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Introduction To compare the clinical outcomes and healthcare utilization of patients enrolled in the multidisciplinary Diabetic Foot in Primary and Tertiary (DEFINITE) Care program with a matched historical cohort and estimate the program’s long-term cost-effectiveness using simulation.Research design and methods This study consisted of two components: a 1-year observational outcome evaluation and a long-term simulation-based cost-effectiveness analysis (CEA). We conducted an observational study to analyze 2798 patients with diabetic foot ulcers (DFUs) enrolled in the program between June 2020 and June 2021 (DEFINITE Care group) and 5462 patients with DFUs from June 2016 to December 2017 as historical controls. One-to-one propensity score matching (PSM) with replacement was conducted to estimate the treatment effect of the program on clinical outcomes and healthcare utilization over 1 year. For the simulation component, a long-term CEA was performed using a Markov state transition model on a simulated cohort of 10 000 patients with DFUs over a 20-year period, assessing transitions between health states, including minor and major amputations and death. The incremental cost-effectiveness ratio (ICER) was calculated for the DEFINITE Care program relative to routine care.Results The estimation of average treatment effects based on propensity scores showed that the DEFINITE Care group exhibited a 9% lower mortality, 5% higher lower extremity amputation (LEA)-free survival, yet a 5% higher minor LEA rate compared with the matched historical controls. Additionally, they experienced fewer inpatient admissions (0.98 fewer episodes) and shorter hospital stays (5.5 fewer days) within 1 year (p-value

Aims: This review aimed to synthesise the evidence related to the incidence of serious and non-serious adverse events with the use of monoclonal antibodies (mAbs) among COVID-19 patients., Methods: Databases were searched from January 2020 to September 2023 for randomized clinical trials (RCTs) that used mAbs for the treatment of COVID-19 regardless of disease severity. Study screening, data extraction and data analysis were performed independently by two reviewers. The Cochrane risk of bias 1.0 tool was used for methodological quality assessment., Results: Sixteen studies were identified for analysis with 9682 participants in the intervention arm and 10 115 participants in the control arm. Seven trials reported hepatoxicity and there was a statistically significant increase in the chance of hepatoxicity among patients treated with mAbs compared to those given standard of care (SoC) or placebo with risk ratio (RR) = 1.70, 95% confidence interval (CI) 1.29-2.24. Five trials reported for neutropenia and there was a statistically significant association of neutropenia with the use of mAbs compared to SoC or placebo with RR = 4.03, 95% CI 1.74-9.34. Ten trials reported any disease-related serious adverse events related to the disease and there was a reduction of risk compared to SoC/placebo,  although this reduction was not statistically significant (RR = 0.88, 95% CI 0.70-1.11)., Conclusions: The use of mAbs was found to be associated with an increased risk of hepatoxicity and neutropenia compared to SoC/placebo among COVID-19 patients with moderate certainty of evidence. Long-term observational studies are recommended to observe post-COVID adverse events related to the use of mAbs., (© 2025 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Through the National Healthcare Group-Khoo Teck Puat Hospital Monogenic Diabetes Registry, we aimed to determine the prevalence and spectrum of maturity-onset diabetes of the young (MODY), describe the long-term renal trajectory of major MODY subtypes, and develop a diagnostic algorithm based on a combination of clinical parameters and biomarkers to refine selection of candidates for genetic testing., Methods: A total of 373 study participants attending secondary care diabetes centres in Singapore were referred for genetic testing. Key inclusion criteria for genetic testing included onset age ≤35 years, body mass index <32.5 kg/m2 and absence of glutamic acid decarboxylase autoantibody., Results: Analysis of 16 genes and one mitochondrial variant led to a molecular diagnosis in 49 participants, with pathogenic variants present mostly in HNF1A (29%), HNF4A (23%) and GCK (15%). Long-term renal trajectory data observed between these major MODY subtypes were not significantly different, but some key observations were typical for each subgroup. For instance, patients with HNF4A-MODY were predisposed to the risk of microvascular complications (i.e., diabetic kidney disease), while patients with GCK-MODY had mild and non-progressive hyperglycaemia. A structured diagnostic algorithm, including readily available biomarkers such as high-sensitive C-reactive protein (hs-CRP) and high-density lipoprotein-cholesterol (HDL-c), provided 71% diagnostic accuracy, achieving a negative predictive value of 0.94 and a sensitivity of 0.68., Conclusion: The prevalence of MODY (13%) is non-trivial among young-onset diabetes referred for genetic testing based on clinical classifiers suggestive of MODY. Current clinical assessment tools may include hs-CRP and HDL-c to refine selection of candidates for genetic testing., (Copyright © 2025 Singapore Medical Journal.)

