Government-led repurposing programmes are reshaping the division of labour in pharmaceutical innovation. A new power drafted into the European Union pharmaceutical reform package will allow the European Medicines Agency (EMA) to add new therapeutic indications to marketed medicines without the marketing authorization holder's consent. Companies oppose this power, but in weighing up enacting the power, society has a poor understanding of its potential to help patients. This study offers the first empirical assessment of the promise of the power. It analyses 198 medicines from 12 years, comparing EMA-authorized labels with those authorized by the US Food and Drug Administration and a leading reference for off-label uses. Sixty-seven per cent of the medicines have at least one additional use supported by clinical evidence, yielding 320 potential new uses. Of these, 39 per cent are for new diseases and 61 per cent for new patient cohorts, a third of the latter concerning paediatric populations. Commentators generally omit discussing repurposing for new patient cohorts, even though it is a focus of the European Commission. The study's results suggest that the power could be used to authorize a meaningful number of evidence-based uses, especially those already authorized in the USA, while also revealing a policy synergy for neglected populations.
Hidradenitis suppurativa (HS), an inflammatory skin disorder characterized by painful nodules and abscesses, has varying prevalence among different races/ethnicities. This study explored the social drivers of health, burden, and impact of HS among different racial and ethnic groups. An online, cross-sectional survey was conducted among adult patients with HS (September 2023-December 2023) in the USA. Patients were recruited through HS Connect (patient advocacy group) and AmeriSpeak (US national sample panel). Descriptive data were collected using patient-reported outcome measures and de novo questions about patients' disease knowledge and perception, healthcare access and utilization, impact on quality of life (QoL), and social impact. All analyses were descriptive and stratified by racial/ethnic groups. The study included 583 patients (mean age, 34.8 years; 95.5% female) representing a range of racial backgrounds: Black or African American (n = 273; 46.8%), white (n = 236; 40.5%), Two or More Races (n = 47; 8.1%), American Indian or Alaska Native (n = 18; 3.1%), Asian (n = 7; 1.2%), and Native Hawaiian and Other Pacific Islander (n = 2; 0.3%). Ethnic representation also varied (Hispanic/Latino = n = 76; 13.0%). Patients of all races and ethnicities reported considerable QoL impact (Dermatology Life Quality Index, EQ-5D-5L), with results for smaller subgroups (n < 10) included for descriptive completeness only and not intended for comparison with other groups. During flaring, most patients used over-the-counter products/medications (54.2%) or nonmedical intervention/home remedy (56.9%) Up to 36.5% of patients reported challenges in procuring food, utilities, medicine/healthcare, phone, clothing, or childcare when needed in the past year. Among those who paid out-of-pocket for their HS treatment, 55.6% reported that it stopped them from visiting a healthcare provider for treatment. The findings indicate a high burden and impact of HS across all races and ethnicities. Patients reported social drivers of health and challenges with healthcare utilization, indicating the need for integrating social workers and care management teams in dermatology practice, which could facilitate improved care of patients with HS. Hidradenitis suppurativa is a painful skin condition that causes lumps and abscesses. It affects people of all races and ethnicities but is more common in Black or African American individuals. This study surveyed 583 adults in the USA to understand how hidradenitis suppurativa affects people from different racial and ethnic backgrounds. Our focus was on how the disease impacts their daily lives, their ability to access healthcare, how often they visit doctors, their quality of life, and their mental and emotional well-being. Most people said that hidradenitis suppurativa lowers their quality of life and makes daily activities harder. During flaring, many used home remedies instead of seeing a doctor. People suffering from hidradenitis suppurativa also reported trouble getting basic needs such as food, medicine, and transportation. These challenges occurred among patients from different racial and ethnic groups; results for very small subgroups (Asian, Native Hawaiian/Other Pacific Islander) are reported descriptively only and should not be interpreted as representative of these groups or compared with other groups. The research underscores the importance of improving awareness and tailoring care for people with hidradenitis suppurativa, particularly those facing barriers to healthcare.
