Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative.

Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non-investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials. Using a 4-point Likert scale, providers described their perception of potential barriers to their practice serving as a site for pediatric clinical trials. Of the 136 providers surveyed, 52/136 (38%) had previously referred a pediatric patient to a trial, and only 17/136 (12%) had ever been an investigator for a pediatric trial. Lack of awareness of existing pediatric trials was a major barrier to patient referral by providers, in addition to consideration of trial risks, distance to the site, and time needed to discuss trial participation with parents. Overall, providers perceived greater challenges related to parental concerns and parent or child logistical barriers than study implementation and ethics or regulatory barriers as barriers to their practice serving as a trial site. Providers who had previously been an investigator for a pediatric trial were less likely to be concerned with potential barriers than non-investigators. Understanding the barriers that limit pediatric providers from collaboration or inhibit their participation is key to designing effective interventions to optimize pediatric trial participation

Interpreting the Global Enteric Multicenter Study (GEMS) Findings on Sanitation, Hygiene, and Diarrhea

Sanitation and hygiene are global concerns, as reflected in international development and human rights policy . The Sustainable Development Goals (SDGs) include target 6.2: to “achieve access to adequate and equitable sanitation and hygiene for all and end open defecation”. Globally, about 2.5 billion people do not use improved sanitation, of whom 1 billion defecate in the open. Fecal contamination of the environment and poor handwashing are responsible for an estimated 577,000 deaths annually. This is likely an underestimation: there is emerging evidence that poor sanitation and hygiene contribute to undernutrition and could be responsible for approximately half of all child stunting. Much of the health impact of inadequate sanitation and hygiene is attributed to diarrheal disease and its secondary effects. However, diarrhea is difficult to measure, and sanitation and hygiene are difficult to link to health outcomes

CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A–HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a “lock and key” interaction is typical of innate receptor–ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

BackgroundDiagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.Case presentationA 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.ConclusionThis report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment

An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force

Abstract Background Guideline developers and other users of systematic reviews need information about whether a medical or preventive intervention is likely to benefit or harm some patients more (or less) than the average in order to make clinical practice recommendations tailored to these populations. However, guidance is lacking on how to include patient subpopulation considerations into the systematic reviews upon which guidelines are often based. In this article, we describe methods developed to consistently consider the evidence for relevant subpopulations in systematic reviews conducted to support primary care clinical preventive service recommendations made by the U.S. Preventive Services Task Force (USPSTF). Proposed approach Our approach is grounded in our experience conducting systematic reviews for the USPSTF and informed by a review of existing guidance on subgroup analysis and subpopulation issues. We developed and refined our approach based on feedback from the Subpopulation Workgroup of the USPSTF and pilot testing on reviews being conducted for the USPSTF. This paper provides processes and tools for incorporating evidence-based identification of important sources of potential heterogeneity of intervention effects into all phases of systematic reviews. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. Conclusions Further testing and evaluation are necessary to refine this proposed approach and demonstrate its utility to the producers and users of systematic reviews beyond the context of the USPSTF. Gaps in the evidence on important subpopulations identified by routinely applying this process in systematic reviews will also inform future research needs

Enhancing Optical Up-Conversion Through Electrodynamic Coupling with Ancillary Chromophores

In lanthanide-based optical materials, control over the relevant operating characteristics–for example transmission wavelength, phase and quantum efficiency–is generally achieved through the modification of parameters such as dopant/host combination, chromophore concentration and lattice structure. An alternative avenue for the control of optical response is through the introduction of secondary, codoped chromophores. Here, such secondary centers act as mediators, commonly bridging the transfer of energy between primary absorbers of externally sourced optical input and other sites of frequency-converted emission. Utilizing theoretical models based on experimentally feasible, three-dimensional crystal lattice structures; a fully quantized theoretical framework provides insights into the locally modified mechanisms that can be implemented within such systems. This leads to a discussion of how such effects might be deployed to either enhance, or potentially diminish, the efficiency of frequency up-conversion

The Heavy Metal Survey: Star Formation Constraints and Dynamical Masses of 21 Massive Quiescent Galaxies at z~1.4-2.2

