Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.

Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the ß-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.

Development and validation of a robotic system for milling individualized jawbone cavities in oral and maxillofacial surgery.

OBJECTIVES: This study aimed to develop and validate a robotic system capable of performing accurate and minimally invasive jawbone milling procedures in oral and maxillofacial surgery. METHODS: The robotic hardware system mainly includes a UR5E arm (Universal Robots, Denmark) and the binocular positioning system (FusionTrack 250, Atracsys LLC, Switzerland). The robotic software (Dental Navi 3.0.0, Yakebot Technology Ltd., China) is capable of generating cutting tool paths based on three-dimensional shape description files, typically in the stereolithography format, and selected cutting tool parameters, as well as designing surgical accessories. Fully impacted supernumerary tooth models in the maxilla were fabricated using software and three-dimensional printing. Following the planning of a customized cavity to fully expose the tooth, maxillary bone milling was performed on both the robot and static guide groups (n = 8). After milling, all models underwent scanning for assessment. RESULTS: In the experiment with fully buried supernumerary tooth models in the maxilla, the root mean square, translation error, over-removal rate, and maximum distance were significantly smaller in the robot group compared to the static guide group. Moreover, the overlap ratio and Dice coefficient were significantly greater in the robot group. No statistically significant differences were observed between the two groups in terms of the rotation error (P = 0.80) or under-removal rate (P = 0.92). CONCLUSIONS: This study has developed a robotic system for milling individualized jawbone cavities in oral and maxillofacial surgery, and its accuracy has been preliminarily verified to meet clinical requirements. CLINICAL SIGNIFICANCE: The robotic system can achieve precise, minimally invasive, individualized jawbone milling in a variety of oral and maxillofacial surgeries, including tooth autotransplantation, surgical reshaping for zygomatic fibrous dysplasia, removal of fully impacted supernumerary or impacted teeth, and endodontic microsurgery, among other relevant clinical applications.

Review on Recent Advance of 3DP-Based Pediatric Drug Formulations.

Three-dimensional printing (3DP) has emerged as a game-changing technology in the pharmaceutical industry, providing novel formulation development in the pharmaceutical sector as a whole, which improved patients' individualized therapy. The pediatric population is among the key targets for individualized therapy. Children are a diverse group that includes neonates, infants, and toddlers, each with unique physiological characteristics. Treatment adherence has a significant impact on safe and effective pharmacotherapy in the pediatric population. Improvement of therapeutic dosage forms that provide for the special demands of the pediatric population is a significant challenge for the pharmaceutical industry. Scientists have actively explored 3DP, a quick prototype manufacturing method that has emerged in recent years from many occupations due to its benefits of modest operation, excellent reproducibility, and vast adaptability. This review illuminates the most widely used 3DP technology and its application in the development of pediatric-friendly drug formulations. This 3DP technology allows optimization of pediatric dosage regimens and cases that require individualized treatment, such as geriatrics, renal impairment, liver impairment, critically ill, pregnancy populations, and drugs with nonlinear pharmacokinetics. The fast evolution of 3DP expertise, in addition to the introduction of pharmaceutical inks, has enormous promise for patient dosage form customization.

A comparative study of femoral artery and combined femoral and axillary artery cannulation in veno-arterial extracorporeal membrane oxygenation patients.

