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The potential impact of new pneumococcal conjugate vaccines (PCVs) is assessed by using immune responses to predict their effectiveness against invasive pneumococcal disease (IPD). This analysis predicted the serotype-specific effectiveness against IPD of a new 15-valent PCV (V114) for the serotypes shared with a 13-valent PCV (PCV13), in a US pediatric population given a 3 + 1 dosing regimen. Beginning with the known serotype-specific antibody concentrations after vaccination with placebo, 7-valent PCV (PCV7) and PCV13, reverse cumulative distribution curves were used, along with published serotype-specific vaccine effectiveness of PCV7 and PCV13, to derive a protective antibody concentration (Cp) for each PCV13 serotype in V114. Serotype-specific effectiveness was predicted using the Cp estimates and the respective serotype-specific antibody concentrations of placebo and V114 recipients in recent pediatric clinical trials. Predicted serotype-specific V114 effectiveness values ranged from 86% to 99% for PCV7 serotypes and from 59% to 97% for (non-PCV7) PCV13 serotypes. V114 serotype-specific effectiveness against IPD in a US pediatric population was predicted to be largely comparable to that of PCV7 and PCV13 for shared serotypes, with models suggesting likelihood of high overall benefit gained from increased serotype 3 effectiveness, and additional protection against serotypes 22 F and 33 F.

All data used for quantitative analysis in review, with links to references and additional details

One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an “effect marker.” An effect marker could be a target engagement, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher-than-optimal dosing can increase toxicity in later trials (and in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose. Clin Cancer Res; 22(6); 1318–24. ©2015 AACR.

Pharmacometric models can enhance clinical decision making, with covariates exposing potential contributions to variability of subpopulation characteristics, for example, demographics or disease status. Intuitive visualization of models with multiple covariates is needed because sparsity of data in visualizations trellised by covariate values can raise concerns about the credibility of the underlying model. V2ACHER, introduced here, is a stepwise transformation of data that can be applied to a variety of static (non‐ordinary‐differential‐equation‐based) pharmacometric analyses. This work uses four examples of increasing complexity to show how the transformation elucidates the relationship between observations and model results and how it can also be used in visual predictive checks to confirm the quality of a model. V2ACHER facilitates consistent, intuitive, single‐plot visualization of a multicovariate model with a complex data set, thereby enabling easier model communication for modelers and for cross‐functional development teams and facilitating confident use in support of decisions.

Use of magnetic resonance (MR) imaging in the emergency department continues to increase. Although computed tomography is the first-line imaging modality for most head and neck emergencies, MR is superior in some situations and imparts no ionizing radiation. This article provides a symptom-based approach to nontraumatic head and neck pathologic conditions most relevant to emergency head and neck MR imaging, emphasizing relevant anatomy, "do not miss" findings affecting clinical management, and features that may aid differentiation from potential mimics. Essential MR sequences and strategies for obtaining high-quality images when faced with patient motion and other technical challenges are also discussed.

Many studies have explored the possibility of using cranial ultrasound for discerning intracranial pathologies like tumors, hemorrhagic stroke, or subdural hemorrhage in clinical scenarios where computer tomography may not be accessible or feasible. The visualization of intracranial anatomy on B-mode ultrasound is challenging due to the presence of the skull that limits insonation to a few segments on the temporal bone that are thin enough to allow transcranial transmission of sound. Several artifacts are produced by hyperechoic signals inherent in brain and skull anatomy when images are created using temporal windows.While the literature has investigated the accuracy of diagnosis of intracranial pathology with ultrasound, we lack a reference source for images acquired on cranial topography on B-mode ultrasound to illustrate the appearance of normal and abnormal structures of the brain and skull. Two investigators underwent hands-on training in Cranial point-of-care ultrasound (c-POCUS) and acquired multiple images from each patient to obtain the most in-depth images of brain to investigate all visible anatomical structures and pathology within 24 hours of any CT/MRI imaging done.Most reproducible structures visible on c-POCUS included bony parts and parenchymal structures. Transcranial and abdominal presets were equivalent in elucidating anatomical structures. Brain pathology like parenchymal hemorrhage, cerebral edema, and hydrocephalus were also visualized.We present an illustrated anatomical atlas of cranial ultrasound B-mode images acquired in various pathologies in a critical care environment and compare our findings with published literature by performing a scoping review of literature on the subject.