In this paper, we present the Heavy Metal Survey, which obtained ultra-deep medium-resolution spectra of 21 massive quiescent galaxies at $1.4\lesssim z\lesssim 2.2$ with Keck/LRIS and MOSFIRE. With integration times of up to 16 hrs per band per galaxy, we observe numerous Balmer and metal absorption lines in atmospheric windows. We successfully derive spectroscopic redshifts for all 21 galaxies and for 19 we also measure stellar velocity dispersions ($\sigma_v$), ages, and elemental abundances, as detailed in an accompanying paper. Except for one emission-line AGN, all galaxies are confirmed as quiescent through their faint or absent H$\alpha$ emission and evolved stellar spectra. For most galaxies exhibiting faint H$\alpha$, elevated [NII]/H$\alpha$ suggests a non-star-forming origin. We calculate dynamical masses ($M_{\rm dyn}$) by combining $\sigma_v$ with structural parameters obtained from HST/COSMOS(-DASH), and compare them with stellar masses ($M_*$) derived using spectrophotometric modeling, considering various assumptions. For a fixed initial mass function (IMF), we observe a strong correlation between $M_{\rm dyn}/M_*$ and $\sigma_v$. This correlation may suggest that a varying IMF, with high-$\sigma_v$ galaxies being more bottom-heavy, was already in place at $z\sim2$. When implementing the $\sigma_v$-dependent IMF found in the cores of nearby early-type galaxies and correcting for biases in our stellar mass and size measurements, we find a low scatter in $M_{\rm dyn}/M_*$ of 0.14 dex. However, these assumptions result in unphysical stellar masses, which exceed the dynamical masses by 34%. This tension suggests that distant quiescent galaxies do not simply grow inside-out into today's massive early-type galaxies and the evolution is more complicated.Comment: Submitted to ApJ (25 pages, 11 figures

Sustaining effective COVID-19 control in Malaysia through large-scale vaccination

Introduction: As of 3rd June 2021, Malaysia is experiencing a resurgence of COVID-19 cases. In response, the federal government has implemented various non-pharmaceutical interventions (NPIs) under a series of Movement Control Orders and, more recently, a vaccination campaign to regain epidemic control. In this study, we assessed the potential for the vaccination campaign to control the epidemic in Malaysia and four high-burden regions of interest, under various public health response scenarios. Methods: A modified susceptible-exposed-infectious-recovered compartmental model was developed that included two sequential incubation and infectious periods, with stratification by clinical state. The model was further stratified by age and incorporated population mobility to capture NPIs and micro-distancing (behaviour changes not captured through population mobility). Emerging variants of concern (VoC) were included as an additional strain competing with the existing wild-type strain. Several scenarios that included different vaccination strategies (i.e. vaccines that reduce disease severity and/or prevent infection, vaccination coverage) and mobility restrictions were implemented. Results: The national model and the regional models all fit well to notification data but underestimated ICU occupancy and deaths in recent weeks, which may be attributable to increased severity of VoC or saturation of case detection. However, the true case detection proportion showed wide credible intervals, highlighting incomplete understanding of the true epidemic size. The scenario projections suggested that under current vaccination rates complete relaxation of all NPIs would trigger a major epidemic. The results emphasise the importance of micro-distancing, maintaining mobility restrictions during vaccination roll-out and accelerating the pace of vaccination for future control. Malaysia is particularly susceptible to a major COVID-19 resurgence resulting from its limited population immunity due to the country's historical success in maintaining control throughout much of 2020

Pointing control for the SPIDER balloon-borne telescope

We present the technology and control methods developed for the pointing system of the SPIDER experiment. SPIDER is a balloon-borne polarimeter designed to detect the imprint of primordial gravitational waves in the polarization of the Cosmic Microwave Background radiation. We describe the two main components of the telescope's azimuth drive: the reaction wheel and the motorized pivot. A 13 kHz PI control loop runs on a digital signal processor, with feedback from fibre optic rate gyroscopes. This system can control azimuthal speed with < 0.02 deg/s RMS error. To control elevation, SPIDER uses stepper-motor-driven linear actuators to rotate the cryostat, which houses the optical instruments, relative to the outer frame. With the velocity in each axis controlled in this way, higher-level control loops on the onboard flight computers can implement the pointing and scanning observation modes required for the experiment. We have accomplished the non-trivial task of scanning a 5000 lb payload sinusoidally in azimuth at a peak acceleration of 0.8 deg/s$^2$, and a peak speed of 6 deg/s. We can do so while reliably achieving sub-arcminute pointing control accuracy.Comment: 20 pages, 12 figures, Presented at SPIE Ground-based and Airborne Telescopes V, June 23, 2014. To be published in Proceedings of SPIE Volume 914

Item-specific overlap between hallucinatory experiences and cognition in the general population: A three-step multivariate analysis of international multi-site data

Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively