Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

Gaps in the Global Regulatory Frameworks for the Use of Artificial Intelligence (AI) in the Healthcare Services Sector and Key Recommendations.

Artificial Intelligence (AI) has shown remarkable potential to revolutionise healthcare by enhancing diagnostics, improving treatment outcomes, and streamlining administrative processes. In the global regulatory landscape, several countries are working on regulating AI in healthcare. There are five key regulatory issues that need to be addressed: (i) data security and protection-measures to cover the "digital health footprints" left unknowingly by patients when they access AI in health services; (ii) data quality-availability of safe and secure data and more open database sources for AI, algorithms, and datasets to ensure equity and prevent demographic bias; (iii) validation of algorithms-mapping of the explainability and causability of the AI system; (iv) accountability-whether this lies with the healthcare professional, healthcare organisation, or the personified AI algorithm; (v) ethics and equitable access-whether fundamental rights of people are met in an ethical manner. Policymakers may need to consider the entire life cycle of AI in healthcare services and the databases that were used for the training of the AI system, along with requirements for their risk assessments to be publicly accessible for effective regulatory oversight. AI services that enhance their functionality over time need to undergo repeated algorithmic impact assessment and must also demonstrate real-time performance. Harmonising regulatory frameworks at the international level would help to resolve cross-border issues of AI in healthcare services.

Pathogen genomic surveillance status among lower resource settings in Asia.

Asia remains vulnerable to new and emerging infectious diseases. Understanding how to improve next generation sequencing (NGS) use in pathogen surveillance is an urgent priority for regional health security. Here we developed a pathogen genomic surveillance assessment framework to assess capacity in low-resource settings in South and Southeast Asia. Data collected between June 2022 and March 2023 from 42 institutions in 13 countries showed pathogen genomics capacity exists, but use is limited and under-resourced. All countries had NGS capacity and seven countries had strategic plans integrating pathogen genomics into wider surveillance efforts. Several pathogens were prioritized for human surveillance, but NGS application to environmental and human-animal interface surveillance was limited. Barriers to NGS implementation include reliance on external funding, supply chain challenges, trained personnel shortages and limited quality assurance mechanisms. Coordinated efforts are required to support national planning, address capacity gaps, enhance quality assurance and facilitate data sharing for decision making.

Para-Hydroxycinnamic Acid Mitigates Senescence and Inflammaging in Human Skin Models.

Para-hydroxycinnamic acid (pHCA) is one of the most abundant naturally occurring hydroxycinnamic acids, a class of chemistries known for their antioxidant properties. In this study, we evaluated the impact of pHCA on different parameters of skin aging in in vitro skin models after H2O2 and UV exposure. These parameters include keratinocyte senescence and differentiation, inflammation, and energy metabolism, as well as the underlying molecular mechanisms. Here we demonstrate that pHCA prevents oxidative stress-induced premature senescence of human primary keratinocytes in both 2D and 3D skin models, while improving clonogenicity in 2D. As aging is linked to inflammation, referred to as inflammaging, we analyzed the release of IL-6, IL-8, and PGE2, known to be associated with senescence. All of them were downregulated by pHCA in both normal and oxidative stress conditions. Mechanistically, DNA damage induced by oxidative stress is prevented by pHCA, while pHCA also exerts a positive effect on the mitochondrial and glycolytic functions under stress. Altogether, these results highlight the protective effects of pHCA against inflammaging, and importantly, help to elucidate its potential mechanisms of action.

Epidemiology of work-related injuries, musculoskeletal disorders and dermatitis among hospital food service workers in a tertiary hospital in Asia.

BACKGROUND: Despite the relative importance, the prevalence of workplace safety and health issues in hospital food service workers is not well studied. This study describes the epidemiology of work-related injuries and occupational diseases among hospital food service workers (FSWs) in a tertiary hospital in Singapore. METHODS: Using a total population sampling approach, a cross-sectional self-administered questionnaire was distributed to all FSWs employed at a major tertiary hospital in Singapore. RESULTS: The response rate was 98.4% (n = 125). The overall prevalence of workplace injuries and musculoskeletal symptoms was 35% (n = 43) and 53% (n = 65) respectively. The most common workplace injuries were cuts/lacerations (35.8%), muscle strain (25.4%) and burns (19.4%). The prevalence of workplace injuries among staff performing food preparation duties was higher at 56.3% as compared to 21.6% among staff with no food preparation duties (p < 0.01). The prevalence of workplace injuries among staff performing cooking duties was also higher at 47.5%, compared to 29.3% among staff with no cooking duties (p = 0.05). Staff performing food preparation duties had a higher prevalence of musculoskeletal symptoms at 66.7% as compared to 44.6% among staff with no food preparation duties (p = 0.02). Obese staff had a higher prevalence of musculoskeletal symptoms at 78.9%, compared to overweight staff at 53.8% and staff with normal weight at 43.1% (p = 0.03). CONCLUSION: FSWs with jobs involving cooking and preparation of food, and those with obesity, are at higher risk of sustaining workplace injuries or musculoskeletal symptoms. Targeted interventions should be implemented for injury prevention and to mitigate these risks.

Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial. METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit. CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Scaffolds and the scaffolding domain: an alternative paradigm for caveolin-1 signaling.

Caveolin-1 (Cav1) is a 22 kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. Scaffolds were originally described as SDS-resistant oligomers composed of 10-15 Cav1 monomers observable as 8S complexes by sucrose velocity gradient centrifugation. Recently, cryoelectron microscopy (cryoEM) and super-resolution microscopy have shown that 8S complexes are interlocking structures composed of 11 Cav1 monomers each, which further assemble modularly to form higher-order scaffolds and caveolae. In addition, Cav1 can act as a critical signaling regulator capable of direct interactions with multiple client proteins, in particular, the endothelial nitric oxide (NO) synthase (eNOS), a role believed by many to be attributable to the highly conserved and versatile scaffolding domain (CSD). However, as the CSD is a hydrophobic domain located by cryoEM to the periphery of the 8S complex, it is predicted to be enmeshed in membrane lipids. This has led some to challenge its ability to interact directly with client proteins and argue that it impacts signaling only indirectly via local alteration of membrane lipids. Here, based on recent advances in our understanding of higher-order Cav1 structure formation, we discuss how the Cav1 CSD may function through both lipid and protein interaction and propose an alternate view in which structural modifications to Cav1 oligomers may impact exposure of the CSD to cytoplasmic client proteins, such as eNOS.

Philippine retinoblastoma initiative multi-eye center study 2010-2020.

AIM: To provide a comprehensive and more representative national data on the disease, especially on treatment options and outcomes, and to determine access of retinoblastoma patients from Luzon, Visayas and Mindanao to eye care, and determine if access is associated with delay in consultation, staging and outcomes. METHODS: Cohort study of retinoblastoma patients seen in eleven institutions located in the three major areas of the Philippines namely Luzon, Vizayas and Mindanao from 2010-2020. RESULTS: Totally 636 patients, involving 821 eyes, were included. Majority (57%) were from Luzon and were seen in institutions in Luzon (72%). Annually, 58±10 new cases were seen with 71% having unilateral disease. Median delay of consultation remained long at 9 (3, 17)mo, longest in patients with unilateral disease (P<0.02) and those from the Visayas (P<0.003). Based on the International Retinoblastoma Staging System, only 35% of patients had Stage 1 while 47% already had extraocular disease. Enucleation was the most common treatment received by 484 patients while intravenous chemotherapy was received by 469. There were 250 (39%) patients alive, 195 (31%) dead, 85 (13%) abandoned, 17 (3%) refused and 89 (14%) with no data. CONCLUSION: This study presents the largest cohort of retinoblastoma patients in the Philippines in terms of patients' and participating institutions' number and geographical location and type of institution (private and public). It also presents more comprehensive data on the treatments used and outcomes (survival, globe salvage, and vision retention rates). Delay in consultation was still long among patients leading to advanced disease stage and lower survival rate. Despite increasing capacity to diagnose and manage retinoblastoma in the country, the delay of consultation remains long primarily due to accessibility issues to eye care institutions especially in the Visayas and financial concerns. The delay was still significant that overall survival rate remain low.

Promoting Collaboration of Regulators and Patients in Improving Drug Safety and Regulatory Decision Making.

Pharmacovigilance involves a continuous process of evaluating, monitoring and communicating the safety profile of a medicine throughout its life cycle. This process involves a range of stakeholders, including national regulatory authorities, industry, health organisations, healthcare providers and patients. Although patients are the end users of medicines and experts in their medical conditions, patient involvement is still nascent in the Asia-Pacific region. While there are positive examples and encouraging trends, several key challenges currently hinder systemic patient involvement in drug safety and regulatory decision making. Systemic issues such as a lack of formalised frameworks or platforms, underdeveloped communication and information exchange channels, and paternalistic health systems constrain greater patient involvement and collaborative regulator-patient activities. Addressing these challenges will greatly advance collaboration among regulators, patients, and patient advocates to enhance drug safety and regulatory decision making.

Tension Pneumopericardium Causing Cardiogenic Shock due to Blunt Injury to the Chest.

Pneumopericardium is an exceptionally uncommon phenomenon in the setting of blunt polytrauma. It is imperative for trauma providers to identify tension pneumopericardium despite its rarity. A 22-year-old male motorcyclist presented to the hospital after colliding with a car going approximately 50 mph. The patient was hemodynamically unstable and had diminished breath sounds bilaterally. Bilateral chest tubes were placed, yielding little improvement in condition. While obtaining CT imaging, pneumopericardium was promptly identified. Pulses were lost immediately before pericardiocentesis, and resuscitative thoracotomy was performed. The pericardial sac was tense and an immediate gush of air released upon incising the sac. The patient was taken immediately to the Operating Room for further exploration and repair.

Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids.

Mutant KRAS regulates transposable element (TE) RNA and interferon-stimulated gene (ISG) expression, but it remains unclear whether diverse mutations in KRAS affect different TE RNAs throughout the genome. We analyzed the transcriptomes of 3D human lung cancer spheroids that harbor KRAS(G12C) mutations to determine the landscape of TE RNAs regulated by mutant KRAS(G12C). We found that KRAS(G12C) signaling is required for the expression of LINE- and LTR-derived TE RNAs that are distinct from TE RNAs previously shown to be regulated by mutant KRAS(G12D) or KRAS(G12V). Moreover, KRAS(G12C) inhibition specifically upregulates SINE-derived TE RNAs from the youngest Alu subfamily AluY. Our results reveal that TE RNA dysregulation in KRAS-driven lung cancer cells is mutation-dependent, while also highlighting a subset of young, Alu-derived TE RNAs that are coordinately activated with innate immunity genes upon KRAS(G12C) inhibition.

Successes and Opportunities during the Pandemic: Reflections and Revelations from a Vaccine Development Perspective.

The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 in Singapore to honor the memory of the late Professor Sir Alasdair Breckenridge, CoRE's founding Chair, and foster dialogue on global biomedical and regulatory perspectives, challenges, and advances. The 2022 Sir Alasdair Breckenridge Lecture "Success and Opportunities in the Pandemic" was delivered by Dr Penny M Heaton, former CEO of the Bill & Melinda Gates Foundation Research Institute and current Global Therapeutics Lead for Vaccines at Johnson & Johnson. Dr Heaton highlighted key lessons on the importance of trust, collaboration, and transparency in the context of health care and vaccine production.

A hospital-based return-to-work programme in Singapore.

Return to Work (RTW) programmes have become imperative in manpower scarce countries. This paper describes a RTW programme in a Singapore tertiary hospital, reports patient outcomes and discusses the practicality and effectiveness of the programme. Seventy-three workers participated in the programme over a two-year period. A statistically significant increase in work ability and self-perceived overall health status from first contact with worker (baseline) to discharge was observed. Continued programme participation till first RTW was associated with higher work ability and self-perceived overall health status at baseline. The RTW Coordinator-anchored multidisciplinary model which provided holistic support to the worker and addressed stakeholder interests were central to the programme's success. Greater awareness of RTW programme benefits will improve sustained participation. Our RTW programme features, implementation experiences and participant reported effectiveness may inform the development of improved return to work models.

Artificial intelligence innovation in healthcare: Relevance of reporting guidelines for clinical translation from bench to bedside.

Artificial intelligence (AI) and digital innovation are transforming healthcare. Technologies such as machine learning in image analysis, natural language processing in medical chatbots and electronic medical record extraction have the potential to improve screening, diagnostics and prognostication, leading to precision medicine and preventive health. However, it is crucial to ensure that AI research is conducted with scientific rigour to facilitate clinical implementation. Therefore, reporting guidelines have been developed to standardise and streamline the development and validation of AI technologies in health. This commentary proposes a structured approach to utilise these reporting guidelines for the translation of promising AI techniques from research and development into clinical translation, and eventual widespread implementation from bench to bedside.

The Outcomes of App-Based Health Coaching to Improve Dietary Behavior Among Nurses in a Tertiary Hospital: Pilot Intervention Study.

BACKGROUND: At the workplace, health care workers face multiple challenges in maintaining healthy dietary behaviors, which is the major factor behind obesity. A hospital-wide mass health screening exercise showed an increasing trend in the prevalence of obesity and median BMI from 2004 to 2019, as well as a higher crude obesity rate among shift workers. OBJECTIVE: We aimed to evaluate the effectiveness of mobile app-based health coaching and incentives for achieving weight loss from better dietary choices among hospital nurses. METHODS: We conducted a pilot study from June 2019 to March 2020, involving the use of a health-coaching app by 145 hospital nurses over 6 months. Weight and BMI were self-reported, and food scores were calculated. Data among overweight nurses, shift work nurses, and incentive groups were analyzed. RESULTS: A total of 61 nurses were included in the final analysis. Of these 61 nurses, 38 (62%) lost weight. The median percentage weight loss was 1.2% (IQR 0%-2.9%; P<.001), and the median decrease in BMI was 0.35 (IQR -0.15 to 0.82; P<.001), but they were not clinically significant. The median improvement in the food score was 0.4 (IQR 0-0.8). There was no difference between the incentive and nonincentive groups. A total of 49 (34%) participants engaged for ≥8 weeks. CONCLUSIONS: The study demonstrated an association between the use of app-based health coaching and the attainment of some weight loss in nurses, without a significant improvement in the food score. Incentives may nudge on-boarding, but do not sustain engagement.