OBJECTIVE. We hypothesized that intravitreal silicone oil would show attenuation similar to that of fat on dual-energy CT 190-keV virtual monoenergetic images (VMIs) with high frequency and that th...

Silicone oil is used as an intravitreal injection to treat retinal detachment. This material can spread into the subarachnoid space, where it may be mistaken for acute hemorrhage on single-energy computed tomography. This report describes the appearance of intravitreal silicone oil on dual-energy computed tomography, emphasizing unique virtual monoenergetic imaging characteristics that allow for confident differentiation of silicone oil from hemorrhage as well as from other potential single-energy mimics, such as calcium and iodine.

BACKGROUND AND PURPOSE: In parathyroid CT, a noncontrast phase aids discrimination of parathyroid lesions (not iodine-containing) from thyroid tissue (iodine-containing). When thyroid iodine is pathologically diminished, this differentiation is difficult with standard CT. Because the attenuation of an element is maximal near its K-edge (iodine = 33.2 keV), we hypothesized that dual-energy CT 40-keV virtual monoenergetic images will accentuate thyroid iodine relative to standard images, improving the differentiation of thyroid from parathyroid lesions. Our purpose was to test this hypothesis through quantitative assessment of Hounsfield unit attenuation and contrast-to-noise on dual-energy CT standard (70-keV) and 40-keV noncontrast images. MATERIALS AND METHODS: For this retrospective study including 20 dual-energy parathyroid CTs, we used an ROI-based analysis to assess the attenuation of thyroid tissue, parathyroid lesions, and sternocleidomastoid muscle as well as corresponding contrast-to-noise on standard and 40- keV noncontrast images. Wilcoxon signed rank tests were performed to compare differences between 70 and 40 keV. RESULTS: Absolute and percentage increases in attenuation at 40 keV were significantly greater for thyroid gland than for parathyroid lesions and sternocleidomastoid muscle (P

Network inference is a valuable approach for gaining mechanistic insight from high-dimensional biological data. Existing methods for network inference focus on ranking all possible relations (edges) among all measured quantities such as genes, proteins, metabolites (features) observed, which yields a dense network that is challenging to interpret. Identifying a sparse, interpretable network using these methods thus requires an error-prone thresholding step which compromises their performance. In this article we propose a new method, DEKER-NET, that addresses this limitation by directly identifying a sparse, interpretable network without thresholding, improving real-world performance. DEKER-NET uses a novel machine learning method for feature selection in an iterative framework for network inference. DEKER-NET is extremely flexible, handling linear and nonlinear relations while making no assumptions about the underlying distribution of data, and is suitable for categorical or continuous variables. We test our method on the Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge data, demonstrating that it can directly identify sparse, interpretable networks without thresholding while maintaining performance comparable to the hypothetical best-case thresholded network of other methods.

BACKGROUND AND PURPOSE: Transient loss of consciousness is commonly evaluated in the emergency department. Although typically caused by epileptic seizure, syncope, or psychogenic nonepileptic seizure, the underlying etiology is frequently misdiagnosed. Lateral tongue bites are reportedly a specific clinical finding of seizure. We have observed tongue signal abnormality suggesting bite injury on brain MR imaging after seizures. We hypothesized an association between tongue signal abnormality and seizure diagnosis among patients in the emergency department imaged for transient loss of consciousness. Our purposes were to determine the prevalence of tongue signal abnormality among this population and the predictive performance for seizure diagnosis. MATERIALS AND METHODS: For this retrospective study including 82 brain MR imaging examinations, 2 readers independently assessed tongue signal abnormality on T2-weighted and T2-weighted FLAIR images. Discrepancies were resolved by consensus, and interrater reliability (Cohen κ) was calculated. The final diagnosis was recorded. Proportions were compared using the Fisher exact test. RESULTS: Tongue signal abnormality was present on 19/82 (23%) MR imaging examinations. Interrater reliability was “substantial” (κ = 0.77). Seizure was diagnosed among 18/19 (95%) patients with tongue signal abnormality and 29/63 (46%) patients without it (P