Antibodies are naturally produced safeguarding proteins that the immune system generates to fight against invasive invaders. For centuries, they have been produced artificially and utilized to eradicate various infectious diseases. Given the ongoing threat posed by COVID-19 pandemics worldwide, antibodies have become one of the most promising treatments to prevent infection and save millions of lives. Currently, in silico techniques provide an innovative approach for developing antibodies, which significantly impacts the formulation of antibodies. These techniques develop antibodies with great specificity and potency against diseases such as SARS-CoV-2 by using computational tools and algorithms. Conventional methods for designing and developing antibodies are frequently costly and time-consuming. However, in silico approach offers a contemporary, effective, and economical paradigm for creating next-generation antibodies, especially in accordance with recent developments in bioinformatics. By utilizing multiple antibody databases and high-throughput approaches, a unique antibody construct can be designed in silico , facilitating accurate, reliable, and secure antibody development for human use. Compared to their traditionally developed equivalents, a large number of in silico -designed antibodies have advanced swiftly to clinical trials and became accessible sooner. This article helps researchers develop SARS-CoV-2 antibodies more quickly and affordably by giving them access to current information on computational approaches for antibody creation., 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., (Copyright © 2025 Subramaniam, Mualif, Chan and Abd Halim.)

Importance: Distant metastasis (DM) remains the leading cause of death in patients treated for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). An effective treatment strategy needs to address DM while reducing treatment-related toxic effects., Objective: To assess DM-free survival in patients with HPV-OPSCC treated with neoadjuvant chemotherapy followed by transoral robotic surgery (NECTORS) and neck dissection compared with standard of care, concurrent chemoradiation (CCRT)., Design, Setting, and Participants: This multicenter retrospective cohort study compares prospective data from the NECTORS treatment group with a historical cohort of patients treated with CCRT. Patients with American Joint Committee on Cancer seventh edition stage III and IVa HPV-OPSCC treated with NECTORS and CCRT between February 2010 and September 2021 were included. Data were analyzed in September 2024., Exposures: Patients in the NECTORS arm were treated with 3 cycles of neoadjuvant docetaxel and cisplatin followed by TORS and neck dissection. Patients in the radiation therapy arm were treated with concurrent high-dose cisplatin and radiotherapy., Main Outcomes and Measures: DM-free survival was analyzed with Kaplan-Meier and Cox regression after adjusting for age, sex, tobacco and alcohol use, site, and cancer stage., Results: Of 342 included patients, 282 (82.5%) were male, and the mean (SD) age was 61.4 (9.4) years. A total of 232 patients were treated with CCRT and 110 patients were treated with NECTORS. Within the CCRT arm, 11 patients (4.7%) had locoregional recurrence (LRR), 5 (2.2%) had LRR and DM, and 28 (12.1%) developed distant-only metastasis. For patients treated with NECTORS, 5 (4.5%) developed LRR, 1 (0.9%) developed LRR plus DM, and no patients developed distant-only metastasis. With pseudorandomization matching for T and N stages, 209 patients were matched between the 2 treatment groups for further analysis (105 in the CCRT treatment arm and 104 in the NECTORS arm). The median (range) follow-up period for the CCRT and NECTORS groups were 5.8 (3.8-7.5) years and 5.1 (4.0-5.9) years, respectively. The hazard ratio of developing distant recurrence in the CCRT group was 10.77 (95% CI, 1.40-82.90) in univariate analysis and 9.98 (95% CI, 1.29-77.29) in multivariable analysis. In Kaplan-Meier survival analysis, the risk of developing DM was higher in the CCRT group. The hazard ratio for failure anywhere in the CCRT group was 3.32 (95% CI, 1.23-8.97) in univariate analysis and 3.21 (95% CI, 1.18-8.72) in multivariable analysis., Conclusions and Relevance: In this study, neoadjuvant chemotherapy followed by transoral robotic surgery and neck dissection was an effective treatment option for patients with stage III and IVa HPV-OPSCC. Findings from our study suggest lower rates of DM with NECTORS worthy of further investigation in prospective randomized trials.

