Search

Purpose: In people with cystic fibrosis (pwCF), elexacaftor/tezacaftor/ivacaftor (ETI) therapy is associated with an average improvement in FEV1 of 10–14%. However, a subset of individuals fails to achieve a clinically meaningful increase in spirometric indicators. In this study, we aimed to assess whether the lung clearance index (LCI2.5), a more sensitive indicator of lung involvement, improves following ETI initiation in this population. Methods: We conducted a prospective observational study in a specialized CF center in Italy. PwCF performed a spirometry and a multiple breath nitrogen washout test the day they initiated ETI therapy and after 6 and 12 months. They were grouped according to the 12-month change in FEV1 into two groups: Individuals who experienced a change in FEV1 ≥ a minimal clinically important difference (MCID) of 3% and those who did not. Mean changes in LCI2.5 were estimated using generalized estimating equations. Results: The study included 129 pwCF who initiated ETI at our center (Age Range: 12–36 years). In 20 subjects (15.5%), the FEV1 change was < MCID. These individuals had better baseline pulmonary function than those with FEV1 changes ≥ MCID (Median FEV1: 102.5 vs 87.0%), with the majority (90%) having FEV1 values ≥ 90%. Mean changes in LCI2.5 at 12-month follow-up visit were − 1.44 units (95% CI: − 2.12; − 0.75) in individuals with changes in FEV1 < MCID and − 2.64 units (95% CI: -3.05; -2.23) in those with values ≥ MCID. Conclusion: LCI2.5 is a useful measure to monitor the effectiveness of ETI in pwCF with normal spirometry and limited FEV1 change following treatment initiation. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly aggressive adult brain cancer, characterised by poor prognosis and a dismal five-year survival rate. Despite significant knowledge gains in tumour biology, meaningful advances in patient survival remain elusive. The field of neuro-oncology faces many disease obstacles, one being the paucity of faithful models to advance preclinical research and guide personalised medicine approaches. Recent technological developments have permitted the maintenance, expansion and cryopreservation of GBM explant organoid (GBO) tissue. GBOs represent a translational leap forward and are currently the state-of-the-art in 3D in vitro culture system, retaining brain cancer heterogeneity, and transiently maintaining the immune infiltrate and tumour microenvironment (TME). Here, we provide a review of existing brain cancer organoid technologies, in vivo xenograft approaches, evaluate in-detail the key advantages and limitations of this rapidly emerging technology, and consider solutions to overcome these difficulties. GBOs currently hold significant promise, with the potential to emerge as the key translational tool to synergise and enhance next-generation omics efforts and guide personalised medicine approaches for brain cancer patients into the future. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa is an inflammatory skin disease for which adalimumab is an effective treatment in just over half of cases. Few factors associated with therapeutic response, and therefore potentially predictive of response, are known to date. This real-life study retrospectively explores the existence of such factors in a Belgian cohort of 82 patients, using several response scores: the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Scoring System-55 (iHS4-55), and the dynamic metascore (a combination of the Hurley score, the 2007 version of the Sartorius score, the iHS4 and the HiSCR). Among the factors associated with a good therapeutic response, we find, for example, the "Frictional furunculoid" and "Conglobata" phenotypes, in contrast to the "Scarring folliculitis" phenotype, which is associated with a poorer response to treatment. Other factors associated with a good response to treatment were observed, such as the patient's description of longer flares, or, among others, the presence of inflammatory bowel disease. Subject to our sample size, the window of opportunity for adalimumab, whereby the treatment would be more effective if administered earlier, was not found in this study. [ABSTRACT FROM AUTHOR]

Objective: To review the available literature on variant genital gender‐affirming surgery (GGAS), including the reasons for performing it, the surgeries themselves and their outcomes. Methods: A systematic review on the performance of variant GGAS was conducted (International Prospective Register of Systematic Reviews [PROSPERO] identifier: CRD42022306684) researching PubMed, Embase, Web of Science and Cochrane databases from inception up to 31 December 2023. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were followed, and risk of bias was assessed for each study using the five‐criteria quality assessment checklist. Results: In total 23 case series were included, of which 17 on masculinising and six on feminising surgeries. Patients mainly choose these surgical procedures out of personal desire to avoid risk of complication or because they do not have dysphoria about certain parts of their genitalia. Complications in masculinising surgeries primarily arose from the extended urethra, which could be mitigated through primary perineal urethrostomy. Both phalloplasty and metoidioplasty carried a higher risk of urethral complications when the vagina was preserved. In feminising surgeries, risk of visceral damage and requirement for lifelong self‐dilation could be avoided when vulvoplasty was performed without vaginal canal creation. All studies had a high risk of bias. Conclusion: This review highlights the importance of variant GGAS and acknowledges the preferences of transgender and gender‐diverse individuals. Patients should be informed about the risks and benefits of each step in these procedures. [ABSTRACT FROM AUTHOR]

Representative models of intestinal diseases are transforming our knowledge of the molecular mechanisms of disease, facilitating effective drug screening and avenues for personalised medicine. Despite the emergence of 3D in vitro intestinal organoid culture systems that replicate the genetic and functional characteristics of the epithelial tissue of origin, there are still challenges in reproducing the human physiological tissue environment in a format that enables functional readouts. Here, we describe the latest platforms engineered to investigate environmental tissue impacts, host-microbe interactions and enable drug discovery. This highlights the potential to revolutionise knowledge on the impact of intestinal infection and inflammation and enable personalised disease modelling and clinical translation. [ABSTRACT FROM AUTHOR]

