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. PARTICIPANTS: Patients born with a cleft palate (with or without a cleft lip) undergoing palatal surgery between the ages of 9 months and 18 years. INTERVENTION: Introduction of suprazygomatic maxillary nerve (SZMN) block using ropivacaine 0.2% into clinical protocol in February 2023. MAIN OUTCOME MEASURES: Peri-procedure complications and post-operative opioid administration. RESULTS: The clinical anatomy of the SZMN block is described in a stepwise and pictorial approach from superficial to deep structures. 43 patients underwent surgical interventions involving the palate (either intravelar veloplasty, Furlow palatoplasty or bilateral myomucosal buccinator flaps for palatal lengthening). 22 patients had a general anaesthetic and local anaesthetic infiltration and 21 had an additional SZMN block. There were no local or systemic complications associated with the SZMN block. There was no difference in the total dosing of post-operative (P = .79) opioids between the groups. CONCLUSIONS: We demonstrate the feasibility and safety of this procedure without the use of ultrasound guidance in a heterogenous group of paediatric patients undergoing palatal surgery. Regional anaesthesia should be considered as part of the multi-modal analgesic strategy, although it may be difficult to demonstrate a change in opioid use in clinical settings where enhanced recovery techniques are established, and opioid use is already low.

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. The modified design from the anatomical subunit approximation technique uses a nasal sill flap and obviates the need for nasal sill and lateral lip excision. Tissues of the lip are opened out and reorientated to maximize the anatomical advantage.

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. The translational risks were identified due to a low brain Kpu,u in nonhuman primate studies, which raised concern over the use of an established peripheral biomarker as a surrogate for central target engagement. Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23.

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. This was followed by a re-assessment between 2019 and 2021 of 101 patients (Group 2) following modification of the staging-CT protocol to include only those patients who received chemotherapy. Group 1 included immediate and delayed reconstruction; whereas Group 2 included only the high-risk delayed reconstruction cases. Both groups had CT staging. RESULT: Overall, 30% of Group 1, most likely those who had the delayed reconstruction, had findings which were recommended for further follow-up. This led to a change in staging of the high-risk patients only at the end of 2019 to those who underwent chemotherapy and had delayed reconstruction. Briefly, 56.4% of Group 2 demonstrated incidental findings, 42.1% of them required repeat scanning, 7% were referred to other specialties, and 47.4% did not require further action. There were no cases of occult metastatic breast cancer in either series; however, 1% were diagnosed with de novo primary cancers at non breast sites only in the first series. CONCLUSION: The screening of patients with asymptomatic breast cancer as part of CTA scanning prior to autologous reconstruction is not universally practiced and not supported by the NICE guidelines. This unit changed the practice to stop preoperative staging for low-risk patients by the end of 2019, and reserved it for the high-risk patient groups to reduce cost.

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. For the scoping review, articles were extracted from Embase, PubMed, and Medline, as well as manual searches of reference lists. Results were compiled, grouped, and appraised by date, outcomes, and historical significance. Inclusion criteria consisted of children who underwent primary septoplasty for any indication and were followed up on outcomes of facial growth and nasal function. Literature reviews, opinion articles, case reports, guidelines, or studies not available in English or online were excluded. RESULTS: Evolving anatomical theories relating to midfacial growth in the mid-late 20th century underpinned a progressive ideological shift on the safety and efficacy of septoplasty in children. This is supported by our scoping review, which included 23 articles mutually selected for inclusion by 2 blinded assessors. Several competing methods have been employed to measure endpoints on facial growth and nasal function, but generally indicate primary septoplasty is successful in improving nasal function and preserving midfacial growth. CONCLUSION: Perceptions towards septoplasty on facial growth in the pediatric population have transformed significantly and suggest a growing acceptance of primary septoplasty techniques in patients born with a cleft lip.

