, MRC5 cells, Drosophila

We study a scheduling problem with deteriorating jobs, that is, jobs whose processing times are an increasing function of their start times. We consider the case of a single machine and linear job-independent deterioration. The problem is to determine an optimal combination of the due-date and schedule so as to minimize the sum of due-date, earliness and tardiness penalties. We give an O(n log n) time algorithm to solve this problem. Keywords: single machine scheduling; due-date; deteriorating jobs

We study a problem of scheduling n jobs on a single machine in batches. A batch is a set of jobs processed contiguously and completed together when the processing of all jobs in the batch is finished. Processing of a batch requires a machine setup time dependent on the position of this batch in the batch sequence. Setup times and job processing times are continuously controllable, that is, they are real-valued variables within their lower and upper bounds. A deviation of a setup time or job processing time from its upper bound is called a compression. The problem is to find a job sequence, its partition into batches, and the values for setup times and job processing times such that (a) total job completion time is minimized, subject to an upper bound on total weighted setup time and job processing time compression, or (b) a linear combination of total job completion time, total setup time compression, and total job processing time compression is minimized. Properties of optimal solutions are established. If the lower and upper bounds on job processing times can be similarly ordered or the job sequence is fixed, then O([n.sup.3] log n) and O([n.sup.5]) time algorithms are developed to solve cases (a) and (b), respectively. If all job processing times are fixed or all setup times are fixed, then more efficient algorithms can be devised to solve the problems. doi:10.1057/palgrave.jors.2601537 Keywords: scheduling; single machine; batching; minimizing total completion time; controllable setup and processing times

This paper deals with a single machine scheduling problem with start time dependent job processing times. The job processing times are characterized by decreasing linear functions dependent on their start times. The problem is to find a schedule for which the total weighted completion time is minimized. It is proved that the problem is NP-hard. Some properties of special cases of the general problem are also given. Based on these results, two heuristic algorithms are constructed and their performance is compared. Journal of the Operational Research Society (2002) 53, 688-693. doi: 10.1057/palgrave.jors.2601359 Keywords: computational analysis; scheduling; heuristics; start time dependent processing time; single machine

Objectives: To evaluate the effect of a musculoskeletal ultrasound programme (MUSP) applying real-time ultrasonography with reinforcement of findings by a rheumatologist on improving disease-modifying anti-rheumatic drugs (DMARDs) adherence in rheumatoid arthritis (RA). Method: Eligible RA patients with low adherence score (< 6) on the 8-item Morisky Medication Adherence Scale (MMAS-8) were randomized to either an intervention group (receiving MUSP at baseline) or a control group (no MUSP), and followed up for 6 months. Adherence measures (patient-reported and pharmacy dispensing records) and clinical efficacy data were collected. The MUSP's feasibility and acceptability were assessed. Results: Among 132 recruited RA patients, six without baseline visits were excluded; therefore, 126 patients were analysed (62 intervention and 64 control). The primary outcome (proportion of patients with 1 month MMAS-8 score < 6) was significantly smaller (p = 0.019) in the intervention (35.48%) than the control group (56.25%). However, 3 and 6 month adherence and clinical efficacy outcomes were not significantly different between the two groups (all p > 0.05). All 62 patients completed the MUSP (mean time taken, 9.2 min), with the majority reporting moderately/very much improved understanding of their joint condition (71%) and the importance of regularly taking their RA medication(s) (79%). Most patients (90.3%) would recommend the MUSP to another RA patient. Conclusions: The MUSP improved RA patients' DMARDs adherence in the short term and was feasible and well accepted by patients. Future studies could evaluate whether repeated feedback using MUSP could help to sustain the improvement in DMARD adherence in RA patients, and whether this may be clinically impactful and cost-effective. [ABSTRACT FROM AUTHOR]

