Clinical Use Research Articles

Effective prism diopter for strabismus measurement: Conversion from anterior Prentice position to posterior parallel position and from glass prism to acrylic prism.

In clinical ophthalmology, prisms, commonly made of glass, are labeled based on the prism diopter (PD) value measured in the anterior Prentice position. However, they are often used in the posterior parallel position for practicality, causing a discrepancy between labeled and effective PD. This study proposes a conversion tool to address this issue. Geometric optical analysis was employed to calculate the effective PD of glass prisms in the posterior parallel position. A lookup table was created to convert the labeled PD of the anterior Prentice position to the effective PD when the prism is used in the posterior parallel position. Clinical data from 162 patients with horizontal strabismus were collected to validate the method. Glass prism measurements, converted to effective PD, were compared with acrylic prism results. The variations were significant in glass prism PD with rotation in the anterior Prentice position but stability in the posterior parallel position. Clinical deviations were larger with glass prisms, especially exceeding 30 PD, compared with acrylic prisms. Converted PD from glass prisms correlated well with acrylic prisms (R2 = 0.94, P = 0.002). The half-width of the 95% limit of agreement was ±12.32 PD. The proposed conversion table is valid, facilitating consistency between clinical and literature-based prism use in different positions and materials.

Therapeutic mechanism and key active ingredients of Yinxing Mihuan Oral Solution in coronary heart disease comorbidity with anxiety: A network pharmacology and molecular docking approach.

Yinxing Mihuan Oral Solution (YMOS) is a Chinese patent medicine for treating coronary heart disease combined anxiety (CHDCA), but the molecular mechanism of its treatment is still unclear. This article aims to understand the molecular mechanism, optimize clinical drug use, and guide new drug development. Using the Swiss Target Prediction database, we obtained the main chemical composition of YMOS. Then we used network pharmacology to identify their potential targets. Network construction, coupled with protein-protein interaction and enrichment analysis was used to identify representative components and core targets. Finally, molecular docking simulation was conducted to further refine the drug-target interaction. Forty-two active chemicals were found in YMOS and 91 target genes related to CHDCA. The treatment effect was found to be associated with 1908 biological processes and 160 pathways, as revealed by the outcomes of the enrichment analysis. The potential therapeutic mechanisms of the drug are closely related to its antioxidant, anti-inflammatory, and vascular function regulation pathways, and the main core targets include albumin, tumor necrosis factor, TP53, AKT serine/threonine kinase 1, interleukin 1 beta, and vascular endothelial growth factor A. The potential molecular mechanisms of YMOS in CHDCA treatment were identified using network pharmacology and molecular docking approaches. The results reveal the systemic biological implications of YMOS. This study has systematically uncovered the molecular mechanism of YMOS for the first time, offering fresh insights for evidence-based clinical applications.

Reimagining Cryptogenic Stroke Care: Collaborative Care and Inpatient Insertable Cardiac Monitors for Detection of Atrial Fibrillation

BACKGROUND Atrial fibrillation (AF) is a known risk factor of ischemic stroke, and AF‐related stroke is twice more likely to be fatal. Long‐term cardiac rhythm monitoring using insertable cardiac monitors (ICMs) has greater diagnostic yield compared with conventional monitoring in detecting AF, and the clinical utility of ICMs is established in cryptogenic stroke, strokes attributable to large‐artery atherosclerosis, and strokes attributable to small‐vessel disease. A registry‐based study was conducted to evaluate the inpatient implantation of ICMs and the feasibility of vascular and interventional neurologists as implanters using novel collaborative clinical care pathway for cryptogenic stroke. METHODS Multiyear data from a hospital‐based registry at a comprehensive stroke center were reviewed to evaluate inpatient ICM implantation and test feasibility of vascular and interventional neurologists as implanters of ICMs together with cardiology using a novel collaborative care pathway. Reviewed data included the number of ICMs, implantation trend, inpatient versus outpatient setting, time to ICM implantation, inpatient workflow, including defined roles of team members, and AF detection rate. RESULTS A total of 290 ICMs for cryptogenic stroke were implanted when patients were in the hospital and 78 as outpatients after discharge during the study period of 3 years. Most inpatient ICM implants were performed by vascular and interventional neurology (n = 181), and ICM use for cryptogenic stroke increased by 130%. The average time to inpatient ICM implant was 4.1 days, with 77% in 5 days and 95.5% within 10 days poststroke. The average time to out‐patient ICM placement was 57 days. AF detection rate of 36.5% was noted at 24 months with a collaborative care pathway. CONCLUSION Inpatient implantation of ICMs is feasible and was performed safely and efficiently by vascular and interventional neurology together with cardiology using a collaborative care pathway. An increase in use of ICMs and higher AF detection rates were noted. Findings support innovative efforts to improve access and close the gaps in the delivery of cryptogenic stroke care to ultimately reduce the secondary stroke burden.