Objective: To study the effectiveness of virtual reality (VR) in reducing anxiety levels in patients undergoing first-time sternotomy for cardiac surgery., Patients and Methods: A total of 100 adult patients scheduled for cardiac surgery at Mayo Clinic in Rochester, Minnesota, USA, was recruited from April 19, 2022, to October 12, 2022. Before surgery, patients wore a physiological monitor to record vital signs. On the day of surgery, patients completed the State-Trait Anxiety Inventory (STAI) and were randomized into two groups: one receiving a tablet-based intervention (control) and the other an immersive VR experience in the preoperative holding area. After the interventions, patients repeated the state anxiety component of the STAI., Results: The results showed that overall state anxiety scores decreased an average of 2.0 points with tablet treatment, but this change failed to reach statistical significance. However, 6 of 20 specific state anxiety features significantly improved with tablet treatment whereas 1 feature significantly worsened. With the VR experience, overall state anxiety scores were significantly reduced by an average of 2.9 points, with improvement in seven state anxiety features (three of which did not overlap with the tablet intervention). Despite a greater reduction in the STAI score with the VR experience, there were no significant differences in the anxiolytic responses between groups. Physiologically, both tablet and VR treatments slightly but significantly reduced pulse rate, with no difference between the groups., Conclusion: Overall, the findings suggest that treatment of older adults with an immersive VR experience before cardiac surgery can significantly reduce overall anxiety. Further investigation determining how such interventions can be optimally implemented in surgical practices and whether such interventions reduce the need for anxiolytic medications and improve the overall patient experience is needed., (Copyright © 2024. Published by Elsevier Inc.)

Aims: This novel longitudinal study investigated the association of the new dysfunctional adiposity index (DAI) with kidney impairment in multi-ethnic Asians with type 2 diabetes mellitus (T2DM), and the mediation effect of pigment epithelium-derived factor (PEDF)., Methods: T2DM adults followed for up to 10.5 years were analyzed (n = 1611). DAI was calculated using a sex-specific formula. Baseline plasma PEDF levels were quantified using immunoassay. Diabetic kidney disease (DKD) was defined as presence of chronic kidney disease and/or albuminuria. The longitudinal outcomes included ≥40 % decline in estimated glomerular filtration rate from baseline (significant eGFR decline), albuminuria progression, and end-stage kidney disease (ESKD)., Results: Baseline DAI was associated with kidney parameters and DKD cross-sectionally, and showed increased discrimination ability. DAI was correlated with PEDF (rho = 0.324, P < 0.001). Additionally, DAI predicted significant eGFR decline (35.8 % prevalence) in the unadjusted (hazard ratio = 1.49, 95 % CI:1.31-1.70) and covariate-adjusted (hazard ratio = 1.23, 95 % CI:1.06-1.41) models; and was associated with ESKD and albuminuria progression. The relationship between DAI and significant eGFR decline was attenuated after accounting for PEDF, which explained 53.6 % of the indirect effect of DAI on significant eGFR decline., Conclusions: Elevated DAI and its associated PEDF may serve as useful indicators for kidney function decline in T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Context: Patients with younger onset of type 2 diabetes (YT2D) have increased risk for kidney failure compared to those with late onset. However, the mechanism of diabetic kidney disease (DKD) progression in this high-risk group is poorly understood., Objective: This work aimed to identify novel biomarkers and potential causal proteins associated with DKD progression in patients with YT2D., Methods: Among YT2D (T2D onset age <40 years), 144 DKD progressors (cases) were matched for T2D onset age, sex, and ethnicity with 292 nonprogressors (controls) and divided into discovery and validation sets. DKD progression was defined as decline of estimated glomerular filtration rate (eGFR) of 3 mL/min/1.73 m2 or greater or 40% decline in eGFR from baseline. A total of 1472 plasma proteins were measured through a multiplex immunoassay that uses a proximity extension assay technology. Multivariable logistic regression was used to identify proteins associated with DKD progression. Mendelian randomization (MR) was used to evaluate causal relationship between plasma proteins and