OBJECTIVETo assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis ...(RMS).
METHODSPatients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.
RESULTSThe cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1–4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.
CONCLUSIONImaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robustcumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
•Designs workflow for personalized prediction of response to first-line chemotherapy.•Performs systematic metabolomic analysis of lung cancer fresh tumor core biopsies.•Machine learning analyses ...differentiate between treatment responses and disease stage.•Predicts response and identifies metabolites associated with patient classifications.
Despite extensive effort, the search for clinically-relevant metabolite biomarkers for early detection, disease monitoring, and outcome prediction in lung cancer remains unfulfilled. Although biofluid evaluation has been explored, the complexity inherent in metabolite data and the dynamic discrepancy between metabolites in biofluids vs. tumor tissue have prevented conclusive results. This proof-of-concept study explored models predictive of staging and chemotherapy response based on metabolomic analysis of fresh, patient-derived non-small cell lung cancer (NSCLC) core biopsies.
Samples (n = 36) were evaluated with high-resolution 2DLC-MS/MS and 13C-glucose enrichment, and the data were comprehensively analyzed with machine learning techniques. Patients were categorized as Disease-Control (DC) encompassing complete-response (CR), partial-response (PR), and stable-disease (SD) and Progressive-Disease (PD) in terms of first-line chemotherapy. Four major types of learning methods (partial least squares discriminant analysis (PLS-DA), support vector machines (SVM), artificial neural networks, and random forests (RF)) were applied to differentiate between positive (DC and CR/PR) and poor (PD and SD/PD) responses, and between stage I/II/III and stage IV disease. Models were trained with forward feature selection based on variable importance and tested on validation subsets.
The models predicted patient classifications in the validation subsets with AUC (95 % CI): DC vs. PD (SVM), 0.970(0.961–0.979); CR/PR vs. SD/PD (PLS-DA), 0.880(0.865–0.895); stage I/II/III vs. IV (SVM), 0.902(0.880–0.924). Highest performing model was SVM for DC vs. PD (balanced accuracy = 0.92; kappa = 0.74).
This study illustrates a comprehensive evaluation of patient tumor-specific metabolic profiles, with the potential to identify disease stage and predict response to first-line chemotherapy.
Emerging technological advances hold potential to assist the long-term care (LTC) workforce in caring for an aging population in the home and LTC settings. Technology may alter workforce needs and ...mitigate rising workforce demand. This study identified and assessed emerging technologies that may assist, replace, and/or support recruitment and retention of the LTC workforce and identified barriers and facilitators to their implementation. We identified a variety of technologies with applications for LTC, created a taxonomy of technology types and functions across LTC settings, and conducted semi-structured interviews with a sample of company leaders to assess perceived impact of their products and services on the LTC workforce. Thematic analysis of those interviews found that technology is not currently positioned to replace the LTC workforce but may facilitate work and support worker recruitment and retention. More rigorous evaluation of technologies in LTC and financing mechanisms are needed to support widespread adoption.
Obesity is associated with cognitive impairments. Long-term mechanisms for this association include consequences of hyperglycemia, dyslipidemia, or other factors comprising metabolic syndrome X. We ...found that hypertriglyceridemia, the main dyslipidemia of metabolic syndrome X, is in part responsible for the leptin resistance seen in obesity. Here we determined whether triglycerides have an immediate and direct effect on cognition. Obese mice showed impaired acquisition in three different cognitive paradigms: the active avoidance T-maze, the Morris water maze, and a food reward lever press. These impairments were not attributable to differences in foot shock sensitivity, swim speed, swimming distance, or voluntary milk consumption. Impaired cognition in obese mice was improved by selectively lowering triglycerides with gemfibrozil. Injection into the brain of the triglyceride triolein, but not of the free fatty acid palmitate, impaired acquisition in normal body weight mice. Triolein or milk (97% of fats are triglycerides), but not skim milk (no triglycerides), impaired maintenance of the N-methyl-d-aspartate component of the hippocampal long-term synaptic potential. Measures of oxidative stress in whole brain were reduced by gemfibrozil. We conclude that triglycerides mediate cognitive impairment as seen in obesity, possibly by impairing maintenance of the N-methyl-d-aspartate component of hippocampal long-term potentiation, and that lowering triglycerides can reverse the cognitive impairment and improve oxidative stress in the brain.
Significance
Affordable hand-held ultrasound is transforming health care as a diagnostic tool with the potential to be as ubiquitous as the stethoscope. Here, we present a platform for advancing ...diagnostic care consisting of an ultrasound-on-chip probe, leveraging state-of-the-art silicon-based semiconductor foundries, paired with a mobile device and artificial-intelligence–guided image interpretation and cloud interconnectivity. Demonstrations across key organs and modes illustrate the imaging capabilities. Presentations of automated guidance for untrained ultrasound users show the potential for further broadening accessibility and utility.