Background/Objectives: Digital twin technology, initially developed for engineering and manufacturing, has entered healthcare. In plastic surgery, digital twins (DTs) have the potential to enhance surgical precision, personalise treatment plans, and improve patient outcomes. This systematic review aims to explore the current use of DTs in plastic surgery and evaluate their effectiveness, challenges, and future potential. Methods: A systematic review was conducted by searching PubMed, Scopus, Web of Science, and Embase databases from their infinity to October 2024. The search included terms related to digital twins and plastic surgery. Studies were included if they focused on applying DTs in reconstructive or cosmetic plastic surgery. Data extraction focused on study characteristics, technological aspects, outcomes, and limitations. Results: After 110 studies were selected for screening, 9 studies met the inclusion criteria, covering various areas of plastic surgery, such as breast reconstruction, craniofacial surgery, and microsurgery. DTs were primarily used in preoperative planning and intraoperative guidance, with reported improvements in surgical precision, complication rates, and patient satisfaction. However, challenges such as high costs, technical complexity, and the need for advanced imaging and computational tools were frequently noted. Limited research exists on using DTs in postoperative care and real-time monitoring. Conclusions: This systematic review highlights the potential of digital twins to revolutionise plastic surgery by providing personalised and precise surgical approaches. However, barriers such as cost, complexity, and ethical concerns must be addressed. Future research should focus on validating clinical outcomes through large-scale studies and developing soft tissue modelling and real-time monitoring capabilities. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focuses on the classification, risk stratification, and metabolic characteristics of acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) and their importance in the advancement of treatment. It discusses current management strategies, including standard chemotherapy regimens and targeted therapies, while highlighting the challenges of drug toxicity and resistance. It also emphasises the importance of understanding metabolic vulnerabilities in leukaemia cells for developing more effective and personalised treatments. Special attention is given to asparaginase therapy and its mechanism of action, limitations, and potential for improvement in both ALL and AML treatment. Acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) remain significant challenges in haematological oncology. This review examines the pathophysiology, classification, and risk stratification of these aggressive malignancies, emphasising their impact on treatment strategies and prognosis. We discuss current standard-of-care treatments, including chemotherapy regimens and targeted therapies, while addressing the associated adverse effects and hypersensitivity reactions. Delving into the metabolic characteristics and vulnerabilities of leukaemia cells, the review highlights the key differences between lymphoid and myeloid leukaemia and how metabolic insights can be utilised for therapeutic purposes, with special focus on asparaginase therapy and its potential for improvement in both ALL and AML treatment. The review conveys the importance of personalised medicine approaches based on individual metabolic profiles and the challenges posed by metabolic heterogeneity and plasticity in leukaemia cells. Combining molecular and metabolic profiling can enhance and refine treatment strategies for acute leukaemia, potentially improving patient outcomes and quality of life. However, integrating these into routine clinical practice requires overcoming various practical, technical, and logistical issues. [ABSTRACT FROM AUTHOR]

The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies. [ABSTRACT FROM AUTHOR]

The relatively recent adoption of Endoscopic Sleeve Gastroplasty (ESG) amongst obese patients has gained approval within the surgical community due to its notable benefits, including significant weight loss, safety, feasibility, repeatability, and potential reversibility. However, despite its promising clinical outcomes and reduced invasiveness, there is still a lack of standardised procedures for performing ESG. Multiple suture patterns and stitching methods have been proposed over time, yet rational tools to quantify and compare their effects on gastric tissues are absent. To address this gap, this study proposed a computational approach. The research involved a case study analyzing three distinct suture patterns (C-shaped, U-shaped and Z-shaped) using a patient-specific computational stomach model generated from magnetic resonance imaging. Simulations mimicked food intake by placing wire features in the intragastric cavity to replicate sutures, followed by applying a linearly increasing internal pressure up to 15 mmHg. The outcomes facilitated comparisons between suture configurations based on pressure–volume behaviours and the distribution of maximum stress on biological tissues, revealing the U-shaped as the more effective in terms of volume reduction, even if with reduced elongation strains and increased tissues stresses, whereas the Z-shaped is responsible of the greatest stomach shortness after ESG. In summary, computational biomechanics methods serve as potent tools in clinical and surgical settings, offering insights into aspects that are challenging to explore in vivo, such as tissue elongation and stress. These methods allow for mechanical comparisons between different configurations, although they might not encompass crucial clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims: Personalised medicine in chronic complex diseases such as rheumatoid arthritis (RA) is within reach but requires international multi-stakeholder collaboration. We exemplify how national implementations of the General Data Protection Regulation (GDPR) have introduced administrative delays and created disincentives for data sharing and collaborative research. Methods: Our Danish/Swedish/Norwegian research collaboration (the 3-year NordForsk-funded "NORA" project) aims to develop a personalised medicine approach for the management of RA, built on the exploitation of unique existing data sources: longitudinal data from clinical rheumatology registries, research cohorts, nationwide health care registries, and biobank material from >20 sample collections. Data and results are shared and accessed remotely by collaborators at secure servers. New biomarker assays and patient-centric implementations of the results are to be explored, validated, and disseminated to patients and health care via the development of digital tools. Results: Following the advice of legal experts at the involved academic or public institutions and private companies, GDPR compliance resulted in >20 legal documents to govern the collaboration (consortium-, joint controller-, research collaboration-, data sharing-, and a series of unique two-way data processing-, and material transfer agreements). Lack of agreed-upon templates, policies, procedures, and a shortage of legal resources have caused considerable delays. Thus, our research consortium has spent more time ensuring GDPR compliance than on actual research activities. Conclusions: The current interpretation and implementation of the legal premises (rather than the GDPR per se) for research collaborations caused unnecessary barriers and delays. Our experiences call for Nordic trust-based code-of-conduct-like framework agreements, and for harmonisation of procedures and templates, lest the Nordic advantage in research be lost. [ABSTRACT FROM AUTHOR]

