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.

A Review of Current Approaches to Pain Management in Knee Osteoarthritis with a Focus on Italian Clinical Landscape.

The global cases of knee osteoarthritis (KOA) are projected to increase by 74.9% by 2050. Currently, over half of patients remain dissatisfied with their pain relief. This review addresses unmet needs for moderate-to-severe KOA pain; it offers evidence and insights for improved management. Italian experts from the fields of rheumatology, physical medicine and rehabilitation, orthopedics, primary care, and pain therapy have identified several key issues. They emphasized the need for standardized care protocols to address inconsistencies in patient management across different specialties. Early diagnosis is crucial, as cartilage responds better to early protective and structural therapies. Faster access to physiatrist evaluation and reimbursement for physical, rehabilitative, and pharmacological treatments, including intra-articular (IA) therapy, could reduce access disparities. Concerns surround the adverse effects of oral pharmacological treatments, highlighting the need for safer alternatives. Patient satisfaction with corticosteroids and hyaluronic acid-based IA therapies reduces over time and there is no consensus on the optimal IA therapy protocol. Surgery should be reserved for severe symptoms and radiographic KOA evidence, as chronic pain post-surgery poses significant societal and economic burdens. The experts advocate for a multidisciplinary approach, promoting interaction and collaboration between specialists and general practitioners, to enhance KOA care and treatment consistency in Italy.

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.

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.

Custom silicone Y-stents for the management of anastomotic stenosis in lung transplant recipients.

BACKGROUND: Airway stenting may be needed to manage anastomotic complications in lung transplant recipients. Conventional stenting strategies may be inadequate due to anatomic variations between the recipient and donor or involvement of both the anastomosis and lobar bronchi. METHODS: We investigated the efficacy of 3D-designed patient-specific silicone Y-stents in managing this scenario. 9 patients with complex airway stenosis underwent custom stent insertion after either failing traditional management strategies or having anatomy not suitable for conventional stents. CT images were uploaded to stent design software to make a virtual stent model. 3D printing technology was then used to make a mold for the final silicone stent which was implanted via rigid bronchoscopy. Forced expiratory volume in 1 s (FEV1) was measured pre- and post-stent placement. RESULTS: 78 % of patients experienced an increase in their FEV1 after stent insertion, (p = 0.001, 0.02 at 30 and 90 days respectively). Unplanned bronchoscopies primarily occurred due to mucous plugging. 2 patients had sufficient airway remodeling allowing for stent removal. CONCLUSIONS: Personalized 3D-designed Y-stents demonstrate promising results for managing complicated airway stenosis, offering improved lung function and potential long-term benefits for lung transplant recipients.

Development of radioiodine-labeled mequitazine for evaluation of hepatic CYP2D activity.

Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: 123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.

Derivation and validation of the first web-based nomogram to predict the spontaneous pregnancy after reproductive surgery using machine learning models.

Objective: Infertility remains a significant global burden over the years. Reproductive surgery is an effective strategy for infertile women. Early prediction of spontaneous pregnancy after reproductive surgery is of high interest for the patients seeking the infertility treatment. However, there are no high-quality models and clinical applicable tools to predict the probability of natural conception after reproductive surgery. Methods: The eligible data involving 1013 patients who operated for infertility between June 2016 and June 2021 in Yantai Yuhuangding Hospital in China, were randomly divided into training and internal testing cohorts. 195 subjects from the Linyi People's Hospital in China were considered for external validation. Both univariate combining with multivariate logistic regression and the least absolute shrinkage and selection operator (LASSO) algorithm were performed to identify independent predictors. Multiple common machine learning algorithms, namely logistic regression, decision tree, random forest, support vector machine, k-nearest neighbor, and extreme gradient boosting, were employed to construct the predictive models. The optimal model was verified by evaluating the model performance in both the internal and external validation datasets. Results: Six clinical indicators, including female age, infertility type, duration of infertility, intraoperative diagnosis, ovulation monitoring, and anti-Müllerian hormone (AMH) level, were screened out. Based on the logistic regression model's superior clinical predictive value, as indicated by the area under the receiver operating characteristic curve (AUC) in both the internal (0.870) and external (0.880) validation sets, we ultimately selected it as the optimal model. Consequently, we utilized it to generate a web-based nomogram for predicting the probability of spontaneous pregnancy after reproductive surgery. Furthermore, the calibration curve, Hosmer-Lemeshow (H-L) test, the decision curve analysis (DCA) and clinical impact curve analysis (CIC) demonstrated that the model has superior calibration degree, clinical net benefit and generalization ability, which were confirmed by both internal and external validations. Conclusion: Overall, our developed first nomogram with online operation provides an early and accurate prediction for the probability of natural conception after reproductive surgery, which helps clinicians and infertile couples make sensible decision of choosing the mode of subsequent conception, natural or IVF, to further improve the clinical practices of infertility treatment.