Background Several COVID-19 vaccines have been authorized, and the need for rapid, further modification is anticipated. This work uses a Model-Based Meta-Analysis (MBMA) to relate, across species, immunogenicity to peak viral load (VL) after challenge and to clinical efficacy. Together with non-clinical and/or early clinical immunogenicity data (ECID), this enables prediction of a candidate vaccine’s clinical efficacy. The goal of this work was to enable the accelerated development of vaccine candidates by supporting Go/No-Go and study design decisions, and the resulting MBMA can be instrumental in decisions not to progress candidates to late stage development. Methods A literature review with pre-specified inclusion/exclusion criteria enabled creation of a database including nonclinical serum neutralizing titers (SN), peak VL after challenge with SARS-CoV-2 (VL), along with data from several clinical vaccine candidates. Rhesus Macaque (RM) and golden hamster (GH) were selected (due to availability and consistency of data) for MBMA modeling. For both RM and GH, peak post-challenge VL in lung and nasal tissues were used as surrogates for clinical disease and were related to pre-challenge SN via the MBMA. The VL predictions from the RM MBMA were scaled to incidence rates in humans, with a scaling factor between RM and human SN estimated using early Phase 3 efficacy data. This enabled clinical efficacy predictions based on ECID. To qualify the model’s predictive power, efficacies of COVID-19 vaccine candidates were compared to those predicted from the MBMA and their respective Ph1/2 SN data. More recently available clinical data enable building a clinical MBMA; comparing this to the RM MBMA further supports SN as predictive. Results The MBMA analyses identified a sigmoidal decrease in VL (increasing protection) with increase in SN in all three species, with more SN needed (in both RM and GH) for protection in nasal swabs than in BAL (see figure). The comparison between predicted and reported clinical efficacies demonstrated the model’s predictive power across vaccine platforms. RM and GH MBMA Protection Models and Translational Prediction with Observed Efficacies Sizes of circles indicate relative weight of the data in the respective quantitative model. Model and data visualizations have been harmonized (across tissue-types) separately for each of RM and GH using VACHER (Lommerse, et al., CPT:PSP, in press). Conclusion By quantifying adjustments needed between species and assays, translational MBMA can inform development decisions by using nonclinical SN and VL, and ECID to predict protection from COVID-19. Disclosures Anna Largajolli, PhD, Certara (Employee) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Bhargava Kandala, PhD, Merck & Co., Inc. (Employee, Shareholder) Akshita Chawla, PhD, Merck & Co., Inc. (Employee, Shareholder) Seth H. Robey, PhD, Merck & Co., Inc. (Employee, Shareholder) Kenny Watson, PhD, Certara (Employee, Shareholder) Raj Thatavarti, MS, Certara (Employee, Shareholder) Sheri Dubey, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Rik de Greef, MSc, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Pharmacometric models can enhance clinical decision making, with covariates exposing potential contributions to variability of subpopulation characteristics, for example, demographics or disease status. Intuitive visualization of models with multiple covariates is needed because sparsity of data in visualizations trellised by covariate values can raise concerns about the credibility of the underlying model. V2ACHER, introduced here, is a stepwise transformation of data that can be applied to a variety of static (non‐ordinary‐differential‐equation‐based) pharmacometric analyses. This work uses four examples of increasing complexity to show how the transformation elucidates the relationship between observations and model results and how it can also be used in visual predictive checks to confirm the quality of a model. V2ACHER facilitates consistent, intuitive, single‐plot visualization of a multicovariate model with a complex data set, thereby enabling easier model communication for modelers and for cross‐functional development teams and facilitating confident use in support of decisions.

BACKGROUND AND PURPOSE: Among patients undergoing serial neck CTs, we have observed variability in the appearance of the pharyngolaryngeal venous plexus, which comprises the postcricoid and posterior pharyngeal venous plexuses. We hypothesize changes in plexus appearance from therapeutic neck irradiation. The purposes of this study are to describe the CT appearance of the pharyngolaryngeal venous plexus among 2 groups undergoing serial neck CTs—patients with radiation therapy–treated laryngeal cancer and patients with medically treated lymphoma—and to assess for changes in plexus appearance attributable to radiation therapy. MATERIALS AND METHODS: For this retrospective study of 98 patients (49 in each group), 448 contrast-enhanced neck CTs (222 laryngeal cancer; 226 lymphoma) were assessed. When visible, the plexus anteroposterior diameter was measured, and morphology was categorized. RESULTS: At least 1 plexus component was identified in 36/49 patients with laryngeal cancer and 37/49 patients with lymphoma. There were no statistically significant differences in plexus visibility between the 2 groups. Median anteroposterior diameter was 2.1 mm for the postcricoid venous plexus and 1.6 mm for the posterior pharyngeal venous plexus. The most common morphology was “bilobed” for the postcricoid venous plexus and “linear” for the posterior pharyngeal venous plexus. The pharyngolaryngeal venous plexus and its components were commonly identifiable only on follow-up imaging. CONCLUSIONS: Head and neck radiologists should be familiar with the typical location and variable appearance of the pharyngolaryngeal plexus components so as not to mistake them for neoplasm. Observed variability in plexus appearance is not attributable to radiation therapy.

Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody under development to prevent RSV infection in infants. A model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinically relevant endpoints (e.g. incidence rates) in humans, including lower respiratory tract infection (LRI) in infants, was presented previously. This model accounted for variable exposure to RSV over the course of the season through a force-of-infection (FOI) function modulating the overall risk of RSV infection over time. The objective of the current work was to determine whether variations in regional seasonality would impact the efficacy of a clinical trial evaluating MK-1654. Methods A FOI function to describe the degree of RSV exposure as a function of time was created by fitting epidemiological data to a Gaussian function added to a constant baseline value. Clinical trial simulations were conducted using the MBMA to predict seasonal incidence rates (IR) of RSV medically attended lower-respiratory tract infection (MALRI) and efficacies for a range of MK-1654 doses in both temperate and tropical regions. Results Epidemiological data was well captured by the FOI function. Clinical trial simulations indicated that seasonal IRs of RSV were sensitive to differences in the FOI represented by temperate and tropical regions; however, there was no substantial impact on efficacies across MK-1654 dose levels. Consistent with predictions for a temperate climate, MK-1654, when administered at the start of the RSV season in a region with a tropical climate, was also predicted to maintain high efficacy ( > 75%) for the prevention of RSV MALRI for 150 days. Conclusion Simulations indicated that while FOI is a substantial driver of overall RSV incidence rates, MK-1654 efficacy in a late-stage clinical trial is likely to be high, regardless of regional variations in RSV. Disclosures Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Philippe Pierrillas, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Respiratory syncytial virus (RSV) infection is a major cause of severe respiratory illness in both young infants and the elderly. While antibodies represent key correlates of protection, the antibody mechanisms remain poorly understood. Emerging data point to additional humoral Fc-mediated mechanisms of action beyond neutralization. Therefore, to map the humoral correlates of immunity against RSV, antibody responses were profiled in a highly controlled non-human primate challenge model. Six different vaccine platforms were tested in African Green Monkeys, which post-challenge, yielded distinct antibody profiles and viral loads in both upper and lower respiratory tracts. Machine learning was then used to determine antibody features associated with protection. Upper respiratory control involved virus specific IgA levels, neutralization, and complement whereas lower respiratory control involved Fc-mediated mechanisms. These data highlight a collaborative Fab and Fc protective signature, induced selectively by distinct vaccine platforms, and provides mechanistic insights for the rational development of vaccines.

Genetic discoveries have transformed our understanding of many neurologic diseases. Identification of specific causal pathogenic variants has improved understanding of pathophysiology and enabled replacement of many confusing eponyms and acronyms with more meaningful and clinically relevant genetics-based terminology. In this era of rapid scientific advancement, multidisciplinary collaboration among pediatricians, neurologists, geneticists, radiologists, and other members of the health care team is increasingly important in the care of patients with genetic neurologic diseases. Radiologists familiar with neurogenetic disease add value by (1) recognizing constellations of characteristic imaging findings that are associated with a genetic disease before one is clinically suspected; (2) predicting the most likely genotypes for a given imaging phenotype in clinically suspected genetic disease; and (3) providing detailed and accurate descriptions of the imaging phenotype in challenging cases with unknown or uncertain genotypes. This review aims to increase awareness and understanding of pathogenic variants relating to neurologic disease by (1) briefly reviewing foundational knowledge of chromosomes, inheritance patterns, and mutagenesis; (2) providing concrete examples of and detailed information about specific neurologic diseases resulting from pathogenic variants; and (3) highlighting clinical and imaging features that are of greatest relevance for the radiologist.