Over the past half-century, ultrasound imaging has become a key technology for assessing an ever-widening range of medical conditions at all stages of life. Despite ultrasound’s proven value, expensive systems that require domain expertise in image acquisition and interpretation have limited its broad adoption. The proliferation of portable and low-cost ultrasound imaging can improve global health and also enable broad clinical and academic studies with great impact on the fields of medicine. Here, we describe the design of a complete ultrasound-on-chip, the first to be cleared by the Food and Drug Administration for 13 indications, comprising a two-dimensional array of silicon-based microelectromechanical systems (MEMS) ultrasonic sensors directly integrated into complementary metal–oxide–semiconductor-based control and processing electronics to enable an inexpensive whole-body imaging probe. The fabrication and design of the transducer array with on-chip analog and digital circuits, having an operating power consumption of 3 W or less, are described, in which approximately 9,000 seven-level feedback-based pulsers are individually addressable to each MEMS element and more than 11,000 amplifiers, more than 1,100 analog-to-digital converters, and more than 1 trillion operations per second are implemented. We quantify the measured performance and the ability to image areas of the body that traditionally takes three separate probes. Additionally, two applications of this platform are described—augmented reality assistance that guides the user in the acquisition of diagnostic-quality images of the heart and algorithms that automate the measurement of cardiac ejection fraction, an indicator of heart health.
Online professional development (PD) can support broader accessibility than traditional face-to-face PD. However online delivery presents challenges for characteristics of high-quality PD, such as ...collaborative knowledge building and community development, that have proven positive outcomes in face-to-face modes. A few comparative studies have demonstrated equivalent outcomes when PD activities have been translated from a successful face-to-face implementation to an online format. This study investigates whether an online version of PD for high school biology teachers on using computer-supported complex systems curriculum and instruction can achieve the same high impact as the face-to-face version. We describe changes in design decisions to accommodate the online mode and measure impact on teachers' perceptions of their experiences and student outcomes. The results show positive teacher perceptions in both PD formats and roughly equal student outcomes. However, teachers articulated other benefits to online activities that indicate opportunities for improved access to high-quality PD.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization ...of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Minnesota became the fourth state to begin newborn screening (NBS) for X‐linked adrenoleukodystrophy (X‐ALD) in 2017. As there is limited retrospective data available on NBS for X‐ALD, we analyzed ...Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0‐LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X‐ALD and all were subsequently confirmed to have X‐ALD, with zero false positives. The birth prevalence of X‐ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X‐ALD. Phenotypes of these family members included self‐reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X‐ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population‐based screening for X‐ALD.
To determine visual acuity improvement in children with strabismic and combined strabismic-anisometropic (combined-mechanism) amblyopia treated with optical correction alone and to explore factors ...associated with improvement.
Prospective, multicenter, cohort study.
We included 146 children 3 to <7 years old with previously untreated strabismic amblyopia (n = 52) or combined-mechanism amblyopia (n = 94).
Optical treatment was provided as spectacles (prescription based on a cycloplegic refraction) that were worn for the first time at the baseline visit. Visual acuity with spectacles was measured using the Amblyopia Treatment Study HOTV visual acuity protocol at baseline and every 9 weeks thereafter until no further improvement in visual acuity. Ocular alignment was assessed at each visit.
Visual acuity 18 weeks after baseline.
Overall, amblyopic eye visual acuity improved a mean of 2.6 lines (95% confidence interval CI, 2.3-3.0), with 75% of children improving ≥ 2 lines and 54% improving ≥ 3 lines. Resolution of amblyopia occurred in 32% (95% CI, 24%-41%) of the children. The treatment effect was greater for strabismic amblyopia than for combined-mechanism amblyopia (3.2 vs 2.3 lines; adjusted P = 0.003). Visual acuity improved regardless of whether eye alignment improved.
Optical treatment alone of strabismic and combined-mechanism amblyopia results in clinically meaningful improvement in amblyopic eye visual acuity for most 3- to <7-year-old children, resolving in at least one quarter without the need for additional treatment. Consideration should be given to prescribing refractive correction as the sole initial treatment for children with strabismic or combined-mechanism amblyopia before initiating other therapies.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Creating nurse-driven protocols empower nurses to practice at the top of their scope and provide early interventions. This article describes the development and implementation of an evidence-based, ...nurse-driven resuscitation protocol for cardiac surgical patients who suffer cardiac arrest using a theoretical framework and leadership-driven process. Readers will gain knowledge of the collaborative process required to develop and implement a complex practice change. Process measures, outcomes, and lessons learned are presented.
PDF