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. PARTICIPANTS: 2007 children born with cleft lip ± alveolus (CL ± A) and 2724 with cleft lip and palate (CLP) born between 2000 and 2012. MAIN OUTCOME MEASURE: The proportion of children with ICD-10 codes for additional congenital malformations by the sidedness (left, right or bilateral) of orofacial clefts. RESULTS: For CL ± A phenotypes, there was no evidence for a difference in the prevalence of additional anomalies between left (22%, reference), right (22%, aOR 1.02, 95% CI 0.80 to 1.28; P = .90) and bilateral clefts (23%, aOR 1.09, 95% CI 0.75 to 1.57; P = .66). For CLP phenotypes, there was evidence of a lower prevalence of additional malformations in left (23%, reference) compared to right (32%, aOR 1.54, 95% CI 1.25 to 1.91; P < .001) and bilateral clefts (33%, aOR 1.64, 95% CI 1.35 to 1.99; P < .001). CONCLUSIONS: The prevalence of additional congenital malformations was similar across sidedness subtypes with CL ± A phenotypes but was different for sidedness subtypes within CLP cases. These data support the hypothesis that CL ± A has a different underlying aetiology from CLP and that within the CLP phenotype, right sided CLP may lie closer in aetiology to bilateral CLP than it does to left sided CLP.

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. Considerations for future comparative studies in cleft care are discussed.

Are NHS cleft services in England ready for delegation to integrated care systems?

Cleft care services in the UK have been nationally funded since centralisation 25 years ago and during this time have been able to demonstrate improved clinical outcomes. Integrated care systems have been introduced into legislature as part of the Health Care Act of 2022 and will be responsible for the paradigm shift of allocating funds on a regional basis for cleft care services in England from 2024. The proposed population-based funding formulas present an opportunity to improve current inequities in cleft care, including access to speech therapy and adult services. However, the regional footprint of integrated care systems does not align with that of the centralised cleft service system and represents a threat to the standardised patient-centred care that has taken two decades to build. Awareness needs to be raised so that cleft care providers can proactively adapt to this mandatory change to service funding to ensure that clinical standards are maintained and continue to improve.

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. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. METHODS: Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. RESULTS: Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. CONCLUSIONS: This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

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. PATIENTS: Patients born between 2000-2014 with a complete unilateral cleft lip and palate (UCLP). MAIN OUTCOMES MEASURE: 5-Year-Old's Index scores. RESULTS: 378 children were included. 256 (68%) had a left sided UCLP and 122 (32%) had a right sided UCLP. 5-Year-Old's index scores ranged from 1 (good) to 5 (poor). There was a higher proportion of patients getting good scores (1 and 2) in left UCLP (43%) compared to right UCLP (37%) but there was weak evidence for a difference (Adjusted summary odds ratio 1.27, 95% CI 0.87 to 1.87; P = .22). CONCLUSIONS: Whilst maxillary growth may be different for left versus right sided UCLP, definitive analysis requires older growth indices and arch forms.

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. MAIN OUTCOME MEASURES: Cleft sidedness as a co-occurrence, an outcome or an exposure. RESULTS: Forty studies were eligible for inclusion and confirmed the predilection for the occurrence of left sided cleft lips; 12 studies reported cleft sidedness co-occurring with another phenotype, 11 studies report sidedness as an outcome and 17 studies as an exposure. Phenotypes which were reported to co-occur with either left or right sided clefts included congenital dental anomalies, handedness and additional congenital anomalies. Variables investigated as a potential cause of left or right sided clefts as an outcome included chromosomal anomalies, genetic variants and environmental factors. Outcomes investigated in relation to cleft sidedness as an exposure included facial anatomical features, facial growth, educational attainment, functional and psychological characteristics. More studies showed worse outcomes in right sided clefts versus left sided clefts than vice versa, although studies were inconsistent, and a quality assessment was not performed. CONCLUSIONS: The field of cleft sidedness research is expanding and there are promising early findings to differentiate cause and outcome by sidedness of the cleft.

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 in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.

Patient Factors Influencing Speech Outcomes in Velopharyngeal Function Following Initial Cleft Palate Repair: A Systematic Review and Meta-Analysis.