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

BACKGROUND AND PURPOSE: Internal auditory canal diverticula are focal lucencies along the anterior-inferior aspect of the internal auditory canal fundus. Studies in adults report conflicting data on the etiology and clinical relevance of this finding. We would expect a pediatric study to help elucidate the significance of internal auditory canal diverticula. The primary goals of this study were to determine the temporal bone CT prevalence of diverticula among pediatric patients and to assess possible hearing loss and anatomic associations. MATERIALS AND METHODS: For this retrospective study including 283 pediatric temporal bone CTs, 4 neuroradiologists independently assessed for diverticula. Discrepancies were resolved by consensus. One neuroradiologist assessed for an enlarged vestibular aqueduct, labyrinthine dysplasia, cochlear cleft, and otospongiosis. Patient demographics, audiologic data, and pertinent clinical history were recorded. One-way analysis of variance and the Fisher exact test were used to assess possible associations between diverticula and specific patient characteristics. RESULTS: Diverticula were observed in 42/283 patients (14.8%) and were more commonly bilateral. There was no significant association with age, sex, hearing loss, enlarged vestibular aqueduct, labyrinthine dysplasia, or cochlear cleft. A statistically significant association was observed with otospongiosis (P = .013), though only 1 study patient had this disease. CONCLUSIONS: Internal auditory canal diverticula are a common finding on pediatric temporal bone CT. In the absence of clinical or imaging evidence for otospongiosis, diverticula likely fall within the range of a normal anatomic variation. Familiarity with these findings may prevent neuroradiologists from recommending unnecessary additional testing in pediatric patients with isolated internal auditory canal diverticula.

Respiratory syncytial virus (RSV) infection is a major cause of respiratory illness in infants and the elderly. Although several vaccines have been developed, none have succeeded in part due to our incomplete understanding of the correlates of immune protection. While both T cells and antibodies play a role, emerging data suggest that antibody-mediated mechanisms alone may be sufficient to provide protection. Therefore, to map the humoral correlates of immunity against RSV, antibody responses across six different vaccines were profiled in a highly controlled nonhuman primate-challenge model. Viral loads were monitored in both the upper and lower respiratory tracts, and machine learning was used to determine the vaccine platform-agnostic antibody features associated with protection. Upper respiratory control was associated with virus-specific IgA levels, neutralization, and complement activity, whereas lower respiratory control was associated with Fc-mediated effector mechanisms. These findings provide critical compartment-specific insights toward the rational development of future vaccines.

Merck & Co, Inc (Kenilworth, NJ) is investing in approaches to enrich clinical trial data and augment decision making through use of digital health technologies, outpatient sampling, and real‐time data access. As part of this strategy, a phase I study was conducted to explore a few technologies of interest. In this fixed‐sequence two‐period trial, 16 healthy subjects were administered 50‐mg once‐daily sitagliptin packaged in a bottle that electronically captured the date and time study medication was dispensed (period 1) and in a traditional pharmacy bottle (period 2). Dried blood spot samples were collected for sitagliptin concentration analysis on select study days, both in clinic and at home, with collection time recorded using an electronic diary in period 1 and by clinic staff in period 2. Study results demonstrated the feasibility and subject acceptance of collecting digital adherence data and outpatient dried blood spot samples in clinical trials and highlighted areas for future improvements.

Excitement around and investment in oncology drug development are at unprecedented levels. To maximize the health impact and productivity of this research and development investment, quantitative modeling should impact key decisions in early clinical oncology including Go/No-Go decisions based on early clinical data, and dose selection for late stage studies. See related article by Bottino et al., p. 6633

Anti-N-methyl-d-aspartate receptor encephalitis is an increasingly recognized autoimmune disorder that results in substantial morbidity, prolonged hospital stays, and even death. The diagnosis is often delayed or unrecognized entirely as a result of absent or only subtle initial magnetic resonance imaging findings and a nonspecific clinical syndrome. The discovery of early imaging findings in this disease may help clinicians to more aggressively treat this autoimmune encephalitis and to potentially lessen morbidity and mortality. We report a novel case of anti-N-methyl-d-aspartate receptor encephalitis characterized by early evidence of increased cerebral perfusion on arterial spin labeling perfusion imaging, a finding that preceded laboratory diagnosis and conventional magnetic resonance imaging abnormalities. Further investigation is needed to firmly establish the pathologic basis of this finding.

Background Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. Methods Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. Findings The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. Interpretation An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at

Dual-energy computed tomography (DECT) has many current and evolving applications in neuroradiology including material decomposition, improving conspicuity of iodinated contrast enhancement, and artifact reduction. However, there are multiple challenges in incorporating DECT into practice including hardware selection, postprocessing software requirements, technologist and physician training, and numerous workflow issues. This article reviews in a question-and-answer format common issues that arise when incorporating DECT into a busy neuroradiology practice.