Objective: More than 130 susceptibility loci for rheumatoid arthritis (RA) have been identified with genome-wide association studies (GWAS). To investigate the genetic predisposition of Chinese anti-cyclic-citrullinated-peptides-antibody-positive RA, we carried out an exome sequencing study., Methods: Patients were recruited from three major public hospitals in Singapore, Tan Tock Seng Hospital (TTSH), Singapore General Hospital and National University Health System. Controls came from an established exome collection and from the TTSH Health Control Biobank. All the participants were of Chinese descent. We performed whole-exome sequencing (WES) in 595 ACPA-positive RA patients and 1281 controls and validated the candidate variants by genotyping 795 RA cases and 600 controls., Results: The discovery cohort yielded 73 susceptibility SNVs that reached statistical significance. In the validation study with an independent cohort, two SNVs remained significant: PCNXL4 (p-value 1.50x10 -5 ) and DHRS7 (p-value 6.02x10 -5 ). The majority of known susceptibility foci are not captured by exome sequencing., Conclusion: In this WES study of ACPA-positive RA in Chinese patients, we discovered two new variants in PCNXL4 and DHRS7 associated with risk of the disease.

Objectives: To evaluate urinary activated leucocyte cell adhesion molecule (ALCAM) and CD6 as predictors of lupus nephritis (LN) progression or disease resolution across a 1-year study., Methods: Serum and urine samples from biopsy proven LN subjects (n = 122) were prospectively collected over the course of a year at 3- or 6-month intervals (weeks 0, 12, 26, and 52) across multiple study sites and assessed for soluble ALCAM and CD6 levels. Urine creatinine from the same urine sample was used to normalize the levels of urinary ALCAM and urinary CD6. Measured levels of serum and urine ALCAM and CD6 were then analyzed against disease metrics cross-sectionally and longitudinally., Results: Cross-sectional analysis at baseline revealed that urinary ALCAM significantly correlated with urine protein creatinine ratio (UPCR), renal SLEDAI, and the Physician Global Assessment (PGA), and negatively correlated with serum C3 and C4. Receiver operating characteristic (ROC) curve analysis demonstrated that urinary ALCAM is a predictor of LN with an area under the curve (AUC) of 0.97, compared with urinary CD6 with an AUC of 0.71. Importantly, the change in urinary ALCAM over a 3-month period distinguished between non-responders and responders at week 52., Conclusion: Urinary ALCAM is reflective of changes in LN and may be predictive of response status., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chen, Wong, Tan, Tay, Tan, Chan, Ho, Cheng, Teoh, Chiu, Wang, Saad, Kanesvaran, Li, Ng, Tuan and Yuen.)

The increasing prevalence of heart failure (HF) in ageing populations drives demand for echocardiography (echo). There is a worldwide shortage of trained sonographers and long waiting times for expert echo. We hypothesised that artificial intelligence (AI)-enhanced point-of-care echo can enable HF screening by novices. The primary endpoint was the accuracy of AI-enhanced novice pathway in detecting reduced LV ejection fraction (LVEF) < 50%. Symptomatic patients with suspected HF (N = 100, mean age 61 ± 15 years, 56% men) were prospectively recruited. Novices with no prior echo experience underwent 2-weeks' training to acquire echo images with AI guidance using the EchoNous Kosmos handheld echo, with AI-automated reporting by Us2.ai (AI-enhanced novice pathway). All patients also had standard echo by trained sonographers interpreted by cardiologists (reference standard). LVEF < 50% by reference standard was present in 27 patients. AI-enhanced novice pathway yielded interpretable results in 96 patients and took a mean of 12 min 51 s per study. The area under the curve (AUC) of the AI novice pathway was 0.880 (95% CI 0.802, 0.958). The sensitivity, specificity, positive predictive and negative predictive values of the AI-enhanced novice pathway in detecting LVEF < 50% were 84.6%, 91.4%, 78.5% and 94.1% respectively. The median absolute deviation of the AI-novice pathway LVEF from the reference standard LVEF was 6.03%. AI-enhanced novice pathway holds potential to task shift echo beyond tertiary centres and improve the HF diagnostic workflow., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential., Objectives: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment., Methods: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance., Results: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70)., Conclusions: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518)., Competing Interests: Funding Support and Author Disclosures The DAPA-Shuttle1 study was an investigator-initiated trial funded by AstraZeneca via the externally sponsored scientific research program (ESR-18-13712; Principal Investigator: Dr Titze). The SSIS Project was realized with grant support from Duke-NUS Medical School (Duke-NUS-KBrFA/2019/0026) to Dr Titze. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Titze has received one personal speaker fee from AstraZeneca in the past 4 years. Dr Greasley has been an employee of and shareholder in AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)