This study aims to evaluate the outcomes of a new PND initiative designed to optimize healthcare delivery in a highly consanguineous population. A descriptive study was conducted at a major tertiary referral center for genetic diseases in Saudi Arabia with a large scope objective to improve the existing prenatal diagnosis (PND) process. Consequently, a new prenatal workflow featuring a structured checklist, a dedicated prenatal board, and enhanced genetic counseling has been implemented since September 2023. The study included all prenatal cases with a documented autosomal recessive (AR) disease. The program processed 1128 cases, with 952 cleared by the prenatal checklist. In total, the board has discussed 160 variants of unknown significance (VUS), of which 122 (76%) were upgraded to likely pathogenic/pathogenic. Remarkably, the prenatal checklist enhanced patient safety and reduced serious harm incidents, while the prenatal board facilitated precision medicine by leveraging collective expertise in variant interpretation. This initiative significantly improved the healthcare, safety, and accessibility of PND services. The prenatal board and checklist streamlined decision-making, minimized errors, and enhanced patient outcomes. The model provides a cost-effective approach to preventing genetic diseases in highly consanguineous populations and serves as a replicable framework for similar settings worldwide.
Tanzania has adopted artificial intelligence (AI)-assisted chest X-ray screening for tuberculosis (TB), including the use of CAD4TB version 6, which is registered by the Tanzania Medicines and Medical Devices Authority (TMDA). While GeneXpert, practical reference standard used in routine practice, remains the primary bacteriological confirmatory test in routine practice, there is currently no established national threshold for CAD4TB use in either active case finding (ACF) or passive case finding (PCF) settings. This study evaluates the implementation and operational use of CAD4TB version 6 within mobile TB screening units in Tanzania and highlights challenges affecting its effective use. We conducted a retrospective analysis of screening data from 11,923 individuals collected from mobile clinics equipped with digital X-ray, CAD4TB version 6, and GeneXpert systems. Comparisons were made between manual chest X-ray interpretation, CAD4TB scores, and GeneXpert results within the subset of individuals who underwent confirmatory testing. The findings reveal substantial inconsistencies in screening workflows, including non-uniform use of CAD4TB prior to GeneXpert testing, missing radiological records, and deviations from intended protocols across sites. Descriptive analysis showed that CAD4TB scores generally aligned with GeneXpert-positive cases within the tested subset; however, due to selective application of GeneXpert and incomplete data, these observations cannot be interpreted as measures of diagnostic accuracy. This study should be interpreted as an implementation and operational assessment of AI-assisted TB screening rather than a diagnostic accuracy or threshold-setting study. The findings highlight important gaps in protocol adherence, data completeness, and workflow standardization, underscoring the need for prospective, protocol-driven studies to establish validated national thresholds for CAD4TB use in Tanzania.
Therapeutic plasma exchange (TPE) is being increasingly utilized in the clinical management of severe rheumatic immune diseases, providing an effective means for rapidly removing pathogenic autoantibodies and inflammatory mediators. However, the non-selective nature of this technique can also lead to the unintended clearance of concomitantly administered antirheumatic drugs, potentially compromising therapeutic efficacy and disease control. Therefore, effective management of potential drug removal process during TPE and the implementation of individualized risk assessment are crucial for optimizing treatment outcomes in patients undergoing TPE. The variability in the extent of drug removal during TPE is primarily determined by their distinct pharmacokinetic characteristics, necessitating the establishment of a systematic, evidence-based strategy for adjusting drug administration regimens in patients receiving TPE treatment. This review synthesizes current evidence from 65 studies on the removal of antirheumatic drugs during TPE, identifying key determinants influencing clearance rates, including volume of distribution, protein binding, molecular size, and elimination half-life. Our analysis reveals that the risk of drug removal exists as a continuous spectrum: large monoclonal antibodies (e.g., rituximab, natalizumab), characterized by a large molecule size, low volume of distribution, with which mostly confined to the vascular space, are cleared with high efficiency. This finding supports the clinical recommendation of administering such drugs after TPE. For drugs with limited direct evidence, we propose a predictive model based on fundamental pharmacokinetic parameters to estimate their removal risk and guide clinical decision-making. Based on this evidence, we have constructed a stratified clinical management framework. It aims to maintain effective therapeutic drug exposure levels during chronic TPE therapy and to provide a rationale for the judicious application of TPE in overdose scenarios. Implementing this pharmacokinetic-informed, risk-adapted individualized strategy is important for ensuring treatment continuity, enhancing patient safety, and advancing empiricism-based therapy towards precision medicine.
