Objective To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. Study design ...Six subjects with Pompe disease (including 4 cross-reacting immunologic material–negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. Results Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. Conclusion B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.
Future X-ray astrophysics experiments require multiplexed readout of high fill-factor, kilo-pixel arrays of transition-edge sensors (TESs), with very high spectral resolution over a broad range of ...energies. In this paper we report on a prototype kilo-pixel array of Mo/Au TESs readout with 8-column by 32-row time-division multiplexing (TDM). This system is being used to demonstrate the critical detector and readout technology for ESA's Athena X-IFU, and when complete will be used in laboratory astrophysics experiments. Our array and TDM readout have demonstrated a combined full-width-at-half-maximum energy resolution, including > 200 pixels, of: 1.95 eV for Ti-Kα (4.5 keV), 1.97 eV for Mn-Kα (5.9 keV), 2.16 eV for Co-Kα (6.9 keV), 2.33 eV for Cu-Kα (8 keV), 3.26 eV for Br-Kα (11.9 keV). The 1 sigma statistical errors are ≤0.01 eV for all spectra. These results meet the broad-band resolution requirements for X-IFU with margin.
A high-energy neutrino event detected by IceCube on 22 September 2017 was coincident in direction and time with a gamma-ray flare from the blazar TXS 0506+056. Prompted by this association, we ...investigated 9.5 years of IceCube neutrino observations to search for excess emission at the position of the blazar. We found an excess of high-energy neutrino events, with respect to atmospheric backgrounds, at that position between September 2014 and March 2015. Allowing for time-variable flux, this constitutes 3.5σ evidence for neutrino emission from the direction of TXS 0506+056, independent of and prior to the 2017 flaring episode. This suggests that blazars are identifiable sources of the high-energy astrophysical neutrino flux.
Most medical faculty receive little or no training about how to be effective teachers, even when they assume major educational leadership roles. To identify the competencies required of an effective ...teacher in medical education, the authors developed a comprehensive conceptual model. After conducting a literature search, the authors met at a two-day conference (2006) with 16 medical and nonmedical educators from 10 different U.S. and Canadian organizations and developed an initial draft of the "Teaching as a Competency" conceptual model. Conference participants used the physician competencies (from the Accreditation Council for Graduate Medical Education ACGME) and the roles (from the Royal College's Canadian Medical Education Directives for Specialists CanMEDS) to define critical skills for medical educators. The authors then refined this initial framework through national/regional conference presentations (2007, 2008), an additional literature review, and expert input. Four core values grounded this framework: learner engagement, learner-centeredness, adaptability, and self-reflection. The authors identified six core competencies, based on the ACGME competencies framework: medical (or content) knowledge; learner- centeredness; interpersonal and communication skills; professionalism and role modeling; practice-based reflection; and systems-based practice. They also included four specialized competencies for educators with additional programmatic roles: program design/implementation, evaluation/scholarship, leadership, and mentorship. The authors then cross-referenced the competencies with educator roles, drawing from CanMEDS, to recognize role-specific skills. The authors have explored their framework's strengths, limitations, and applications, which include targeted faculty development, evaluation, and resource allocation. The Teaching as a Competency framework promotes a culture of effective teaching and learning.
Placebo medications, by definition, are composed of inactive ingredients that have no physiological effect on symptoms. Nonetheless, administration of placebo in randomized controlled trials (RCTs) ...and in clinical settings has been demonstrated to have significant impact on many physical and psychological complaints. Until recently, conventional wisdom has suggested that patients must believe that placebo pills actually contain (or, at least, might possibly contain) active medication in order to elicit a response to placebo. However, several recent RCTs, including patients with irritable bowel syndrome (IBS), chronic low back pain, and episodic migraine, have demonstrated that individuals receiving open-label placebo (OLP) can still experience symptomatic improvement and benefit from honestly described placebo treatment.
This paper describes an innovative multidisciplinary trial design (n = 280) that attempts to replicate and expand upon an earlier IBS OLP study. The current study will compare OLP to double-blind placebo (DBP) administration which is made possible by including a nested, double-blind RCT comparing DBP and peppermint oil. The study also examines possible genetic and psychological predictors of OLP and seeks to better understand participants' experiences with OLP and DBP through a series of extensive interviews with a randomly selected subgroup.
