N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.

Radiation therapy with phenotypic medicine: towards N-of-1 personalization.

In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient's own small datasets. With PM, clinicians may guide patients' RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.

CURATE.AI-assisted dose titration for anti-hypertensive personalized therapy: study protocol for a multi-arm, randomized, pilot feasibility trial using CURATE.AI (CURATE.AI ADAPT trial).

Aims: Artificial intelligence-driven small data platforms such as CURATE.AI hold potential for personalized hypertension care by assisting physicians in identifying personalized anti-hypertensive doses for titration. This trial aims to assess the feasibility of a larger randomized controlled trial (RCT), evaluating the efficacy of CURATE.AI-assisted dose titration intervention. We will also collect preliminary efficacy and safety data and explore stakeholder feedback in the early design process. Methods and results: In this open-label, randomized, pilot feasibility trial, we aim to recruit 45 participants with primary hypertension. Participants will be randomized in 1:1:1 ratio into control (no intervention), home blood pressure monitoring (active control; HBPM), or CURATE.AI arms (intervention; HBPM and CURATE.AI-assisted dose titration). The home treatments include 1 month of two-drug anti-hypertensive regimens. Primary endpoints assess the logistical (e.g. dose adherence) and scientific (e.g. percentage of participants for which CURATE.AI profiles can be generated) feasibility, and define the progression criteria for the RCT in a 'traffic light system'. Secondary endpoints assess preliminary efficacy [e.g. mean change in office blood pressures (BPs)] and safety (e.g. hospitalization events) associated with each treatment protocol. Participants with both baseline and post-treatment BP measurements will form the intent-to-treat analysis. Following their involvement with the CURATE.AI intervention, feedback from CURATE.AI participants and healthcare providers will be collected via exit survey and interviews. Conclusion: Findings from this study will inform about potential refinements of the current treatment protocols before proceeding with a larger RCT, or potential expansion to collect additional information. Positive results may suggest the potential efficacy of CURATE.AI to improve BP control. Trial registration number: NCT05376683.

Comparing the Performance of Multiple Small-Data Personalized Tacrolimus Dosing Models for Pediatric Liver Transplant: A Retrospective Study.

Tacrolimus is a potent immunosuppressant used after pediatric liver transplant. However, tacrolimus's narrow therapeutic window, reliance on physicians' experience for the dose titration, and intra- and inter-patient variability result in liver transplant patients falling out of the target tacrolimus trough levels frequently. Existing personalized dosing models based on the area-under-the-concentration over time curves require a higher frequency of blood draws than the current standard of care and may not be practically feasible. We present a small-data artificial intelligence-derived platform, CURATE.AI, that uses data from individual patients obtained once daily to model the dose and response relationship and identify suitable doses dynamically. Retrospective optimization using 6 models of CURATE.AI and data from 16 patients demonstrated good predictive performance and identified a suitable model for further investigations.Clinical Relevance- This study established and compared the predictive performance of 6 personalized tacrolimus dosing models for pediatric liver transplant patients and identified a suitable model with consistently good predictive performance based on data from pediatric liver transplant patients.

Anterior cruciate ligament rupture and associated Segond fracture: Incidence and effect on associated ligamentous and meniscal injuries.

Introduction: The Segond fracture is an avulsion fracture of the lateral tibial plateau and is widely considered to be pathognomonic of anterior cruciate ligament (ACL) rupture. In addition to ACL rupture, Segond fractures have also been noted to be associated with significant intra-articular pathology such as meniscal injuries as well as extra-articular pathology such as collateral ligament injuries. This is likely due to the fact that the presence of a Segond fracture may represent increased rotatory instability. Whilst several studies have demonstrated the association of a Segond fracture with significant intra-articular pathology, there is a paucity of literature assessing if the combination of an ACL rupture and Segond fracture gives rise to higher rates of concomitant ligamentous and meniscal injuries. The primary objective of this study is to determine if patients with ACL ruptures associated with Segond fractures have higher rates of concomitant ligamentous and meniscal injury, when compared to patients with ACL ruptures without a Segond fracture. Methods: A retrospective review of all patients who underwent ACL reconstruction in a single institution between 2014 to 2018 was conducted. A review of the patients' demographics, operative notes, and radiographs was performed. X-rays and MRI scans were double-read by a board-certified radiologist and Orthopaedic surgeon. Results: A total of 414 subjects were included. The incidence of Segond fracture was 2.4%. The mean age was 24.7±7.4 (range 16 to 60) years and 26.7±7.6 (range 16 to 38) years in patients with and without Segond fractures respectively. 89.9% of patients suffered a non-contact mechanism of injury, with sports injuries being most common (79.5%). There was a significantly higher rate of isolated lateral meniscus tears in patients with Segond fractures compared to those without (50% v.s. 20.8%) based on pre-operative MRI. (p<0.05) There were no other significant differences in associated ligamentous injuries. Conclusion: The incidence of Segond fracture associated with ACL rupture is 2.4%. There is a significantly higher risk of a concomitant isolated lateral meniscus tear in ACL ruptures associated with a Segond fracture. There is no significantly higher risk of concomitant ligamentous injuries in ACL ruptures associated with a Segond fracture.