Latest Developments in Early Detection and Effective Treatment of Cancer: A Meeting Report.

Despite a lower estimated rate of cancer incidence in Iran compared to the global average, the trend is unfortunately increasing. This necessitates the implementation of early detection of cancer and targeted therapies to effectively treat various types of cancer. Therefore, the 5th "International Royan Cancer Conference: From Bench to Bedside" was held to focus on critical cancer-related aspects such as gene- and cell therapy, immunotherapy, oligonucleotides in cancer treatment, biosensors for detection, and drug delivery. The 2-day conference took place in February 2024 at the Royan Institute, Tehran. This collaborative effort brought together experts from both basic and clinical research fields. The primary objective of the conference was to address clinical challenges and harness the potential of basic sciences for early cancer diagnosis and treatment, with a robust emphasis on ethical considerations. The conference aimed to ensure optimal patient care while advancing scientific understanding in the field and facilitating effective research collaborations among researchers and enthusiasts dedicated to combating cancer.

Impact of withholding early parenteral nutrition on 2-year mortality and functional outcome in critically ill adults.

PURPOSE: In critically ill adults, withholding parenteral nutrition until 1 week after intensive care admission (Late-PN) facilitated recovery as compared with early supplementation of insufficient enteral nutrition with parenteral nutrition (Early-PN). However, the impact on long-term mortality and functional outcome, in relation to the estimated nutritional risk, remains unclear. METHODS: In this prospective follow-up study of the multicenter EPaNIC randomized controlled trial, we investigated the impact of Late-PN on 2-year mortality (N = 4640) and physical functioning, assessed by the 36-Item Short Form Health Survey (SF-36; in 3292 survivors, responding 819 [738-1058] days post-randomization). To account for missing data, we repeated the analyses in two imputed models. To identify potential heterogeneity of treatment effects, we investigated the impact of Late-PN in different nutritional risk subgroups as defined by Nutritional Risk Screening-2002-score, modified NUTrition Risk in the Critically Ill-score, and age (above/below 70 years), and we evaluated whether there was statistically significant interaction between classification to a nutritional risk subgroup and the effect of the randomized intervention. Secondary outcomes were SF-36-derived physical and mental component scores (PCS & MCS). RESULTS: Two-year mortality (20.5% in Late-PN, 19.8% in Early-PN; P = 0.54) and physical functioning (70 [40-90] in both study-arms; P = 0.99) were similar in both groups, also after imputation of missing physical functioning data. Likewise, Late-PN had no impact on 2-year mortality and physical functioning in any nutritional risk subgroup. PCS and MCS were similar in both groups. CONCLUSION: Late-PN did not alter 2-year survival and physical functioning in adult critically ill patients, independent of anticipated nutritional risk.

Bridging the Divide: A Review on the Implementation of Personalized Cancer Medicine.

The shift towards personalized cancer medicine (PCM) represents a significant transformation in cancer care, emphasizing tailored treatments based on the genetic understanding of cancer at the cellular level. This review draws on recent literature to explore key factors influencing PCM implementation, highlighting the role of innovative leadership, interdisciplinary collaboration, and coordinated funding and regulatory strategies. Success in PCM relies on overcoming challenges such as integrating diverse medical disciplines, securing sustainable investment for shared infrastructures, and navigating complex regulatory landscapes. Effective leadership is crucial for fostering a culture of innovation and teamwork, essential for translating complex biological insights into personalized treatment strategies. The transition to PCM necessitates not only organizational adaptation but also the development of new professional roles and training programs, underscoring the need for a multidisciplinary approach and the importance of team science in overcoming the limitations of traditional medical paradigms. The conclusion underscores that PCM's success hinges on creating collaborative environments that support innovation, adaptability, and shared vision among all stakeholders involved in cancer care.

Evaluation of relationship between memory and temperament in 18-28 years old students.

