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Expert determination is a form of dispute resolution in which the parties use a subject-matter expert, rather than a judge, mediator, or arbitrator with legal training, to decide the dispute. [...]

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

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors.Objective: To determine whether the high in vitropotency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans.Methods: The effect of LY3202626 versus vehicle on amyloid-ß (Aß) levels was evaluated in a series of in vitroassays, as well as in in vivoand multi-part clinical pharmacology studies. Aß levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoctest and clinical data used summary statistics.Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50of 0.275±0.176?nM for lowering Aß1–40and 0.228±0.244?nM for Aß1–42in PDAPP neuronal cultures. In dogs, CSF Aß1hboxxconcentrations were significantly reduced by ~80% at 9 hours following a 1.5?mg/kg dose. In humans, CSF Aß1–42was reduced by 73.1±7.96 % following administration of 6?mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans.Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

IMPORTANCE: β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. OBJECTIVE: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures. DESIGN, SETTING, AND PARTICIPANTS: The Study of LY3002813 in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels. INTERVENTIONS: Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance. MAIN OUTCOMES AND MEASURES: Change in amyloid, tau, and clinical decline after donanemab treatment. RESULTS: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, −0.54; 95% CI, −0.66 to −0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001). CONCLUSIONS AND RELEVANCE: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03367403

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

Low-friction coatings are used on bearings for two reasons. The first is as a backup lubricant if the primary (fluid) lubricant fails or is insufficient to prevent surface-to-surface contact. Lubricant [...]

Background: LY3202626 is a small molecule inhibitor of ß-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-ß (Aß)1–40and Aß1–42concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD).Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia.Methods: Patients received daily 3?mg or 12?mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline.Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo.Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

We report on the low-temperature growth of crystalline Ga2O3films on Si, sapphire, and glass substrates using plasma-enhanced atomic layer deposition (PEALD) featuring a hollow-cathode plasma source. Films were deposited by using triethylgallium (TEG) and Ar/O2plasma as metal precursor and oxygen co-reactant, respectively. Growth experiments have been performed within 150–240 °C substrate temperature and 30–300 W radio-frequency (rf) plasma power ranges. Additionally, each unit AB-type ALD cycle was followed by an in situAr plasma annealing treatment, which consisted of an extra (50–300 W) Ar plasma exposure for 20 s ending just before the next TEG pulse. The growth per cycle (GPC) of the films without Ar plasma annealing step ranged between 0.69 and 1.31 Å/cycle, and as-grown refractive indices were between 1.67 and 1.75 within the scanned plasma power range. X-ray diffraction (XRD) measurements showed that Ga2O3films grown without in situAr plasma annealing exhibited amorphous character irrespective of substrate temperature and rf power values. With the incorporation of the in situAr plasma annealing process, the GPC of Ga2O3films ranged between 0.76 and 1.03 Å/cycle along with higher refractive index values of 1.75–1.79. The increased refractive index (1.79) and slightly reduced GPC (1.03 Å/cycle) at 250 W plasma annealing indicated possible densification and crystallization of the films. Indeed, X-ray measurements confirmed that in situplasma annealed films grow in a monoclinic β-Ga2O3crystal phase. The film crystallinity and density further enhance (from 5.11 to 5.60 g/cm3) by increasing the rf power value used during in situAr plasma annealing process. X-ray photoelectron spectroscopy (XPS) measurement of the β-Ga2O3sample grown under optimal in situplasma annealing power (250 W) revealed near-ideal film stoichiometry (O/Ga of ∼1.44) with relatively low carbon content (∼5 at. %), whereas 50 W rf power treated film was highly non-stoichiometric (O/Ga of ∼2.31) with considerably elevated carbon content. Our results demonstrate the effectiveness of in situAr plasma annealing process to transform amorphous wide bandgap oxide semiconductors into crystalline films without needing high-temperature post-deposition annealing treatment.

Changes need to be made to reduce the number of emails generated by the Florida Courts E-Filing Portal. The Federal PACER system accomplishes the same task with a single email [...]