Clinical Utility of Virtual Kitchen Errand Task for Children (VKET-C) as a Functional Cognition Evaluation for Children with Developmental Disabilities

Background/Objectives: This study evaluated the clinical utility of a virtual reality (VR)-based kitchen error task for children (VKET-C) to assess functional cognition in children. Methods: In total, 38 children aged 7–12 years were included, comprising 23 typically developing (TD) children and 15 children with developmental disabilities (DDs), including autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability. While performing the VKET-C, performance errors were analyzed. The Stockings of Cambridge (SOC) and Spatial Working Memory (SWM) tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess cognitive function. The Brunner–Munzel test was performed to compare performance errors between the TD and DD groups, and correlations between performance errors and cognitive measures were analyzed. Results: Omission and commission errors were significantly different between the groups (p < 0.001), with no significant difference in motor errors (p > 0.05). Omission errors were correlated with the initial thinking time mean (ITMN) in all items of the SOC task and the between errors (BE) of the SWM task. Commission errors were correlated with the ITMN in the difficult items of the SOC task and the BE of the SWM task. Additionally, motor errors were significantly correlated with problems solved in minimum moves (PSMM) and ITMN in the difficult items of the SOC task and BE in the SWM task. Conclusions: The VKET-C shows promise as an effective tool for assessing executive function and working memory in children with DDs, offering an engaging and ecologically valid alternative to traditional methods.

Diagnostic performance of digital tomosynthesis for postoperative assessment of acetabular fractures and pelvic ring injuries

IntroductionDigital tomosynthesis (DTS) has broad non-orthopaedic applications and has seen limited use within orthopaedics for imaging of the wrist. The utility of DTS for assessing reduction and hardware placement following operative treatment of pelvic ring injuries and acetabular fractures has not previously been investigated.MethodsAll operatively treated acetabular fractures and pelvic ring injuries that underwent surgical fixation within a one-year time span received both a computed tomography (CT) scan and a DTS scan as part of their routine postoperative imaging workup. Three orthopaedic traumatologists independently reviewed the images for face-value clinical utility. Radimetrics and PCXMC software were utilized on a subset of the study population's DTS and CT studies to calculate the effective and organ radiation doses delivered.Results52 patients (22 acetabular fractures, 22 pelvic ring injuries, 7 pelvic ring and acetabular fractures, 2 femoral head & acetabular fractures) were included. DTS was considered adequate to assess reduction 83% of the time, hardware position 83% of the time, and sufficient to replace the CT scan 67% of the time. DTS was associated with an 8.3 times lower effective radiation dose than CT. All organ doses were lower for DTS than CT.DiscussionDTS appears to have face-value clinical utility for assessing reduction and hardware position following surgical treatment of acetabular fractures and pelvic ring injuries. Given that DTS is associated with significantly lower radiation doses to patients, further study utilizing more objective criteria is warranted.

Balancing Objective Markers and Subjective Experience in Eating Disorder Diagnoses: Commentary on Dang et al. (2024).

The results of Dang et al.'s recent systematic review and meta-analysis suggested that individuals diagnosed with other specified feeding or eating disorder (OSFED) and those diagnosed with specified eating disorders (EDs, such as bulimia nervosa) endorse similar, elevated levels of ED-related cognitions (but not behaviors). The DSM has traditionally conceptualized EDs primarily as disturbances in eating behavior, and the diagnostic boundaries for EDs are based on objective markers, such as behavioral frequencies and weight. Although focusing on objective markers for ED diagnoses and severity indices has advantages (e.g., clinical communication, measurement), pitfalls include diagnostic migration and low emphasis on ED cognitions. Dang et al.'s findings provide a basis for rethinking DSM's conceptualization of EDs as primarily behavioral. This commentary discusses the potential merits and challenges of emphasizing subjective cognitions when assigning ED diagnoses. We explore how objective markers (e.g., behavioral frequency, weight) and subjective experience (e.g., fear of weight gain) may be balanced to improve the clinical utility of ED diagnoses. In all, research that more deeply phenotypes the subjective experiences of people with EDs across contexts, identities, and cultures will enrich our understanding of eating pathology and may inform diagnostic revisions.

