IMPORTANCE: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple ...sclerosis (MS) and concomitant SARS-CoV-2 infections. OBJECTIVE: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. DESIGN, SETTING, AND PARTICIPANTS: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. EXPOSURES: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. MAIN OUTCOMES AND MEASURES: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. RESULTS: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 82.7%), were female (1202 74.0%), and had relapsing-remitting MS (1255 80.4%). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio OR, 2.8 95% CI, 1.6-4.8; intensive care unit/required ventilator support, OR, 3.5 95% CI, 1.6-7.8; death, OR, 25.4 95% CI, 9.3-69.1; age every 10 years: hospitalization only, OR, 1.3 95% CI, 1.1-1.6; intensive care unit/required ventilator support, OR, 1.3 95% CI, 0.99-1.7; death, OR, 1.8 95% CI, 1.2-2.6). CONCLUSIONS AND RELEVANCE: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.
We propose a novel segmentation approach based on deep 3D convolutional encoder networks with shortcut connections and apply it to the segmentation of multiple sclerosis (MS) lesions in magnetic ...resonance images. Our model is a neural network that consists of two interconnected pathways, a convolutional pathway, which learns increasingly more abstract and higher-level image features, and a deconvolutional pathway, which predicts the final segmentation at the voxel level. The joint training of the feature extraction and prediction pathways allows for the automatic learning of features at different scales that are optimized for accuracy for any given combination of image types and segmentation task. In addition, shortcut connections between the two pathways allow high- and low-level features to be integrated, which enables the segmentation of lesions across a wide range of sizes. We have evaluated our method on two publicly available data sets (MICCAI 2008 and ISBI 2015 challenges) with the results showing that our method performs comparably to the top-ranked state-of-the-art methods, even when only relatively small data sets are available for training. In addition, we have compared our method with five freely available and widely used MS lesion segmentation methods (EMS, LST-LPA, LST-LGA, Lesion-TOADS, and SLS) on a large data set from an MS clinical trial. The results show that our method consistently outperforms these other methods across a wide range of lesion sizes.
Contact inhibition of locomotion (CIL), the repulsive response of cells upon cell–cell contact, has been the predominant paradigm for contact-mediated responses. However, it is difficult for CIL ...alone to account for the complex behavior of cells within a multi-cellular environment, where cells often migrate in cohorts such as sheets, clusters, and streams. Although cell–cell adhesion and mechanical interactions play a role, how individual cells coordinate their migration within a multicellular environment remains unclear. Using micropatterned substrates to guide cell migration and manipulate cell–cell contact, we show that contacts between different regions of cells elicit different responses. Repulsive responses were limited to interaction with the head of a migrating cell, while contact with the tail of a neighboring cell promoted migration toward the tail. The latter behavior, termed contact following of locomotion (CFL), required the Wnt signaling pathway. Inhibition of the Wnt pathway disrupted not only CFL but also collective migration of epithelial cells, without affecting the migration of individual cells. In contrast, inhibition of myosin II with blebbistatin disrupted the migration of both individual epithelial cells and collectives. We propose that CFL, in conjunction with CIL, plays a major role in guiding and coordinating cell migration within a multicellular environment.
The wave union (WU) method is a well-known method in time-to-digital converters (TDCs) and can improve TDC performances without consuming extra logic resources. However, an earlier study concluded ...that the WU method is not suitable for UltraScale field-programmable gate array (FPGA) devices, due to more severe bubble errors. This article proves otherwise and presents new strategies to pursue high-resolution TDCs in Xilinx UltraScale 20 nm FPGAs. Combining our new subtapped delay line (sub-TDL) architecture (effective in removing bubbles and zero-width bins) and the WU method, we found that the wave union method is still powerful in UltraScale devices. We also compared the proposed TDC with the TDCs combining the dual sampling structure and the sub-TDL technique. A binning method is introduced to improve the linearity. Moreover, we derived a formula of the total measurement uncertainties for a single-stage TDL-TDC to obtain its root-mean-square resolution. Compared with the previously published FPGA-TDCs, we presented (for the first time) much more detailed precision analysis for single-TDL TDCs.
This paper presents low nonlinearity, compact, and multichannel time-to-digital converters (TDC) in Xilinx 28 nm Virtex 7 and 20 nm UltraScale field-programmable gate arrays (FPGAs). The proposed ...TDCs integrate several innovative methods that we have developed: 1) the subtapped delay line averaging topology; 2) tap timing tests; 3) a direct compensation architecture; and 4) a mixed calibration method. The code density tests show that the proposed TDCs have much better linearity performances than previously reported ones. Our approach is cost-effective in terms of the consumption of logic resources. To demonstrate this, we implemented 96 channel TDCs in both FPGAs, using less than 25% of the logic resources. The achieved least significant bit (LSB) is 10.5 ps for Virtex 7 and 5.0 ps for UltraScale FPGAs. After the compensation and calibration, the differential nonlinearity (DNL) is within -0.05, 0.08 LSB with σDNL = 0.01 LSB, and the integral nonlinearity (INL) is within -0.09, 0.11 LSB with σINL = 0.04 LSB for the Virtex 7 FPGA. The DNL is within -0.12, 0.11 LSB with σDNL = 0.03 LSB, and the INL is within -0.15, 0.48 LSB with σINL = 0.20 LSB for the UltraScale FPGA.
We present a hardware-friendly deep learning architecture with one-dimensional convolutional neural networks (1D CNN) for fast analyzing fluorescence lifetime imaging (FLIM) data. A 1D CNN shows ...unparalleled advantages; they are more straightforward, quicker to train, and faster than high dimensional CNNs. 1D CNNs can be easily applied to multi-exponential fluorescence decay models. Compared with traditional least-square methods, superior performances of 1D CNNs on fluorescence lifetime image reconstruction have been validated using simulated data. We also employ the proposed 1D CNN to analyze two-photon FLIM images of functionalized gold nanoprobes in Hek293 and human prostate cancer cells. The results further demonstrate that 1D CNNs are fast and can accurately extract lifetime parameters from fluorescence signals. Our study shows that 1D CNNs have great potential in various real-time FLIM applications.
The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an ...important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
Summary Background Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine ...the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis. Methods In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18–55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00879658. Findings Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17–57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29–69) for siponimod 0·5 mg (43 patients), 66% (48–80) for siponimod 1·25 mg (42 patients), 72% (57–84) for siponimod 2 mg (45 patients), and 82% (70–90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious). Interpretation Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial. Funding Novartis Pharma AG.
IMPORTANCE: Estimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable. OBJECTIVE: To describe the incidence of ...antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center. EXPOSURES: At least 24 hours of any parenteral or oral antibiotic therapy. MAIN OUTCOMES AND MEASURES: Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians. RESULTS: In 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non–clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics. CONCLUSIONS AND RELEVANCE: Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.
Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T
(IET2), which ...is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.
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