IMPORTANCE: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. OBJECTIVE: To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. DESIGN, SETTING, AND PARTICIPANTS: AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. INTERVENTIONS: Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. RESULTS: Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. CONCLUSIONS AND RELEVANCE: Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573

Sir: I am a rabid admirer of Rod Liddle and think he is the most sensible person on the planet. But his attitude to smoking has made him slip back [...]

Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40and Aβ1–42in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.

Clear cell carcinoma represents a distinct histologic type of müllerian carcinoma that is resistant to conventional chemotherapy. Expression of programmed cell death ligand (PD-L1) has been associated with immune evasion in numerous tumor types and may be used to identify patients who will benefit from targeted immunotherapy, particularly in the setting of mismatch repair defects. We evaluated PD-L1 expression in 23 ovarian clear cell carcinomas and 21 endometrial clear cell carcinomas, and correlated expression with mismatch repair status. Tumor PD-L1 staining was seen in 43% of ovarian tumors and 76% of endometrial tumors, including 71% of cases (67% of ovarian and 75% of endometrial) with mismatch repair defects. Extensive tumoral staining (>50%) was seen in only one case (an endometrial case with MSH6 loss). However, tumoral PD-L1 expression remained common in mismatch repair-intact tumors and mismatch repair status was not significantly correlated with PD-L1 expression. The increased incidence of PD-L1 positivity in tumor cells (P=0.04) in endometrial vs ovarian clear cell carcinomas suggests differences in the tumor microenvironment of these histologically and molecularly similar tumors that may inform treatment options. These results suggest that clear cell histology may be a useful susceptibility marker for immunotherapy targeting the PD-1/PD-L1 axis irrespective of mismatch repair status, particularly in endometrial carcinomas.

Empagliflozin was found to decrease mortality in patients with type 2 diabetes mellitus (T2DM) and a prior cardiovascular disease (CVD) event.

Mismatch repair (MMR)-deficient endometrial carcinomas (ECs) bearing Lynch syndrome (LS)-associated germline mutations or sporadic MLH1promoter hypermethylation (MLH1hm) are highly immunogenic and may represent excellent candidates for therapies targeting the programmed cell death (PD)/programmed cell death ligand-1 (PD-L1) immune checkpoint pathway. This study evaluates PD-L1 expression in MMR-deficient ECs including LS-associated and MLH1hmcases, in comparison with MMR-intact tumors. Immunohistochemistry for PD-L1/CD274 was performed on 38 MMR-deficient and 29 MMR-intact ECs. Staining was scored in the tumor and the peritumoral immune compartment. The majority of MMR-deficient tumors were PD-L1 positive (53%) in at least a subset of tumor cells. LS-associated tumors were more likely to be PD-L1 positive relative to MLH1hmtumors (70% vs. 33%, P=0.05). Only 10% of MMR-intact ECs demonstrated any tumoral PD-L1 expression; this was significantly lower than was observed in MMR-deficient tumors (P=0.0005). When reviewed by histologic grade, PD-L1 expression remained highest in LS-associated ECs followed by MLH1hmand MMR-intact carcinomas, respectively. The MMR immunohistochemical pattern most uniformly associated with PD-L1 expression was MSH6 loss. Immune PD-L1 expression was seen in 100% of MMR-deficient and 66% of MMR-intact cases. This study represents the first to characterize differences in PD-L1 expression between LS-associated and MLH1hmendometrial cancers. It demonstrates that tumoral PD-L1 expression is more common in LS-associated endometrial cancers relative to MLH1hmand MMR-intact tumors, although sporadic cancers often show PD-L1 positive immune staining. These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects.

Thinking, Fast and Slow By Daniel Kahneman Daniel Kahneman's new book ties together the research done by him and many others over the past half century to provide a clear [...]

Sir: It is extraordinary that Paul Johnson (And another thing, 17 January) of all people should misquote from The Rime of the Ancient Mariner. Most of us learnt at school [...]