Calibration, Clinical Utility and Specificity of Clinical Decision Support Tools in Inflammatory Bowel Disease

Background and AimsClinical decision support tools (CDSTs) have been developed to predict response to vedolizumab (VDZ) and ustekinumab (UST) in Crohn’s disease (CD) and ulcerative colitis (UC). In addition to assessing their discrimination performance, our study aimed to evaluate their calibration, clinical utility and specificity. MethodsWe included 280 CD and 218 UC patients initiating VDZ, and 194 CD patients initiating UST. We assessed discrimination by comparing rates of effectiveness outcomes between response probability groups forecasted by CDSTs. Calibration curves and decision curve analysis evaluated the calibration and clinical utility of VDZ-CDSTs. Additionally, we examined the agreement between UST-CDST and VDZ-CDST in assigning response probability groups among CD patients starting UST. ResultsIn the overall cohort, CDSTs allocated 7.2%, 50.0% and 42.8% of the patients to the low, intermediate and high response probability groups, respectively. VDZ-CDSTs groups demonstrated significant differences in the rates of clinical and endoscopic response and remission, while UST-CDST groups showed significant discrimination only for clinical remission. Although VDZ-CDSTs overestimated clinical remission rates, they more accurately predicted rates of VDZ persistence without need for surgery or dose escalation. Compared to empirically treating all patients with VDZ, VDZ-CDSTs yielded higher net benefits in selecting patients who would continue VDZ without need for surgery or dose escalation. Finally, the agreement between UST-CDST and VDZ-CDST in predicting response was 73.7%. ConclusionVDZ-CDSTs significantly discriminated response to VDZ and were more beneficial in identifying patients who would continue therapy without requiring surgery or dose escalation, compared to treating all patients empirically.

The effect of autoclave cycles on the mechanical properties and surface roughness of NiTi archwires: ex-vivo study

ObjectivesTo evaluate the effect of the universal and rapid autoclave cycles on the mechanical properties and surface roughness of nickel-titanium archwires following clinical use.Material and methodsThirty-six NiTi archwires (0.016 × 0.022 inch) were equally divided into a control group (Group A) and 2 experimental groups (Group B & C). Wires in group A were tested in the “as-received” form. Wires in the two other groups were installed in patients mouth for 4 weeks, and then autoclaved using the rapid-cycle (Group B) or the universal-cycle (Group C). All wires were subjected to 3-point bending test to calculate the elastic limit, modulus of elasticity, spring-back, yield strength, resilience and toughness. Atomic force microscopy (AFM) was used for surface roughness qualitative and quantitative analysis.ResultsGroup B showed significantly higher values of elastic limit, modulus of elasticity, resilience, yield strength and toughness than the other two groups. No significant differences were detected between groups A and C (P > 0.05). Group B showed significantly lower average surface roughness than the other two groups, but no significant differences were detected between groups A and C (P > 0.05).ConclusionsThe mechanical properties and surface roughness of clinically used NiTi wires were less affected by the universal-cycle than the rapid-cycle autoclaving. However, the difference between the effect of both autoclave cycles was diminutive.Clinical relevanceThe mechanical properties and surface roughness of the tested NiTi wires were not notably altered by clinical use and autoclaving.

Clinical burden and healthcare resource utilization associated with managing sickle cell disease with recurrent vaso-occlusive crises in France

