Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The ...increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.
Influenza C virus (ICV) is a common yet under-recognized cause of acute respiratory illness. ICV seropositivity has been found to be as high as 90% by 7-10 years of age, suggesting that most people ...are exposed to ICV at least once during childhood. Due to difficulty detecting ICV by cell culture, epidemiologic studies of ICV likely have underestimated the burden of ICV infection and disease. Recent development of highly sensitive RT-PCR has facilitated epidemiologic studies that provide further insights into the prevalence, seasonality, and course of ICV infection. In this review, we summarize the epidemiology and clinical characteristics of ICV.
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within ...these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Background. We performed a prospective study to determine the disease burden of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) in older adults in comparison with influenza virus. ...Methods. During 3 consecutive winters, we enrolled Davidson County (Nashville, TN) residents aged ≥50 years admitted to 1 of 4 hospitals with acute respiratory illness (ARI). Nasal/throat swabs were tested for influenza, RSV, and HMPV with reverse-transcriptase polymerase chain reaction. Hospitalization rates were calculated. Results. Of 1042 eligible patients, 508 consented to testing. Respiratory syncytial virus was detected in 31 participants (6.1%); HMPV was detected in 23 (4.5%) patients; and influenza was detected in 33 (6.5%) patients. Of those subjects aged ≥65 years, 78% received influenza vaccination. Compared with patients with confirmed influenza, patients with RSV were older and more immunocompromised; patients with HMPV were older, had more cardiovascular disease, were more likely to have received the influenza vaccination, and were less likely to report fever than those with influenza. Over 3 years, average annual rates of hospitalization were 15.01, 9.82, and 11.81 per 10 000 county residents due to RSV, HMPV, and influenza, respectively. Conclusions. In adults aged ≥50 years, hospitalization rates for RSV and HMPV were similar to those associated with influenza.
Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. However, estimates of the RSV hospitalization burden have varied, and precision has been limited by ...the use of age strata grouped in blocks of 6 to ≥ 12 months.
We analyzed data from a 5-year, prospective, population-based surveillance for young children who were hospitalized with laboratory-confirmed (reverse-transcriptase polymerase chain reaction) RSV acute respiratory illness (ARI) during October through March 2000-2005. The total population at risk was stratified by month of age by birth certificate information to yield hospitalization rates.
There were 559 (26%) RSV-infected children among the 2149 enrolled children hospitalized with ARI (85% of all eligible children with ARI). The average RSV hospitalization rate was 5.2 per 1000 children <24 months old. The highest age-specific rate was in infants 1 month old (25.9 per 1000 children). Infants ≤ 2 months of age, who comprised 44% of RSV-hospitalized children, had a hospitalization rate of 17.9 per 1000 children. Most children (79%) were previously healthy. Very preterm infants (<30 weeks' gestation) accounted for only 3% of RSV cases but had RSV hospitalization rates 3 times that of term infants.
Young infants, especially those who were 1 month old, were at greatest risk of RSV hospitalization. Four-fifths of RSV-hospitalized infants were previously healthy. To substantially reduce the burden of RSV hospitalizations, effective general preventive strategies will be required for all young infants, not just those with risk factors.
We estimated the effectiveness of four monovalent pandemic influenza A (H1N1) vaccines (three unadjuvanted inactivated, one live attenuated) available in the U.S. during the pandemic. Patients with ...acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospectively recruited, consented, and tested for influenza. Analyses were restricted to October 2009 through April 2010, when pandemic vaccine was available. Patients testing positive for pandemic influenza by real-time RT-PCR were cases; those testing negative were controls. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, patient age, timing of illness, insurance status, enrollment site, and presence of high-risk medical conditions. Pandemic virus was detected in 1,011 (15%) of 6,757 enrolled patients. Fifteen (1%) of 1,011 influenza positive cases and 1,042 (18%) of 5,746 test-negative controls had record-verified pandemic vaccination >14 days prior to illness onset. Adjusted effectiveness (95% confidence interval) for pandemic vaccines combined was 56% (23%, 75%). Adjusted effectiveness for inactivated vaccines alone (79% of total) was 62% (25%, 81%) overall and 32% (-92%, 76%), 89% (15%, 99%), and -6% (-231%, 66%) in those aged 0.5 to 9, 10 to 49, and 50+ years, respectively. Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination >7 rather than >14 days prior to illness onset was considered (61%∶ 12%, 82%). Inactivated non-adjuvanted pandemic vaccines offered significant protection against confirmed pandemic influenza-associated medical care visits in young adults.