SOX10 (Sry-related HMg-Boxgene 10) is a key nuclear transcription factor in the differentiation of neural crest progenitor cells to melanocytes. It has been shown to be a sensitive and specific marker of malignant melanoma of multiple histologic types. We evaluated the immunohistochemical profile of SOX10 in 107 sentinel lymph nodes and compared it to S100 protein, HMB-45, and Melan-A. Seventy-seven lymph nodes originally reported as positive for metastatic melanoma, and 30 reported as negative were reviewed. SOX10 identified metastatic melanoma in 58 of 58 (100) positive cases included in the final analysis. SOX10 staining showed a statistically significant increase in staining intensity when compared with S100 protein, HMB-45, and Melan-A (P=0.000, 0.000, and 0.003, respectively). In addition, there was a statistically significant increase in percentage of tumor cells stained by SOX10, compared with S100 protein, HMB-45, and Melan-A (P=0.015, 0.000, and 0.001, respectively). SOX10 stained nodal nevi in a similar manner to S100 protein and Melan-A in 4 cases. Interpretation of nodal nevus staining (negative by HMB-45) was significantly aided by the crisp nuclear staining produced by SOX10 as compared with the obscuring cytoplasmic staining produced by S100 protein and Melan-A in 3 cases. Identification of micrometastases was facilitated by the nuclear staining pattern of SOX10 and lack of background dendritic cell staining seen in S100 protein. We conclude that given the sensitivity and specificity of SOX10 for detecting metastatic melanoma in sentinel lymph nodes, it is a reliable marker for supplementing and potentially replacing traditionally utilized immunohistochemical stains.

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated.Objectives (1) Assess individual oral hydrocortisone pharmacokinetics; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; (3) determine potential individualized treatment regimens based on each subject's pharmacokinetic and pharmacodynamic parameters.Methods Thirty-four patients (18 boys, 16 girls, aged 1.4 to 18.1 years) with CAH underwent 6-hour pharmacokinetic studies. Results were analyzed by noncompartmental methods to obtain the area under the curve (AUC) for cortisol, 17-hydroxyprogesterone, and androstenedione; maximum concentration and time-to-maximum concentration for cortisol; and minimum and time-to-minimum concentration for 17-hydroxyprogesterone and androstenedione.Results Mean (SD) cortisol half-life and Cmaxwere 1.01 (0.20) hours and 24.4 (5.4) μg/dL, respectively. The AUCs for cortisol, 17-hydroxyprogesterone and androstenedione were 40.8 (14.5) μg hour/dL, 29,490 (23,539) ng hour/dL, and 680 (795) ng hour/dL, respectively. No significant relationships existed between cortisol AUCs and the AUCs of either 17-hydroxyprogesterone (P= 0.32) or androstenedione (P= 0.99); nor were there differences between the change-from-baseline concentrations for cortisol with either 17-hydroxyprogesterone (P= 0.80) or androstenedione (P= 0.40). Cortisol simulations indicated that although four daily doses decreased 24-hour hypercortisolemia and hypocortisolemia, substantial periods of each remained.Conclusions Concentration profiles of cortisol, 17-hydroxyprogesterone, and androstenedione are highly variable in children with CAH, and knowledge of them can assist in personalizing the therapy of CAH patients. Hydrocortisone's rapid half-life and the lack of a sustained-released product make it difficult to closely approximate normal circadian profiles.