Objective: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a critical support technique for cardiac surgery patients. This study compares the outcomes of femoral artery cannulation vs. combined femoral and axillary artery cannulation in post-cardiotomy VA-ECMO patients. This study aimed to compare the clinical outcomes of critically ill patients post-cardiac surgery under VA-ECMO support using different cannulation strategies. Specifically, the focus was on the impact of femoral artery (FA) cannulation vs. combined femoral artery and axillary artery (FA+AA) cannulation on patient outcomes. Methods: Through a retrospective analysis, we compared 51 adult patients who underwent cardiac surgery and received VA-ECMO support based on the cannulation strategy employed-FA cannulation in 27 cases vs. FA+AA cannulation in 24 cases. Results: The FA+AA group showed significant advantages over the FA group in terms of the incidence of chronic renal failure (CRF) (37.50% vs. 14.81%, p = 0.045), preoperative blood filtration requirement (37.50% vs. 11.11%, p = 0.016), decreased platelet count (82.67 ± 44.95 vs. 147.33 ± 108.79, p = 0.014), and elevated creatinine (Cr) levels (151.80 ± 60.73 vs. 110.26 ± 57.99, p = 0.041), although the two groups had similar 30-day mortality rates (FA group 40.74%, FA+AA group 33.33%). These findings underscore that a combined approach may offer more effective hemodynamic support and better clinical outcomes when selecting an ECMO cannulation strategy. Conclusion: Despite the FA+AA group patients presenting with more preoperative risk factors, this group has exhibited lower rates of complications and faster recovery during ECMO treatment. While there has been no significant difference in 30-day mortality rates between the two cannulation strategies, the FA+AA approach may be more effective in reducing complications and improving limb ischemia. These findings highlight the importance of individualized treatment strategies and meticulous monitoring in managing post-cardiac surgery ECMO patients.

Surgery paradigm for locally advanced breast cancer following neoadjuvant systemic therapy.

Locally advanced breast cancer (LABC) remains a significant clinical challenge, particularly in developing countries. While neoadjuvant systemic therapy (NST) has improved the pathological complete response (pCR) rates, particularly in HER2-positive and triple-negative breast cancer patients, surgical management post-NST continues to evolve. The feasibility of omitting surgery and the increasing consideration of breast-conserving surgery, immediate reconstruction in LABC patients are important areas of exploration. Accurate assessment of tumor response to NST through advanced imaging and minimally invasive biopsies remains pivotal, though challenges persist in reliably predicting pCR. Additionally, axillary lymph node management continues to evolve, with emerging strategies aiming to minimize the extent of surgery in patients who achieve nodal downstaging post-NST. Minimizing axillary lymph node dissection in favor of less invasive approaches is gaining attention, though further evidence is needed to establish its oncological safety. The potential for personalized treatment approaches, reducing surgical morbidity, and improving quality of life are key goals in managing LABC, while maintaining the priority of achieving favorable long-term outcomes.

Machine Learning Approaches to Evaluate Heterogeneous Treatment Effects in Randomized Controlled Trials: A Scoping Review.

BACKGROUND: Estimating heterogeneous treatment effects (HTEs) in randomized controlled trials (RCTs) has received substantial attention recently. This has led to the development of several statistical and machine learning (ML) algorithms to assess HTEs through identifying individualized treatment effects. However, a comprehensive review of these algorithms is lacking. We thus aimed to catalog and outline currently available statistical and ML methods for identifying HTEs via effect modeling using clinical RCT data and summarize how they have been applied in practice. STUDY DESIGN AND SETTING: We performed a scoping review using pre-specified search terms in MEDLINE and Embase, aiming to identify studies that assessed HTEs using advanced statistical and ML methods in RCT data published from 2010 to 2022. RESULTS: Among a total of 32 studies identified in the review, 17 studies applied existing algorithms to RCT data, and 15 extended existing algorithms or proposed new algorithms. Applied algorithms included penalized regression, causal forest, Bayesian causal forest, and other meta-learner frameworks. Of these methods, causal forest was the most frequently used (7 studies) followed by Bayesian causal forest (4 studies). Most applications were in cardiology (6 studies), followed by psychiatry (4 studies). We provide example R codes to illustrate how to implement these algorithms. CONCLUSION: This review identified and outlined various algorithms currently used to identify HTEs and individualized treatment effects in RCT data. Given the increasing availability of new algorithms, analysts should carefully select them after examining model performance and considering how the models will be used in practice.

A protracted war against cancer drug resistance.

Currently, even the most effective anti-cancer therapies are often limited by the development of drug resistance and tumor relapse, which is a major challenge facing current cancer research. A deep understanding of the molecular and biochemical bases of drug efficacy that can help predict the clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, have facilitated studies identifying and elucidating the underlying mechanisms. In this review, we focus on several important issues on cancer drug resistance and provide a framework for understanding the common ways by which cancers develop resistance to therapeutic agents. With the increasing arsenal of novel anticancer agents and techniques, there are now unprecedented opportunities to understand and overcome drug resistance. The proteolysis targeting chimera (PROTAC) technology, immunotherapy, nanomedicine, and real-time monitoring of drug response all provide effective approaches for combating drug resistance. In addition to the advancement of therapeutic technologies, the revolution of treatment concept is also of great importance. We can take advantage of the interplay between drug sensitive and resistant subclones for combating cancer. However, there remains a long way to go in the protracted war against cancer drug resistance.