This overview examines the latest developments and applications of 3D and 4D printing in the health care and pharmaceutical field. The technique of creating a 3D object from a 3D model in the required size and shape is known as 3D printing. Whereas, 4D printing is the establishment of intricate three-dimensional formations that can change form in response to various external inputs. Applying 3D printing technology 3D printing, the healthcare industry has produced significant strides toward a patient-centred approach. The future of biomedical science and patient-centered care could be completely transformed by 3D printing with further advancements in research and development. 3D, 4D Technology used in printing is one of the most advanced industrial technologies available worldwide. The 3D and 4D printing pharmaceutical enterprises have completed the shift from centralised to distributed systems for the purpose of creating dosage forms. The goal of the study is to support the research goal of determining the degree to which patient-specific treatment is enhanced and healthcare outcomes are improved through the use of printing technologies in pharmaceuticals. Beyond this thorough analysis, the study highlights potential and problems from several angles and comparative aspects between 3D and 4D printing. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is any cancer that starts in the colon or the rectum and presents a significant health concern. It is the third most diagnosed and the second deadliest cancer, with an estimated 153,020 new cases and 52,550 deaths in 2023. The severity of colon cancer may be attributed to its ability to avoid the host immune system and growth suppressors, its asymptomatic nature in the early stages, its association with a continually ageing population and unfavourable diet and obesity. The composition of the gut microbiome plays an important role in the development of CRC and presents as an important target in early detection and in predicting treatment outcomes in CRC. This study aims to identify microbiome‐specific derived clusters in CRC patients and conduct subsequent survival analysis using the specific microbiome features within clusters. Methods: Consensus clustering and feature selection, involving a Kruskal–Wallis test, a random forest and least absolute shrinkage and selection operator (LASSO) were applied resulting in the identification of differently expressed microbiomes between clusters. Lastly, survival analysis was performed on the selected features using Kaplan‐Meier curves and Cox regression. K‐means clustering, as selected using consensus clustering interpretation, presented three distinct clusters with clear differences in alpha and beta diversity and baseline clinical variables. Results: A total 1311 of the 1406 microbes were selected using the Kruskal Wallis and passed to the random forest and LASSO, which narrowed the dataset to 140 features. Following the survival analysis, eight microbiome species, namely N4likevirus, Ambidensovirus, Synechococcus, Thermithiobacillus, Hydrocarboniphaga, Rhodovibrio, Gloeobacter and Candidatus Nitrosotenuis, were selected as significant in clustering and survival. Conclusion: This study reveals the heterogeneity of the CRC microbiome and its effect on disease prognosis and necessitates further exploration of the biological mechanisms of these selected microbiomes as well further investigation of whether the approach depicted here is applicable to other cancer types. [ABSTRACT FROM AUTHOR]

Copyright of Farmacia is the property of Societatea de Stiinte Farmaceutice Romania and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The healthcare landscape has undergone a profound transformation due to digitalisation in recent decades, shifting from manual practices to automated processes. Digital biomarkers have become increasingly important in healthcare across multiple domains for regular monitoring of health parameters, aiding in early disease detection and prevention. The present narrative review aims to explore the utility and advantages of digital biomarkers in healthcare. Notably, the literature emphasises portable biomarkers capable of actively recording user data. These advanced biomarkers efficiently identify physiological, biochemical and psychological parameters, offering predictive capabilities for health conditions and treatment outcomes. In this dynamic healthcare landscape, digital science has brought transformative changes. Investments in digital health show promising outcomes for disease management and patient care. Overall, the integration of digital biomarkers into healthcare represents a significant leap forward in improving healthcare delivery, diagnosis and treatment. It leverages technology to enhance the precision and efficiency of healthcare, ultimately benefiting both healthcare professionals and patients. While the scope of digital biomarkers continues to expand and is expected to grow in the future, addressing potential challenges is essential for sustained innovation in this field. [ABSTRACT FROM AUTHOR]

Pharmacogenomic (PGx) testing can help personalise psychiatric prescribing and improve on the currently adopted trial-and-error prescribing approach. However, widespread implementation is yet to occur. Understanding factors influencing implementation is pertinent to the psychiatric PGx field. Normalisation Process Theory (NPT) seeks to understand the work involved during intervention implementation and is used by this review (PROSPERO: CRD42023399926) to explore factors influencing PGx implementation in psychiatry. Four databases were systematically searched for relevant records and assessed for eligibility following PRISMA guidance. The QuADS tool was applied during quality assessment of included records. Using an abductive approach to codebook thematic analysis, barrier and facilitator themes were developed using NPT as a theoretical framework. Twenty-nine records were included in the data synthesis. Key barrier themes included a PGx knowledge gap, a lack of consensus in policy and guidance, and uncertainty towards the use of PGx. Facilitator themes included an interest in PGx use as a new and improved approach to prescribing, a desire for a multidisciplinary approach to PGx implementation, and the importance of fostering a climate for PGx implementation. Using NPT, this novel review systematically summarises the literature in the psychiatric PGx implementation field. The findings highlight a need to develop national policies on using PGx, and an education and training workforce plan for mental health professionals. By understanding factors influencing implementation, the findings help to address the psychiatric PGx implementation gap. This helps move clinical practice closer towards a personalised psychotropic prescribing approach and associated improvements in patient outcomes. Future policy and research should focus on the appraisal of PGx implementation in psychiatry and the role of pharmacists in PGx service design, implementation, and delivery. [ABSTRACT FROM AUTHOR]

