Evolving role of staging CT scans during CT-angiography for DIEP flap reconstruction planning.

Background: Preoperative planning with CT-angiography (CTA) in deep inferior epigastric perforator (DIEP) flap reconstruction is an essential preoperative tool. The aim of this study was to describe the management of the incidental findings following the introduction and further modification of a combined CTA and CT-staging preoperative protocol which includes chest, abdomen, pelvis, and musculoskeletal system.

Material And Methods: A retrospective case series of 292 patients (Group 1) with breast cancer who underwent DIEP flap between 2015 and 2019.

The Preservation Technique for Incomplete Unilateral Cleft Lip Reconstruction.

The incomplete unilateral cleft lip shares many of the same phenotypic characteristics as a complete unilateral cleft lip, but key differences include an intact nasal sill, a relative excess of skin in the lateral lip element, and favorable skeletal support. Surgical techniques for incomplete unilateral cleft lips should be tailored to the specific anatomical characteristics, be simple and reliable to perform, and minimize the risk of secondary deformity. Here we describe the "preservation technique" for incomplete unilateral cleft lip reconstruction.

Demystifying the Suprazygomatic Maxillary Nerve Block in Paediatric Cleft Palate Surgery.

Objective: To consider the clinical anatomy, safety and effectiveness of the suprazygomatic maxillary nerve block in cleft palate surgery.

Design: Observational case series.

Setting: Single cleft centre in the United Kingdom.

Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.

Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson's disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized.

Septoplasty During Primary Cleft Lip Reconstruction: A Historical Perspective and Scoping Review.

Background: Traditional surgical approaches excluded septoplasty at primary cleft lip reconstruction due to concerns about restricted nasal and midfacial growth. Modern opinion in the treatment of cleft lip has increasingly employed primary septoplasty; this scoping review and historical perspective aims to chronicle the evolution of septoplasty in patients born with cleft lip and palate and discuss current evidence.

Methods: The historical perspective explicitly contrasts American and European perceptions of septoplasty in cleft lip deformity and the competing anatomical theories of the role of the septum on midfacial and nasal growth.

Cleft lip Sidedness and the Association with Additional Congenital Malformations.

Objective: To investigate the association between the sidedness of orofacial clefts and additional congenital malformations.

Design: Linkage of a national registry of cleft births to national administrative data of hospital admissions.

Setting: National Health Service, England.

Analysis and Reporting of Randomized Trials in Cleft Palate Surgery: Learning from the Timing of Primary Surgery (TOPS) Trial.

The Timing of Primary Surgery (TOPS) trial was published August 2023 in the New England Journal of Medicine and is a milestone achievement for a study focused on cleft palate. Due to the complexity of outcome reporting in cleft and the rarity of such comparative trials, TOPS presents a useful opportunity to critically review the design, analysis and reporting strategies utilised. This perspective article focused on the inclusion of participants, the choice of the primary outcome measure and the analysis of ordinal data within the trial.

Exploring jump experience, risk perception, anxiety and self-confidence in skydiving: A mixed methods approach.

Skydivers are required to interpret person-context characteristics to overcome inherent internal challenges (i.e., fear and anxiety) and external challenges (i.

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define.

The Influence of Sidedness in Unilateral Cleft Lip and Palate on Mid Facial Growth at Five Years of Age.

Objective: To determine whether facial growth at five years is different for children with a left versus right sided cleft lip and palate.

Design: Retrospective cohort study.

Setting: Seven UK regional cleft centres.

Sidedness in Unilateral Orofacial Clefts: A Systematic Scoping Review.

Objective: An overview of the literature relating to the sidedness of unilateral cleft lip with or without cleft palate to map current knowledge on the cause and impact of directional asymmetry.

Design: Scoping review with a systematic search of Medline and Embase from inception to May 2023.

Patients, Participants: Humans born with a left or right unilateral cleft lip with or without a cleft palate.

Effects of LRRK2 Inhibitors in Nonhuman Primates.

Toxicology studies in nonhuman primates were conducted to evaluate selective, brain penetrant inhibitors of LRRK2. GNE 7915 was limited to 7-day administration in cynomolgus monkeys at 65 mg/kg/day or limited to 14 days in rhesus at 22.5 mg/kg b.

Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease.

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties.

The Implications of Laterality in Unilateral Cleft Lip Reconstruction: A Global Survey of Cleft Surgeons.

Objective: To explore the impact of directional laterality in complete Unilateral Cleft Lip (UCL) amongst the global cleft surgeon community.

Design: Cross-sectional survey study.

Setting: Global distribution of online survey distributed in English and Spanish.

Perspective on the current state of the LRRK2 field.

Almost 2 decades after linking LRRK2 to Parkinson's disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development.

The CLEFT Student Section: Engaging the future of cleft through fundraising; Structure of the section and results from inaugural year.

Background: There is a disparity in access, quality, and sustainability of cleft care in low and middle income countries, where burden of disease is greatest. CLEFT-Bridging the Gap (registered charity number: 1194581) is a UK-based charity that aims is to solve this through teaching, empowerment and development of sustainable cleft services. A Student Section, composed of medical, dental and speech and language therapy students, was established to support these endeavours through fundraising.

Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson's disease.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes.

Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease.

Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp-sp cross-coupling technologies.

Prenatal Mercury Exposure and Neurodevelopment up to the Age of 5 Years: A Systematic Review.

Neurodevelopmental delays can interfere with children's engagement with the world and further development, and may have negative consequences into adulthood. Mercury is highly toxic and may negatively influence neurodevelopment because it can freely cross the placenta and accumulate in the fetal brain. We searched four publication databases (Embase, PsycINFO, PubMed/MEDLINE, Scopus) for studies examining the relationship between early life mercury exposure and scores on neurodevelopmental performance measures in children aged 0 to 5 years old.

Current Surgical Practice for Children Born with a Cleft lip and/or Palate in the United Kingdom.

Objective: This study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate (CL ± P) in the United Kingdom (UK).

Design: Data forms completed at the time of surgery included details on timing, technique, and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.

Adapting Elements of Cleft Care Protocols in Low- and Middle-income Countries During and After COVID-19: A Process-driven Review With Recommendations.

A consortium of global cleft professionals, predominantly from low- and middle-income countries, identified adaptations to cleft care protocols during and after COVID-19 as a priority learning area of need. A multidisciplinary international working group met on a videoconferencing platform in a multi-staged process to make consensus recommendations for adaptations to cleft protocols within resource-constrained settings. Feedback was sought from a roundtable discussion forum and global organizations involved in comprehensive cleft care.