Clinical impact of complex percutaneous coronary intervention in the pre-TAVR workup.

INTRODUCTION AND OBJECTIVES: In patients undergoing percutaneous coronary intervention (PCI) in the workup for transcatheter aortic valve replacement (TAVR), the clinical impact of coronary revascularization complexity remains largely unknown. This study sought to examine the impact of PCI complexity on clinical outcomes after TAVR in patients undergoing PCI in the preprocedural workup. METHODS: This was a multicenter study including consecutive patients scheduled for TAVR with concomitant significant coronary artery disease. Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation with 2 stents implanted, total stent length > 60 mm, or chronic total occlusion. The rates of major adverse cardiac events (MACE), including cardiovascular mortality, myocardial infarction, and coronary revascularization were evaluated. RESULTS: A total of 1550 patients were included, of which 454 (29.3%) underwent complex PCI in the pre-TAVR workup. After a median follow-up period of 2 [1-3] years after TAVR, the incidence of MACE was 9.6 events per 100 patients-years. Complex PCI significantly increased the risk of cardiovascular death (HR, 1.44; 95%CI, 1.01-2.07), nonperiprocedural myocardial infarction (HR, 1.52; 95%CI, 1.04-2.21), and coronary revascularization (HR, 2.46; 95%CI, 1.44-4.20). In addition, PCI complexity was identified as an independent predictor of MACE after TAVR (HR, 1.44; 95%CI, 1.09-1.83; P = .009). CONCLUSIONS: In TAVR candidates with significant coronary artery disease requiring percutaneous treatment, complex revascularization was associated with a higher risk of MACE. The degree of procedural complexity should be considered a strong determinant of prognosis in the PCI-TAVR population.

Three-Dimensional Bioprinting of GelMA Hydrogels with Culture Medium: Balancing Printability, Rheology and Cell Viability for Tissue Regeneration.

Three-dimensional extrusion bioprinting technology aims to become a fundamental tool for tissue regeneration using cell-loaded hydrogels. These biomaterials must have highly specific mechanical and biological properties that allow them to generate biosimilar structures by successive layering of material while maintaining cell viability. The rheological properties of hydrogels used as bioinks are critical to their printability. Correct printability of hydrogels allows the replication of biomimetic structures, which are of great use in medicine, tissue engineering and other fields of study that require the three-dimensional replication of different tissues. When bioprinting cell-loaded hydrogels, a small amount of culture medium can be added to ensure adequate survival, which can modify the rheological properties of the hydrogels. GelMA is a hydrogel used in bioprinting, with very interesting properties and rheological parameters that have been studied and defined for its basic formulation. However, the changes that occur in its rheological parameters and therefore in its printability, when it is mixed with the culture medium necessary to house the cells inside, are unknown. Therefore, in this work, a comparative study of GelMA 100% and GelMA in the proportions 3:1 (GelMA 75%) and 1:1 (GelMA 50%) with culture medium was carried out to determine the printability of the gel (using a device of our own invention), its main rheological parameters and its toxicity after the addition of the medium and to observe whether significant differences in cell viability occur. This raises the possibility of its use in regenerative medicine using a 3D extrusion bioprinter.

Risk Factors for Therapeutic Failure and One-Year Mortality in Patients with Intramedullary Nail-Associated Infection after Trochanteric and Subtrochanteric Hip Fracture Repair.

Despite the implications of trochanteric and subtrochanteric intramedullary (IM) nail infection for patients with hip fracture, little is known about risk factors for therapeutic failure and mortality in this population. We performed a retrospective observational analysis including patients diagnosed with trochanteric and subtrochanteric IM nail infection at a Spanish academic hospital during a 10-year period, with a minimum follow-up of 22 months. Of 4044 trochanteric and subtrochanteric IM nail implants, we identified 35 cases of infection during the study period (0.87%), 17 of which were chronic infections. Patients with therapeutic failure (n = 10) presented a higher average Charlson Comorbidity Index (CCI) (5.40 vs. 4.21, p 0.015, CI 0.26-2.13) and higher rates of polymicrobial (OR 5.70, p 0.033, CI 1.14-28.33) and multidrug-resistant (OR 7.00, p 0.027, CI 1.24-39.57) infections. Upon multivariate analysis, polymicrobial infection and the presence of multidrug-resistant pathogens were identified as independent risk factors for therapeutic failure. Implant retention was associated with an increased risk of failure in chronic infection and was found to be an independent risk factor for overall one-year mortality in the multivariate analysis. Our study highlights the importance of broad-spectrum empirical antibiotics as initial treatment of trochanteric and subtrochanteric IM nail-associated infection while awaiting microbiological results. It also provides initial evidence for the importance of implant removal in chronic IM-nail infection.