Precision in dosing is crucial for optimizing therapeutic outcomes and preventing overdosing, especially in preterm infants. Traditional manual adjustments to adapt the dose often lead to inaccuracies, contamination risks, and reduced precision. To overcome these challenges, semi-solid extrusion 3D printing was used to create personalised gel-based caffeine dosage forms. The hydrogels, made from agar and hydroxypropyl methylcellulose, demonstrated excellent rheological properties, ensuring uniform extrusion and accurate shape retention during and after printing. This gel formulation allowed for precise adjustments of caffeine volume and content tailored to a neonate weighing 1.36 kg, achieving a recovery of 103.46%, well within acceptable limits. Additionally, three production batches confirmed the process's reproducibility with minimal variability. Forced degradation studies showed that both pure caffeine and caffeine in the gel matrix exhibited similar stability profiles, confirming the drug's chemical integrity. The printed gel dosage forms also displayed immediate-release characteristics, with over 80% of caffeine released within 45 min, highlighting their suitability for rapid therapeutic action. These findings emphasise the potential of SSE 3DP and gel-based formulations to produce personalised drug delivery systems with high precision, reproducibility, and reliability. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is a promising intervention for treatment-resistant psychiatric disorders. However, conventional TMS typically utilises a one-size-fits-all approach when determining stimulation targets. Recent retrospective brain circuit-based analyses using lesion network mapping have suggested that a left dorsal lateral prefrontal cortex target has a higher efficacy for alleviating depression symptoms, a dorsomedial prefrontal cortex target is more effective for anxiety symptoms, and a rostromedial prefrontal cortex target is effective for schizophrenia-associated psychiatric symptoms. Nonetheless, symptom-specific brain circuit targeting has not been tested prospectively. We conducted a narrative review of selected literature to investigate individualised targeting for TMS and discuss potential future directions to elucidate the efficacy of this approach. [ABSTRACT FROM AUTHOR]

Background: The aging paradox highlights the coexistence of increased life expectancy with a persistent desire to maintain a youthful appearance, driven by biological, psychological, and social factors. Advances in healthcare have extended human lifespans, yet societal pressure to appear youthful remains strong. Understanding the genetic, epigenetic, and environmental contributors to skin aging is crucial for optimising aesthetic procedures. Methods: This literature review synthesises research on the aging paradox, genetic influences on skin aging, and the effectiveness of non-surgical aesthetic interventions. The review involved a comprehensive search across databases including PubMed, Google Scholar, Web of Science, and Scopus using keywords like "aging paradox", "genetic imprint", "non-surgical aesthetics", "epigenetics", and "anti-aging treatments". Studies were selected based on relevance, credibility, recency, and diversity of perspectives. Results: The review identified 64 studies relevant to the aging paradox and non-surgical interventions. These studies underscore the significant roles of genetic variations and epigenetic mechanisms, such as DNA methylation and microRNA regulation, in determining aging trajectories and treatment responses. The proposed "PERSONAL" (Personalised Epigenetic Regime for Skin Optimisation, Nurturing Aesthetic Longevity) paradigm advocates for a comprehensive, personalised approach, integrating genetic and epigenetic profiling to tailor treatments to individual needs. Conclusions: By leveraging the complex interplay of genetic, epigenetic, and environmental factors, practitioners can enhance the precision and efficacy of non-surgical aesthetic interventions, improving patient satisfaction and promoting long-term skin health. Continuous monitoring and iterative adjustments within this paradigm are essential for achieving optimal outcomes. Level of evidence: Level 4, therapeutic study [ABSTRACT FROM AUTHOR]

Simple Summary: This research is the first comprehensive study in New Zealand to categorise and examine the characteristics of breast cancer based on HER2 status. We explored three HER2 categories: HER2-zero, HER2-low, and HER2-positive, in women diagnosed with invasive breast cancer. Utilising Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), our study analysed data spanning 21 years, revealing that most women underwent HER2 testing. Significantly, many cases previously not recognised as having significant HER2 levels were in fact HER2-low, qualifying them for newer, targeted drug therapies. These findings are particularly crucial as they suggest that newer therapies could benefit a larger segment of patients, notably those with advanced breast cancer; approximately 60% of these women might now benefit from these innovative HER2-targeted treatments. The study underscores the urgent need for standardised HER2 testing to personalise and optimise treatment, enhancing outcomes for patients with invasive breast cancer. Objectives: To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low, and HER2-zero invasive breast cancers in New Zealand. The study will reveal the proportion of women who may benefit from new HER2-targeted antibody drug conjugate (ADC) therapies. Methods: Utilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories—HER2-zero, HER2-low, HER2-positive. Results: From 2009–2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% of those formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates that 60% of women with advanced breast cancer may potentially benefit from the new HER2-directed ADCs (approximately 120 women per year). Conclusions: The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes. [ABSTRACT FROM AUTHOR]

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature. [ABSTRACT FROM AUTHOR]

Telemedicine in heart failure (HF) management may positively impact health outcomes, but varied effects in studies hinder guidance in HF guidelines. Evidence on the effectiveness of telemedicine in HF subpopulations is limited. We conducted a scoping review to evaluate and synthesise evidence on the effectiveness of telemedicine across HF subpopulations that could guide telemedicine strategies in routine practice. Meta-analyses concerning randomised controlled trials (RCTs) with subgroup analyses on telemedicine effectives were identified in PubMed. We identified 15 RCTs, encompassing 21 different subgroups based on characteristics of HF patients. Findings varied across studies and no definite evidence was found about which patients benefit most from telemedicine. Subgroup definitions were inconsistent, not always a priori defined and subgroups contained few patients. Some studies found heterogeneous effects of telemedicine on mortality and hospitalisation across subgroups defined by: New York Heart Association (NYHA) classification, previous HF decompensation, implantable device, concurrent depression, time since hospital discharge and duration of HF. Patients represented in the RCTs were mostly male, aged 65–75 years, with HF with reduced ejection fraction and NYHA class II/III. Traditional RCTs have not been able to provide clinicians with guidance; continuous real-world evidence generation could enhance monitoring and identify who benefits from telemedicine. [ABSTRACT FROM AUTHOR]

Personalised medicine, facilitated by advancements like 3D printing, may offer promise in oncology. This scoping review aims to explore the applicability of 3D printing for personalised pharmaceutical dosage forms in paediatric cancer care, focusing on treatment outcomes and patient experiences. Following the Joanna Briggs Institute (JBI) methodology, a comprehensive search strategy was implemented to identify the relevant literature across databases including PubMed, Embase, and Web of Science. Three independent reviewers conducted study selection and data extraction, focusing on studies involving paediatric patients under 18 years old and pharmaceutical dosage forms manufactured using 3D printing technology. From 2752 records screened, only six studies met the inclusion criteria, none of which specifically targeted paediatric cancer patients. These studies examined aspects of acceptability, including swallowability, taste, and feasibility of 3D-printed formulations for children. While the studies demonstrated the potential benefits of 3D printing in paediatric medication, particularly in personalised dosing, there is a notable lack of evidence addressing its acceptability in paediatric cancer patients. Further interdisciplinary collaborative research is needed in this area to fully assess preferences and acceptability among children with cancer and their parents or caregivers. [ABSTRACT FROM AUTHOR]

The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings. [ABSTRACT FROM AUTHOR]

Parkinson's Disease is the second most prevalent neurological disorder globally, and its cause is still largely unknown. Likewise, there is no cure, and existing treatments do little more than subdue symptoms before becoming ineffective. It is increasingly important to understand the factors contributing to Parkinson's Disease aetiology so that new and more effective pharmacotherapies can be established. In recent years, there has been an emergence of research linking gut dysbiosis to Parkinson's Disease via the gut–brain axis. Advancements in microbial profiling have led to characterisation of a Parkinson's-specific microbial signature, where novel treatments that leverage and correct gut dysbiosis are beginning to emerge for the safe and effective treatment of Parkinson's Disease. Preliminary clinical studies investigating microbiome-targeted therapeutics for Parkinson's Disease have revealed promising outcomes, and as such, the aim of this review is to provide a timely and comprehensive update of the most recent advances in this field. Faecal microbiota transplantation has emerged as a novel and potential frontrunner for microbial-based therapies due to their efficacy in alleviating Parkinson's Disease symptomology through modulation of the gut–brain axis. However, more rigorous clinical investigation, along with technological advancements in diagnostic and in vitro testing tools, are critically required to facilitate the widespread clinical translation of microbiome-targeting Parkinson's Disease therapeutics. [ABSTRACT FROM AUTHOR]

Background: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. Methods and results: A single‐centre, retrospective cohort study was conducted. TB was assessed using the hot‐spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan–Meier analyses investigated their utility as a predictor of disease‐free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty‐seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261–5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076–4.357, P = 0.030) predicted LNM. Biopsy‐assessed H&E ITB (OR = 2.749, 95% CI = 1.258–6.528, P = 0.022) was an independent predictor of LNM. In Kaplan–Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261–6.809) and DFS (HR = 2.072, 95% CI = 1.031–4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45–8.053, P = 0.005). Conclusion: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post‐neoadjuvant therapy‐treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings. [ABSTRACT FROM AUTHOR]

Opinion Statement: Soft tissue sarcomas (STS) are a rare and heterogeneous group of cancers. Treatment options have changed little in the past thirty years, and the role of neoadjuvant chemotherapy is controversial. Accurate risk stratification is crucial in STS in order to facilitate clinical discussions around peri-operative treatment. Current risk stratification tools used in clinic, such as Sarculator, use clinicopathological characteristics and may be specific to anatomical site or to histology. More recently, risk stratification tools have been developed using molecular or immunological data. Combining Sarculator with other risk stratification tools may identify novel patient groups with differential clinical outcomes. There are several considerations when translating risk stratification tools into widespread clinical use, including establishing clinical utility, health economic value, being applicable to existing clinical pathways, having strong real-world performance, and being supported by investment into infrastructure. Future work may include incorporation of novel modalities and data integration techniques. [ABSTRACT FROM AUTHOR]

Every year, more than 19 million cancer cases are diagnosed, and this number continues to increase annually. Since standard treatment options have varying success rates for different types of cancer, understanding the biology of an individual's tumour becomes crucial, especially for cases that are difficult to treat. Personalised high-throughput profiling, using next-generation sequencing, allows for a comprehensive examination of biopsy specimens. Furthermore, the widespread use of this technology has generated a wealth of information on cancer-specific gene alterations. However, there exists a significant gap between identified alterations and their proven impact on protein function. Here, we present a bioinformatics pipeline that enables fast analysis of a missense mutation's effect on stability and function in known oncogenic proteins. This pipeline is coupled with a predictor that summarises the outputs of different tools used throughout the pipeline, providing a single probability score, achieving a balanced accuracy above 86%. The pipeline incorporates a virtual screening method to suggest potential FDA/EMA-approved drugs to be considered for treatment. We showcase three case studies to demonstrate the timely utility of this pipeline. To facilitate access and analysis of cancer-related mutations, we have packaged the pipeline as a web server, which is freely available at https://loschmidt.chemi.muni.cz/predictonco/. Scientific contribution This work presents a novel bioinformatics pipeline that integrates multiple computational tools to predict the effects of missense mutations on proteins of oncological interest. The pipeline uniquely combines fast protein modelling, stability prediction, and evolutionary analysis with virtual drug screening, while offering actionable insights for precision oncology. This comprehensive approach surpasses existing tools by automating the interpretation of mutations and suggesting potential treatments, thereby striving to bridge the gap between sequencing data and clinical application. [ABSTRACT FROM AUTHOR]

Genetic heterogeneity in ovarian cancer indicates the need for personalised treatment approaches. Currently, very few G-protein coupled receptors (GPCRs) have been investigated for active targeting with nanomedicines such as antibody-conjugated drugs and drug-loaded nanoparticles, highlighting a neglected potential to develop personalised treatment. To address the genetic heterogeneity of ovarian cancer, a future personalised approach could include the identification of unique GPCRs expressed in cancer biopsies, matched with personalised GPCR-targeted nanomedicines, for the delivery of lethal drugs to tumour tissue before, during and after surgery. Here we report on the systematic analysis of public ribonucleic acid-sequencing (RNA-seq) gene expression data, which led to prioritisation of 13 GPCRs as candidates with frequent overexpression in ovarian cancer tissues. Subsequently, primary ovarian cancer cells derived from ascites and ovarian cancer cell lines were used to confirm frequent gene expression for the selected GPCRs. However, the expression levels showed high variability within our selection of samples, therefore, supporting and emphasising the need for the future development of case-to-case personalised targeting approaches. [ABSTRACT FROM AUTHOR]

