Ocular Safety and Toxicology of Subretinal Gene Therapy With rAAV.hPDE6A in Nonhuman Primates.

Purpose: Reports of gene therapy-associated retinal atrophies and inflammation have highlighted the importance of preclinical safety assessments of adeno-associated virus (AAV) vector systems. We evaluated in nonhuman primates (NHPs) the ocular safety and toxicology of a novel AAV gene therapy targeting retinitis pigmentosa caused by mutations in PDE6A, which has since been used in a phase I/II clinical trial (NCT04611503).

Methods: A total of 34 healthy cynomolgus animals (Macaca fascicularis) were treated with subretinal injections of rAAV.

First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors.

Background: Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach.

The Diagnostic Assessment of Inherited Platelet Function Defects.

In this article, our goal is to offer an introduction and overview of the diagnostic approach to inherited platelet function defects (iPFDs) for clinicians and laboratory personnel who are beginning to engage in the field. We describe the most commonly used laboratory methods and propose a diagnostic four-step approach, wherein each stage requires a higher level of expertise and more specialized methods. It should be noted that our proposed approach differs from the ISTH Guidance on this topic in some points.

Optic nerve sheath schwannoma: illustrative case.

Background: Optic nerve schwannomas are an extremely rare pathology in neurosurgery. Their origin is rather debatable given the structure of the optic nerve, which does not typically have Schwann cells therein. However, a number of clinical cases of optic nerve tumors classified as schwannomas have been described in the literature.

Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma.

Left neck and right biceps muscle vibrations have similar effects on perceived body orientation.

Vibrating muscles to manipulate proprioceptive input creates the sensation of an apparent change in body position. This study investigates whether vibrating the right biceps muscle has similar effects as vibrating the left posterior neck muscles. Based on previous observations, we hypothesized that both types of muscle vibration would shift the perception of healthy subjects' subjective straight-ahead (SSA) orientation in the horizontal plane to the left.

Myocardial Inflammation in Cardiac Transthyretin Amyloidosis: Prevalence and Potential Prognostic Implications.

Background: Despite previous histopathologic evidence for its presence, the role of myocardial inflammation in the development and progression of cardiac transthyretin amyloidosis (ATTR-CA) remains insufficiently understood. Thus, this study sought to characterize the prevalence and potential prognostic implications of myocardial inflammation in ATTR-CA.

Methods: A retrospective observational study including patients with ATTR-CA diagnosed by endomyocardial biopsy was conducted.

Influence of two different printing methods on the accuracy of full-guided implant insertion - a laboratory study in undergraduate dental students.

Objectives: The aim of the present study was to compare the accuracy of fully guided implant insertion in vitro achieved by two fabrication methods in a cohort of undergraduates. We hypothesized that both methods achieve a comparable accuracy.

Methods: Surface scans and cone beam computed tomography images of 48 mandibular models were matched.

Revisiting the electrophysiological correlates of valence and expectancy in reward processing - A multi-lab replication.

Two event-related brain potential (ERP) components, the frontocentral feedback-related negativity (FRN) and the posterior P300, are key in feedback processing. The FRN typically exhibits greater amplitude in response to negative and unexpected outcomes, whereas the P300 is generally more pronounced for positive outcomes. In an influential ERP study, Hajcak et al.

Randomised In Vitro Study Investigating PEEP-Stability During Application of CPAP With Binasal Prongs and Face Masks.

Aim: Face masks and binasal prongs are commonly used interfaces for applying continuous positive airway pressure (CPAP) in neonatology. We aimed to assess CPAP stability in a randomised controlled in vitro study.

Methods: In a simulated resuscitation scenario of a 1000-g preterm infant with respiratory distress, 20 operators (10 with/without neonatology experience) aimed to maintain a CPAP of 5 cmHO as precisely as possible using face masks or binasal prongs in random order.

The therapeutic potential of vitamins A, C, and D in pancreatic cancer.

The pancreatic ductal adenocarcinoma (PDAC) is among the deadliest tumor diseases worldwide. While treatment options have generally become more diverse, little progress has been made in the treatment of PDAC and the median survival time for patients with locally advanced PDAC is between 8.7 and 13.