PVA-based formulations as a design-technology platform for orally disintegrating film matrices.

In the majority of pharmaceutical applications, polymers are employed extensively in a diverse range of pharmaceutical products, serving as indispensable components of contemporary solid oral dosage forms. A comprehensive understanding of the properties of polymers and selection the appropriate methods of characterization is essential for the design and development of novel drug delivery systems and manufacturing processes. Orally disintegrating film (ODF) formulations are considered to be a potential substitute to traditional oral dosage forms and an alternative method of drug administration for children and uncooperative adult patients, including those with swallowing difficulties. A multitude of pharmaceutical formulations with varying mechanical and biopharmaceutical properties have emerged from the modification of the original polymeric bulk. Here we propose different formulation approaches, i.e. solvent casting (SC), 3D printing (3DP), electrospinning (ES), and lyophilization (LP) that enabled us to adjust the disintegration time and the release profile of poorly water soluble haloperidol (HAL, BCS class II) from PVA (polyvinyl alcohol) based polymer films while maintaining similar hydrogel composition. In this study, the solubility of haloperidol in aqueous solution was improved by the addition of lactic acid. The prepared films were evaluated for their morphology (SEM, micro-CT), physicochemical and biopharmaceutical properties. TMDSC, TGA and PXRD were employed for extensive thermal and structural analysis of fabricated materials and their stability. These results allowed us to establish correlations between preparation technology, structural characteristics and properties of PVA films and to adapt the suitable manufacturing technique of the ODFs to achieve appropriate HAL dissolution behaviour.

Adjusted versus Targeted Fortification in Extremely Low Birth Weight Preterm Infants: Fortin Study-A Randomized Clinical Trial.

Fortified human milk is the first choice for preterm infants. Although individualized fortification is recommended, the optimal method for this population remains uncertain. We conducted a comparative study assessing the growth effects of adjusted (AF) and targeted fortification (TF) in extremely low birth weight (ELBW) infants. This single-center, randomized, controlled clinical trial was conducted at a tertiary neonatal unit in Spain. Eligible participants were premature infants with a birthweight of <1000 g exclusively fed with human milk. A total of 38 patients were enrolled, 15 of them randomized to AF group and 23 to TF group. AF was based on blood urea nitrogen (BUN) concentration and TF on human milk analysis. The primary outcome was weight gain velocity (g/kg/day). No significant differences were found in weight gain velocity at 28 days, at 36 weeks of postmenstrual age, at discharge, nor during the intervention. Protein intake was significantly higher in the AF group (5.02 g/kg/day vs. 4.48 g/kg/day, p = 0.001). No differences were found in the lipid, carbohydrate, and energy intake; in the weight z score change between the different time points; nor in the length and head circumference growth. Both AF and TF are comparable methods of fortification and provide the appropriate growth rate in ELBW infants.

Uncemented Customized Hollow Stems in Tumor Endoprosthetic Replacement-A Good Opportunity to Protect the Adjacent Joint in Children?

This study aimed to retrospectively analyze the follow-up results of cases in which the adjacent joint was preserved using a custom-made uncemented short-stem design (hollow stem) with optional external flanches in tumor endoprosthetic replacement due to bone sarcomas in 13 patients (with an average age of 9.6 years) between 2017 and 2023. Reconstructions were proximal femur (n = 6), intercalary femur (n = 4), intercalary tibia (n = 2), and proximal humerus (n = 1) tumor prostheses. The hollow body was used distally in 10 of the megaprotheses, proximally in 1, and both proximally and distally in 2 of them. The average distance from the joints was 6 cm in stems with flanches and 11.8 cm in stems without flanches. No aseptic loosening or deep infection was observed during an average follow-up of 34 months. Except for one case with a tibial intercalary prosthesis that needed a revision, all cases were well osteointegrated and all lower extremity cases could bear full weight without pain. In cases where the remaining bone stock after bone resection is insufficient for a standard stem implantation, reconstruction with a patient-specific short hollow-stem design appears to be a good alternative to protect healthy joints with high prosthesis survival and low revision rates in the short-term follow-up.