Background: Mizaj (Temperament) is a concept to express individual differences in Persian medicine and according to this theory, there is a relationship between Mizaj type and the abilities of different body organs. This cross-sectional study aimed to investigate the relationship between the type of Mizaj and the memory score (Quotient). Methods: The target population was the 18 to 38 years old students of Babol University of Medical Sciences. Mojahedi's Mizaj questionnaire (MMQ) was used for determining the whole Mizaj. The physical Persian version of Wechsler Memory Scale III (WMS III) was used to assess memory score. The collected data were analyzed by SPSS Version 22 and the chi square (x2) and t-test were run and p- value 0.05 was considered as significant difference. Results: Forty-two of participants were females and 18 were males. The average age of them was 23.6 (21-27). The average of Memory Quotient (MQ) was 122.1 ± 5.7. The average of MQ in warm Mizaj was 125.46 ± 1.2 and in cold Mizaj was 118.79 ± 6.5. The difference between two groups is statistically significant (p< 0.001). The average of MQ in dry Mizaj was 124.16 ± 2.67 and in wet Mizaj was 118.40 ± 7.64. The difference between two groups is statistically significant (P= 0.005). Conclusion: The results showed there are significant relationship between memory score and warm/cold Mizaj and dry /wet Mizaj. It means students with warm or dry Mizaj had better memory score than students with cold or wet Mizaj. This relation was also detected between subtypes of memory and Mizaj expect between working memory and dry/wet Mizaj. These results are in accordance with theories in PM which indicate people with warm Mizaj and dry Mizaj have better memory and people with cold Mizaj and wet Mizaj have weaker memory and are more at risk of memory dysfunction.

Real-world outcomes in patients with malignancy and moderate-to-severe psoriasis treated with guselkumab.

Background: The treatment of psoriasis in patients with a personal history of cancer is a matter of debate and limited evidence is available to guide clinicians. Objectives: To report a multicenter real-life experience of a group of patients with psoriasis undergoing treatment with guselkumab and a history of cancer. Methods: We conducted a multicenter retrospective Spanish study enrolling patients with moderate-to-severe plaque psoriasis and neoplasia being treated with guselkumab for their psoriasis. Results: Twenty patients with moderate-to-severe psoriasis and at least 12 weeks of ongoing treatment were included. For the analysis, a 52 week follow-up period was evaluated in terms of efficacy and safety. Most of the malignancies in these patients were solid tumors. The percentage of patients achieving psoriasis area and severity index ≤3 at week 12 and week 52 was 80% and 87.5%, respectively, whereas 68.8% of patients achieved psoriasis area and severity index ≤1. A 52-week survival rate of 100% in the study population was observed (n = 20), including those patients with concomitant active cancers (n = 14). No adverse effects or dropouts related to guselkumab safety profile were detected. Limitations: Modest sample size and the retrospective nature of the study. Conclusion: Guselkumab not only demonstrates high effectiveness in treating psoriasis but also exhibits a favorable safety profile in patients with neoplasms.

Targeting Tumor Heterogeneity by Breaking a Stem Cell and Epithelial Niche Interaction Loop.

Tumor heterogeneity, the presence of multiple distinct subpopulations of cancer cells between patients or among the same tumors, poses a major challenge to current targeted therapies. The way these different subpopulations interact among themselves and the stromal niche environment, and how such interactions affect cancer stem cell behavior has remained largely unknown. Here, it is shown that an FGF-BMP7-INHBA signaling positive feedback loop integrates interactions among different cell populations, including mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration but also, with certain modifications, in cancer progression. The reciprocal dependence of basal stem cells and luminal epithelium is based on basal-derived BMP7 and luminal-derived INHBA, which promote their respective expansion, and is regulated by stromal-epithelial FGF signaling. Targeting this interaction loop, for example, by reducing the function of one or more of its components, inhibits organ regeneration and breast cancer progression. The results have profound implications for overcoming drug resistance because of tumor heterogeneity in future targeted therapies.

Assessment of Nocturnal Blood Pressure: Importance of Determining the Time in Bed-A Pilot Study.

Objectives: Nocturnal blood pressure (BP) monitoring is essential for evaluating cardiovascular risk and guiding treatment decisions. However, the standardized narrow-fixed nighttime period between 10 p.m. and 6 a.m. may not accurately reflect individual sleep schedules. This pilot study aimed to investigate the comparability between the standardized nighttime period and actual time in bed (TIB) regarding BP assessment. Further, our goal was to evaluate the clinical relevance of the observed BP differences. Methods: A total of 30 participants underwent 24 h ambulatory blood pressure monitoring (ABPM). Patient-specific TIB was precisely assessed through an accelerometer and a position sensor from the SOMNOtouch NIBP™ (SOMNOmedics GmbH, Randersacker, Germany). We analysed the effect of considering individual TIB as nighttime instead of the conventional narrow-fixed interval on the resulting nocturnal BP levels and dipping patterns. Results: We observed differences in both systolic and diastolic BP between the standardized nighttime period and the TIB. Furthermore, a notable percentage of patients (27%) changed their dipping pattern classification as a function of the nighttime definition adopted. We found strong correlations between the start (r = 0.75, p < 0.01), as well as the duration (r = -0.42, p = 0.02) of TIB and the changes in dipping pattern classification. Conclusions: Definition of nocturnal period based on the individual TIB leads to clinically relevant changes of nocturnal BP and dipping pattern classifications. TIB is easily detected using a body position sensor and accelerometer. This approach may thus improve the accuracy of cardiovascular risk evaluation and enhance treatment strategies.

