Background/Objective: With the rapid advancement in surgical technologies, new workflows for mandibular reconstruction are constantly being evaluated. Cutting guides are extensively employed for defining osteotomy planes but are prone to errors during fabrication and positioning. A virtually defined osteotomy plane and drilling holes in robotic surgery minimize potential sources of error and yield highly accurate outcomes. Methods: Ten mandibular replicas were evaluated after cutting-guided saw osteotomy and robot-guided laser osteotomy following reconstruction with patient-specific implants. The descriptive data analysis summarizes the mean, standard deviation (SD), median, minimum, maximum, and root mean square (RMS) values of the surface comparison for 3D printed models regarding trueness and precision. Results: The saw group had a median trueness RMS value of 2.0 mm (SD ± 1.7) and a precision of 1.6 mm (SD ± 1.4). The laser group had a median trueness RMS value of 1.2 mm (SD ± 1.1) and an equal precision of 1.6 mm (SD ± 1.4). These results indicate that robot-guided laser osteotomies have a comparable accuracy to cutting-guided saw osteotomies, even though there was a lack of statistical significance. Conclusions: Despite the limited sample size, this digital high-tech procedure has been shown to be potentially equivalent to the conventional osteotomy method. Robotic surgery and laser osteotomy offers enormous advantages, as they enable the seamless integration of precise virtual preoperative planning and exact execution in the human body, eliminating the need for surgical guides in the future.

El Hierro is the smallest and westernmost island of the Canary Islands, whose population derives from an admixture of different ancestral components and that has been subjected to genetic isolation. We established the \"El Hierro Genome Study\" to characterize the health status and the genetic composition of ~10% of the current population of the island, accounting for a total of 1054 participants. Detailed demographic and clinical data and a blood sample for DNA extraction were obtained from each participant. Genomic genotyping was performed with the Global Screening Array (Illumina). The genetic composition of El Hierro was analyzed in a subset of 416 unrelated individuals by characterizing the mitochondrial DNA (mtDNA) and Y-chromosome haplogroups and performing principal component analyses (PCAs). In order to explore signatures of isolation, runs of homozygosity (ROHs) were also estimated. Among the participants, high blood pressure, hypercholesterolemia, and diabetes were the most prevalent conditions. The most common mtDNA haplogroups observed were of North African indigenous origin, while the Y-chromosome ones were mainly European. The PCA showed that the El Hierro population clusters near 1000 Genomes\' European population but with a shift toward African populations. Moreover, the ROH analysis revealed some individuals with an important portion of their genomes with ROHs exceeding 400 Mb. Overall, these results confirmed that the \"El Hierro Genome\" cohort offers an opportunity to study the genetic basis of several diseases in an unexplored isolated population.

With ageing, the risk of frailty increases, becoming a common condition that exposes older people to an increased risk of multiple adverse health outcomes. In Valencia (Spain), the ValueCare project develops and applies a value-based care approach that addresses the multidimensional nature of frailty by implementing integrated and personalized care to tackle psychosocial frailty. A pre-post controlled design with a baseline measurement at inclusion, at the end of implementation and a follow-up measurement after 6 months of intervention. In Valencia (Spain), 120 participants over 65 years of age are recruited from primary care centres to receive the ValueCare comprehensive and personalised care plan according to the results and are compared with 120 participants receiving \"usual care\". An assessment questionnaire is designed using validated instruments, and a personalised care plan is developed specifically for each participant based on the results obtained. The study protocol has been registered under the ISRCTN registration number ISRCTN25089186. Addressing frailty as a multidimensional and multifactorial risk condition requires the development and implementation of comprehensive assessments and care. In this context, this study will provide new insights into the feasibility and effectiveness of a value-based methodology for integrated care supported by ICT for older people experiencing frailty.

Next-generation sequencing (NGS) significantly enhances precision medicine (PM) by offering personalized approaches to diagnosis, treatment, and prevention of unmet medical needs. Little is known about the current situation of PM in Asia. Thus, we aimed to conduct an overview of the progress and gaps in PM in Asia and enrich it with in-depth insight into the possibilities of future PM in Thailand. This scoping review focused on Asian countries starting with non-cancer studies, including rare and undiagnosed diseases (RUDs), non-communicable diseases (NCDs), infectious diseases (IDs), and pharmacogenomics, with a focus on NGS. Subsequent in-depth interviews with experts in Thailand were performed, and a thematic analysis served as the main qualitative methodology. Out of 2898 searched articles, 387 studies were included after the review. Although most of the studies focused on cancer, 89 (23.0%) studies were related to RUDs (17.1%), NCDs (2.8%), IDs (1.8%), and pharmacogenomics (1.3%). Apart from medicine and related sciences, the studies were mostly composed of PM (61.8%), followed by genetics medicine and bioinformatics. Interestingly, 28% of articles were conducted exclusively within the fields of medicine and related sciences, emphasizing interdisciplinary integration. The experts emphasized the need for sustainability-driven political will, nurturing collaboration, reinforcing computational infrastructure, and expanding the bioinformatic workforce. In Asia, developments of NGS have made remarkable progress in PM. Thailand has extended PM beyond cancer and focused on clinical implementation. We summarized the PM challenges, including equity and efficiency targeting, guided research funding, sufficient sample size, integrated collaboration, computational infrastructure, and sufficient trained human resources.

It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.