Current update on the neurological manifestations of long COVID: more questions than answers.

Since the outbreak of the COVID-19 pandemic, there has been a global surge in patients presenting with prolonged or late-onset debilitating sequelae of SARS-CoV-2 infection, colloquially termed long COVID. This narrative review provides an updated synthesis of the latest evidence on the neurological manifestations of long COVID, discussing its clinical phenotypes, underlying pathophysiology, while also presenting the current state of diagnostic and therapeutic approaches. Approximately one-third of COVID-19 survivors experience prolonged neurological sequelae that persist for at least 12-months post-infection, adversely affecting patients' quality of life.

CT angiography of acute aortic syndrome in patients with chronic kidney disease.

The term acute aortic syndrome (AAS) refers to a range of different entities, including dissection, intramural haematoma and penetrating atherosclerotic ulcer. Patients with chronic renal disease and particularly those with dominant polycystic kidney disease are susceptible to this pathology, given the underlying renal arteriopathy and hypertension. Imaging plays a crucial role in diagnosing, grading and guiding management of these patients, with computed tomography angiography (CTA) being on the frontline.

Associations of inferior frontal sulcal hyperintensities on brain MRI with cerebral small vessel disease, cognitive function, and depression symptoms.

Inferior frontal sulcal hyperintensities (IFSH) observed on fluid-attenuated inversion recovery (FLAIR) MRI have been proposed as indicators of elevated cerebrospinal fluid waste accumulation in cerebral small vessel disease (CSVD). However, to validate IFSH as a reliable imaging biomarker, further replication studies are required. The objective of this study was to investigate associations between IFSH and CSVD, and their potential repercussions, i.

Compromised Nipple-Areola Complex Perfusion after Reduction Mammaplasty or Mastopexy: A Retrospective Evaluation of Different Treatments.

Background: Necrosis of the nipple-areolar complex (NAC) is a rare but devastating complication after reduction mammaplasty or mastopexy. Various approaches for improving compromised perfusion of the NAC have been described. However, detailed data on this topic in the literature is still scarce.

Perceptions of science, science communication, and climate change attitudes in 68 countries - the TISP dataset.

Science is integral to society because it can inform individual, government, corporate, and civil society decision-making on issues such as public health, new technologies or climate change. Yet, public distrust and populist sentiment challenge the relationship between science and society. To help researchers analyse the science-society nexus across different geographical and cultural contexts, we undertook a cross-sectional population survey resulting in a dataset of 71,922 participants in 68 countries.

A comparison on safety and efficacy between 24 Fr versus 18 Fr pneumatic balloon dilators for percutaneous treatment of renal stones between 10 and 20 mm: results from a contemporary cohort.

Purpose: To assess differences in safety and efficacy between 24 and 18 Fr pneumatic balloon dilators for percutaneous nephrolithotripsy (PCNL) of renal stones between 10 and 20 mm.

Methods: Patients were randomized to dilatation with a 24 Fr (Group A) versus 18 Fr (Group B) Ultraxx pneumatic dilator (Cook Medical). In all procedures percutaneous puncture was performed under ultrasound guidance.

Sleep for infants after discharge from a neonatal ward: Expert- and parent endorsed strategies.

Background: This study aims to outline sleep strategies grounded in scientific research and endorsed by sleep experts, integrating parental input into the evaluation process, to assist parents in supporting infant sleep after discharge from a neonatal ward.

Methods: A Delphi method, consisting of three rounds, was employed. Sleep strategies based on scientific literature were presented to sleep experts and parents of infants discharged from a neonatal ward.

Comparison of 1D and 3D volume measurement techniques in NF2-associated vestibular schwannoma monitoring.

To compare 1D (linear) tumor volume calculations and classification systems with 3D-segmented volumetric analysis (SVA), focusing specifically on their effectiveness in the evaluation and management of NF2-associated vestibular schwannomas (VS). VS were clinically followed every 6 months with cranial, thin-sliced (< 3 mm) MRI. We retrospectively reviewed and used T1-weighted post-contrast enhanced (gadolinium) images for both SVA and linear measurements.

Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy.

First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer.

Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes.