We present RNNbow, an interactive tool for visualizing the gradient flow during backpropagation in training of recurrent neural networks. By visualizing the gradient, as opposed to activations, ...RNNbow offers insight into how the network is learning. We show how it illustrates the vanishing gradient and the training process.
Once you have a product, distributing it becomes the next challenge for any entrepreneur. At TRASH (one-tap video editing), we looked to TikTok as a potential marketing channel. As early learnings ...started to roll in, we decided to share what’s going on inside this exploding and mysterious beast. The advantage of having a deep tech company that uses AI to help speed the process of editing video is that we can do it for “free.” This is pretty cool when you consider that editing a semi-pro video...
Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost ...importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013.
We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996–99, 2000–03 comparator, 2004–07, 2008–10). We estimated life expectancy by calendar period of initiation of ART.
88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008–10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000–03 (adjusted HR 0·71, 95% CI 0·61–0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008–10 than in those who started in 2000–03 (0·57, 0·49–0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008–10 (vs 2000–03) in the first year (0·48, 0·34–0·67) and second and third years (0·29, 0·21–0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men.
Even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements.
UK Medical Research Council, UK Department for International Development, EU EDCTP2 programme.
Background
U.S. Army Chemical Corps veterans handled and sprayed herbicides in Vietnam resulting in exposure to Agent Orange and its contaminant 2,3,7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD or dioxin). ...This study examined the long‐term health effects associated with herbicide exposure among these Vietnam veterans.
Methods
A health survey of these 1,499 Vietnam veterans and a group of 1,428 non‐Vietnam veterans assigned to chemical operations jobs was conducted using a computer‐assisted telephone interview (CATI) system. Exposure to herbicides was assessed by analyzing serum specimens from a sample of 897 veterans for dioxin. Logistic regression analyses were used to estimate the risk of selected medical outcomes associated with herbicide exposure.
Results
Odds ratios for diabetes, heart disease, hypertension, and chronic respiratory disease were elevated, but not significantly (P > 0.05) for those who served in Vietnam. However, they were significantly elevated among those Vietnam veterans who sprayed herbicides: diabetes, odds ratio (OR) = 1.50 (95% confidence interval 95%CI = 1.15–1.95); heart disease, OR = 1.52 (1.18–1.94); hypertension, OR = 1.32 (1.08–1.61); and chronic respiratory condition, OR = 1.62 (1.28–2.05). Hepatitis was associated with Vietnam service, but not with herbicide application.
Conclusions
Vietnam veterans who were occupationally exposed to herbicide experienced a higher risk of several chronic medical conditions relative to other non‐Vietnam veterans. A potential selection bias is of concern. However, there were relatively high participation rates in both the Vietnam and non‐Vietnam veteran groups, and the prevalence rates of some of these medical conditions among non‐Vietnam veterans were comparable to general populations. Therefore, self‐selection factors are considered unlikely to have biased the study results. Am. J. Ind. Med. 2006. Published 2006 Wiley‐Liss, Inc.
Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has ...dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison’s disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.
•Leukodystrophies are genetic disorders affecting the white matter of the central nervous system.•Most leukodystrophies have motor deficits that often dominate the clinical picture, especially in pediatric patients.•Brain MRI is the foundational investigation in a patient with a suspected leukodystrophy or genetic leukoencephalopathy.•The number of disorders with established therapies is small in number and require prompt recognition and downstream testing.•Partnering MRI pattern analysis and next-generation sequencing may lead to higher diagnostic yield and more timely diagnosis.
Undervaccination (receiving fewer than the recommended number of SARS-CoV-2 vaccine doses) could be associated with increased risk of severe COVID-19 outcomes—ie, COVID-19 hospitalisation or ...death—compared with full vaccination (receiving the recommended number of SARS-CoV-2 vaccine doses). We sought to determine the factors associated with undervaccination, and to investigate the risk of severe COVID-19 outcomes in people who were undervaccinated in each UK nation and across the UK.
We used anonymised, harmonised electronic health record data with whole population coverage to carry out cohort studies in England, Northern Ireland, Scotland, and Wales. Participants were required to be at least 5 years of age to be included in the cohorts. We estimated adjusted odds ratios for undervaccination as of June 1, 2022. We also estimated adjusted hazard ratios (aHRs) for severe COVID-19 outcomes during the period June 1 to Sept 30, 2022, with undervaccination as a time-dependent exposure. We combined results from nation-specific analyses in a UK-wide fixed-effect meta-analysis. We estimated the reduction in severe COVID-19 outcomes associated with a counterfactual scenario in which everyone in the UK was fully vaccinated on June 1, 2022.