Toward Model-Informed Precision Dosing for Remimazolam: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Remimazolam, widely used for procedural sedation and general anesthesia, is a new ultra short-acting benzodiazepine for intravenous sedation and anesthesia. We aim to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of remimazolam and its metabolite CNS 7054 in healthy Chinese volunteers using population analysis and suggest an optimal dosing regimen for sedation therapy. Data were collected from a single-center, placebo-controlled, randomized, and dose-escalation clinical pharmacology study. Forty-six healthy volunteers received a single infusion dose of remimazolam, while nine healthy subjects received a continuous infusion of remimazolam. A population PK/PD model was established and RxODE and Shiny in R were used to design the remimazolam dosing regimens. A three-compartment model best described the PK of remimazolam and a two-compartment model with one transit compartment was adopted for CNS 7054. The relationship between exposure and the bispectral index was best described using an effect compartment model with an inhibitory sigmoid model. Additionally, a web-based dashboard was developed to provide individualized dosing regimens, complemented by a graphical illustration of the PK/PD profiles of the proposed dosing regimen. The established population PK/PD model characterized the dose-exposure-response relationship of remimazolam well, which could be applied to optimize individual dosing regimens.

Individualized multi-modal MRI biomarkers predict 1-year clinical outcome in first-episode drug-naïve schizophrenia patients.

Background: Antipsychotic medications offer limited long-term benefit to about 30% of patients with schizophrenia. We aimed to explore the individual-specific imaging markers to predict 1-year treatment response of schizophrenia. Methods: Structural morphology and functional topological features related to treatment response were identified using an individualized parcellation analysis in conjunction with machine learning (ML). We performed dimensionality reductions using the Pearson correlation coefficient and three feature selection analyses and classifications using 10 ML classifiers. The results were assessed through a 5-fold cross-validation (training and validation cohorts, n = 51) and validated using the external test cohort (n = 17). Results: ML algorithms based on individual-specific brain network proved more effective than those based on group-level brain network in predicting outcomes. The most predictive features based on individual-specific parcellation involved the GMV of the default network and the degree of the control, limbic, and default networks. The AUCs for the training, validation, and test cohorts were 0.947, 0.939, and 0.883, respectively. Additionally, the prediction performance of the models constructed by the different feature selection methods and classifiers showed no significant differences. Conclusion: Our study highlighted the potential of individual-specific network parcellation in treatment resistant schizophrenia prediction and underscored the crucial role of feature attributes in predictive model accuracy.

Outcomes of Painful Hips After Hip Arthroscopy Surgery for Femoroacetabular Impingement.

The benefits of hip arthroscopic surgery for femoroacetabular impingement are well-established. Hip arthroscopic surgery rates have risen dramatically over the last decade. Some patients, however, may continue to experience hip symptoms after surgery and are dissatisfied with their inability to return to desired optimal activity levels. The purpose of the study is to understand the long-term outcomes of patients with painful hips after hip arthroscopy for femoroacetabular impingement. This is a retrospective study of the outcomes of painful hips after hip arthroscopy for femoroacetabular impingement, with four to 14-year follow-up from 2008 to 2022. A total of 84 hip arthroscopies were performed. Most of the patients had labral tear debridement and shaving of the aspherical femoral head also known as cam lesion, and five patients had repair for labral tear. There were eight patients who had bilateral hip involvement. There were 27 men and 57 females between the second to fifth decades. The electronic patient's records and radiological images were reviewed, and patient outcomes were graded as pain-free hip (asymptomatic) or painful hip (persistent pain and symptoms of instability). After hip arthroscopy surgery, 55% (46) of hips were graded pain-free in patients who were mostly in their 20s and 30s, while 45% (38) of hips had persistent pain. These patients were in their third or fifth decade. In the painful hip cohort, 33 patients had one hip arthroscopic surgery, while five patients had multiple repeat hip arthroscopies in the same hip over a three to six-year period. Bilateral hip arthroscopies were performed at different times in eight patients of which five individuals experienced painful hip outcomes. There were seven females and one male in their 30s and 40s. The labral tear was repaired in five patients, and two patients had painful hip outcomes. Both were females in their 20s and 30s. Patients with chronic painful hips after hip arthroscopic surgery were investigated to identify the cause of the pain. If no cause was established, then they were finally referred to pain specialist clinicians for pain management. This cohort had seven patients between 28 and 43 years. Six were female and one was male. Total hip replacement (THR) was performed in four patients (4.7%). Conversely, 95.3% of patients did not need THR during the study period of 14 years. Hip arthroscopy can be an effective treatment for femoroacetabular impingement. Careful patient selection and a holistic approach are vital for a good patient outcome. The success rate of the pain-free hip after hip arthroscopy decreases with increasing age of the patient, particularly in the female gender. Patients with grade II and more degenerative chondral changes do not perform well. Patients in their fourth and fifth decade can benefit from hip arthroscopy provided a comprehensive discussion of the expected outcomes is conducted prior to surgery. Overall, hip arthroscopy remains a valuable tool, but it is important to be conscious of its limitations and potential challenges.

Precision medicine activities and opportunities for shaping maternal and neonatal health in Qatar.

Precision Medicine (PM) is a transformative clinical medicine strategy that aims to revolutionize healthcare by leveraging biological information and biomarkers. In the context of maternal and neonatal health, PM enables personalized care from preconception through the postnatal period. Qatar has emerged as a key player in PM research, with dedicated programs driving advancements and translating cutting-edge research into clinical applications. This article delves into neonatal and maternal health in Qatar, emphasizing PM programs and initiatives that have been implemented. It also features noteworthy clinical cases that demonstrate the effectiveness of precision interventions. Furthermore, the article highlights the role of pharmacogenomics in addressing various maternal health conditions. The review further explores potential advancements in the application of PM in maternal and neonatal healthcare in Qatar.

[Box: see text].

A Bayesian multivariate hierarchical model for developing a treatment benefit index using mixed types of outcomes.

BACKGROUND: Precision medicine has led to the development of targeted treatment strategies tailored to individual patients based on their characteristics and disease manifestations. Although precision medicine often focuses on a single health outcome for individualized treatment decision rules (ITRs), relying only on a single outcome rather than all available outcomes information leads to suboptimal data usage when developing optimal ITRs. METHODS: To address this limitation, we propose a Bayesian multivariate hierarchical model that leverages the wealth of correlated health outcomes collected in clinical trials. The approach jointly models mixed types of correlated outcomes, facilitating the "borrowing of information" across the multivariate outcomes, and results in a more accurate estimation of heterogeneous treatment effects compared to using single regression models for each outcome. We develop a treatment benefit index, which quantifies the relative benefit of the experimental treatment over the control treatment, based on the proposed multivariate outcome model. RESULTS: We demonstrate the strengths of the proposed approach through extensive simulations and an application to an international Coronavirus Disease 2019 (COVID-19) treatment trial. Simulation results indicate that the proposed method reduces the occurrence of erroneous treatment decisions compared to a single regression model for a single health outcome. Additionally, the sensitivity analyses demonstrate the robustness of the model across various study scenarios. Application of the method to the COVID-19 trial exhibits improvements in estimating the individual-level treatment efficacy (indicated by narrower credible intervals for odds ratios) and optimal ITRs. CONCLUSION: The study jointly models mixed types of outcomes in the context of developing ITRs. By considering multiple health outcomes, the proposed approach can advance the development of more effective and reliable personalized treatment.

Developing Patient-Derived 3D-Bioprinting models of pancreatic cancer.

