Visual understanding of 3-D environments in real time, at low power, is a huge computational challenge. Often referred to as simultaneous localization and mapping (SLAM), it is central to ...applications spanning domestic and industrial robotics, autonomous vehicles, and virtual and augmented reality. This paper describes the results of a major research effort to assemble the algorithms, architectures, tools, and systems software needed to enable delivery of SLAM, by supporting applications specialists in selecting and configuring the appropriate algorithm and the appropriate hardware, and compilation pathway, to meet their performance, accuracy, and energy consumption goals. The major contributions we present are: 1) tools and methodology for systematic quantitative evaluation of SLAM algorithms; 2) automated, machine-learning-guided exploration of the algorithmic and implementation design space with respect to multiple objectives; 3) end-to-end simulation tools to enable optimization of heterogeneous, accelerated architectures for the specific algorithmic requirements of the various SLAM algorithmic approaches; and 4) tools for delivering, where appropriate, accelerated, adaptive SLAM solutions in a managed, JIT-compiled, adaptive runtime context.
IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders ...are associated with significant childhood morbidity and mortality. OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly. DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children’s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase–AKT (serine/threonine kinase)–mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders. RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size. CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.
•Transoral surgery is FDA approved for removal of oropharynx cancer.•Credentialing and quality assurance can standardize surgical clinical trials.•Our results may apply to other surgical disciplines ...and clinical trials.
Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA.
E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections.
120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients.
We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The numerical injection analysis (NINJA) project is a collaborative effort between members of the numerical-relativity and gravitational wave data-analysis communities. The purpose of NINJA is to ...study the sensitivity of existing gravitational-wave search and parameter-estimation algorithms using numerically generated waveforms and to foster closer collaboration between the numerical-relativity and data-analysis communities. The first NINJA project used only a small number of injections of short numerical-relativity waveforms, which limited its ability to draw quantitative conclusions. The goal of the NINJA-2 project is to overcome these limitations with long post-Newtonian-numerical-relativity hybrid waveforms, large numbers of injections and the use of real detector data. We report on the submission requirements for the NINJA-2 project and the construction of the waveform catalog. Eight numerical-relativity groups have contributed 56 hybrid waveforms consisting of a numerical portion modeling the late inspiral, merger and ringdown stitched to a post-Newtonian portion modeling the early inspiral. We summarize the techniques used by each group in constructing their submissions. We also report on the procedures used to validate these submissions, including examination in the time and frequency domains and comparisons of waveforms from different groups against each other. These procedures have so far considered only the ( , m) = (2, 2) mode. Based on these studies, we judge that the hybrid waveforms are suitable for NINJA-2 studies. We note some of the plans for these investigations.
Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus ...placebo, in patients receiving remdesivir and other standard care.
In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing.
From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio RRR 1·08 95% CI 0·97-1·20; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 0·97-1·34; p=0·13). Mortality was lower in the tixagevimab-cilgavimab group (61 9%) versus placebo group (86 12%; hazard ratio HR 0·70 95% CI 0·50-0·97; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0·83 0·68-1·01; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group.
Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.
US National Institutes of Health (NIH) and Operation Warp Speed.
The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five ...complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.
Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.
Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.
IMPORTANCE: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia. OBJECTIVE: To compare atropine, 0.01%, eye drops ...with placebo for slowing myopia progression in US children. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (−1.00 diopters D to −6.00 D spherical equivalent refractive error SER). INTERVENTION: Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation. MAIN OUTCOME AND MEASURES: Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo. RESULTS: A total of 187 children (mean SD age, 10.1 1.8 years; age range, 5.1-12.9 years; 101 female 54%; 34 Black 18%, 20 East Asian 11%, 30 Hispanic or Latino 16%, 11 multiracial 6%, 6 West/South Asian 3%, 86 White 46%) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95% CI) change in SER from baseline was −0.82 (−0.96 to −0.68) D and −0.80 (−0.98 to −0.62) D in the atropine and placebo groups, respectively (adjusted difference = −0.02 D; 95% CI, −0.19 to +0.15 D; P = .83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was −0.04 D (95% CI, −0.25 to +0.17 D). Adjusted mean (95% CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = −0.002 mm; 95% CI, −0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009 mm (95% CI, −0.115 to 0.134 mm). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03334253
A unifying framework is described for nonsingular data transformations. It is shown that a wide class of existing transformations may be expressed in this framework, allowing compound transformations ...to be performed in one step. Validity conditions for such transformations are developed as is the form of the transformed program and data. Constructive algorithms to generate data transformations for different applications are described and applied to example programs. It is shown that they can have a significant impact on program performance and may be used in situations where traditional loop transformations are inappropriate.
IMPORTANCE: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and ...reduced risk of AMD. OBJECTIVE: To investigate the association between metformin use and age-related macular degeneration (AMD). DESIGN, SETTING, AND PARTICIPANTS: The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. INTERVENTIONS: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. MAIN OUTCOMES AND MEASURES: Prevalence of AMD in the treatment arms. RESULTS: Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean SD age at randomization, 49 9 years), sex (1128 71% male), race and ethnicity (784 49% White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean SD, 8.0 9.3 vs 8.5 9.3 years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02). CONCLUSIONS AND RELEVANCE: These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.
Corona-virus Disease 2019 (COVID-19) has had a huge impact on the delivery of healthcare worldwide, particularly elective surgery. There is a lack of data regarding risk of postoperative COVID-19 ...infection in children undergoing elective surgery, and regarding the utility of pre-operative COVID-19 testing, and preoperative “cocooning” or restriction of movements. The purpose of this present study was to examine the safety of elective paediatric Otolaryngology surgery during the COVID-19 pandemic with respect to incidence of postoperative symptomatic COVID-19 infection or major respiratory complications.
Prospective cohort study of paediatric patients undergoing elective Otolaryngology surgery between September and December 2020. Primary outcome measure was incidence of symptomatic COVID-19 or major respiratory complications within the 14 days after surgery. Parents of prospectively enrolled patients were contacted 14 days after surgery and enquiry made regarding development of postoperative symptoms, COVID-19 testing, or diagnosis of COVID-19.
302 patients were recruited. 125 (41.4%) underwent preoperative COVID-19 RT-PCR testing. 66 (21.8%) restricted movements prior to surgery. The peak 14-day COVID-19 incidence during the study was 302.9 cases per 100,000 population. No COVID-19 infections or major respiratory complications were reported in the 14 day follow-up period.
The results of our study support the safety of elective paediatric Otolaryngology surgery during the pandemic, in the setting of community incidence not exceeding that observed during the study period.
•Corona-virus Disease 2019 had had a major impact on healthcare delivery globally.•It is safe to proceed with elective paediatric surgery during the current pandemic when community transmission levels are low.•Further work is required to elucidate the exact role of ‘cocooning’/self-isolating in the role of disease prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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