Introduction: n-of-1 trials are undertaken to optimise the evaluation of health technologies in individual patients. They involve a single patient receiving treatments, both interventional and control, consecutively over set periods of time, the order of which is decided at random. Although n-of-1 trials are undertaken in medical research it could be argued they have the utility to be undertaken more frequently. We undertook the National Institute for Health Research (NIHR) commissioned DIAMOND (Development of generalisable methodology for n-of-1 trials delivery for very low volume treatments) project to develop key points to assist clinicians and researchers in designing and conducting n-of-1 trials. Methods: The key points were developed by undertaking a stakeholder workshop, followed by a discussion within the study team and then a stakeholder dissemination and feedback event. The stakeholder workshop sought to gain the perspectives of a variety of stakeholders (including clinicians, researchers and patient representatives) on the design and use of n-of-1 trials. A discussion between the study team was held to reflect on the workshop and draft the key points. Lastly, the stakeholders from the workshop were invited to a dissemination and feedback session where the proposed key points were presented and their feedback gained. Results: A set of 22 key points were developed based on the insights from the workshop and subsequent discussions. They provide guidance on when an n-of-1 trial might be a viable or appropriate study design and discuss key decisions involved in the design of n-of-1 trials, including determining an appropriate number of treatment periods and cycles, the choice of comparator, recommended approaches to randomisation and blinding, the use of washout periods and approaches to analysis. Conclusions: The key points developed in the project will support clinical researchers to understand key considerations when designing n-of-1 trials. It is hoped they will support the wider implementation of the study design. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this narrative review is to explore the advantages and limitations of VHs in delivering healthcare, including access to specialized professionals, streamlined communication, efficient scheduling, integration of electronic health records, ongoing monitoring, and support, transcending geographical boundaries, and resource optimization. Methods: Review of literature. Results: The national healthcare systems are facing an alarming rise in pressure due to global shifts. Virtual hospitals (VH) offer a practical solution to numerous systemic challenges, including rising costs and increased workloads for healthcare providers. VH also facilitate the delivery of personalized services and enable the monitoring of patients beyond the conventional confines of healthcare settings, reducing the reliance on waiting medicine carried out in doctors' offices or hospitals. Conclusion: VH can mirror the conventional healthcare referral system. [ABSTRACT FROM AUTHOR]

Copyright of Douleur et Analgésie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022–31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high–income countries were performed. Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use (p < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6–0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: −0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p < 0.001). TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability. [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence (AI) has become a pivotal tool in advancing contemporary personalised medicine, with the goal of tailoring treatments to individual patient conditions. This has heightened the demand for access to diverse data from clinical practice and daily life for research, posing challenges due to the sensitive nature of medical information, including genetics and health conditions. Regulations like the Health Insurance Portability and Accountability Act (HIPAA) in the U.S. and the General Data Protection Regulation (GDPR) in Europe aim to strike a balance between data security, privacy, and the imperative for access. Results: We present the Gemelli Generator - Real World Data (GEN-RWD) Sandbox, a modular multi-agent platform designed for distributed analytics in healthcare. Its primary objective is to empower external researchers to leverage hospital data while upholding privacy and ownership, obviating the need for direct data sharing. Docker compatibility adds an extra layer of flexibility, and scalability is assured through modular design, facilitating combinations of Proxy and Processor modules with various graphical interfaces. Security and reliability are reinforced through components like Identity and Access Management (IAM) agent, and a Blockchain-based notarisation module. Certification processes verify the identities of information senders and receivers. Conclusions: The GEN-RWD Sandbox architecture achieves a good level of usability while ensuring a blend of flexibility, scalability, and security. Featuring a user-friendly graphical interface catering to diverse technical expertise, its external accessibility enables personnel outside the hospital to use the platform. Overall, the GEN-RWD Sandbox emerges as a comprehensive solution for healthcare distributed analytics, maintaining a delicate equilibrium between accessibility, scalability, and security. [ABSTRACT FROM AUTHOR]

In recent years, thanks to significant advances in basic science and biotechnologies, nephrology has witnessed a deeper understanding of the mechanisms leading to various conditions associated with or causing kidney disease, opening new perspectives for developing specific treatments. These new possibilities have brought increased challenges to physicians, who face with a new complexity in disease characterization and selection the right treatment for individual patients. We chose four therapeutic situations: anaemia in chronic kidney disease (CKD), heart failure in CKD, IgA nephropathy (IgAN) and membranous nephropathy (MN). The literature search was made through PubMed. Anaemia management remains challenging in CKD; a personalized therapeutic approach is often needed. Identifying patients who could benefit from a specific therapy is also an important goal for patients with CKD and heart failure with reduced ejection fraction. Several new treatments are under clinical development for IgAN; interestingly, they target specifically the pathogenetic mechanisms of the disease. The understanding of MN pathogenesis as an autoimmune disease and the discovery of several autoantibodies allows a better characterization of patients. High-sensible techniques for lymphocyte counting open the possibility of more personalized use of anti CD20 therapies. [ABSTRACT FROM AUTHOR]

The article focuses on the transformative impact of digital technologies in personalized medicine, highlighting their adoption in medical practice and the integration of AI-based solutions. It explores the benefits observed from the perspectives of physicians, data scientists, and patients, emphasizing improved diagnosis accuracy, continuous disease monitoring, and the legal challenges associated with AI use in clinical settings within the European Union.