INTRODUCTION: Pancreatic cancer (PC) remains a challenging malignancy, and adjuvant chemotherapy is critical in improving patient survival post-surgery. However, the intrinsic heterogeneity of PC necessitates personalized treatment strategies, highlighting the need for reliable preclinical models. OBJECTIVES: This study aimed to develop novel patient-derived preclinical PC models using three-dimensional bioprinting (3DP) technology. METHODS: Patient-derived PC models were established using 3DP technology. Genomic and histological analyses were performed to characterize these models and compare them with corresponding patient tissues. Chemotherapeutic drug sensitivity tests were conducted on the PC 3DP models, and correlations with clinical outcomes were analyzed. RESULTS: The study successfully established PC 3DP models with a modeling success rate of 86.96%. These models preserved genomic and histological features consistent with patient tissues. Drug sensitivity testing revealed significant heterogeneity among PC 3DP models, mirroring clinical variability, and potential correlations with clinical outcomes. CONCLUSION: The PC 3DP models demonstrated their utility as reliable preclinical tools, retaining key genomic and histological characteristics. Importantly, drug sensitivity profiles in these models showed potential correlations with clinical outcomes, indicating their promise in customizing treatment strategies and predicting patient prognoses. Further validation with larger patient cohorts is warranted to confirm their potential clinical utility.

Consistency and stability of individualized cortical functional networks parcellation at 3.0 T and 5.0 T MRI.

Background: Individualized cortical functional networks parcellation has been reported as highly reproducible at 3.0 T. However, in view of the complexity of cortical networks and the greatly increased sensitivity provided by ultra-high field 5.0 T MRI, the parcellation consistency between different magnetic fields is unclear. Purpose: To explore the consistency and stability of individualized cortical functional networks parcellation at 3.0 T and 5.0 T MRI based on spatial and functional connectivity analysis. Materials and methods: Thirty healthy young participants were enrolled. Each subject underwent resting-state fMRI at both 3.0 T and 5.0 T in a random order in less than 48 h. The individualized cortical functional networks was parcellated for each subject using a previously proposed iteration algorithm. Dice coefficient was used to evaluate the spatial consistency of parcellated networks between 3.0 T and 5.0 T. Functional connectivity (FC) consistency was evaluated using the Euclidian distance and Graph-theory metrics. Results: A functional cortical atlas consisting of 18 networks was individually parcellated at 3.0 T and 5.0 T. The spatial consistency of these networks at 3.0 T and 5.0 T for the same subject was significantly higher than that of inter-individuals. The FC between the 18 networks acquired at 3.0 T and 5.0 T were highly consistent for the same subject. Positive cross-subject correlations in Graph-theory metrics were found between 3.0 T and 5.0 T. Conclusion: Individualized cortical functional networks at 3.0 T and 5.0 T showed consistent and stable parcellation results both spatially and functionally. The 5.0 T MR provides finer functional sub-network characteristics than that of 3.0 T.

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics.

Antisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability of each ASO ranges from thousands of patients worldwide to single individuals based on the prevalence of the causative pathogenic variant. It was shown that development of individualized ASOs was feasible within an academic setting, starting with Milasen for the treatment of a patient with CLN7 Batten's disease in the USA. Inspired by this, the Dutch Center for RNA Therapeutics (DCRT) was established by three academic medical centers in the Netherlands with a track record in ASO development for progressive, genetic neurodegenerative, neurodevelopmental, and retinal disorders. The goal of the DCRT is to bundle expertise and address national ethical, regulatory, and financial issues related to ASO treatment, and ultimately to develop individualized ASOs for eligible patients with genetic diseases affecting the central nervous system in an academic, not-for-profit setting. In this perspective, we describe the establishment of the DCRT in 2020 and the achievements so far, with a specific focus on lessons learned: the need for processes and procedures, the need for global collaboration, the need to raise awareness, and the fact that N-of-1 is N-of-a-few.

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics Many rare diseases have a genetic cause. Antisense oligonucleotides (ASOs) are short pieces of modified DNA that have therapeutic potential for some patients with rare diseases. However, often this is in a patient-specific setting, meaning individualized therapy development is required, which has little commercial opportunity for pharmaceutical companies. It was shown however that individualized ASOs can be developed by academics, starting with Milasen, which was developed for a unique DNA variant found in a child with Batten's disease in the USA. Following in the footstep of these academic pioneers we established the Dutch Center for RNA Therapeutics (DCRT), which aims to develop individualized ASOs for eligible patients with eye or brain diseases in a not-for-profit setting. Our goal is to bundle expertise and address national, ethical, regulatory and financial issues related to individualized ASO development. In this perspective review we outline the achievements since establishing the DCRT in 2020, with a focus on lessons learnt along the way: the need for processes and procedures, the need for global collaboration, the need to raise awareness and the fact that very often ASOs developed for a single person, could be applied also to a few other patients with the same DNA variants.

