Combining Search, Social Media, and Traditional Data Sources to Improve Influenza Surveillance

We present a machine learning-based methodology capable of providing real-time ("nowcast") and forecast estimates of influenza activity in the US by leveraging data from multiple data sources including: Google searches, Twitter microblogs, nearly real-time hospital visit records, and data from a participatory surveillance system. Our main contribution consists of combining multiple influenza-like illnesses (ILI) activity estimates, generated independently with each data source, into a single prediction of ILI utilizing machine learning ensemble approaches. Our methodology exploits the information in each data source and produces accurate weekly ILI predictions for up to four weeks ahead of the release of CDC's ILI reports. We evaluate the predictive ability of our ensemble approach during the 2013-2014 (retrospective) and 2014-2015 (live) flu seasons for each of the four weekly time horizons. Our ensemble approach demonstrates several advantages: (1) our ensemble method's predictions outperform every prediction using each data source independently, (2) our methodology can produce predictions one week ahead of GFT's real-time estimates with comparable accuracy, and (3) our two and three week forecast estimates have comparable accuracy to real-time predictions using an autoregressive model. Moreover, our results show that considerable insight is gained from incorporating disparate data streams, in the form of social media and crowd sourced data, into influenza predictions in all time horizon

Safety and tolerability of SRX246, a vasopressin 1a antagonist, in irritable Huntington\u27s disease patients—A randomized phase 2 clinical trial

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Epidemic Wave Dynamics Attributable to Urban Community Structure: A Theoretical Characterization of Disease Transmission in a Large Network.

BACKGROUND: Multiple waves of transmission during infectious disease epidemics represent a major public health challenge, but the ecological and behavioral drivers of epidemic resurgence are poorly understood. In theory, community structure—aggregation into highly intraconnected and loosely interconnected social groups—within human populations may lead to punctuated outbreaks as diseases progress from one community to the next. However, this explanation has been largely overlooked in favor of temporal shifts in environmental conditions and human behavior and because of the difficulties associated with estimating large-scale contact patterns. OBJECTIVE: The aim was to characterize naturally arising patterns of human contact that are capable of producing simulated epidemics with multiple wave structures. METHODS: We used an extensive dataset of proximal physical contacts between users of a public Wi-Fi Internet system to evaluate the epidemiological implications of an empirical urban contact network. We characterized the modularity (community structure) of the network and then estimated epidemic dynamics under a percolation-based model of infectious disease spread on the network. We classified simulated epidemics as multiwave using a novel metric and we identified network structures that were critical to the network's ability to produce multiwave epidemics. RESULTS: We identified robust community structure in a large, empirical urban contact network from which multiwave epidemics may emerge naturally. This pattern was fueled by a special kind of insularity in which locally popular individuals were not the ones forging contacts with more distant social groups. CONCLUSIONS: Our results suggest that ordinary contact patterns can produce multiwave epidemics at the scale of a single urban area without the temporal shifts that are usually assumed to be responsible. Understanding the role of community structure in epidemic dynamics allows officials to anticipate epidemic resurgence without having to forecast future changes in hosts, pathogens, or the environment

Clustering and conservation patterns of human microRNAs

MicroRNAs (miRNAs) are ∼22 nt-long non-coding RNA molecules, believed to play important roles in gene regulation. We present a comprehensive analysis of the conservation and clustering patterns of known miRNAs in human. We show that human miRNA gene clustering is significantly higher than expected at random. A total of 37% of the known human miRNA genes analyzed in this study appear in clusters of two or more with pairwise chromosomal distances of at most 3000 nt. Comparison of the miRNA sequences with their homologs in four other organisms reveals a typical conservation pattern, persistent throughout the clusters. Furthermore, we show enrichment in the typical conservation patterns and other miRNA-like properties in the vicinity of known miRNA genes, compared with random genomic regions. This may imply that additional, yet unknown, miRNAs reside in these regions, consistent with the current recognition that there are overlooked miRNAs. Indeed, by comparing our predictions with cloning results and with identified miRNA genes in other mammals, we corroborate the predictions of 18 additional human miRNA genes in the vicinity of the previously known ones. Our study raises the proportion of clustered human miRNAs that are <3000 nt apart to 42%. This suggests that the clustering of miRNA genes is higher than currently acknowledged, alluding to its evolutionary and functional implications