DKD progression., Results: Forty-two plasma proteins were associated with DKD progression, independent of traditional cardiorenal risk factors, baseline eGFR, and urine albumin-to-creatinine ratio. The proteins identified were related to inflammatory and remodeling biological processes. Our findings suggest angiogenin as one of the top signals (odds ratio = 5.29; 95% CI, 2.39-11.73; P = 4.03 × 10-5). Furthermore, genetically determined plasma angiogenin level was associated with increased odds of DKD progression., Conclusion: Large-scale proteomic analysis identified novel proteomic biomarkers for DKD progression in YT2D. Genetic evidence suggest a causal role of plasma angiogenin in DKD progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancers worldwide. The majority of the new cases were from Asia and are the leading cause of cancer in China. The main treatment is surgery and radiotherapy with chemotherapy for advanced cases. With the advancement of targeted therapies, the objective of this study was to investigate the efficacy and safety of targeted therapies in NPC., Methods: Databases were searched from inception to Aug 2023, comparing molecular targeted therapies (MTT) with conventional chemotherapy, chemotherapy or surgery. Study screening, data extraction, and data analysis were conducted independently by two investigators. The Cochrane Risk of Bias tool 1.0 was used for the quality of the studies., Results: There was a total of ten eligible studies with 471 participants in the treatment arm and 469 participants in the control arm. Most studies had an unclear risk of bias assessment. Upon network meta-analysis, cetuximab was found to be the most effective regimen for complete response (CR), bevacizumab was found to be the most effective regimen for partial response (PR), nimotuzumab was found to be the most effective regimen for overall survival rate (OS) and progression-free survival (PFS). Pairwise meta-analysis showed that MTT had a significantly better response than conventional therapies in complete response. GRADE analysis reported low certainty of evidence for CR and very low certainty of evidence for other efficacy outcomes. There was a higher chance of bleeding with MTT and was statistically significant., Conclusion: It was observed that targeted therapies were found to be a promising strategy for NPC especially recurrent and/or metastatic NPC, but the most appropriate therapy still needs to be evaluated., Trial Registration: This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) with a registration number of INPLASY202380024., Competing Interests: Declarations. Ethics approval and consent to participate: Not relevant. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Aims: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear., Methods: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD., Results: Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations., Conclusions: Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Macroscopic loss of extracellular matrix can lead to chronic defects in skin wound healing, but supplementation of extracellular matrix holds promise for facilitating wound closure, particularly in diabetic wound healing. We recently showed that the extracellular matrix proteoglycan agrin accelerates cutaneous wound healing by improving mechanoperception of migrating keratinocytes and allowing them to respond to mechanical stresses through matrix metalloproteinase 12 (MMP12). RNA-sequencing analysis revealed that in addition to a disorganized extracellular matrix, agrin-depleted skin cells have impaired YAP/TAZ transcriptional outcomes, leading us to hypothesize that YAP/TAZ, as central mechanosensors, drive the functionality of agrin-MMP12 signaling during cutaneous wound repair. In this study, we demonstrate that agrin activates YAP/TAZ during migration of keratinocytes after wounding in vitro and in vivo. Mechanistically, YAP/TAZ sustain agrin and MMP12 protein expression during migration after wounding through positive feedback. YAP/TAZ silencing abolishes agrin-MMP12-mediated force recognition and geometrical constraints. Importantly, soluble agrin therapy accelerates wound closure in diabetic mouse models by engaging MMP12-YAP. Because patients with diabetic foot ulcers and impaired wound healing have reduced expression of agrin-MMP12 that correlates with YAP/TAZ inactivation, we propose that timely activation of YAP/TAZ by soluble agrin therapy can accentuate mechanobiological microenvironments for efficient wound healing, under normal and diabetic conditions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)