Objective This retrospective, real-world claims database analysis described the clinical burden and healthcare resource utilization (HCRU) among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in France. Methods The French National Health Data System database (système national des données de santé) was used to identify eligible patients from January 1, 2012, to March 1, 2019. Inclusion criteria were a SCD diagnosis, ≥2 VOCs/year for ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data to March 1, 2020. Patients with hereditary persistence of fetal hemoglobin or hematopoietic stem cell transplant in their medical records were excluded. Clinical complications, mortality, treatment use, and HCRU were evaluated during follow-up. Results Overall, 4602 patients with SCD with recurrent VOCs were eligible; their mean (standard deviation [SD]) age was 19.8 (13.5) years, and 51.8% were female. Patients experienced a mean (SD) of 3.82 (3.57) VOCs per patient per year (PPPY). Prevalent complications were anemia or leukocytosis (44.1%), infections (42.0%), and organ failure (38.2%). In total, 101 (2.2%) patients died during follow-up (mean age of death [SD]: 39.3 [17.5] years; mortality rate: 0.64 deaths per 100 person-years). Most patients received opioids (89.1%) and hydroxycarbamide (72.8%). Patients had a mean of 5.7 inpatient hospitalizations, 6.0 emergency room visits, 6.6 outpatient visits, and 13.4 outpatient prescriptions PPPY. Conclusions Patients with SCD with recurrent VOCs in France have substantial clinical complications, mortality, and HCRU despite currently available treatment options. Innovative treatments that reduce frequency of or eliminate VOCs are needed to alleviate the burden associated with SCD.

Do vaginal swabs alter empirical clinical management in obstetrics and gynaecology: A retrospective case-series and activity-based costing of the vaginal swab.

Vaginal swab microbiological testing is commonly performed as routine clinical management for various obstetric and gynaecological presentations. The clinical utility and cost-effectiveness of vaginal swab microscopy, culture and susceptibilities (MCS) in altering empirical management is ill-defined. To describe the clinical use of vaginal swabs in a tertiary women's hospital emergency department (ED), measure the impact of vaginal swabs on altering empirical clinical management, and to determine the economic cost of vaginal swab MCS. Retrospective case-series of vaginal swabs collected at a single, tertiary women's ED between January 2021 and July 2021. Symptomatology, clinical diagnosis, test results, and pre-swab and post-swab clinical management were determined upon medical record review. Economic costs of vaginal swab MCS were retrospectively determined via internal accounting records, permitting unit-level activity-based costing. A total of 660 vaginal swabs from 584 clinical episodes were included. Vulvovaginitis was the most common indication for swab collection (34.5%, 167 samples). Altered empirical management was observed in 9.8% of all swabs (95% CI 7.4-12.2%), with marked variability between clinical indications. Antimicrobial initiation was the most common alteration in management (8.9%, 95% CI 8.7-9.1%). The estimated cost of vaginal swab MCS was $29.71 AUD; labour, consumables and disposal costs accounted for 69.3, 29.8 and 0.9%, respectively. The impact of vaginal swab MCS on empirical clinical management is context-specific and variable. The majority of swabs performed do not impact upon empirical management. Antimicrobial initiation is appreciably more common than antimicrobial cessation with vaginal swab results.

ITRAQ-Based Proteomic Analysis Unveils NCAM1 as a Novel Regulator in Doxorubicin-Induced Cardiotoxicity and DT-010-Exerted Cardioprotection

Background: Doxorubicin (DOX) causes lethal cardiotoxicity, which limits its clinical utility. The molecular mechanisms and effective strategies to combat its cardiotoxicity need further exploration. DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine( TMP), is considered a promising candidate for treating DOX-induced cardiotoxicity. In this study, we aimed to investigate the underlying molecular mechanisms of DOX-induced cardiotoxicity and the cardioprotective effects of DT-010. Methods: Isobaric tags for relative and absolute quantitation (iTRAQ) in proteomics analysis was employed to analyze the differentially expressed proteins in DOX-injuried hearts. Gene ontology (GO) enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out to evaluated the potential mechanisms of DOXinduced cardiotoxicity. The effects of NCAM1 on DOX-induced cardiotoxicity in H9c2 cells, as well as the cardioprotection of DT-010 were assessed through NACM1siRNA transfection, cell viability assay, cell apoptosis staining, reactive oxygen species measurement, and western blotting. Results: Proteomics analysis revealed that several signaling pathways, including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, were involved in DOX-induced cardiotoxicity. NCAM1 is one of the significantly changed proteins. DT-010 treatment regulated NCAM1 protein expression. Silencing NCAM1 in DOX-treated H9c2 cells decreased cell viability, increased cell apoptosis and reactive oxygen species (ROS) generation, and attenuated the cardioprotective effects of DT-010. Furthermore, NCAM1 knockdown promoted p38 activation and inhibited the expressions of peroxisome proliferator-activated receptor gamma coactivator- 1 alpha (PGC-1α) and heme oxygenase-1 (HO-1) in DOX-treated cells. Conclusion: These findings indicate a definite role of NCAM1 in DOX-induced cardiotoxicity and DT-010-exerted cardioprotection, which is mediated through the p38 and Sirt1/PGC- 1α/HO-1 pathway.