BACKGROUND: Individualizing and optimizing treatment of relapsing-remitting multiple sclerosis patients is a challenging problem, which would benefit from a clinically valid decision support. Stühler et al. presented black box models for this aim which were developed and internally evaluated in a German registry but lacked external validation.
METHODS: In patients from the French OFSEP registry, we independently built and validated models predicting being free of relapse and free of confirmed disability progression (CDP), following the methodological roadmap and predictors reported by Stühler. Hierarchical Bayesian models were fit to predict the outcomes under 6 disease-modifying treatments given the individual disease course up to the moment of treatment change. Data was temporally split on 2017, and models were developed in patients treated earlier (n = 5517). Calibration curves, discrimination, mean squared error (MSE) and relative percentage of root MSE (RMSE%) were assessed by external validation of models in more-recent patients (n = 3768). Non-Bayesian fixed-effects GLMs were also applied and their outcomes were compared to these of the Bayesian ones. For both, we modelled the number of on-therapy relapses with a negative binomial distribution, and CDP occurrence with a binomial distribution.
RESULTS: The performance of our temporally-validated relapse model (MSE: 0.326, C-Index: 0.639) is potentially superior to that of Stühler\'s (MSE: 0.784, C-index: 0.608). Calibration plots revealed miscalibration. Our CDP model (MSE: 0.072, C-Index: 0.777) was also better than its counterpart (MSE: 0.131, C-index: 0.554). Results from non-Bayesian fixed-effects GLM models were similar to the Bayesian ones.
CONCLUSIONS: The relapse and CDP models rebuilt and externally validated in independent data could compare and strengthen the credibility of the Stühler models. Their model-building strategy was replicable.

OBJECTIVE: The Precision Oncology Platform (POP) trial represents the effort of the Portuguese Oncology Institute of Porto (IPO Porto) for joining other leading European institutions in both \'Personalised Cancer Medicine for all EU citizens\' (PCM4EU), and \'PRecisIon Cancer MEdicine RepurpOsing SystEm Using Pragmatic Clinical Trials\' (PRIME-ROSE) consortia, enabling the development of the Portuguese version of the Drug Rediscovery Protocol (DRUP)-like Clinical Trial (DLCT), based on the experience of the DRUP trial developed in The Netherlands.
METHODS: The POP trial is a phase II, pragmatic multicentric, non-randomised, open-label study, designed entirely like the other DLCTs. Its primary objective is to describe anti-tumour activity of targeted anticancer drugs in patients with advanced malignancies harbouring actionable molecular alterations. The primary endpoint is disease control rate (DCR). Secondary endpoints encompass treatment-related grade ≥3 adverse events, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives will assess biomarkers, resource use and costs, and patient-reported outcome measures (PROMs).
CONCLUSIONS: The POP trial will offer access to innovative treatments for patients without further therapeutic options and provide evidence on efficacy and safety of molecularly-guided treatments. Methodologically, it represents a pioneer approach in Portugal, including a pay-for-performance model embedded in the clinical trial. The POP trial represents a unique opportunity to integrate clinical research within cancer care, pursuing an evidence-based precision oncology strategy, and facilitating its rational and cost-effective implementation into the Portuguese healthcare system.

BACKGROUND: We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort.
METHODS: Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications.
RESULTS: C4 individuals were less likely to develop T2D, were slightly older at T2D diagnosis, had lower HbA1c values, and were less likely to be prescribed T2D medications (P < .05). Genetic variants in MAS1 and IGF2R, major components of the C4 PS, were associated with fewer overall T2D prescriptions.
CONCLUSIONS: We have confirmed C4 individuals are a lower risk subpopulation of patients with T2D.

BACKGROUND: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines.
METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications.
RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes.
CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events.
BACKGROUND: NCT04049149.

BACKGROUND: Patient-reported outcomes measures (PROMs) are increasingly being collected within cancer clinical trials, yet limited literature on the feasibility and acceptability of doing so.
METHODS: We collected parent-proxy and adolescent (≥12 years old) PROMs through a longitudinal, psychosocial sub-study (\'PRISM-Impact\') embedded in a precision medicine trial for children with poor prognosis cancer (\'PRISM\'). We report on feasibility (response, participation, and attrition rates; follow-up and responding to elevated distress) and acceptability (parents\' perceived benefit/burden of participation; and impact on decision to participate in PRISM) of PRISM-Impact.
RESULTS: Over the reporting period, 462 families were eligible for PRISM-Impact. Family and adolescent response rates were 53% and 45%, respectively. Parents whose child had relapsed were more likely to participate in PRISM-Impact than parents whose child had not (p < 0.001). Parent and adolescent attrition rates were 30% and 56% respectively. We conducted 478 calls for intake and to follow-up on missing questionnaires, and 122 calls to respond to elevated distress. Parents reported wanting to participate in PRISM-Impact for altruistic reasons and because they valued psychosocial research. Parents reported little-to-no burden and some benefit from participating in PRISM-Impact, with little change in ratings overtime. Most parents felt that participating in PRISM-Impact did not impact their desire to participate in PRISM (72%), with some feeling more eager to participate (19%).
CONCLUSIONS: PRISM-Impact response rates were comparable to other psycho-oncology studies, despite the poor prognosis population. Integration of PROMs within a paediatric oncology trial is acceptable to parents, and may provide a more comprehensive assessment of the impact of trial participation.