OBJECTIVE: Identification of patient factors influencing velopharyngeal function for speech following initial cleft palate repair. DESIGN: A literature search of relevant databases from inception until 2018 was performed using medical subject headings and keywords related to cleft palate, palatoplasty and speech assessment. Following three stage screening data extraction was performed. SETTING: Systematic review and meta-analysis of relevant literature. PATIENTS/PARTICIPANTS: Three hundred and eighty-three studies met the inclusion criteria, comprising data on 47 658 participants. INTERVENTIONS: Individuals undergoing initial palatoplasty. MAIN OUTCOME MEASURES: Studies including participants undergoing initial cleft palate repair where the frequency of secondary speech surgery and/or velopharyngeal function for speech was recorded. RESULTS: Patient factors reported included cleft phenotype (95% studies), biological sex (64%), syndrome diagnosis (44%), hearing loss (28%), developmental delay (16%), Robin Sequence (16%) and 22q11.2 microdeletion syndrome (11%). Meta-analysis provided strong evidence that rates of secondary surgery and velopharyngeal dysfunction varied according to cleft phenotype (Veau I best outcomes, Veau IV worst outcomes), Robin Sequence and syndrome diagnosis. There was no evidence that biological sex was associated with worse outcomes. Many studies were poor quality with minimal follow-up. CONCLUSIONS: Meta-analysis demonstrated the association of certain patient factors with speech outcome, however the quality of the evidence was low. Uniform, prospective, multi-centre documentation of preoperative characteristics and speech outcomes is required to characterise risk factors for post-palatoplasty velopharyngeal insufficiency for speech. SYSTEMATIC REVIEW REGISTRATION: Registered with PROSPERO CRD42017051624.

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. PARTICIPANTS: Cleft surgeons from around the world. MAIN OUTCOME MEASURES: Survey participant perception of the impact of laterality on: (1) cleft presentation (2) surgical challenge and (3) surgical outcomes. RESULTS: Responses were received from 453 cleft surgeons located in 54 countries around the world. 221 (49%) had previously considered differences in patients presenting with a left- versus right-sided UCL. 95 (21%) considered right-sided clefts more difficult to reconstruct, 37 (8%) reported left-sided clefts to be more difficult and 321 (71%) reported no difference in difficulty between the cleft sides. Higher volume cleft surgeons, characterised by those reporting cleft as their principal area of practice and performing >20 cleft operations per year, were more likely to have both previously considered differences in laterality in cleft and to report right-sided unilateral cleft lip to be more difficult to primarily reconstruct. 395 (87%) did not consider surgical outcomes to be influenced by cleft laterality. CONCLUSIONS: This survey reports perceptions on cleft laterality from a large body of global surgeons and suggests a trend for increased difficulty in right-sided compared to left-sided cleft lip reconstruction, where such laterality-associated difficulty is perceived.

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. AIMS: 1) examine effectiveness of the Student Section, 2) explore students' perception of cleft care, 3) provide a framework for similar groups. METHODS: Cross-sectional survey study design. Likert-Scale responses to questions regarding organisation and experience of the section were collected. Data was analysed using Chi statistical test, ordinal data assessed using Wilcoxon-Signed Rank test. RESULTS: 40/64 ambassadors responded to the survey. 90% had a positive perception on the organisation of the section, this correlated with group size (p = 0.012) and number of fundraising events organised (p = 0.032). 85% had an overall positive experience, scores for consideration of a career in cleft significantly improved from 2.25 (95%CI: 1.95-2.55) to 3.30 (95%CI: 3.03-3.57) (p < 0.001). CONCLUSION: This study presents the first example of a nationwide student group involved with a charitable cleft organisation.

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. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia.

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. SETTING: Data were obtained from the Cleft Collective, a national longitudinal cohort study. PATIENTS: Between 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. RESULTS: The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips (UCL) were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips (BCL) were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bimodal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (P < .001) and a 5 to 7-day postoperative regime used more commonly for soft palatoplasties (P < .001). Perioperative steroids were used more commonly in palatoplasties than cheiloplasties (P < .001) but tranexamic acid use was equivalent (P = .73). CONCLUSIONS: This study contributes to our understanding of current cleft surgical pathways in the UK and will provide a baseline for analysis of the effectiveness of utilized protocols.

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.Foundational principles were agreed to enable recommendations to be globally relevant and two areas of focus within the specified topic were identified. First the safety aspects of cleft surgery protocols were scrutinized and COVID-19 adaptations, specifically in the pre- and perioperative periods, were highlighted. Second, surgical procedures and cleft care services were prioritized according to their relationship to functional outcomes and time-sensitivity. The surgical procedures assigned the highest priority were emergent interventions for breathing and nutritional requirements and primary palatoplasty. The cleft care services assigned the highest priority were new-born assessments, pediatric support for children with syndromes, management of acute dental or auditory infections and speech pathology intervention.A collaborative, interdisciplinary and international working group delivered consensus recommendations to assist with the provision of cleft care in low- and middle-income countries. At a time of global cleft care delays due to COVID-19, a united approach amongst global cleft care providers will be advantageous to advocate for children born with cleft lip and palate in resource-constrained settings.

Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1H-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-1H-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 sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.