The numbers of people undervaccinated on June 1, 2022 were 26 985 570 (45·8%) of 58 967 360 in England, 938 420 (49·8%) of 1 885 670 in Northern Ireland, 1 709 786 (34·2%) of 4 992 498 in Scotland, and 773 850 (32·8%) of 2 358 740 in Wales. People who were younger, from more deprived backgrounds, of non-White ethnicity, or had a lower number of comorbidities were less likely to be fully vaccinated. There was a total of 40 393 severe COVID-19 outcomes in the cohorts, with 14 156 of these in undervaccinated participants. We estimated the reduction in severe COVID-19 outcomes in the UK over 4 months of follow-up associated with a counterfactual scenario in which everyone was fully vaccinated on June 1, 2022 as 210 (95% CI 94–326) in the 5–15 years age group, 1544 (1399–1689) in those aged 16–74 years, and 5426 (5340–5512) in those aged 75 years or older. aHRs for severe COVID-19 outcomes in the meta-analysis for the age group of 75 years or older were 2·70 (2·61–2·78) for one dose fewer than recommended, 3·13 (2·93–3·34) for two fewer, 3·61 (3·13–4·17) for three fewer, and 3·08 (2·89–3·29) for four fewer.
Rates of undervaccination against COVID-19 ranged from 32·8% to 49·8% across the four UK nations in summer, 2022. Undervaccination was associated with an elevated risk of severe COVID-19 outcomes.
UK Research and Innovation National Core Studies: Data and Connectivity.
Abstract
Despite improvements in peptide-based tumor antigen discovery, success in eliciting a clinically meaningful T cell response to these peptides has been limited. The choice of antigen delivery ...platform strongly impacts the quality, quantity, and durability of induced immune responses. DPX is a unique, water-free, lipid-based formulation that can deliver peptides, proteins, and small molecules specifically to antigen presenting cells (APCs), eliciting a targeted, robust, and sustained T cell-based immune response. DPX allows for antigenic peptides to remain at the site of injection without significant diffusion into surrounding tissues, in direct contrast to most emulsion-based delivery methods. Maveropepimut-S (MVP-S; formerly known as DPX-Survivac) is a DPX formulation that incorporates 5 HLA-restricted peptides derived from the anti-apoptotic protein survivin, which is commonly overexpressed in advanced cancers including ovarian cancer. Prior efforts with these same peptides emulsified in Montanide ISA 51 VG provided limited clinical benefit and no objective responses (Lennerz 2014). We now show in pre-clinical models that, when packaged in DPX, these peptides elicit higher avidity, more abundant and cytolytically-active survivin-specific T cells than standard emulsion-based formulations. Early clinical studies with MVP-S in advanced ovarian cancer patients have shown a persistent, survivin-specific T cell response, which in a subset of patients lasted more than 2 years. The recently completed phase 2 study of MVP-S and low-dose cyclophosphamide (CPA) in advanced and recurrent ovarian cancer subjects (DeCidE1), provided encouraging clinical benefit across multiple measures (ORR = 26% & DCR = 79% on target lesions, mOS = 19.9 months in evaluable patients). We now show that majority of patients in this study had survivin-specific T cells on treatment by in vitro tetramer staining (87%) and ex vivo ELISPOT analyses (56%). Importantly, 75% of patients deriving clinical benefit had active survivin-specific T cells by ex vivo ELISPOT analyses. Immunophenotyping of the longitudinally collected PBMCs showed evidence of sustained T cell proliferation by tetramer staining across time and did not show increased expression of immunosuppressive markers (e.g., PD-1, Tim3), suggesting that MVP-S induced T cells remain active over time. TCRβ analyses of tumor TCR repertoires further showed the ability of de novo elicited survivin-specific T cells to infiltrate on-treatment tumours. Collectively, these preclinical and clinical data show that MVP-S treatment effectively elicits a robust, persistent, survivin-specific T cell response. These data also provide compelling evidence that clinical benefit in DeCidE1 patients is most evident in those with survivin-specific T cells. Finally, these data further underscore the unique capacity of DPX technology to effectively elicit peptide-specific, T cell based immune responses when conventional formulations do not.
Citation Format: Yogesh Bramhecha, Oliver Dorigo, Valarmathy Kaliaperumal, Heather Torrey, Walead Ebrahimizadeh, Kelcey Patterson, Brennan Dirk, Moamen Bydoun, Barry Kennedy, Aurelio Lobo, Genevieve Weir, Jeremy Graff, Stephan Fiset, Olga Hrytsenko. Survivin peptides formulated in the DPX delivery platform rather than standard emulsions, elicit a robust, sustained T cell response to survivin in advanced and recurrent ovarian cancer patients abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA026.
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