Health-Related Quality of Life Long-Term Study in Lung Transplant Patients: A Single-Center Experience.

INTRODUCTION: Health-related quality of life (HRQL) assessment plays a crucial role in the follow-up care of lung transplanted (LTx) patients. Previous reports have indicated that the HRQL achieved by these patients is often poorer compared to that of healthy individuals. However, the factors contributing to this lower HRQL remain unclear. This prospective study aimed to assess the effectiveness of using both a generic and a disease-specific HRQL instrument in evaluating the outcomes of patients who have undergone LTx. METHODS: A total of 111 LTx patients were enrolled in the study, with 88 survivors completing the 5-year follow-up and 23 nonsurvivors identified within the first 3 y. Among the participants, 84 underwent double LTx, while 27 received a single LTx. Patients were interviewed before LTx, at 6 mo post-transplantation, and annually thereafter. Two validated instruments were utilized: the Euro quality of life five dimensions, a generic measure, and the St. George's Respiratory Questionnaire (SGRQ), a disease-specific questionnaire. RESULTS: The study showed significant improvements in Euro Quality of Life five Dimensions scores from 6 mo after LTx. Specifically, the percentage of patients without Mobility problems increased from 23% before LTx to 71% at 5 y (P = <0.001), while the ability to self-care improved from 48% to 100% (P = <0.001). The ability to carry out usual activities improved from 13% to 86% (P = <0.001), and the proportion of patients without anxiety and depression increased from 50% to 86% (P > 0.004). However, there was no significant improvement observed in Pain, with only a slight reduction from 57% to 42.8% (P = 0.22). The SGRQ also showed improvements in all dimensions (symptoms, impact, activities) (P < 0.001). However, by the fifth year, the HRQL scores remained below normal reference values. Chronic graft dysfunction was associated with a decline in SGRQ scores. Bilateral LTx patients exhibited better SGRQ scores compared to unilateral LTx patients from the first year post-transplantation. Notably, there were no differences in scores between nonsurvivors and survivors. CONCLUSIONS: The study highlights the long-term improvement in HRQL among LTx patients, with greater improvements observed in physical dimensions compared to psychological dimensions. Bilateral LTx was associated with better SGRQ scores than unilateral LTx, and chronic graft dysfunction primarily affected SGRQ scores. These findings underscore the importance of utilizing both generic and specific HRQL instruments in assessing LTx outcomes.

Application of machine learning algorithms in classifying postoperative success in metabolic bariatric surgery: Acomprehensive study.

Objectives: Metabolic bariatric surgery is a critical intervention for patients living with obesity and related health issues. Accurate classification and prediction of patient outcomes are vital for optimizing treatment strategies. This study presents a novel machine learning approach to classify patients in the context of metabolic bariatric surgery, providing insights into the efficacy of different models and variable types. Methods: Various machine learning models, including Gaussian Naive Bayes, Complement Naive Bayes, K-nearest neighbour, Decision Tree, K-nearest neighbour with RandomOverSampler, and K-nearest neighbour with SMOTE, were applied to a dataset of 73 patients. The dataset, comprising psychometric, socioeconomic, and analytical variables, was analyzed to determine the most efficient predictive model. The study also explored the impact of different variable groupings and oversampling techniques. Results: Experimental results indicate average accuracy values as high as 66.7% for the best model. Enhanced versions of K-nearest neighbour and Decision Tree, along with variations of K-nearest neighbour such as RandomOverSampler and SMOTE, yielded the best results. Conclusions: The study unveils a promising avenue for classifying patients in the realm of metabolic bariatric surgery. The results underscore the importance of selecting appropriate variables and employing diverse approaches to achieve optimal performance. The developed system holds potential as a tool to assist healthcare professionals in decision-making, thereby enhancing metabolic bariatric surgery outcomes. These findings lay the groundwork for future collaboration between hospitals and healthcare entities to improve patient care through the utilization of machine learning algorithms. Moreover, the findings suggest room for improvement, potentially achievable with a larger dataset and careful parameter tuning.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Is Unilateral Lymphadenectomy an Option in Selected Patients with Prostate Cancer?

