Reliability of dynamic causal modelling of resting-state magnetoencephalography.

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting-state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between-subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within-subject between-session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, and between-epochs; (ii) within-subject between-session; and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders.

Evaluation of open and minimally invasive spinal surgery for the treatment of thoracolumbar metastatic epidural spinal cord compression: a systematic review.

BACKGROUND: Metastatic epidural spinal cord compression (MESCC) is a debilitating sequela of cancer that results in pain, disability, and neurologic deficits. Surgical techniques have included open surgical (OS) techniques with anterior and/or posterior decompression and fusion procedures. Further technical evolution has led to minimally invasive spinal (MIS) decompression and fusion. The objective of this study is to compare MIS to OS techniques in the treatment of thoracolumbar MESCC. METHODS: A review of the literature was performed using PubMed database. Inclusion criteria included patients 18 years or older, thoracolumbar MESCC, and surgeries with instrumented fusion. A total of 451 articles met the inclusion criteria and further analysis narrowed them down to 81 articles. Variables collected included blood loss, length of stay, operative time, pre- and postoperative Frankel grade, and complications. RESULTS: A total of 5726 papers were collected, with a total of 81 papers meeting final inclusion criteria: 26 papers with MIS technique and 55 with OS. A total of 2267 patients were evaluated. They were split into three surgical subtypes of MIS and OS: posterior decompression and fusion, partial corpectomy, and complete corpectomy. Overall, MIS had lower operative time, blood loss, and complications compared to OS. A timeline analysis showed reduction of complication rates in MIS surgery between papers published over a 28-year period. CONCLUSION: MESCC carries significant morbidity and mortality. Surgical approaches for palliative treatment should account for this fact. We conclude that MIS techniques offer a viable alternative to traditional OS approaches with lower overall morbidity and complications.

Utility of intraoperative ultrasonography for resection of pituitary adenomas: a comparative retrospective study.

BACKGROUND: The evolution of pituitary surgery has made it a safe and effective form of treatment; however, risks of inadequate tumor resection, cerebrospinal fluid (CSF) leak, pituitary dysfunction, and vascular injury still exist. The use of intraoperative ultrasonography (IOUS) in pituitary surgery has been well described. Recent advancements in ultrasound technology have allowed for expanded utility as described here. METHODS: A retrospective review was performed between January 2016 and December 2019. One hundred thirty-eight patients (mean age 53.7 years, 47% females) were identified undergoing transsphenoidal surgery for pituitary tumors. Thirty-four patients had IOUS performed using a side-firing ultrasound probe, while 104 did not. Data was analyzed for preoperative (demographics, clinical, and radiographic features), perioperative (blood loss, operative time), and postoperative (complications, length of stay, hormone remission, and extent of resection) outcomes. RESULTS: There were no significant differences in patient age, gender, tumor volume, Knosp grade, and hormone-secreting status between the two groups. Patients treated using IOUS had significantly higher rates of gross total resection (79% vs. 44%, p = 0.0008), shorter operative times (74 vs. 146 min, p < 0.0001), lower blood loss (119 vs. 284 cc, p < 0.0001), and hospital stays (2.9 vs. 4.2 days, p = 0.001). Overall complication rates were lower in the IOUS group compared to standard pituitary surgery but did not reach significance. CONCLUSIONS: Recent improvements in ultrasound technology have allowed for miniaturization of probes capable of delivering high-resolution images. The use of IOUS in transsphenoidal pituitary surgery may significantly increase rates of gross total resection, while decreasing blood loss, hospital LOS, and operative time.

Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity.

BACKGROUND: Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). METHODS: Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of  human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. RESULTS: Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. CONCLUSION: These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients.

The potent BACE1 inhibitor LY2886721 elicits robust central Aß pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Estimation of the inter- and intrasubject variability of the diurnal serum cortisol rhythm in healthy male subjects to evaluate the biomarker potential for drug target engagement.