Microvascular Inflammation of Kidney Allografts and Clinical Outcomes.

The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).

Sensitivity improvement of a deuterium-deuterium neutron generator based in vivo neutron activation analysis (IVNAA) system.

Our lab has been developing a deuterium-deuterium (DD) neutron generator-based neutron activation analysis (NAA) system to quantify metals and elements in the human body in vivo. The system has been used to quantify metals such as manganese, aluminum, sodium in bones of a living human. The technology provides a useful way to assess metal exposure and to estimate elemental deposition, storage and biokinetics. It has great potential to be applied in the occupational and environmental health fields to study the association of metal exposure and various health outcomes, as well as in the nutrition field to study the intake of essential elements and human health. However, the relatively low sensitivity of the system has greatly limited its applications. Neutron moderation plays an important role in designing an IVNAA facility, as it affects thermal neutron flux in irradiation cave and radiation exposure to the human subject. This study aims to develop a novel thermal neutron enhancement method to improve the sensitivity of the in vivo neutron activation analysis (IVNAA) system for elemental measurement but still maintain radiation dose. Utilizing a compact DD neutron source, we propose a new and practical moderator design that combines high density polyethylene with heavy water to enhance thermal neutrons by reducing thermal neutron absorption. All material dimensions are calculated by PHITS, a general-purpose Monte Carlo simulation program. The improvement of the new design predicted by the Monte Carlo simulation for the quantification of one of the elements, manganese was verified by experimental irradiation of manganese-doped bone equivalent phantoms. For the same radiation dose, a 67.9% thermal neutron flux enhancement is reached. With only 4.2% increase of radiation dose, the simulated thermal neutron flux and activation can be further increased by 84.2%. A 100% thermal neutron enhancement ratio is also achievable with a 20% dose increase. The experimental results clearly show higher manganese activation gamma ray counts for each specific phantom, with a significantly reduced minimum detection limit. Additionally, the photon dose was suppressed. The thermal neutron enhancement method can increase the number of useful neutrons significantly but maintain the radiation dose. This greatly decreased the detection limit of the system for elemental quantification at an acceptable dose, which will broadly expand the application of the technology in research and clinical use. The method can also be applied to other neutron medical applications, including neutron imaging and radiotherapy.

Insights into the Phytochemical Profile and Therapeutical Potential of Withania Somnifera (L.) Dunal

Abstract: Withania somnifera (L.) Dunal (W. somnifera) is an herb commonly known by its English name Winter Cherry, and Ashwagandha in Hindi. It has been used as a traditional Rasayana herb for a long time. It is a rich reservoir of bioactive compounds known as withanolides, namely, withaferin-A and withanolide-D. Its current research covers many aspects of human health, which include anti-stress, anti-tumor, 9immuno-modulatory, hypocholesterolemic, hepatoprotective, hypoglycemic, diuretic, anti-convulsant, neurotropic, adaptogenic, and cardioprotective properties. This overview W. somnifera traditional uses, phytochemical, and pharmacological activities. However, in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxicological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a health-promoting herb.

Inflammation and resolution in obesity.

Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular diseaseand type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β,NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)inflammasome,tumour necrosis factor (TNF)and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.

Prognostic Value of Systemic Inflammation, Nutritional Status and Sarcopenia in Patients With Amyotrophic Lateral Sclerosis.