BACKGROUND: Evidence regarding the relationship between the laterality of lymph node invasion (LNI) and the prostatic lobe affected is limited. Our aim was to review our records of patients with exclusively unilateral localised prostate cancer (PCa) with metastatic LN involvement. METHODS: Between 2006 and 2023, after radical prostatectomy and extended pelvic lymphadenectomy at our centre, thirty patients with intermediate-high risk unilateral PCa and pN1 disease were identified. To perform a retrospective study, data were obtained from a prospective collected database approved by the ethical committee at the Valencian Oncology Institute Foundation. Descriptive and comparative statistical analysis was made using software R. The Fisher's Exact test was employed to analyse the categorical variables. In terms of continuous variables, both tumour volume and number of nodes retrieved exhibited normality; Hence Student's T-test was employed. Mann-Whitney U test was utilized for the number of positive nodes. RESULTS: The median age and prostate specific antigen (PSA) at diagnosis were 66 years old (interquartile range (IQR): 63.3-70.9) and 14.6 ng/mL (IQR: 7.4-21.5), respectively. Median follow-up time was 67 months (IQR: 35.9-92.9). Nineteen patients (63%) had a Gleason score of 7, and the rest had a Gleason score of 8-10. Most patients (73%) had locally advanced disease. Baseline characteristics were comparable between groups (p-value > 0.05). Twenty-two patients (73%) had concordance between the laterality of the PCa lesion and the LNI. All the patients with right prostatic cancer had exclusive ipsilateral LNI. CONCLUSIONS: In our experience, the majority of patients with unilateral PCa had exclusively ipsilateral LNI. However, sparing contralateral LN dissection in unilateral PCa should not be an option. To date, extended pelvic LN dissection remains the gold standard for N-staging and cannot be replaced yet by unilateral pelvic LN dissection until high quality evidence supports this scenario.

Ergonomics, musculoskeletal disorders, treatment and return to work: a conceptual framework for intervention programs.

Musculoskeletal disorders are one of the most recurrent diseases among manual workers worldwide. The objective of this study was to analyze primary results of a systematic review on ergonomics, musculoskeletal disorders, treatment, and return to work in blue-collar workers to form a new conceptual framework applicable to intervention programs in this area. This study was based on the available scientific evidence we identified. Descriptive data and their trending topics areas were used to form the conceptual framework. The trend shows that working conditions can be represented as a three-axis scheme with a multidimensional conceptual framework considering ergonomic risks, the treatment of affected workers and the determinants related to working conditions. These results may help future research in the field of ergonomics as well as emerging topics focused on intervention programs.

Los trastornos musculoesqueléticos son una de las enfermedades más recurrentes entre los trabajadores que realizan operaciones manuales a nivel mundial. El objetivo de este estudio fue analizar los resultados primarios de una revisión sistemática sobre ergonomía, trastornos musculoesqueléticos, tratamiento y retorno al trabajo en trabajadores operativos para formar un nuevo marco conceptual aplicable a los programas de intervención en esta área. Este estudio se basó en la evidencia científica disponible identificada. Se utilizaron datos descriptivos y sus áreas de temas de tendencia para formar el marco conceptual. La tendencia muestra que las condiciones de trabajo pueden representarse como un esquema de tres ejes con un marco conceptual multidimensional que considera los riesgos ergonómicos, el tratamiento de los trabajadores afectados y los determinantes relacionados con las condiciones de trabajo. Estos resultados podrían ayudar a futuras investigaciones en el campo de la ergonomía, así como a temas emergentes centrados en programas de intervención.