OBJECTIVE: Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement. MATERIALS AND METHODS: This open-label, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods. RESULTS: Three significant cortisol concentration peaks were observed at ~7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the >dinner-induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively. CONCLUSIONS: Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic-pituitary-adrenocortical (HPA) axis.

A population PK model for citalopram and its major metabolite, N-desmethyl citalopram, in rats.

A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague-Dawley (SD) rats at doses: 0.3, 1, 3, and 10 mg/kg IV and 10 mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60 mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quantification limit (BLQ < 0.1 ng/mL) were included in the analyses and treated as censored information. The disposition of citalopram was best described by a 3-compartment model and its desmethyl metabolite by a 2-compartment model. Several models for the absorption rate were explored (e.g. first, zero order and combined first and zero order absorption, Michaelis-Menten, lag time) in combination with dose and/or time dependent covariate effects. Dose dependent oral bioavailability properties were also identified in this analysis. Citalopram IV clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was adequately described using a Michaelis-Menten clearance with different parameters depending on the strain. This analysis demonstrates a very complex absorption/metabolism process explaining the highly non-linear pharmacokinetics observed across all the doses. This is the first combined parent/metabolite population PK analysis in both SD and Wistar rats over a wide range of IV and PO dosages for citalopram, a compound that exhibits highly nonlinear oral pharmacokinetics in rats.

Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.

BACKGROUND: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. METHODS: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. RESULTS: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg). CONCLUSIONS: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Cost-effectiveness of antiplatelet therapy to prolong primary patency of hemodialysis graft.

INTRODUCTION: The Dialysis Access Consortium (DAC) study group previously reported that treatment with extended-release dipyridamole plus aspirin (DASA) resulted in a significant but clinically modest improvement in primary unassisted arteriovenous graft (AVG) patency. Utilizing DAC published data, the objective of this study is to evaluate the cost effectiveness of antiplatelet interventions aimed at preventing loss of primary AVG patency in hemodialysis (HD) patients. METHODS: We performed a cost-utility analysis, using a decision analysis tree model with a 12-month time horizon and a third party payer perspective. Interventions included DASA with and without concurrent aspirin, aspirin alone, and no prophylaxis. The modeled population was defined as adult (≥ 18 years of age) end-stage renal disease (ESRD) patients who had undergone placement of a new AVG in the United States. The outcomes were costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios, and net monetary benefit. Probabilities were based upon published studies performed by the DAC Study Group while costs of medications and procedures were drawn from public sources. Utilities of health states were derived from published reports and the Short Form 6D (SF-6D) instrument. RESULTS: Aspirin alone is the most cost effective strategy for AVG pharmacologic prophylaxis, as compared to no prophylaxis or DASA with or without concurrent aspirin. The results are robust on multiple scenario analyses using both deterministic and Monte Carlo probabilistic sensitivity analyses. Accounting for both costs and QALY, using aspirin alone to prevent AVG thrombosis can potentially reduce healthcare costs by $24,679,412 per year compared to no aspirin use, at a willingness-to-pay of $50,000/ QALY. CONCLUSIONS: Aspirin monotherapy compared favorably to other strategies based on cost per QALY. Our findings support the use of aspirin prophylaxis in HD patients with a new AVG who do not have a contraindication to aspirin.

Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations.

OBJECTIVES: A modified insulin tolerance test (ITT) can be used to simulate a physiological stress state through the induction of controlled hypoglycemia in healthy volunteers. This allows for evaluation of hypothalamic-pituitary-adrenocortical axis response to stress via a surge in cortical release. However, a consequence of severe, prolonged hypoglycemia is QT interval prolongation. The aim of this analysis was to confirm that blood glucose lowering to 60 mg/dL (previously identified as adequate for inducing stress) has low risk of inducing clinically significant QT prolongation. MATERIALS AND METHODS: Continuous ECG monitoring was conducted as a planned sub study of an open-label, 2-period study involving 18 healthy male subjects. The QTcF response to hypoglycemia was measured over 2 identical periods, ~ 7 days apart. RESULTS: An indirect- response model adequately described the pharmacological relationship between blood glucose and QTcF intervals over the time-course of the ITT. The model correctly identified the steep glucose-QT relationship as an on-off response with a large Hill coefficient of 59 and the threshold glucose, EC50, as ~ 57 mg/dL with narrow between-subject variability of 10%. Simulated QTcF profiles over the course of an ITT did not demonstrate any QTcF interval changes of clinical concern, defined as QTcF observation > 500 ms, if hypoglycemia did not reach below 60 mg/dL. The statistical prediction that the chance of a mean QTcF observation > 500 ms was < 0.0001. CONCLUSIONS: Results support that an ITT maintained at or above 60 mg/dL is unlikely to cause QT prolongation in healthy volunteers and does not warrant continuous ECG monitoring in this group of subjects.