Nutritional status, systemic inflammatory responses and muscle mass are associated with the prognosis of patients with amyotrophic lateral sclerosis (ALS). However, the optimal biomarker for predicting prognosis remains unclear. This study aimed to identify the optimal indicators of survival among the nutrition-based, inflammation-based and muscle mass-related markers for ALS patients. We enrolled ALS patients from January 2014 to December 2019. Experienced neurologists followed up with the participants until January 2022. This study included a total of 17 nutritional, systemic inflammatory or muscle mass-related indicators. Maximally selected rank statistics determined the cut-off points for these indicators. Kaplan-Meier estimation was used to assess survival. Uni- and multivariate Cox proportional hazards models were used to determine the effects of indicators on survival. Finally, time-dependent receiver operating characteristic (time-ROC) curves and the C-index were calculated to evaluate the predictive efficacy of different indicators. A total of 506 patients with ALS were enrolled in this study, including 288 males (56.9%) and 218 females (43.1%), with a mean age of 54.2 ± 10.5 years. Among these ALS patients, 334 cases (68.0%) either died or underwent tracheotomy. In univariate Cox proportional hazards regression, 11 indicators were significantly associated with ALS survival (p < 0.05). And systemic immune inflammation (SII), platelet-to-lymphocyte ratio (PLR), modified geriatric nutritional risk index (mGNRI), creatinine and sarcopenia index (SI, (creatinine/cystatin C) × 100) were determined as independent predictors (p < 0.05) in multivariate Cox proportional hazards regression. A higher SI predicted longer survival (hazard ratio, 0.59; 95% confidence interval [CI], 0.46-0.76; p < 0.001). The results of time-ROC and C-index analyses indicated that SI had the best predictive efficacy for ALS survival, with a C-index of 0.65 (95% CI, 0.54-0.75) for 1-year, 0.61 (95% CI, 0.57-0.65) for 3-year and 0.59 (95% CI, 0.55-0.62) for 5-year survival. Across different subgroups, SI had the highest C-index in men and women, limb onset and aged < 60 year ALS patients, compared with other indicators. However, cystatin C was the best indicator for predicting the survival of ALS patients with bulbar onset, whereas the prognostic nutritional index (PNI) was the best for those aged ≥60 years. The serum SI demonstrates superior prognostic ability compared to other inflammation-based, nutrition-based and muscle mass-related indicators for patients with ALS. Given its simplicity and availability, it is well suited for clinical use in evaluating the prognosis of ALS patients.

Exploring RNA therapeutics for urea cycle disorders.

RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.

First-Trimester Prediction Models Based on Maternal Characteristics for Adverse Pregnancy Outcomes: A Systematic Review and Meta-Analysis.

Early risk stratification can facilitate timely interventions for adverse pregnancy outcomes, including preeclampsia (PE), small-for-gestational-age neonates (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). To perform a systematic review and meta-analysis of first-trimester prediction models for adverse pregnancy outcomes. The PubMed database was searched until 6 June 2024. First-trimester prediction models based on maternal characteristics were included. Articles reporting on prediction models that comprised biochemical or ultrasound markers were excluded. Two authors identified articles, extracted data and assessed risk of bias and applicability using PROBAST. A total of 77 articles were included, comprising 30 developed models for PE, 15 for SGA, 11 for sPTB and 35 for GDM. Discriminatory performance in terms of median area under the curve (AUC) of these models was 0.75 [IQR 0.69-0.78] for PE models, 0.62 [0.60-0.71] for SGA models of nulliparous women, 0.74 [0.72-0.74] for SGA models of multiparous women, 0.65 [0.61-0.67] for sPTB models of nulliparous women, 0.71 [0.68-0.74] for sPTB models of multiparous women and 0.71 [0.67-0.76] for GDM models. Internal validation was performed in 40/91 (43.9%) of the models. Model calibration was reported in 21/91 (23.1%) models. External validation was performed a total of 96 times in 45/91 (49.5%) of the models. High risk of bias was observed in 94.5% of the developed models and in 58.3% of the external validations. Multiple first-trimester prediction models are available, but almost all suffer from high risk of bias, and internal and external validations were often not performed. Hence, methodological quality improvement and assessment of the clinical utility are needed.

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers.

Extensive investigations spanning multiple levels of inquiry, from genetic to behavioural studies, have sought to unravel the mechanistic foundations of attention-deficit hyperactivity disorder (ADHD), with the aspiration of developing efficacious treatments for this condition. Despite these efforts, the pathogenesis of ADHD remains elusive. In this Review, we reflect on what has been learned about ADHD while also providing a framework that may serve as a roadmap for future investigations. We emphasize that ADHD is a highly heterogeneous disorder with multiple aetiologies that necessitates a multifactorial dimensional phenotype, rather than a fixed dichotomous conceptualization. We highlight new findings that suggest a more brain-wide, 'global' view of the disorder, rather than the traditional localizationist framework, which asserts that a limited set of brain regions or networks underlie ADHD. Last, we underscore how underpowered studies that have aimed to associate neurobiology with ADHD phenotypes have long precluded the field from making progress. However, a new age of ADHD research with refined phenotypes, advanced methods, creative study designs and adequately powered investigations is beginning to put the field on a good footing. Indeed, the field is at a promising juncture to advance the neurobiological understanding of ADHD and fulfil the promise of clinical utility.