Recent issues of this publication have emphasised how educational psychologists and child psychologists have worked to support students with anxiety issues. The September 2012 Special Edition (issue 144) reviewed a one-day conference on Anxiety, Autism and Attachment, and in the December issue (issue 145) Thornbery (2012) described the impact of a FRIENDS programme on anxiety and coping strategies in primary-aged children. This study noted raised anxiety scores, heightened awareness or 'elevated risk' following the intervention. [ABSTRACT FROM AUTHOR]

We investigate selective-area atomic layer deposition (ALD) of copper onto nanofabricated palladium structures for plasmonic applications in electro-optic conversion devices. We examine arrays of nanofabricated tip shaped electrodes for the formation of geometrically asymmetric tunnel junctions. We find ALD growth to be sensitive to sample pretreatment, and demonstrate that UV-ozone treatment is effective for initiating growth. We show that nucleation density and grain evolution are important properties of growth because ALD deposited topological features are on the same scale as the nanostructures. We predict electric-field intensities within the gap region between electrodes to scale exponentially with ALD growth. We establish the basis for ALD tuning of plasmonic nanostructures.

Neuropsychiatric symptoms are prevalent in mild cognitive impairment (MCI) and Alzheimer disease (AD) and commonly measured using the Neuropsychiatric Inventory (NPI). Based on existing exploratory literature, we report preliminary validation of three NPI Questionnaire (NPI-Q-10) subscales that measure clinically meaningful symptom clusters.

The atomic layer deposition (ALD) of SrO thin films from strontium bis(tri(isopropyl)cyclopentadienyl) (Sr(C5iPr3H2)2) and H2O was studied by using in situ real-time spectroscopic ellipsometry (RTSE), ex situ X-ray photoelectron spectroscopy (XPS), and grazing-incidence X-ray diffraction (GI-XRD). It is found that with H2O as the oxidant, deposition temperature strongly affects film composition. At 250 °C films consist of polycrystalline Sr(OH)2while at 350 °C polycrystalline SrO is observed. The growth per cycle (GPC) is found to be sensitive not only to the crystalline phase (Sr(OH)2vs SrO) but also the crystalline orientation. For films prepared at high temperatures and subsequently cooled for continued growth at lower temperatures, an unusual transient growth per cycle (GPC) enhancement of over 160% for more than 100 cycles is observed. The enhancement is found to be related to the orientation of the Sr(OH)2phase, which is influenced by the underlying crystal texture of the substrate. Substrate nucleation effects were also observed for growth on SiO2/Si substrates. A Sr silicate layer with stoichiometry close to Sr2SiO4forms spontaneously during ALD growth and transiently enhances the GPC.

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.

Implementation of consensus guidelines for esophageal variceal hemorrhage yields improved outcomes. We evaluated guideline adherence and outcomes after variceal hemorrhage at a university hospital (UH) and a staff-model health maintenance organization (HMO).

Solanezumab is a humanized anti-amyloid monoclonal antibody being developed as a passive immunization treatment to slow the progression of Alzheimer disease (AD). Pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after a single dose of solanezumab were compared between Japanese and white patients with AD.

Atomic layer deposition (ALD) was utilized as a synthesis method to deposit monolayers of Pt onto WC substrates for applications as oxygen reduction reaction electrocatalysts. Samples utilizing various Pt ALD cycles were characterized using surface analytical methods and scanning electron microscopy, whereas cyclic voltammetry was used to determine whether the oxygen reduction reaction takes place on the catalyst surface. ALD Pt was found to deposit onto WC substrates following an island growth mechanism. When few Pt ALD cycles are used, discrete Pt particles first formed and dispersed over the WC substrate, but at least 100 ALD cycles is required for the WC substrate to be covered with Pt. Whereas Pt monolayers are not obtained, ALD Pt on WC still shows activity for the oxygen reduction reaction. Cyclic voltammetry conducted in an O2-saturated 0.5 M H2SO4electrolyte indicate that as few as 20 Pt ALD cycles on WC is needed to produce oxygen reduction reaction activity that is comparable to Pt bulk. Efforts to make Pt films that are even thinner and more monolayer-like are desired, and potential approaches are discussed.