Hi5 Protocol for the Use of Microfocused Ultrasound with Visualization.

Background: Microfocused ultrasound with visualization (MFU-V) is used for lifting and tightening of facial tissues. Standard protocols are completed in a single session. Despite excellent outcomes, we identified several barriers of entry for a significant number of patients. Therefore, we devised an individualized pan-facial protocol that is delivered as a series of short, intense treatments to address these issues. Methods: We enrolled 12 participants with mild-to-moderate skin and fibromuscular laxity to receive one superficial and one deep pass per visit (average 280 lines). Qualitative improvements were rated by both patients and physicians at 6 or 10 months due to COVID-19 delays. Changes in the submentum and eyebrow heights were quantified. Results: Ten patients (age range: 31-61 years) underwent an average of four MFU-V treatments. Two patients were excluded after massive weight gain. Skin and fibromuscular ptosis and overall soft tissue laxity improved in all patients. Mean brow height increased by 1.7 mm, whereas the mean submental lift was 78.7 mm2. All patients and treating physicians rated an improvement in appearance, whereas independent physicians rated improvements in 87% of cases. Four patients self-rated as "markedly improved." Pain was rated at up to 6.2 (out of 10). Although mask-wearing was mandatory, loss of elasticity, wrinkles, and skin roughness all improved. Superficial welts (n = 5), erythema (n = 3), tenderness (n = 3), and mild bruising (n = 2) occurred, but all resolved within a few days and no severe or permanent adverse events occurred. Conclusion: The Hi5 protocol was noninferior to standard single-session protocols and improved brow heights and submental lifting.

Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

Robust central reduction of amyloid-ß in humans with an orally available, non-peptidic ß-secretase inhibitor.

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-ß peptide (Aß) is critical for Alzheimer's disease (AD) pathogenesis. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aß-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aß reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aß reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

The effects on metabolic clearance when administering a potent CYP3A autoinducer with the prototypic CYP3A inhibitor, ketoconazole.

Ketoconazole is recognized as the prototypical CYP3A inhibitor and is often used to determine the metabolic CYP3A liabilities of new chemical entities in preclinical and clinical studies. Ketoconazole has been commercially available for approximately 30 years and was marketed before drug-metabolizing enzymes were well characterized; consequently, little is known about its metabolic profile. Semagacestat, a γ-secretase inhibitor investigated as a potential therapy for Alzheimer's disease, was determined to be a potent CYP3A autoinducer in human hepatocytes. Two human studies were conducted to assess the induction potential of semagacestat. In the first study (study 1, n = 20), semagacestat increased the mean apparent clearance (CL/F) of oral midazolam (76-324 l/h) and nifedipine (63-229 l/h) as predicted from hepatocytes. In a second (steady-state) study (study 2, n = 20), semagacestat CL/F increased from 22 after a single dose to 31 l/h. Ketoconazole decreased semagacestat CL/F by 32% after a single dose of semagacestat [geometric means ratio estimate, 0.68; 90% confidence interval (CI). 0.64, 0.73] and 46% at steady state (geometric means ratio estimate. 0.54; 90% CI, 0.51, 0.58). Ketoconazole area under the concentration-time curve over 8 h decreased 49% from first to last day of semagacestat dosing. Semagacestat significantly increases the oral clearance of CYP3A substrates, confirming its inducer designation. More importantly, when administered with a potent CYP3A inducer at steady state, ketoconazole's plasma exposure decreased, indicating that it may also be cleared by CYP3A, other inducible enzymes or transporters, or both.

Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies.

Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple-dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects.

Leveraging the neurosurgical operating room for therapeutic development in NeuroOncology.

Glioblastoma (GBM) remains a disease with a dismal prognosis. For all the hope and promise immunotherapies and molecular targeted therapies have shown for systemic malignancies, these treatments have failed to show any promise in GBM. In this context, the paradigm of investigation of therapeutics for this disease itself must be examined and modifications considered. The unique challenge of the presence of blood-brain and blood-tumor barriers (BBB/BTB) raises questions about both the true levels of systemic drug delivery to the affected tissues. Window-of-opportunity (WoO) trials in neuro-oncology allow for proof-of-concept at the start of a classic phase I-II-III clinical trial progression. For therapeutics that do not have the ability to cross the BBB/BTB, direct delivery into tumor and/or tumor-infiltrated brain in the setting of a surgical procedure can provide a novel route of therapeutic access. These approaches permit neurosurgeons to play a greater role in therapeutic development for brain tumors.

New Therapeutics in Alzheimer's Disease Longitudinal Cohort study (NTAD): study protocol.

INTRODUCTION: With the pressing need to develop treatments that slow or stop the progression of Alzheimer's disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease. METHODS AND ANALYSIS: The New Therapeutics in Alzheimer's Disease study (NTAD) aims to identify a biomarker set from magneto/electroencephalography that is sensitive to disease and progression over 1 year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer's disease and 30 healthy controls aged between 50 and 85 years. Measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and MRI) of all participants will be taken at baseline. These measurements will be repeated after approximately 1 year on participants with Alzheimer's disease or mild cognitive impairment, and clinical and cognitive assessment of these participants will be repeated again after approximately 2 years. To assess reliability of magneto/electroencephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer's disease will also undergo repeat magneto/electroencephalography 2 weeks after baseline. Baseline and longitudinal changes in neurophysiology are the primary analyses of interest. Additional outputs will include atrophy and cognitive change and estimated numbers needed to treat each arm of simulated clinical trials of a future disease-modifying therapy. ETHICS AND DATA STATEMENT: The study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

Insights on Skin Quality and Clinical Practice Trends in Asia Pacific and a Practical Guide to Good Skin Quality from the Inside Out.

Objective: We sought to examine the current skin quality trends and gaps in clinical practice in the Asia Pacific region and develop a practical guide to improve skin quality. Methods: Medical practitioners from 11 countries in the Asia Pacific region completed an online survey on current trends in skin quality treatment. A panel of 12 leading experts convened for a virtual meeting to develop a practical guide for skin quality improvement. Results: A total of 153 practitioners completed the survey. The four most common skin quality issues were uneven skin tone, skin surface unevenness, skin laxity, and sebaceous gland hyperactivity and enlarged pores. Most practitioners reported using a combination of treatment modalities for each skin quality issue. It was also observed that each treatment modality could be used to treat several skin quality issues. A multimodal approach targeting different interrelated issues across the tissue planes was recommended for balanced results. The panel developed a practical guide for the appropriate combinations and sequence of treatments, and created treatment protocols for specific skin quality outcome goals. The guide employed an "inside-out" approach, treating the deeper tissue planes prior to the superficial layers to achieve harmonious results. Limitations: Future studies are needed to support the recommended treatment protocols for skin quality improvement. Conclusion: These findings provide valuable insights on current skin quality trends and gaps in clinical practice. The practical guide provides a framework for practitioners to customize their treatment plan according to each patient's needs.

Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases.

BACKGROUND: Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma. METHODS: A retrospective chart review was performed of 1162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow-up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected. RESULTS: Eight hundred and twenty-seven patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD. CONCLUSION: In a single-institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such as dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.