The current evidence on whether annual diabetic retinopathy (DR) screening intervals can be extended was reviewed. A systematic review protocol was followed (PROSPERO ID: CRD42022359590). Original longitudinal articles that specifically assessed DR screening intervals were in English and collected data after 2000 were included. Two reviewers independently conducted the search and reviewed the articles for quality and relevant information. The heterogeneity of the data meant that a meta‐analysis was not appropriate. Twelve publications were included. Studies were of good quality and many used data from DR screening programs. Studies fit into three categories; those that assessed specific DR screening intervals, those that determined optimal DR screening intervals and those that developed/assessed DR screening risk equations. For those with type 2 diabetes, extending screening intervals to 3‐ to 4‐yearly in those with no baseline DR appeared safe. DR risk equations considered clinical factors and allocated those at lower risk of DR progression screening intervals of up to five years. Those with baseline DR or type 1 diabetes appeared to have a higher risk of progression to STDR and needed more frequent screening. DR screening intervals can be extended to 3–5 yearly in certain circumstances. These include patients with type 2 diabetes and no current DR, and those who have optimal management of other risk factors such as glucose and blood pressure. [ABSTRACT FROM AUTHOR]

This document is an editorial titled "Musculoskeletal pain phenotypes and personalised pain medicine" published in the journal Frontiers in Pain Research. The editorial discusses the concept of phenotypes in personalized medicine and its application to musculoskeletal pain. It highlights four articles within the research topic that explore different approaches to personalized pain medicine. These articles cover topics such as pain stratification options, sex differences in musculoskeletal pain, personalized diagnosis of non-specific back pain, and considerations for optimizing antidepressant use in pain management. The editorial also mentions the potential role of artificial intelligence in advancing personalized pain medicine. [Extracted from the article]

Opinion statement: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need. [ABSTRACT FROM AUTHOR]

Background: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual's genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual's genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants ('CYP2D6-PGx antipsychotics'). Aims: This study aims to investigate differences between demographic groups prescribed 'CYP2D6-PGx antipsychotics' and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance. Methods: A cross-sectional study took place extracting data from 243 patients' medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of 'CYP2D6-PGx antipsychotic' prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of 'CYP2D6-PGx antipsychotic' versus 'non-CYP2D6-PGx antipsychotic'. Results: Two-thirds (164) of patients had been prescribed a 'CYP2D6-PGx antipsychotic' (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a 'CYP2D6-PGx antipsychotic'. Conclusions: This study demonstrated high rates of prescribing 'CYP2D6-PGx-antipsychotics' in an EIP cohort, providing a rationale for further exploration of how PGx testing can be implemented in EIP services to personalise the prescribing of drugs for psychosis. [ABSTRACT FROM AUTHOR]

Cefotaxime administration is recommended in doses of 3–12 g/day in adults with a Glomerular Filtration Rate (GFR) > 5 mL/min. This study aimed to assess the impact of renal function and obesity on cefotaxime concentrations in intensive care unit (ICU) patients. A retrospective cohort study was conducted on consecutive ICU patients receiving continuous cefotaxime infusion between 2020 and 2022 [IRBN992021/CHUSTE]. Doses were not constant; consequently, a concentration-to-dose ratio (C/D) was considered. Statistical analysis was performed to assess the relationship between cefotaxime concentrations, renal function, and obesity. A total of 70 patients, median age 61 years, were included, with no significant difference in cefotaxime concentrations between obese and non-obese patients. However, concentrations varied significantly by GFR, with underdosing prevalent in patients with normal to increased renal function and overdosing in those with severely impaired renal function. Adjustment of cefotaxime dosing according to GFR was associated with improved target attainment. Cefotaxime dosing in critically ill patients should consider renal function, with higher initial doses required in patients with normal to increased GFR and lower doses in those with severely impaired renal function. Therapeutic drug monitoring may aid in optimising dosing regimens. Prospective studies are warranted to validate these findings and inform clinical practice. [ABSTRACT FROM AUTHOR]

Precision medicine (PM), also termed stratified, individualised, targeted, or personalised medicine, embraces a rapidly expanding area of research, knowledge, and practice. It brings together two emerging health technologies to deliver better individualised care: the many "-omics" arising from increased capacity to understand the human genome and "big data" and data analytics, including artificial intelligence (AI). PM has the potential to transform an individual's health, moving from population-based disease prevention to more personalised management. There is however a tension between the two, with a real risk that this will exacerbate health inequalities and divert funds and attention from basic healthcare requirements leading to worse health outcomes for many. All areas of medicine should consider how this will affect their practice, with PM now strongly encouraged and supported by government initiatives and research funding. In this review, we discuss examples of PM in current practice and its emerging applications in primary care, such as clinical prediction tools that incorporate genomic markers and pharmacogenomic testing. We look towards potential future applications and consider some key questions for PM, including evidence of its real-world impact, its affordability, the risk of exacerbating health inequalities, and the computational and storage challenges of applying PM technologies at scale. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy worldwide, with most deaths caused by locally advanced and metastatic disease. Treatment of resectable metastases is typically limited to invasive surgery with adjuvant radiotherapy; however, many patients fail to respond and there is minimal data to predict response or propose effective alternatives. Precision medicine could improve this, though genomic biomarkers remain elusive in the high mutational background and genomic complexity of cSCC. A phenotypic approach to precision medicine using patient‐derived ex vivo tumour models is gaining favour for its capacity to directly assess biological responses to therapeutics as a functional, predictive biomarker. However, the use of ex vivo models for guiding therapeutic selection has yet to be employed for metastatic cSCC. This review will therefore evaluate the existing experimental models of metastatic cSCC and discuss how ex vivo methods could overcome the shortcomings of these existing models. Disease‐specific considerations for a prospective methodological pipeline will also be discussed in the context of precision medicine. [ABSTRACT FROM AUTHOR]