Suicide is a leading cause of maternal mortality, yet there are currently no evidence-based perinatal suicide prevention programs. Given the risk of serious outcomes if undetected or inadequately treated, the goal of this study was to further understand the screening and treatment experiences of individuals with perinatal suicidal thoughts and behaviors (STBs). Qualitative data were generated from in-depth interviews with 13 individuals primarily from the United States who experienced perinatal suicidality at least 6 months prior to participation. Thematic analysis was used to examine the experiences of participants with respect to screening and treatment of perinatal STBs. Regarding screening, three major themes were identified: (1) gaps in comprehensive/routine screening for STBs (e.g., infrequent screenings or non-specific to suicide), (2) attitudes toward disclosure of STBs (resulting in omission of symptoms or downplaying of severity), and (3) importance of follow-up after screening. Three themes influenced participants' treatment experiences: (1) providers' engagement in care, (2) shared decision-making between provider and patient, and (3) impact of perinatal-specific treatment programs. Findings from this study highlight critical gaps in screening for and treatment of perinatal STBs. Implementing routine screening and comprehensive follow-up and improving treatment experiences are essential for improving the care of individuals with perinatal STBs and reducing maternal mortality.
Central nervous system (CNS) metastases from Wilms tumor (WT) are exceedingly rare. Intracerebral hemorrhage secondary to metastatic WT is even less common, and the management of such cases is further complicated when patients are receiving a direct oral anticoagulant (DOAC) like Rivaroxaban, for which pediatric reversal guidelines are lacking. We report on the case of a 5-year-old boy with relapsed stage IV Wilms tumor who presented with rapidly progressive neurological deterioration caused by brain metastases with extensive intraparenchymal and intraventricular hemorrhage while receiving Rivaroxaban due to prior thrombosis. An emergent craniotomy and tumor resection was safely performed after emergent reversal of anticoagulation with Rivaroxaban using Andexanet alfa, administered in this pediatric patient with off-label consent in the setting of a life-threatening intracranial hemorrhage requiring emergent neurosurgical intervention. No excessive intraoperative bleeding was noted. Treatment for relapsed WT according to the SIOP-UMBRELLA-Protocol was initiated. Three weeks after Andexanet alfa treatment, a thrombotic event in the left iliac veins occurred, requiring anticoagulation with unfractionated heparin. This case highlights the therapeutic challenges of managing intracranial hemorrhage in a pediatric patient requiring emergent neurosurgical debulking in the setting of Rivaroxaban anticoagulation. To our knowledge, this is the second case reporting on Rivaroxaban reversal through Andexanet alfa in children. Early multidisciplinary intervention, meticulous neurosurgical management and continuation of oncologic therapy can lead to favorable outcomes even in such complex presentations.