SU-101 for the removal of pharmaceutical active compounds by the combination of adsorption/photocatalytic processes.

Pharmaceutical active compounds (PhACs) are some of the most recalcitrant water pollutants causing undesired environmental and human effects. In absence of adapted decontamination technologies, there is an urgent need to develop efficient and sustainable alternatives for water remediation. Metal-organic frameworks (MOFs) have recently emerged as promising candidates for adsorbing contaminants as well as providing photoactive sites, as they possess exceptional porosity and chemical versatility. To date, the reported studies using MOFs in water remediation have been mainly focused on the removal of a single type of PhACs and rarely on the combined elimination of PhACs mixtures. Herein, the eco-friendly bismuth-based MOF, SU-101, has been originally proposed as an efficient adsorbent-photocatalyst for the elimination of a mixture of three challenging persistent PhACs, frequently detected in wastewater and surface water in ng L-1 to mg·L-1 concentrations: the antibiotic sulfamethazine (SMT), the anti-inflammatory diclofenac (DCF), and the antihypertensive atenolol (At). Adsorption experiments of the mixture revealed that SU-101 exhibited a great adsorption capacity towards At, resulting in an almost complete removal (94.1 ± 0.8% for combined adsorption) in only 5 h. Also, SU-101 demonstrated a remarkable photocatalytic activity under visible light to simultaneously degrade DCF and SMT (99.6 ± 0.4% and 89.2 ± 1.4%, respectively). In addition, MOF-contaminant interactions, the photocatalytic mechanism and degradation pathways were investigated, also assessing the toxicity of the resulting degradation products. Even further, recycling and regeneration studies were performed, demonstrating its efficient reuse for 4 consecutive cycles without further treatment, and its subsequent successful regeneration by simply washing the material with a NaCl solution.

Predicting carob tree physiological parameters under different irrigation systems using Random Forest and Planet satellite images.

Introduction: In the context of climate change, monitoring the spatial and temporal variability of plant physiological parameters has become increasingly important. Remote spectral imaging and GIS software have shown effectiveness in mapping field variability. Additionally, the application of machine learning techniques, essential for processing large data volumes, has seen a significant rise in agricultural applications. This research was focused on carob tree, a drought-resistant tree crop spread through the Mediterranean basin. The study aimed to develop robust models to predict the net assimilation and stomatal conductance of carob trees and to use these models to analyze seasonal variability and the impact of different irrigation systems. Methods: Planet satellite images were acquired on the day of field data measurement. The reflectance values of Planet spectral bands were used as predictors to develop the models. The study employed the Random Forest modeling approach, and its performances were compared with that of traditional multiple linear regression. Results and discussion: The findings reveal that Random Forest, utilizing Planet spectral bands as predictors, achieved high accuracy in predicting net assimilation (R² = 0.81) and stomatal conductance (R² = 0.70), with the yellow and red spectral regions being particularly influential. Furthermore, the research indicates no significant difference in intrinsic water use efficiency between the various irrigation systems and rainfed conditions. This work highlighted the potential of combining satellite remote sensing and machine learning in precision agriculture, with the goal of the efficient monitoring of physiological parameters.

The effectiveness of the TRACE online nutrition intervention in improving dietary intake, sleep quality and physical activity levels for Australian adults with food addiction: a randomised controlled trial.