Thin films of crystalline oxides integrated with silicon are of interest for novel devices that utilize the rich variety of functional properties of oxide materials. Growth of crystalline oxides on silicon requires careful control of a nanometer thin transition region to avoid deleterious side reactions such as oxidation of the substrate. Submonolayer surface reconstructions of alkaline earth metals such as Sr are key to controlling the interface for successful growth. Previously, this has only been accomplished using molecular beam epitaxy growth methods, but there is interest to create an alternative process based on atomic layer deposition. In this work we demonstrate the successful deposition of the critical (2x1) Sr/Si reconstruction using SrO ALD deposition combined with oxide desorption. The results show that ALD based crystalline oxide heteroepitaxy is promising.

Nanoelectrodes are of interest for a number of emerging nanoelectronics applications where it is desired to measure the electrical signatures of molecular scale devices. These new applications include molecular electronics and biochemical sensing, for example. A key challenge for nanoelectrode applications is the need to control structure and composition for devices where the active elements are on the order of 1 nm. Thus far, there are relatively few options for nanoelectrodes and existing methods do not allow control of nanoelectrode properties. In this paper we present an alternative method for nanoelectrode devices using Atomic Layer Deposition (ALD). ALD provides the subnanometer control required for molecular-scale devices and a means for scale-up. In addition, ALD provides a means to investigate the influence of atomic structure and chemical bonding on molecular scale measurements. Electrical data including tunneling spectroscopy are used to demonstrate the formation and properties of nanoscale devices with ALD.

Reaction pathways of the β-diketones acetylacetone and dipivaloylmethane on Si(100)-2 × 1 are analyzed using density functional theory calculations and compared with experimental data. Of the multiple pathways available to the molecules, hydroxyl dissociation via a 1,7 H-shift mechanism is determined to be the dominant adsorption pathway. Several other pathways including [2 + 4] addition, [2 + 2] CO intradimer addition, [2 + 2] CO intradimer addition with OH dissociation on an adjacent dimer, [2 + 2] CC intradimer addition, and “ene” addition are also found to be barrierless with respect to the entrance channel, and have small barriers relative to an adsorption precursor intermediate. Pathways involving 1,3 and 1,2 intramolecular H-shifts are found to be highly activated and are expected to be inaccessible at room temperature. Several product interconversions are considered as well. The results are compared with experiment and provide insight to the competitive adsorption pathways for multifunctional molecules on silicon.

Monolithic nanoscopic tunnel junctions fabricated by atomic layer deposition are used to investigate the reversible adsorption and detection of a vapor phase molecule by inelastic electron tunneling spectroscopy. Molecular adsorption of acetic acid at room temperature is enhanced by a direct current electric field between the electrodes to attract and trap the molecules. Step-like features in current versus time plots are observed and assigned to discrete adsorption events. Inelastic electron tunneling spectra recorded at cryogenic temperatures match the signatures of acetic acid vibrational modes and indicate that the molecules are generally physisorbed in the junction. Annealing the tunnel junctions above room temperature desorbs molecules from the junction, and the removal of molecular features is verified by the tunneling spectra. Molecules are readsorbed in the same tunnel junctions at room temperature, which demonstrates reversible adsorption.

The stability of the water-terminated Si(100)-2 × 1 surface in the 300−550 K temperature range is investigated with ultrahigh vacuum scanning tunneling microscopy experiments and density functional theory calculations. For temperatures below 450 K the surface is found to be stable from hydroxyl decomposition and surface oxidation. In the range of 450−550 K, new surface features associated with oxygen insertion into the silicon dimer bond are observed. It is found that the rate of hydroxyl decomposition and oxygen insertion does not follow simple first order kinetics with respect to the surface hydroxyl groups. Density functional theory calculations of oxygen insertion pathways point toward a catalytic effect of the dangling bonds and suggest that in the 450−550 K range the insertion events should predominantly occur next to unoccupied surface sites. A model is proposed where the dangling bonds diffuse along the dimer rows and promote hydroxyl decomposition. Kinetic Monte-Carlo simulations are used to compare the model with both experiments and density functional theory calculations, and an insertion activation barrier of 1.8 eV is found to give a good fit to the experimental data. On the basis of the findings, a strategy to increase hydroxyl group stability is demonstrated using water termination at cryogenic temperatures.