Enterovirus D68 (EV-D68) is a nonpolio enterovirus associated with severe respiratory illness and acute flaccid myelitis (AFM), a polio-like illness causing paralysis in children. AFM outbreaks have ...been associated with increased circulation and genetic diversity of EV-D68 since 2014, although the virus was discovered in the 1960s. The mechanisms by which EV-D68 targets the central nervous system are unknown. Since enteroviruses are human pathogens that do not routinely infect other animal species, establishment of a human model of the central nervous system is essential for understanding pathogenesis. Here, we describe two human spinal cord organoid (hSCO)-based models for EV-D68 infection derived from induced, pluripotent stem cell (iPSC) lines. One hSCO model consists primarily of spinal motor neurons, while the another model comprises multiple neuronal cell lineages, including motor neurons, interneurons, and glial cells. These hSCOs can be productively infected with contemporary strains, but not a historic strain, of EV-D68 and produce extracellular virus for at least 2 weeks without appreciable cytopathic effect. By comparison, infection with hSCO with another enterovirus, echovirus 11, causes significant structural destruction and apoptosis. Together, these findings suggest that EV-D68 infection is not the sole mediator of neuronal cell death in the spinal cord in those with AFM and that secondary injury from the immune response likely contributes to pathogenesis. IMPORTANCE AFM is a rare condition that causes significant morbidity in affected children, often contributing to life-long sequelae. It is unknown how EV-D68 causes paralysis in children, and effective therapeutic and preventative strategies are not available. Mice are not native hosts for EV-D68, and thus, existing mouse models use immunosuppressed or neonatal mice, mouse-adapted viruses, or intracranial inoculations. To complement existing models, we report two hSCO models for EV-D68 infection. These three-dimensional, multicellular models comprised human cells and include multiple neural lineages, including motor neurons, interneurons, and glial cells. These new hSCO models for EV-D68 infection will contribute to understanding how EV-D68 damages the human spinal cord, which could lead to new therapeutic and prophylactic strategies for this virus.
Tigers are critically endangered due to deforestation and persecution. Yet in places, Sumatran tigers (Panthera tigris sumatrae) continue to coexist with people, offering insights for managing ...wildlife elsewhere. Here, we couple spatial models of encounter risk with information on tolerance from 2386 Sumatrans to reveal drivers of human-tiger conflict. Risk of encountering tigers was greater around populated villages that neighboured forest or rivers connecting tiger habitat; geographic profiles refined these predictions to three core areas. People's tolerance for tigers was related to underlying attitudes, emotions, norms and spiritual beliefs. Combining this information into socio-ecological models yielded predictions of tolerance that were 32 times better than models based on social predictors alone. Pre-emptive intervention based on these socio-ecological predictions could have averted up to 51% of attacks on livestock and people, saving 15 tigers. Our work provides further evidence of the benefits of interdisciplinary research on conservation conflicts.
Natural infection as well as vaccination with live or attenuated viruses elicit tissue resident, CD8
memory T cell (Trm) response. Trm cells so elicited act quickly upon reencounter with the priming ...agent to protect the host. These Trm cells express a unique molecular signature driven by the master regulators-Runx3 and Hobit. We previously reported that intranasal instillation of a subunit vaccine in a prime boost vaccination regimen installed quick-acting, CD8
Trm cells in the lungs that protected against lethal vaccinia virus challenge. It remains unexplored whether CD8
Trm responses so elicited are driven by a similar molecular signature as those elicited by microbes in a real infection or by live, attenuated pathogens in conventional vaccination. We found that distinct molecular signatures distinguished subunit vaccine-elicited lung interstitial CD8
Trm cells from subunit vaccine-elicited CD8
effector memory and splenic memory T cells. Nonetheless, the transcriptome signature of subunit vaccine elicited CD8
Trm resembled those elicited by virus infection or vaccination. Clues to the basis of tissue residence and function of vaccine specific CD8
Trm cells were found in transcripts that code for chemokines and chemokine receptors, purinergic receptors, and adhesins when compared to CD8
effector and splenic memory T cells. Our findings inform the utility of protein-based subunit vaccination for installing CD8
Trm cells in the lungs to protect against respiratory infectious diseases that plague humankind.
Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness (URI) in infants are limited.
This prospective cohort enrolled previously healthy term ...infants during inpatient or outpatient visits for acute URI or bronchiolitis during September to May 2004 to 2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time reverse-transcriptase polymerase chain reaction.
Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup and 27% URI. Among infants with bronchiolitis, 76% had respiratory syncytial virus (RSV), 18% human rhinovirus (HRV), 10% influenza, 2% coronavirus, 3% human metapneumovirus and 1% parainfluenza virus. Among infants with croup, 39% had HRV, 28% parainfluenza virus, 28% RSV, 11% influenza, 6% coronavirus and none human metapneumovirus. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% parainfluenza virus and 4% human metapneumovirus. Individual viruses exhibited distinct seasonal, demographic and clinical expression.
The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.
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