Morbidity and mortality during chemotherapy in older adults with haematological malignancy can be unpredictable. The Haemato‐Oncology Frailty (HOF) score was previously found to predict outcomes in a cohort of patients with plasma cell myeloma. In this study, we assess its utility in assessing frailty in patients with lymphoma, and compare its performance to that of two other frailty scores. The HOF score was able to predict progression‐free survival in this population, and was also shown to have potential in assessing the dynamism of frailty during chemotherapy. It performed well when compared to the Charlson Comorbidity Index (CCI) score and the Haematopoietic Cell Transplantation‐Specific Comorbidity Index (HCTCI), although the study was not powered to assess for non‐inferiority. The HOF score is a new score with the potential for application in different haematological malignancies. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort. Methods: Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models' performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites. Results: Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model. Discussion: The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing. [ABSTRACT FROM AUTHOR]

The sociology of diagnosis has shown that diagnosis not only serves to label the underlying cause of disease but also to provide access to services and resources. Elaborating on this double‐affordance of diagnosis, this article examines how precision medicine reconfigures diagnosis as a label and as a process in regulatory and clinical settings. Reporting from an ethnographic case study of the introduction of immunotherapy for lung cancer, the paper unfolds the uncertainties involved in dissecting diagnosis into layers and examines the efforts and negotiations it takes to enable these layers to work both as clinical entities and regulative entities with the purpose of delineating access to treatment. I suggest that the work of subdividing diseases into molecularly defined categories for the purpose of delineating treatment‐eligible populations can be labelled 'diagnostic sub‐stratification' and argue that it is pertinent to understand the political capacity of this strategy. Diagnostic sub‐stratification involves a push of diagnosis from the clinic 'up' into the regulatory system and 'out' into the laboratories, obscuring who is accountable for the diagnostic categories employed to define patients' treatment access. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bacteriophage therapy is a promising approach to treating bacterial infections. Research and development of bacteriophage therapy is intensifying due to the increase in antibiotic resistance and the faltering development of new antibiotics. Bacteriophage therapy uses bacteriophages (phages), i.e., prokaryotic viruses, to specifically target and kill pathogenic bacteria. The legal handling of this type of therapy raises several questions. These include whether phage therapeutics belong to a specially regulated class of medicinal products, and which legal framework should be followed with regard to the various technical ways in which phage therapeutics can be manufactured and administered. The article shows to which class of medicinal products phage therapeutics from wild type phages and from genetically modified (designer) phages do or do not belong. Furthermore, the article explains which legal framework is relevant for the manufacture and administration of phage therapeutics, which are manufactured in advance in a uniform, patient-independent manner, and for tailor-made patient-specific phage therapeutics. For the systematically coherent, successful translation of phage therapy, the article considers pharmaceutical law and related legal areas, such as genetic engineering law. Finally, the article shows how the planned legislative revisions of Directive 2001/83/EC and Regulation (EC) No 726/2004 may affect the legal future of phage therapy. [ABSTRACT FROM AUTHOR]

Background: The advent of Personalized Medicine (PM) holds significant promise in revolutionizing healthcare by tailoring treatments to individual patients based on their data. However, its successful implementation requires the seamless integration of innovative technologies and presents formidable challenges in terms of sustainability. To tackle these challenges head-on, the International Consortium for Personalized Medicine (ICPerMed) was established, and the IC2PerMed project, as part of this consortium, seeks to foster collaboration between the European Union (EU) and China in the field of Personalized Medicine. Based on the results collected by the project, the objective of this study is to discern the key priorities for the implementation of Personalised Medicine concerning Information and Communication Technologies (ICT) and Big Data and digital solutions, with a particular emphasis on data management and protection. Methods: A Delphi survey was conducted to gather expert's consensus on the main priorities for actions on Information and Communication Technologies (ICT) and Big Data and digital solutions in the field of Personalized Medicine. Results: The survey identified seven priorities in the area of Big Data and digital solutions, including data interoperability, standards, security measures, and international partnerships. Additionally, twelve priorities were identified for the innovation-to-market process, emphasizing cost-effectiveness, need assessment, and value definition in resource allocation. Conclusions: The effective implementation of new technologies in Personalized Medicine research and practice is essential for the advancement of healthcare systems in both the European and Chinese contexts. The identified priorities play a pivotal role in promoting the sustainability of health systems and driving innovation in the implementation of Personalized Medicine. Addressing challenges related to data interoperability, standards, security, international collaboration, cost-effectiveness, and value assessment is of utmost importance in order to propel the progress of Personalized Medicine in healthcare systems. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment with targeted agents is an emerging concept for cholangiocarcinoma, a rare cancer with a lack of effective therapies. However, there is limited real-world evidence regarding the use of targeted agents using molecular profiling data from liquid biopsies in clinical practice. This single-centre retrospective study aimed to characterise treatment efficacy and predictors of clinical benefit in cholangiocarcinoma following targeted therapies. Our findings suggest that patients with exposure to targeted agents and response to such treatment are the greatest beneficiaries of this personalized treatment approach; those with previous localised approaches such as surgery had further benefit, suggesting that localised treatment options can be considered in appropriate cases. Further research is needed to identify patients who are most likely to benefit from targeted agents using the liquid biopsy approach and evaluate the optimal sequence of such therapies to maximise treatment response and survival outcomes in this challenging clinical population. Background: Cholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients. Methods: All consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional-hazards models. Results: Of the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in the FGFR2 (N = 21), IDH1 (N = 7) and BRCA2 (N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49–12.78), 5.65 (95% CI, 3.71–7.13), 5.55 (2.79–12.58) and 29.01 (24.21–42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p = 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p = 0.002) and OS (p = 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p < 0.001). Conclusions: Patients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies. [ABSTRACT FROM AUTHOR]