Trigonometry-Integrated 'Lift' Technique (TILT) for Restoring Volar Tilt in Distal Radius Fractures: Description of Technique and Preliminary Results.

BACKGROUND: Restoration of extra-articular and intra-articular parameters are important considerations during operative fixation of distal radius fractures. Restoration of volar tilt by using visual estimation and the 'lift' technique has previously been described. The aim of our study was to describe a mathematical technique for accurately restoring the volar tilt of the distal radius to acceptable anatomic values. METHODS: A retrospective review of cases performed using the trigonometry-integrated ' lift' technique (TILT) was performed. This technique uses the pre-operative volar tilt angle as well as the dimensions of the implant to calculate the 'lift' required to restore volar tilt. Intra-operative angles were measured using a marked transparency overlay on fluoroscopic images. Pre-operative and post-operative volar tilt were measured and analysed. RESULTS: Twenty-seven fractures were included in the study, with 20 being classified as Arbeitsgemeinschaft für Osteosynthesefragen (AO) C-type. Pre-'lift' volar tilt ranged from 0° to -20°. Post-'lift' volar tilt ranged from 2° to 16°, with all but three cases ranging from 5° to 15°. The mean volar tilt achieved was 10.2°. CONCLUSIONS: The trigonometry-integrated 'lift' technique resulted in reliable intra-operative restoration of anatomic volar tilt in distal radius fractures.

Inpatient cost for hip fracture patients managed with an orthogeriatric care model in Singapore.

INTRODUCTION: The estimated incidence of hip fractures worldwide was 1.26 million in 1990 and is expected to double to 2.6 million by 2025. The cost of care for hip fracture patients is a significant economic burden. This study aimed to look at the inpatient cost of hip fractures among elderly patients placed under a mature orthogeriatric co-managed system. METHODS: This study was a retrospective analysis of 244 patients who were admitted to the Department of Orthopaedics of Tan Tock Seng Hospital, Singapore, in 2011 for hip fractures under a mature orthogeriatric hip fracture care path. Information regarding costs, surgical procedures performed and patient demographics was collected. RESULTS: The mean cost of hospitalisation was SGD 13,313.81. The mean cost was significantly higher for the patients who were managed surgically than for the patients who were managed non-surgically (SGD 14,815.70 vs. SGD 9,011.38; p < 0.01). Regardless of whether surgery was performed, the presence of complications resulted in a higher average cost (SGD 2,689.99 more than if there were no complications; p = 0.011). Every additional day from admission to time of surgery resulted in an increased cost of SGD 575.89, and the difference between the average cost of surgery within 48 hours and that of surgery > 48 hours was SGD 2,716.63. CONCLUSION: Reducing the time to surgery and preventing pre- and postoperative complications can help reduce overall costs. A standardised care path that empowers allied health professionals can help to reduce perioperative complications, and a combined orthogeriatric care service can facilitate prompt surgical treatment.

Projecting the environmental profile of Singapore's landfill activities: Comparisons of present and future scenarios based on LCA.

This article aims to generate the environmental profile of Singapore's Semakau landfill by comparing three different operational options associated with the life cycle stages of landfilling activities, against a 'business as usual' scenario. Before life cycle assessment or LCA is used to quantify the potential impacts from landfilling activities, an attempt to incorporate localized and empirical information into the amounts of ash and MSW sent to the landfill was made. A linear regression representation of the relationship between the mass of waste disposed and the mass of incineration ash generated was modeled from waste statistics between years 2004 and 2009. Next, the mass of individual MSW components was projected from 2010 to 2030. The LCA results highlighted that in a 'business as usual' scenario the normalized total impacts of global warming, acidification and human toxicity increased by about 2% annually from 2011 to 2030. By replacing the 8000-tonne barge with a 10000-tonne coastal bulk carrier or freighter (in scenario 2) a grand total reduction of 48% of both global warming potential and acidification can be realized by year 2030. Scenario 3 explored the importance of having a Waste Water Treatment Plant in place to reduce human toxicity levels - however, the overall long-term benefits were not as significant as scenario 2. It is shown in scenario 4 that the option of increased recycling championed over all other three scenarios in the long run, resulting in a total 58% reduction in year 2030 for the total normalized results. A separate comparison of scenarios 1-4 is also carried out for energy utilization and land use in terms of volume of waste occupied. Along with the predicted reductions in environmental burdens, an additional bonus is found in the expanded lifespan of Semakau landfill from year 2032 (base case) to year 2039. Model limitations and suggestions for improvements were also discussed.