BACKGROUND: Few interventions for food addiction (FA) report on dietary intake variables. The present study comprised a three-arm randomised controlled trial in adults with symptoms of FA. The aim was to evaluate dietary intake, sleep and physical activity resulting from a dietitian-led telehealth intervention at 3 months. METHODS: Adults with ≥3 symptoms of FA and a body mass index > 18.5 kg/m2 were recruited. Dietary intake including energy, nutrients and diet quality were assessed by a validated food frequency questionnaire in addition to sleep quality and physical activity (total min) and compared between groups and over time. Personalised dietary goals set by participants were examined to determine whether improvements in percent energy from core and non-core foods were reported. RESULTS: The active intervention group was superior compared to the passive intervention and control groups for improvements in percent energy from core (6.4%/day [95% confidence interval (CI) -0.0 to 12.9], p = 0.049), non-core foods (-6.4%/day [95% CI -12.9 to 0.0], p = 0.049), sweetened drinks (-1.7%/day [95% CI -2.9 to -0.4], p = 0.013), takeaway foods (-2.3%/day [95% CI -4.5 to -0.1], p = 0.045) and sodium (-478 mg/day [95% CI -765 to -191 mg], p = 0.001). CONCLUSIONS: A dietitian-led telehealth intervention for Australian adults with FA found significant improvements in dietary intake variables. Setting personalised goals around nutrition and eating behaviours was beneficial for lifestyle change.

Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

BACKGROUND: Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. METHODS: Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. RESULTS: This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. CONCLUSION: After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.

Feeding Dairy Goats Dehydrated Orange Pulp Improves Cheese Antioxidant Content.

Agroindustrial by-products constitute an alternative source of feed livestock, and their use contributes to the sustainability of livestock systems and the circular bioeconomy. The effects of replacing cereal (0%, 40%, and 80%) with dehydrated orange pulp (DOP) in the diet of goats on the antioxidant and fatty acid (FA) contents of cheeses were evaluated. For a more suitable understanding of the role of coagulant enzymes in establishing the properties of the cheese, the effect of milk-clotting with animal and vegetable rennet was also analysed. The rennet did not substantially affect the FA or the antioxidant compounds, and the use of DOP did not affect the FA contents. However, the α-tocopherol levels, total phenolic compounds (TPC), and total antioxidant capacity (TAC) in cheeses increased as the percentage of DOP replacing cereals increased. Moreover, the high correlation obtained between the TAC and the TPC (r = 0.73) and α-tocopherol (r = 0.62) contents indicated the important role played by these compounds in improving the antioxidant capacity of the cheese. In conclusion, DOP is a suitable alternative to cereals in the diet of goats and improves the antioxidant status of the cheese produced.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Biological treatments in childhood asthma.

PURPOSE OF REVIEW: The aim is to update the information currently available for the use of biologics in severe asthma in children, in order to facilitate their prescription as far as possible. RECENT FINDINGS: The appearance of biologics for the treatment of severe asthma has meant a revolutionary change in the therapeutic approach to this disease. Currently, five biologics have been approved for severe asthma in children and/or adolescents by the regulatory agencies: omalizumab, mepolizumab, benralizumab, dupilumab and tezepelumab. But despite their positive results in terms of efficacy, there are still relevant points of debate that should induce caution when selecting the most appropriate biologic in a child with severe asthma. Indeed, safety is essential and, for several of the existing treatments, the availability of medium-term to long-term data in this regard is scarce. SUMMARY: The use of biologics can facilitate the therapeutic paradigm shift from pleiotropic treatments to personalized medicine. However, the choice of the most appropriate biologics remains a pending issue. On the other hand, to the extent that several of the biologics have been available for a relatively short time, the most robust evidence in terms of efficacy and safety in children is that of omalizumab.

Cost-effectiveness Analysis of Single-Use Duodenoscope Applied to Endoscopic Retrograde Cholangiopancreatography.

OBJECTIVES: Secondary infections due to transmission via the duodenoscope have been reported in up to 3% of endoscopic retrograde cholangiopancreatographies. The use of single-use duodenoscopes has been suggested. We investigate the cost-effectiveness of these duodenoscopes use in cholangiopancreatography. MATERIALS AND METHODS: A cost-effectiveness analysis was implemented to compare the performance of cholangiopancreatographies with reusable duodenoscopes versus single-use duodenoscopes. Effectiveness was analyzed by calculating quality-adjusted life years (QALY) from the perspective of the National Health System. Possibility of crossover from single-use to reusable duodenoscopes was considered. A willingness-to-pay of €25,000/QALY was set, the incremental cost-effectiveness ratio (ICER) was calculated, and deterministic and probabilistic sensitivity analyses were performed. RESULTS: Considering cholangiopancreatographies with single-use and reusable duodenoscopes at a cost of €2900 and €1333, respectively, and a 10% rate of single-use duodenoscopes, ICER was greater than €3,000,000/QALY. A lower single-use duodenoscope cost of €1211 resulted in an ICER of €23,583/QALY. When the unit cost of the single-use duodenoscope was €1211, a crossover rate of more than 9.5% made the use of the single-use duodenoscope inefficient. CONCLUSIONS: Single-use duodenoscopes are cost-effective in a proportion of cholangiopancreatographies if its cost is reduced. Increased crossover rate makes single-use duodenoscope use not cost-effective.

Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

PURPOSE: We describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype. METHODS: The patients underwent extensive clinical examinations. Exome sequencing was done in 4 affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the complementary DNA, protein, and mitochondrial level. Alternative splicing was evaluated using complementary DNA long-read sequencing. RESULTS: All patients presented with early-onset, slowly progressive axonal CMT, and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found. CONCLUSION: We expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these 2 clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.

Restrictive diets are unnecessary for colonoscopy: Non-inferiority randomized trial.

Background and study aims In colonoscopy, preparation is often regarded as the most burdensome part of the intervention. Traditionally, specific diets have been recommended, but the evidence to support this policy is insufficient. The aim of this study was to evaluate the impact of the decision not to follow a restrictive diet on bowel preparation and colonoscopy outcomes. Patients and methods This was a multicenter, controlled, non-inferiority randomized trial with FIT-positive screening colonoscopy. The subjects were assigned to follow the current standard (1-day low residue diet [LRD]) or a liberal diet. The allocation was balanced for the risk of inadequate cleansing using the Dik et al. score. All participants received the same instructions for morning colonoscopy preparation. The primary outcome was the rate of adequate preparations as defined by the Boston Bowel Preparation Scale. Secondary outcomes included tolerability and measures of colonoscopy performance and quality. Results A total of 582 subjects were randomized. Of these, 278 who received the liberal diet and 275 who received the 1-day LRD were included in the intent-to-treat analysis. Non-inferiority was demonstrated with adequate preparation rates of 97.8% in the 1-day LRD and 96.4% in the liberal diet group. Tolerability was higher with the liberal diet (94.7% vs. 83.2%). No differences were found with respect to cecal intubation time, aspirated volume, or length of the examination. Global and right colon average adenoma detection rates per colonoscopy were similar. Conclusions The liberal diet was non-inferior to the 1-day LRD, and increased tolerability. Colonoscopy performance and quality were not affected. (NCT05032794).

Anti-Cholinergic Effects of the Phenolic Extract from the Astragalus crenatus Plant: A Computational and Network Pharmacology Study.

Investigations into cholinesterase inhibition have received attention from researchers in recent years for the treatment of Alzheimer's disease. Cholinesterase enzymes, namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), hold pivotal significance in Alzheimer's disease (AD) treatment. In this study, we utilized the ethanolic extract of Astragalus crenatus followed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) to separate and identify at least 21 compounds in the extract. Rosmarinic acid exhibited the highest concentration (96.675 ± 1.3 mg/g extract), succeeded by hesperidin (79.613 ± 1.2 mg/g extract), hesperetin (75.102 ± 1.4 mg/g extract), rutin (68.156 ± 1.6 mg/g extract), chlorogenic acid (67.645 ± 1.5 mg/g extract), fisetin (66.647 ± 2.3 mg/g extract), and hyperoside (63.173 ± 1.5 mg/g extract). A. crenatus extract efficiently inhibited both AChE and BChE activities in a dosage-dependent manner. Molecular docking was employed to scrutinize the anticholinesterase mechanisms of the identified phytocompounds. Notably, a network pharmacology analysis was executed for the most efficacious compound. Based on binding energies, hesperidin emerged as the most potent inhibitor against both AChE and BChE, exhibiting scores of -10.5 Kcal/mol and -9.8 Kcal/mol, respectively. Due to its dual inhibition of AChE and BChE activities, hesperidin from Astragalus crenatus holds promise for the development of novel therapeutics aimed at neurological disorders, particularly AD.