New trends on personalized sunscreens.

BACKGROUND/PURPOSE: Nowadays, there are emerging trends in customized and personalized photoprotection, focusing on the innovative approaches to enhance sun protection efficacy tailored to individual needs. METHODS: We conducted an electronic search of the following databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Skin Group Specialised Skin Register, and TESEO. Specific search terms related to personalized photoprotection and the variables of age, genetic predisposition, skin phototype, photodermatosis, and physiological conditions such as pregnancy, as well as lifestyle habits were used. RESULTS/CONCLUSION: The article highlights the challenges and opportunities in adopting personalized photoprotection strategies, aiming to promote skin health and prevent the harmful effects of UV radiation in the era of precision medicine.

Exploring Pelvic Symptom Dynamics in Relation to the Menstrual Cycle: Implications for Clinical Assessment and Management.

BACKGROUND: Pelvic floor dysfunctions (PFDs) encompass an array of conditions with discrepant classification systems, hampering accurate prevalence estimation. Despite potentially affecting up to 25% of women during their lifetime, many remain undiagnosed, underestimating the true extent. OBJECTIVES: This cross-sectional study aimed to examine the impacts of the menstrual cycle on PFDs and dysfunctions. Secondary objectives included investigating differences between athletic and nonathletic women. METHODS: An online questionnaire examined the effects of the menstrual cycle (MC) on 477 women's pelvic symptoms (aged 16-63 years), stratified by athletic status. This ad hoc instrument built upon a validated screening tool for female athletes. RESULTS: Most participants reported symptom fluctuations across menstrual phases, with many modifying or reducing exercise participation. A concerning number experienced daily undiagnosed pelvic floor symptoms, emphasizing needs for comprehensive medical evaluation. CONCLUSIONS: Exacerbated pelvic symptoms showed complex relationships with menstruation, highlighting the importance of considering the MC in customized clinical management approaches. Symptoms demonstrated differential links to menstruation, indicating needs for individualized evaluation and tailored treatment plans based on symptom profiles and hormonal interactions. Educating professionals and patients remains essential to enhancing awareness, detection, and therapeutic outcomes. Further controlled longitudinal research should elucidate intricate relationships between menstrual cycles and pelvic symptom variability.

A Survey on Blood Pressure Measurement Technologies: Addressing Potential Sources of Bias.

Regular blood pressure (BP) monitoring in clinical and ambulatory settings plays a crucial role in the prevention, diagnosis, treatment, and management of cardiovascular diseases. Recently, the widespread adoption of ambulatory BP measurement devices has been predominantly driven by the increased prevalence of hypertension and its associated risks and clinical conditions. Recent guidelines advocate for regular BP monitoring as part of regular clinical visits or even at home. This increased utilization of BP measurement technologies has raised significant concerns regarding the accuracy of reported BP values across settings. In this survey, which focuses mainly on cuff-based BP monitoring technologies, we highlight how BP measurements can demonstrate substantial biases and variances due to factors such as measurement and device errors, demographics, and body habitus. With these inherent biases, the development of a new generation of cuff-based BP devices that use artificial intelligence (AI) has significant potential. We present future avenues where AI-assisted technologies can leverage the extensive clinical literature on BP-related studies together with the large collections of BP records available in electronic health records. These resources can be combined with machine learning approaches, including deep learning and Bayesian inference, to remove BP measurement biases and provide individualized BP-related cardiovascular risk indexes.

Patients' perceptions of the importance of improvements and side effects from mandibular advancement device therapy for obstructive sleep apnea and snoring.

OBJECTIVE: To assess which improvements and side effects are considered most important by patients with OSA treated with a MAD. METHODS: A specific questionnaire consisting of 20 questions, including 10 questions on improvements and 10 on side effects, was developed and mailed to all subjects (54). RESULTS: 42 patients, participated in the survey by answering the questionnaire. The results showed that patients placed greater importance on the positive outcomes of treatment, with the most significant being the reduction in snoring and improvement in sleep quality. On the other hand, the side effects of difficulty speaking with the device, tooth mobility, and foreign body sensation were considered important. CONCLUSIONS: The advantages perceived by the patients appear to outweigh the disadvantages, especially the reduction of snoring, increased productivity, and improved social and intellectual life. Most significant side effects are reversible and short-term, while occlusal changes, is not considered important by patients.