A one-cycle ALD growth reaction on the water terminated Si(100)-2x1 surface is shown to lead to successful nucleation, high metal oxide coverage, and an abrupt metal-oxide/silicon interface as confirmed by XPS, RHEED, and RBS measurements. Photoemission results confirm the coordination states of the hafnium and oxygen atoms. A Hf 4f core level shift is observed and assigned to the presence of the Si-O-Hf bonding environment with the more electronegative Si atom inducing the binding energy shift. This Hf 4f shift is smaller than that reported previously for silicates because of the difference of the semiconductor bonding environment. Experiments indicate that the hydroxyl sites bound to Si(100) are active for ligand exchange reactions. The abrupt interface could be useful for aggressive Effective Oxide Thickness (EOT) scaling.

The Agbada Formation in Robertkiri field is a 2.7-km (9000-ft)-thick succession of Miocene shallow-marine and nonmarine deposits formed as the continental margin of the Niger Delta structurally collapsed under accumulating sediments. A high-resolution sequence-stratigraphic framework for these strata was constructed by combining data from 20 well logs and a 1400-km² (550-mi²) seismic volume. Syndepositional structural collapse occurred along a succession of major, cuspate, offshore-dipping normal faults and associated antithetic faults and rollover anticlines within downdropped blocks. Six fourth-order sequences, each hundreds of meters thick, formed during episodic progradation and retrogradation of deltaic shorelines. Their development was complicated by the thickening of deposits across major growth faults and away from the crests of adjacent rollover anticlines. Successively younger sequences became thinner, more laterally uniform in thickness, and less structurally deformed and contain less growth strata above downdropped fault blocks. Erosion along successively younger sequence boundaries became shallower and broader as accommodation declined and more sediment was bypassed basinward. Areas of deepest sequence boundary incision and most rapid structural deformation shifted basinward over time with regional delta progradation. Stratigraphic patterns across successive downdropped fault blocks suggest that collapse of this continental margin occurred under prograding deltaic deposits on the shelf instead of within lowstand intraslope basins. Differences in the development of successive sequences reflect gradually slowing rates of structural collapse as underlying mobile shale is depleted, allowing deltaic deposition to shift farther basinward. [ABSTRACT FROM AUTHOR]

To assess the accuracy of Senior House Officers at interpreting plain X-rays following their triage by radiographers in an emergency department.

: Some geological events occur infrequently but still have a significant impact upon reservoir characteristics. By their very nature, however, it can be difficult to properly estimate the proportions of uncommon events because they may not appear during limited sampling. For example, even with 40 observations and an event proportion of 0.05, there is a 0.13 chance that no events will be observed. We provide some results and guidance concerning methods to estimate proportions when such events are not detected. Two cases are discussed, estimating proportions without errors in identification and estimating proportions when errors may arise. It is well-known that the distribution of possible proportions in the error-free case can be calculated using Bayesian analysis. If one assumes a standard uniform distribution as the prior for the proportion, Bayesian analysis gives a Beta distribution for the posterior. The situation becomes more complicated, however, when detection errors are included; the true proportion has a distribution consisting of several Beta distributions. The difference in results between the error-free and with-error situations can be considerable. For example, when 10 error-free observations are made and no uncommon events are detected, there is a 0.50 chance that the true proportion exceeds 0.06 and a 0.10 chance that it exceeds 0.19. Including the effects of erroneous identifications, however, increases the median proportion to 0.09 and the upper decile to 0.27. We also examine the case where there may be prior geological information, which can be incorporated by amending the prior distribution of the proportion. We find that the use of such a prior makes little difference unless there are very few observations or there are major differences between the anticipated and the observed proportions.