Sex differences in clinical presentation, treatment response, and side effects of nutritional therapy among patients at nutritional risk A secondary analysis of the randomized clinical trial EFFORT.

BACKGROUND: Considering sex-specific factors has become an increasingly recognized area for research and practice. In the field of clinical nutrition, there is insufficient evidence regarding differences in clinical presentation, treatment response, and side effects of nutritional therapy among female and male patients. METHODS: This secondary analysis investigated differences among female and male patients at risk for malnutrition regarding initial presentation, clinical outcomes, and treatment response in patients included in the Effect of Early NutritionalSupporton Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial comparing individualized nutritional support to usual care. RESULTS: Of 2,028 patients included in the trial 964 were female and 1,064 were male. The nutritional history and clinical presentation of female patients was different: they consumed less food and had a greater loss of appetite than the male population. Male patients had higher risk for mortality at 180 days (27% compared to 19%, adjusted HR 1.35 [95%CI 1.12, 1.63]) and further adverse clinical outcomes. However, there was no difference in the effect of nutritional support on mortality among female and male patients (HR 0.76 [95%CI 0.45, 1.27] compared to 0.81 [95%CI 0.54, 1.21]; p for interaction =0.939). CONCLUSION: Results of this multicenter randomized trial suggest that multimorbid female inpatients, have a different clinical presentation and are more prone to loss of appetite and reduced daily dietary intake compared to male inpatients. Importantly, the favorable response to nutritional interventions was similar in both sexes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02517476.

An investigation into the correlation between intraperitoneal teicoplanin concentrations and treatment outcomes in peritoneal dialysis-associated peritonitis.

Peritoneal dialysis-associated peritonitis (PDAP) is a frequent complication of peritoneal dialysis. The guidelines from the International Society for Peritoneal Dialysis (ISPD) suggest administering teicoplanin through the peritoneal route to treat PDAP, but do not specify the ideal concentration for peritoneal dialysis effluent (PDE). Patients meeting the trial criteria for PDAP in our hospital between July 2022 and December 2023 were enrolled. Data on PDE white blood cell count, PDE neutrophil percentage, clinical symptoms, CRP, and PCT were gathered pre- and post-treatment. Incidences of adverse drug reaction (ADR) and case numbers during treatment were recorded. Subsequently, patients were categorized into cured and uncured groups for evaluating the relationship between PDE teicoplanin concentration and treatment effectiveness. The self-control study results on teicoplanin efficacy indicated intraperitoneal teicoplanin administration achieved an efficacy rate of 88.9% and an ADR incidence of 5.5% in treating PDAP patients. There was no observed correlation between teicoplanin blood concentration and PDE concentration. PDE teicoplanin concentrations on days 1, 3, 5, and 7 post-dosing were higher inthe cured group, with a significant contrast in PDE concentration on day 5 between the 18.98 ± 2.43 mg/L of the cured group and the 12.07 ± 2.68 mg/L of the uncured group. ROC curve revealed a higher likelihood of cure in patients when PDE teicoplanin concentration exceeded 15.138 mg/L on day 5 post-dosing. Univariate and multifactorial studies identified 24-h urine volume and the number of daily abdominal dialysis sessions as influential factors in PDE teicoplanin concentration on day 5. A positive correlation was found between 24-h urine volume and PDE teicoplanin concentration, with PDAP patients having urine volume over 537 mL showing significantly higher drug concentrations. Conversely, the number of daily PDAP sessions was negatively correlated with PDE teicoplanin concentrations, indicating that patients with 1∼3 daily PDAP sessions had notably higher PDE teicoplanin concentrations compared to those with 4∼6 sessions. Therefore, PDAP patients who use intraperitoneal teicoplanin could effectively control infection by monitoring the PDE teicoplanin concentration (>15.138 mg/L) on day 5 after dosing.