Periodontitis, a chronic inflammatory disease, is increasingly prevalent among young people and impairs their quality of life. Adverse childhood experiences (ACE), depressive symptoms, and suboptimal health status (SHS) are linked to health risks and chronic diseases, but their interrelationships with periodontitis in Chinese young adults remain unclear. This study aimed to explore associations among these factors. From December 2024 to May 2025, 2,888 participants (aged 18-35) from Tongji Hospital completed surveys on demographics, ACE, depressive symptoms, and SHS. Periodontitis was diagnosed according to the 2018 criteria. Simple, parallel, and chain mediation models were used, controlling for age, sex, marital status, and smoking. Periodontitis prevalence was 25.00% and higher in married individuals (P < 0.001) and smokers (P = 0.004). ACE correlated positively with depressive symptoms (r = 0.28, P < 0.001), SHS (r = 0.19, P < 0.001), and periodontitis (r = 0.16, P < 0.001). Mediation analyses showed: Simple model: Depressive symptoms and SHS partially mediated the effect of ACE on periodontitis (indirect effect = 0.011 for both). Parallel model: Only SHS significantly mediated the effect (indirect effect = 0.011). Chain model: ACE was related to periodontitis via "depressive symptoms → SHS" (indirect effect = 0.010), with significant direct and indirect effects. ACE associated with higher periodontitis risk in young people. This association included both a direct link between ACE and periodontitis, and an indirect link through the chain pathway of "depressive symptoms → SHS"; among these pathways, SHS was a key mediator. The study was registered in the Chinese Clinical Trial Registry (ChiCTR) with the registration number ChiCTR2500103464. Childhood trauma can exert long‐term impacts on health, including oral health. This study involving 2,888 Chinese young adults aged 18‐35 found that 25% of the participants had periodontitis. Those who experienced childhood abuse, neglect, or family issues showed a higher association with the disease. The research revealed two pathways linking early trauma to periodontitis: a direct association and an indirect chain of “depressive symptoms → suboptimal health status (e.g., persistent fatigue).” While depressive symptoms played a role, suboptimal health status was the critical mediator. Higher periodontitis rates in married individuals and smokers may relate to stress or lifestyle factors. The findings suggested that early identification of childhood trauma, combined with interventions targeting mental health or overall well‐being (e.g., counseling, health management), could be more effective than oral care alone in prevention. This underscored the association between early‐life experiences and long‐term health and the need for integrated interventions.
Cutaneous gene therapy has the potential to treat a wide range of skin disorders, but effective delivery remains limited by the skin's barrier properties and immune surveillance. Here, we identify AAVrh32.33 as a potent vector for targeting dermal stromal compartments. Following systemic administration in mice, AAVrh32.33 mediated robust and durable transgene expression, with preferential targeting of dermal fibroblasts and hair follicle bulge cells. Expression peaked at one month and persisted for up to two years, highlighting its suitability for chronic conditions. To reduce immunogenicity, a dominant CD8+ T cell epitope was disrupted, generating the IDPΔ variant. This modification attenuated peptide-specific T cell responses while preserving stromal transduction. In human skin explants, IDPΔ achieved high levels of gene expression, primarily in dermal fibroblasts and precursors, confirming translational relevance. Finally, vectors encoding CCL17, CCL20, and CCL22 demonstrated localized targeted therapeutic gene delivery in both healthy and inflamed skin, underscoring the feasibility of using this platform to reshape local immune responses. Together, these findings establish AAVrh32.33 and IDPΔ as promising platforms for durable cutaneous gene therapy, with direct applications in diseases such as vitiligo where long-term modulation of the dermal microenvironment is essential.
Healthcare-seeking behavior is a key factor in how well a health system performs and how fair it is. In Saudi Arabia, public healthcare services are free, yet many people still choose private healthcare, especially in cities like Riyadh. It is important to understand why people seek care from private clinics to help shape health policies, distribute resources better, and improve services across the healthcare system. This study aimed to examine the frequency of private healthcare use, defined as the reported usual or concurrent use of private healthcare services, and to identify sociodemographic, behavioral, and health-related factors associated with this choice among adults in Riyadh, Saudi Arabia. A cross-sectional study was carried out in Riyadh from March to July 2023 using a multistage cluster sampling method. We randomly selected 48 government primary healthcare centers and invited adults aged 18 and older who visited these centers to participate. We collected data electronically with a validated questionnaire that covered sociodemographic details, patterns of healthcare use, reasons for choosing private healthcare, behavioral risk factors, and existing health conditions. We used multivariate logistic regression analysis to find independent predictors of private healthcare use, reporting adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Of 14,239 participants, 72.4% reported using private healthcare services either as a usual source of care or alongside public services. The multivariable analysis revealed several factors to be positively related to private healthcare utilization. Those who were married were more likely to use private healthcare services (AOR 1.23, 95% CI 1.11-1.36). Those with insurance coverage were threefold higher odds of private healthcare use (AOR 3.51, 95% CI 3.13-3.94). Smokers were more likely to seek private healthcare (AOR 1.60, 95% CI 1.45-1.77) than non-smokers, and those who exercised reported increased utilization (AOR 1.83, 95% CI 1.67-2.00). Obesity was also positively related to private healthcare utilization (AOR 1.38, 95% CI 1.12-1.71), and those with heart disease had substantially higher odds of using private healthcare services (AOR 2.09, 95% CI 1.59-2.76). Private healthcare use in Riyadh is common and associated with insurance coverage, marital status, behavioral factors, and certain chronic conditions. These findings provide descriptive insights into factors related to private healthcare utilization among public PHC attendees in Riyadh, without implying causal effects or policy recommendations beyond the scope of the data.