Background: Most neurosurgeons remove clinically symptomatic subdural haematomata, but the techniques they choose remain controversial. Method: The results from sixty-two patients diagnosed with chronic subdural haematoma were evaluated for technique, postoperative computerized tomography (CT) scan results, and complications. Results: Eleven patients had haematomata evacuated using twist drill plus drain, 37 patients had haematomata evacuated with burr hole only, and 14 patients were evacuated with bur r hole plus drain. Of the patients who underwent twist drill and closed system drainage (CSD), 43% had smaller lesions on CT follow up scans, as compared with 74% of those who underwent the burr hole only procedure, and 65% with burr holes with drains. C linical outcome results showed that 64% of twist drill and CSD patients deteriorated as compared with 16% of those with burr holes only and 7% with burr holes and CSDs. Sixty-four per cent of twist-drill patients required repeat evacuations as compared w ith 11% of those with burr holes only, and 7% with burr holes plus drains. Conclusion: The results at our institution indicate that burr-hole evacuation for chronic subdural haematoma is superior to twist-drill evacuation with respect to clinical outcome s and complications.

ObjectiveTo investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping.DesignObservational controlled interrupted time series study.SettingUK primary and secondary care.Participants515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping.InterventionFetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure.Main outcome measuresThe primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally.ResultsProphylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years.ConclusionsThis study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section.

Abstract: A comparison study of magnetic resonance imaging (MR), computed tomography (CT), and plain film evaluation of 113 consecutive spine trauma cases was conducted. The rate of true-positive findings (sensitivity) on MR was shown to be significantly higher than for CT or plain films in the evaluation of soft tissue or ligamentous injury (P<0.001). MR had a significantly lower rate of positive findings for fracture than CT (P<0.001) and was also shown to be significantly less sensitive for fracture than plain films (P<0.001). Spinal cord contusion, epidural hematoma, high-grade stenosis, and ligamentous or soft tissue injury were best evaluated with MR. MR, CT, and plain films are all important modalities for the evaluation of acute spine trauma. It is recommended that, after clinical examination, patients with spine trauma be evaluated first by plain film. If there is clinical or radiologic suspicion for acute spine injury, MR should be the next diagnostic procedure performed. If MR is positive for acute injury, CT may be indicated. CT best defines the extent of bony injury, and MR the extent of soft tissue injury, intrinsic spinal cord pathology, and extrinsic dural sac compression.

Ethanol reduced the in vitro fertilizing capacity of mouse spermatozoa in a dose-dependent manner, at concentrations commonly observed after ethanol ingestion by man and experimental animals (100–400 mg%). At these ethanol levels, sperm motility and the integrity and fertilizing capacity of the oocyte were not affected, nor was parthenogenic cleavage induced. Data indicated that ethanol prevents the capacitation of the spermatozoa. Its inhibitory effect could be reversed by incubation of the alcohol-treated spermatozoa in alcohol-free capacitation medium. At similar concentrations, t-butanol had no effect on fertilization, suggesting that inhibition by ethanol is mediated by a mechanism other than a “solvent” effect. Although the alcohol dehydrogenase inhibitor, pyrazole, prevented the inhibition of fertilization by ethanol, acetaldehyde (the product of ethanol oxidation) was without effect. These data indicate that the inhibition of capacitation by ethanol is mediated via its metabolism by spermatozoa but not by the immediate product of ethanol oxidation.

Focuses on the Aboriginal enlistment in the Armed Forces during World War II. Information on social and political deprivation suffered by Aborigines; Possible enlistment of Aboriginal boys from the age of 14; Mixed reactions to the Army's proposal from Euralian Society; Discussions on other issues.

A 74-year-old man with diffuse large B-cell lymphoma was admitted to our institution for chemotherapy treatment. He developed a neutropenic fever, and blood cultures were drawn. After 48 hours from the time of draw, 2 of 2 blood culture bottles flagged positive. Thin, septate hyphae were seen on Gram stain of both blood culture bottles. In 1 day, gray fluffy mold began growing on chocolate agar plates from both of the positive bottles. A tease prep revealed a Mucorales sporangiophore. The specimen was sent out for further identification, and sequencing identified the mold as Mucor velutinosus.