BACKGROUND AND PURPOSE The aim of the study was to describe the prevalence and characteristics of orbital interstitial fluid seen on magnetic resonance (MR) images of infants and young children. MATERIALS AND METHODS Fat-suppressed axial T2-weighted MR images of 100 consecutive infants and young children (

To estimate in-hospital, 1-yr, and long-term mortality and to assess time trends in incidence and outcomes of sepsis admissions in the intensive care unit.A population-based, multicenter, retrospective cohort study.Patients hospitalized with sepsis in the intensive care unit in seven general hospitals in Israel during 2002-2008.None.Survival data were collected and analyzed according to demographic and background clinical characteristics, as well as features of the sepsis episode, using Kaplan-Meier approach for long-term survival.A total of 5,155 patients were included in the cohort (median age: 70, 56.3% males; median Charlson comorbidity index: 4). The mean number of intensive care unit admissions per month increased over time, while no change in in-hospital mortality was observed. The proportion of patients surviving to hospital discharge was 43.9%. The 1-, 2-, 5-, and 8-yr survival rates were 33.0%, 29.8%, 23.3%, and 19.8%, respectively. Mortality was higher in older patients, patients with a higher Charlson comorbidity index, and those with multiorgan failure, and similar in males and females. One-year age-standardized mortality ratio was 21-fold higher than expected, based on the general population rates.Mortality following intensive care unit sepsis admission remains high and is correlated with underlying patients' characteristics, including age, comorbidities, and the number of failing organ systems.

The rapid identification of protein biomarkers in biofluids is important to drug discovery and development. Here, we describe a general proteomic approach for the discovery and identification of proteins that exhibit a statistically significant difference in abundance in cerebrospinal fluid (CSF) before and after pharmacological intervention. This approach, differential mass spectrometry (dMS), is based on the analysis of full scan mass spectrometry data. The dMS workflow does not require complex mixing and pooling strategies, or isotope labeling techniques. Accordingly, clinical samples can be analyzed individually, allowing the use of longitudinal designs and within-subject data analysis in which each subject acts as its own control. As a proof of concept, we performed multifactorial dMS analyses on CSF samples drawn at 6 time points from n = 6 cisterna magna ported (CMP) rhesus monkeys treated with 2 potent gamma secretase inhibitors (GSI) or comparable vehicle in a 3-way crossover study that included a total of 108 individual CSF samples. Using analysis of variance and statistical filtering on the aligned and normalized LC-MS data sets, we detected 26 features that were significantly altered in CSF by drug treatment. Of those 26 features, which belong to 10 distinct isotopic distributions, 20 were identified by MS/MS as 7 peptides from CD99, a cell surface protein. Six features from the remaining 3 isotopic distributions were not identified. A subsequent analysis showed that the relative abundance of these 26 features showed the same temporal profile as the ELISA measured levels of CSF A beta 42 peptide, a known pharmacodynamic marker for gamma-secretase inhibition. These data demonstrate that dMS is a promising approach for the discovery, quantification, and identification of candidate target engagement biomarkers in CSF.

Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP; 0.04, 0.4, and 4 nM), a selective TRPV1 agonist, administered into the renal pelvis dose-dependently increased ARNA. CAP (4 nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, or 2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (3 aR ,7 aR ) (RP67580) or cis -2-(diphenylmethyl)- N -[(2-iodophenyl)-methyl]-1 azabicyclo[2.2.2]octan-3-amine (L703,606), selective NK1 antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4 nM) and CGRP (0.13 μM) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4 nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and that a TRPV1-dependent mechanism is operant in CGRP action.

Label-free LC-MS profiling is a powerful quantitative proteomic method to study relative peptide abundances between two or more biological samples. Here we demonstrate the use of a previously described comparative LC-MS method, differential mass spectrometry (dMS), to analyze high-resolution Fourier transform mass spectrometry (FTMS) data for detection and quantification of known peptide differences between two sets of complex mixtures. Six standard peptides were spiked into a processed plasma background at fixed ratios from 1.25:1 to 4:1 to make two sets of samples. The resulting mixtures were analyzed by microcapillary LC-FTMS and dMS. dMS successfully identified five out of the six peptides as statistically significant differences (por= 0.005). In this experiment, the smallest fold change reliably detected by our method was 1.5:1, and the errors of estimated ratios of concentrations were less than 20% for peptides spiked at 1.5:1 to 4:1. We conclude that LC-FTMS coupled with dMS is a useful label-free quantitative MS method that can be used to detect subtle yet statistically significant peptide differences in complex protein mixtures, including plasma samples.