The goal of this study was to identify symptoms that occur in children post-SARS-CoV-2 infection, their trajectory over the first-year post-enrollment, and relationship to age. Longitudinal comparison of infected and uninfected cohorts. Participants (0-21 years) with laboratory-confirmed SARS-CoV-2 infection were enrolled as infected. The uninfected cohort was individuals without laboratory evidence of SARS-CoV-2 infection. Primary outcome was presence or absence of symptoms. 852 participants (705 infected, 147 uninfected) completed baseline visits. Of those, 558 infected subjects completed a 12-month post-enrollment visit. Twenty symptoms were identified as more common in infected participants compared to uninfected, at either baseline or 12-months, with symptoms varying by age. Some symptoms in the infected were more frequent at baseline (e.g. fever, weight loss), whereas many symptoms persisted through 12-months. Several symptoms were more frequent at 12-months (e.g. dysmenorrhea, persistent headache). Presence of symptoms at 12-months was not significantly associated with the wave of circulating virus at original infection. Interim analysis at one-year post-enrollment identifies 20 symptoms that infected participants were more likely to report post SARS-CoV-2 infection compared to uninfected, at either visit. Type of symptoms varies by age. Ongoing longitudinal data up to 3-years post-enrollment will increase understanding of long-term symptoms of SARS-CoV-2 infection in children and their trajectory. NCT04830852. Although most children recover fully from SARS-CoV-2 infection, some children experience a variety of prolonged symptoms following infection. Many studies attempting to characterize these symptoms and trajectory are not prospective nor longitudinal and lack comparison to uninfected controls. This longitudinal analysis identifies and characterizes post-COVID symptoms in children and adolescents and their trajectory through the first-year post enrollment compared to an uninfected cohort. 20 post-infection symptoms were identified as occurring more frequently in the infected as compared to uninfected cohort. Age played a critical role in the type and frequency of symptoms after SARS-CoV-2 infection. Gastrointestinal symptoms were prominent.
Home environments shape children's dietary habits, but which factors are most influential is unclear. The study purpose was to identify factors in the home environment associated with child intake of fruit and vegetables (FV) and sugar-sweetened beverages (SSBs) using a national dataset collected in 2013-2015 in the U.S. Data from 5,138 school-aged children (4-15 years old) from 130 U.S. communities were collected in 2013-2015. Parents and/or children completed a dietary screener and additional survey questions to assess household socioeconomic status (SES), grocery shopping sources, home food availability, social support for healthy eating, eating out frequency, and other home eating and related behaviors. Other child characteristics included breastfeeding history, intake of school foods, and participation in other nutrition programs. Community variables included predominant race/ethnicity and SES. Classification and regression trees (CART) identified key predictors of intake. The FV and SSB CARTS had 14 and 12 terminal groups, respectively. Children with the highest FV intake (0.54 SD from mean cups/day; 13% of sample) had fruit more often available at home, dark green vegetables more often available at home, ate dinner with family more often, had SSBs less often available at home, and were breastfed longer. Conversely, children in the two groups with the lowest FV intake either had fruit less often available at home, and family never complimented their eating (-0.86; 2%), or they had family that rarely or sometimes complimented their eating, and perceived school lunches as unhealthy (-0.87; 1%). For SSB intake, the lowest consumers (-0.63 SD from mean tsp/day sugar; 17%) never or rarely had SSBs available at home, and lived in higher SES communities. Children in the two groups with the highest SSB intakes had SSBs available at home more often, and lived in a SNAP-participating household and either ate out less often, used a phone/computer for social networking, and had SSBs available at home very often (1.3; 1%), or they ate out more often, and were breastfed for a shorter duration (1.1; 5%). Home availability of FV and SSBs were the most salient predictors of intake of both FV and SSBs, while other predictors differed between FV and SSB intake. Study findings highlight several actionable home-environment strategies to test in future studies to improve school-aged children's diets.