Identification of clustered microRNAs using an ab initio prediction method

BACKGROUND: MicroRNAs (miRNAs) are endogenous 21 to 23-nucleotide RNA molecules that regulate protein-coding gene expression in plants and animals via the RNA interference pathway. Hundreds of them have been identified in the last five years and very recent works indicate that their total number is still larger. Therefore miRNAs gene discovery remains an important aspect of understanding this new and still widely unknown regulation mechanism. Bioinformatics approaches have proved to be very useful toward this goal by guiding the experimental investigations. RESULTS: In this work we describe our computational method for miRNA prediction and the results of its application to the discovery of novel mammalian miRNAs. We focus on genomic regions around already known miRNAs, in order to exploit the property that miRNAs are occasionally found in clusters. Starting with the known human, mouse and rat miRNAs we analyze 20 kb of flanking genomic regions for the presence of putative precursor miRNAs (pre-miRNAs). Each genome is analyzed separately, allowing us to study the species-specific identity and genome organization of miRNA loci. We only use cross-species comparisons to make conservative estimates of the number of novel miRNAs. Our ab initio method predicts between fifty and hundred novel pre-miRNAs for each of the considered species. Around 30% of these already have experimental support in a large set of cloned mammalian small RNAs. The validation rate among predicted cases that are conserved in at least one other species is higher, about 60%, and many of them have not been detected by prediction methods that used cross-species comparisons. A large fraction of the experimentally confirmed predictions correspond to an imprinted locus residing on chromosome 14 in human, 12 in mouse and 6 in rat. Our computational tool can be accessed on the world-wide-web. CONCLUSION: Our results show that the assumption that many miRNAs occur in clusters is fruitful for the discovery of novel miRNAs. Additionally we show that although the overall miRNA content in the observed clusters is very similar across the three considered species, the internal organization of the clusters changes in evolution

The Azomethine Imine Route to Guanidines. Total Synthesis of (+)-Saxitoxin

Azomethine imines may be readily generated through the interaction of aldehyde aeetals with earboxylie acid hydrazides. These reaetions are most highly favored in pollar aprotie solvents and aeid eatalysis is required. With suitably funetionalized hydrazides these substanees undergo a faeile intramolecular addition to give fused-ring pyrazolidine derivati ves. As a part of these studies, (± )-Saxitoxin (7), the paralytie agent of the Alaska butter elam Saxidomas giganteus, has been synthesized in a totally stereospecific fashion through a sequenee involving as the key steps: (a) intramolecular 1,3-dipolar addition of an azomethine imine to a 2-imidazolone; (b) reductive cleavage of the resulting pyrazolidine ring followed by intramoleeular acylation; and (c) final elaboration of a bis-pseudourea to the requisite guanidine functionality

SDSS-IV MaNGA: the different quenching histories of fast and slow rotators

Do the theorised different formation mechanisms of fast and slow rotators produce an observable difference in their star formation histories? To study this we identify quenching slow rotators in the MaNGA sample by selecting those which lie below the star forming sequence and identify a sample of quenching fast rotators which were matched in stellar mass. This results in a total sample of 194 kinematically classified galaxies, which is agnostic to visual morphology. We use u − r and NUV − u colours from SDSS and GALEX and an existing inference package, STARPY, to conduct a first look at the onset time and exponentially declining rate of quenching of these galaxies. An Anderson-Darling test on the distribution of the inferred quenching rates across the two kinematic populations reveals they are statistically distinguishable (3.2σ). We find that fast rotators quench at a much wider range of rates than slow rotators, consistent with a wide variety of physical processes such as secular evolution, minor mergers, gas accretion and environmentally driven mechanisms. Quenching is more likely to occur at rapid rates (τ≲1 Gyr) for slow rotators, in agreement with theories suggesting slow rotators are formed in dynamically fast processes, such as major mergers. Interestingly, we also find that a subset of the fast rotators quench at these same rapid rates as the bulk of the slow rotator sample. We therefore discuss how the total gas mass of a merger, rather than the merger mass ratio, may decide a galaxy’s ultimate kinematic fate