OLP treatment is a novel strategy for ethically harnessing placebo effects. It has potential to re-frame theories of placebo and to influence how physicians can optimize watch-and-wait strategies for common, subjective symptoms. The current study aims to dramatically expand what we know about OLP by comparing, for the first time, OLP and DBP administration. Adopting a unique, multidisciplinary approach, the study also explores genetic, psychological and experiential dimensions of OLP. The paper ends with an extensive discussion of the "culture" of the trial as well as potential mechanisms of OLP and ethical implications.
ClinicalTrials.gov, identifier: NCT02802241 . Registered on 14 June 2016.
We report in detail on searches for eV-scale sterile neutrinos, in the context of a 3 + 1 model, using eight years of data from the IceCube Neutrino Telescope. By analyzing the reconstructed energies ...and zenith angles of 305,735 atmospheric νμ and νμ events we construct confidence intervals in two analysis spaces: sin2 (2θ24) vs Δm241 under the conservative assumption θ34 = 0; and sin2 (2θ24) vs sin 2 (2θ34) given sufficiently large Δ m241 that fast oscillation features are unresolvable. Detailed discussions of the event selection, systematic uncertainties, and fitting procedures are presented. No strong evidence for sterile neutrinos is found, and the best-fit likelihood is consistent with the no sterile neutrino hypothesis with a p value of 8% in the first analysis space and 19% in the second.
Purpose To conduct a systematic review to guide hand surgeons in an evidenced-based approach in managing postoperative pain. Methods We performed a literature review for primary research articles on ...management of postoperative pain in hand surgery patients using Medical Literature Analysis and Retrieval System Online (MEDLINE; PubMed), Excerpta Medica database (EMBASE), and the Cochrane Collaboration Library. Inclusion criteria were primary journal articles examining treatment of acute postoperative pain based on any modality. Data related to pain assessment, postoperative recovery, and total postoperative analgesic consumption were extracted. Results A total of 903 publications were reviewed; 184 publications underwent abstract review. After applying inclusion and exclusion criteria, 10 primary articles were selected for inclusion in this review. Data were noted to be heterogeneous and findings were compiled. Results were divided into groups evaluating postoperative pain medications or pain infusion catheters. Conclusions Although this review did not demonstrate a best practices model for postoperative pain management, it provides evidence for alternative medications and treatment strategies. The evidence available suggests that postoperative pain control should begin before surgery and that combining multiple strategies for pain treatment is beneficial. Given the increasing attention paid to narcotic prescriptions and the potential for abuse, surgeons should adopt evidence-based pain management practices. We provide an example algorithm for pain treatment in hand surgery based on available data and the authors’ experience. Type of study/level of evidence Therapeutic III.
α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation ...and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human DC functional suppression, here, we used two recently described single-cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of DCs were significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on DC stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids (PUFA) than cord blood-derived AFP. PUFAs bound to AFP increased metabolic skewing and promoted DC functional suppression. PUFAs inhibited DC differentiation in vitro, and ω-6 PUFAs conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit antitumor immunity.
α-Fetoprotein (AFP) is a secreted tumor protein and biomarker with impact on immunity. Fatty acid-bound AFP promotes immune suppression by skewing human dendritic cell metabolism toward glycolysis and reduced immune stimulation.
Coccidioides immitis and Coccidioides posadasii are soil fungi endemic to desert regions of the southwestern United States, and the causative agents of valley fever, or coccidioidomycosis. Studies ...have shown that the distribution of Coccidioides in soils is sporadic and cannot be explained by soil characteristics alone, suggesting that biotic and other abiotic factors should be examined. However, tools to reliably and robustly screen the large number of soils needed to investigate these potential associations have not been available. Thus, we developed a real-time polymerase chain reaction (PCR) assay for testing environmental samples by modifying CocciDx, an assay validated for testing clinical specimens to facilitate coccidioidomycosis diagnosis. For this study, we collected soil samples from previously established locations of C. posadasii in Arizona and new locations in fall 2013 and spring 2014, and screened the extracted DNA with the new assay known as CocciEnv. To verify the presence of Coccidioides in soil using an alternate method, we employed next generation amplicon sequencing targeting the ITS2 region. Results show our modified assay, CocciEnv, is a rapid and robust method for detecting Coccidioides DNA in complex environmental samples. The ability to test a large number of soils for the presence of Coccidioides is a much-needed tool in the understanding of the ecology of the organism and epidemiology of the disease and will greatly improve our understanding of this human pathogen.
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