Expanded hemodialysis (HDx) using medium cut-off dialyzers has been associated with lower all-cause hospitalization rates compared to conventional high-flux hemodialysis. Reductions in hospitalization frequency represent a major driver of healthcare expenditures and may contribute to improved budget sustainability in resource-constrained healthcare systems. The objective of this study was to estimate the budget impact of adopting HDx from the perspective of the Colombian healthcare system, using real-world evidence. A budget impact analysis was developed according to the ISPOR guidelines using a tool built in Microsoft Excel. Clinical effectiveness inputs were derived from a multicenter cohort study (COREXH-E), including an extended dataset and a difference-in-differences analysis to estimate the effect of HDx on hospitalization rate while accounting for unobserved confounding. Cost inputs were obtained from national administrative databases, including hospitalization costs and bundled dialysis payments. The analysis adopted a one-year time horizon and a third-party payer perspective representing the Colombian healthcare system. Budget impact scenarios were evaluated, assuming HDx market uptake rates of 5%, 10%, 20%, and 50%. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty. Adoption of HDx was associated with net cost savings for the Colombian healthcare system across all uptake scenarios. Under hospitalization rates observed in the real-world cohort, estimated annual savings ranged from USD 472,756 to USD 4,727,564 as HDx uptake increased from 5% to 50%. In scenarios reflecting higher hospitalization rates observed in the general Colombian hemodialysis population, annual savings ranged from USD 1,344,401 to USD 13,444,010. Cost savings were primarily driven by reductions in hospitalization frequency. Probabilistic sensitivity analysis showed that HDx was cost-saving in 97.8% of simulations. This study suggests that expanded hemodialysis could result in short-term cost savings for the Colombian healthcare system by reducing hospitalization-related costs without increasing dialysis expenses.
Neuropathic pain caused by spinal cord injury severely compromises patients' quality of life. The clinical application of ropivacaine is limited by its short duration of action and the significant side effects associated with repeated administration. In this study, we developed a Gelatin methacryloyl/hyaluronic acid-based hydrogel (Ropi-GelMA/HA) to enable localized and controlled delivery of ropivacaine by photo-crosslinking. In a rat model of spinal cord contusion, Ropi-GelMA/HA was associated with lower Nav1.3 and TNF-α expression and higher NGF and BDNF expression, together with improved motor recovery in rats with SCI. In vitro studies further supported the hydrogel's favorable biocompatibility and controlled release behavior during the early phase after administration. Under the tested dosing regimens, Ropi-GelMA/HA was associated with reduced hepatorenal toxicity and more durable analgesic efficacy compared with free ropivacaine, resulting in prolonged analgesic effects and improved functional outcomes under localized controlled delivery conditions. These findings highlight the potential clinical utility of Ropi-GelMA/HA in the treatment of neuropathic pain following spinal cord injury.
Inflammatory cytokines influence the pathogenesis and progression of acute myeloid leukaemia (AML), not only by shaping the leukemic microenvironment, but also by supporting leukaemia stem cell survival and resistance to therapy. We, therefore, investigated the associations between the cytokine polymorphisms IFNG+874 A/T, TNFA-857 C/T, and IL1B -31 C/T and AML outcomes, as well as their influence on clinical features. Ninety-three patients with AML and 117 healthy controls were analysed. The T allele of TNFA - 857 C/T (i.e., the high-expression allele) was observed at a significantly higher frequency in the patients with AML vs. the controls (AML vs. control = 24.7% vs. 16.2%, p = 0.04). Patients with the high-expression TT genotype had shorter overall survival (TT vs. CC = 46.0 vs. 224.1 months, p < 0.001). Patients with the high-expression non-CC genotype relapsed more frequently than those with the low-expression CC genotype (relapse vs. non-relapse = 55.8% vs. 26.9%, p = 0.01). No significant associations were observed for the IFNG + 874 A/T and IL1B -31 C/T polymorphism. TNFA - 857 C/T polymorphisms can influence patient susceptibility to AML, as well as its prognosis. This suggests a link between chronic inflammation and leukemogenesis, as well as the potential value of TNFA genotyping in risk assessments.
To develop a semi-automated method to segment "black hole" lesions on post-gadolinium 2D T1-weighted images (GdT1) in multiple sclerosis (MS) that follows radiological intensity rules and perform multi-center validation. Multi-center spin-echo GdT1 images and accompanying proton-density (PD)/T2-weighted images and manual T2 lesion masks of the REFLEXION study (NCT00813709) of suspected/early MS were used. Briefly, the proposed method segments cortical gray matter (GM) to derive a T1-weighted intensity threshold, which is applied inside co-registered T2 lesion masks to segment black hole lesion voxels. It was optimized on a training set (N = 40, 57.5% female, mean age 31.4 ± 8.7 (standard deviation) years), and 274 patients formed the test set (61.3% female, age 31.8 ± 8.4 years). Performance was quantified by the Dice similarity coefficient (DSC) and the intraclass correlation coefficient (ICC) for absolute agreement with manual segmentations. Lesion-wise sensitivity and specificity were calculated. Optimization resulted in: (1) GM selection as minimally 0.8 total WM plus GM partial volume, masked by MNI cortex; (2) normalized mutual information-driven linear co-registration of T2 to GdT1 images, interpolating T2 lesion masks using trilinear interpolation and 0.6 threshold; (3) mean intensity inside GM mask used as upper intensity threshold. The optimized method had acceptable spatial accuracy (DSC: 0.39 ± 0.26) and good volumetric accuracy (ICC: 0.84, 95% CI [0.72, 0.90]. Lesion-wise sensitivity was 0.91 ± 0.19, and lesion-wise specificity was 0.62 ± 0.22. The proposed method to semi-automatically segment black holes from post-gadolinium T1-weighted images shows acceptable performance. As a potential aid to radiologists, the method is not recommended to be used entirely without human intervention. Question T1-hypointense "black hole" lesions reflect disease severity in multiple sclerosis but are not routinely quantified due to a lack of reliable analysis methods. Findings A rule-based semi-automated method for GdT1 "black hole" lesion segmentation was developed and optimized, and then validated in a large unseen multi-center test set. Clinical relevance This method adds quantitative information about GdT1 "black hole" lesions to the radiological assessment of multiple sclerosis disease severity, when false positives are manually removed. This can enhance the characterization of individual patients and advance the understanding of the disease.
The occipital interhemispheric transtentorial approach (OITT) is widely used for accessing lesions in the pineal region. Although reports are scarce, this approach can also be successfully applied to superior cerebellar lesions, involving the quadrangular lobule. We describe the OITT approach for cerebellar quadrangular lobe lesions, providing relevant anatomy, surgical technique, and key technical considerations. Gross total resection can be achieved while preserving normal brain tissue and functionOITT is a safe and low-morbidity route for lesions within the cerebellar quadrangular lobe, as it uses a natural anatomical corridor, avoids manipulation of eloquent areas, and minimizes injury to normal brain tissue.
Geminal difunctionalization of carbonyl-derived building blocks represents a versatile strategy for the rapid generation of sp3-rich molecular architectures. In this context, diazo compounds provide a powerful platform for installing two distinct functional groups, yet the reaction space for carbonyl-derived donor-donor diazo systems remains underdeveloped. Here, we report a metal-free migratory insertion of diazo compounds into C─S bonds of sulfonyl cyanides, enabling the simultaneous installation of sulfone and nitrile functionalities at a single carbon center. Key to this transformation is the in situ generation of highly reactive diazo intermediates via photochemical decomposition of bench-stable oxadiazolines derived from ketones. This substantially expands the accessible coupling partner space, previously limited to aldehydes or boronic acids. The reaction exhibits broad functional group, water, and air tolerance, delivers high yields, and provides excellent diastereoselectivity in constrained cyclic systems. Compatibility with both batch and continuous-flow processing, as well as its application to a realistic medicinal chemistry combinatorial library synthesis, highlights the practical utility of the method.
Ongoing neurodevelopmental care is essential for children with congenital heart disease (CHD). Understanding delivery and uptake of neurodevelopmental care pathways can inform implementation and resource planning. This study applied simulation modelling to explore outcomes from a neurodevelopmental care pathway for children with CHD. The model was developed using data from a Queensland program to explore health service interactions for neurodevelopmental screening, formal assessment, and early intervention, up to five years. Modelling was intended to provide a baseline understanding of the pathway, rather than evaluating against a reference standard. Hypothetical scenarios explored how changes in screening and referrals influenced the identification of developmental concerns, and how developmental concern severity affected intervention referrals. Based on available data, 58% of the cohort remained under routine surveillance and 25% had accessed early intervention for one or more developmental delays. Scenarios defined by increased screening projected up to 55% of the cohort having a developmental concern identified during screening and 45% having a developmental delay identified following assessment. Simulation modelling was useful for understanding outcomes from a neurodevelopmental pathway and how differences in screening and assessment affected health service interactions. Findings may inform policy and resource planning for future neurodevelopmental pathways. This study shows that simulation modelling is a useful approach for evaluating a neurodevelopmental care pathway for children with CHD, to understand movement through neurodevelopmental screening, assessment, and interventions. Scenario-based modelling provides insights into factors influencing pathway engagement, contributing evidence to strengthen understanding of service gaps and areas where improvements can most effectively impact engagement and resourcing. This study identifies neurodevelopmental screening as the most influential stage impacting downstream outcomes, underscoring its importance as a strategic intervention point. This study's approach provides a general framework for evaluating similar pathways and a potential baseline for assessing future policy or service changes.
Despite modest improvement, the lifespan of a child on dialysis continues to be 40 years shorter compared to healthy children. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in these patients. Risk factors for CVD are present even in early stages of chronic kidney disease (CKD) and accelerate as the child's renal function deteriorates. As a result, the highest burden of CVD exists in patients on chronic dialysis. Although dialysis is life-sustaining, the dialysis procedure promotes cardiovascular damage. Both traditional and non-traditional CVD risk factors drive this acceleration. More concerning, the dialysis procedure itself is cardiotoxic. Because of coexisting poor cardiac reserve and altered sympathetic tone in this patient population, dialysis induces repetitive contractile, ischemic injury termed myocardial stunning. This ischemia-reperfusion injury is reversible at first. However, with repetitive episodes, this injury will trigger alterations in cardiac function that decrease contractile function in order to preserve viability. Ultimately, these adaptations lead to remodeling and fibrosis. There is no targeted therapy available to reverse cardiovascular damage in these patients. Intensive monitoring and management of modifiable risks such as hypertension and anemia in the early stages of CKD to optimize cardiovascular health is imperative. However, in late CKD, especially in those patients who are not candidates for preemptive renal transplantation, optimization of the dialysis procedure is critical to prevent acceleration of their CVD burden. Improved assessment of dry weight as well as data-driven fluid management programs may decrease some risk. More importantly, standard implementation of intensified dialysis prescriptions by increasing time or through the addition of convective clearance may mitigate progressive cardiovascular damage and enhance survival. In this review, the pathophysiology of dialysis-induced cardiovascular damage will be reviewed. The management strategies to limit the cardiovascular burden in our patients are also discussed.