Disentangling the causes of mumps reemergence in the United States.

Over the past two decades, multiple countries with high vaccine coverage have experienced resurgent outbreaks of mumps. Worryingly, in these countries, a high proportion of cases have been among those who have completed the recommended vaccination schedule, raising alarm about the effectiveness of existing vaccines. Two putative mechanisms of vaccine failure have been proposed as driving observed trends: 1) gradual waning of vaccine-derived immunity (necessitating additional booster doses) and 2) the introduction of novel viral genotypes capable of evading vaccinal immunity. Focusing on the United States, we conduct statistical likelihood-based hypothesis testing using a mechanistic transmission model on age-structured epidemiological, demographic, and vaccine uptake time series data. We find that the data are most consistent with the waning hypothesis and estimate that 32.8% (32%, 33.5%) of individuals lose vaccine-derived immunity by age 18 y. Furthermore, we show using our transmission model how waning vaccine immunity reproduces qualitative and quantitatively consistent features of epidemiological data, namely 1) the shift in mumps incidence toward older individuals, 2) the recent recurrence of mumps outbreaks, and 3) the high proportion of mumps cases among previously vaccinated individuals.

The Number and Pattern of Viral Genomic Reassortments are not Necessarily Identifiable from Segment Trees.

Reassortment is an evolutionary process common in viruses with segmented genomes. These viruses can swap whole genomic segments during cellular co-infection, giving rise to novel progeny formed from the mixture of parental segments. Since large-scale genome rearrangements have the potential to generate new phenotypes, reassortment is important to both evolutionary biology and public health research. However, statistical inference of the pattern of reassortment events from phylogenetic data is exceptionally difficult, potentially involving inference of general graphs in which individual segment trees are embedded. In this paper, we argue that, in general, the number and pattern of reassortment events are not identifiable from segment trees alone, even with theoretically ideal data. We call this fact the fundamental problem of reassortment, which we illustrate using the concept of the "first-infection tree," a potentially counterfactual genealogy that would have been observed in the segment trees had no reassortment occurred. Further, we illustrate four additional problems that can arise logically in the inference of reassortment events and show, using simulated data, that these problems are not rare and can potentially distort our observation of reassortment even in small data sets. Finally, we discuss how existing methods can be augmented or adapted to account for not only the fundamental problem of reassortment, but also the four additional situations that can complicate the inference of reassortment.

Ligand Centered Reactivity of a Transition Metal Bound Geometrically Constrained Phosphine.

The electronic properties, coordination chemistry and reactivity of metal complexes of a planar (C2v symmetric) acridane-derived geometrically constrained phosphine, P(NNN), are described. On complexation to metal centers, the phosphine was found to adopt a distorted trigonal pyramidal structure with a high barrier to pyramidal inversion (22.3 kcal/mol at 298 K for Au[P(NNN)]Cl). Spectroscopic data and theoretical calculations carried out at the density functional level of theory indicate that P(NNN) is a moderate σ-donor, with significant π-acceptor properties. Despite the distortion undergone by the phosphorus atom on coordination to metal centers, the P(NNN) ligand retains its ability to react with small molecule substrates with polar E-H bonds (MeOH, NH2Ph, NH3). It does so in a concerted fashion across one of the P-N bonds, and reversibly in the case of amine substrates. This cooperative bond activation chemistry may ultimately prove beneficial in catalysis.

The contradictory role of febuxostat in ABCG2 expression and potentiating hypericin-mediated photodynamic therapy in colorectal cancers.

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.

Strategic outline of interventions targeting extracellular matrix for promoting healthy longevity.

The extracellular matrix (ECM), composed of interlinked proteins outside of cells, is an important component of the human body that helps maintain tissue architecture and cellular homeostasis. As people age, the ECM undergoes changes that can lead to age-related morbidity and mortality. Despite its importance, ECM aging remains understudied in the field of geroscience. In this review, we discuss the core concepts of ECM integrity, outline the age-related challenges and subsequent pathologies and diseases, summarize diagnostic methods detecting a faulty ECM, and provide strategies targeting ECM homeostasis. To conceptualize this, we built a technology research tree to hierarchically visualize possible research sequences for studying ECM aging. This strategic framework will hopefully facilitate the development of future research on interventions to restore ECM integrity, which could potentially lead to the development of new drugs or therapeutic interventions promoting health during aging.

Reactivity of a Strictly T-Shaped Phosphine Ligated by an Acridane Derived NNN Pincer Ligand.

The steric tuning of a tridentate acridane-derived NNN pincer ligand allows for the isolation of a strictly T-shaped phosphine that exhibits ambiphilic reactivity. Well-defined phosphorus-centered reactivity towards nucleophiles and electrophiles is reported, contrasting with prior reports on this class of compounds. Reactions towards oxidants are also described. The latter result in the two-electron oxidation of the phosphorus atom from +III to +V and are accompanied by a strong geometric distortion of the NNN pincer ligand. By contrast, cooperative activation of E-H (HCl, HBcat, HOMe) bonds proceeds with retention of the phosphorus redox state. When using H2 O as a substrate, the reaction results in the full disassembly of H2 O to its constituent atoms, highlighting the potential of this platform for small molecule activation reactions.

Glucagon-Like Peptide 1 Receptor Agonists Have the Potential to Revolutionize the Attainment of Target A1C Levels in Type 2 Diabetes-So Why Is Their Uptake So Low?

A target A1C of <7% is the recommended goal for most people with type 2 diabetes. However, many are not achieving this target with their current treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are highly efficacious in achieving glycemic control and could aid primary care providers (PCPs) in getting patients to their A1C target. However, despite their potential, use of GLP-1 receptor agonists in the primary care setting is limited. This review provides guidance for PCPs on how to help patients achieve their glycemic target and overcome perceived barriers of GLP-1 receptor agonist use, with the overall goal of improving PCP confidence in prescribing these agents.

Markov genealogy processes.

We construct a family of genealogy-valued Markov processes that are induced by a continuous-time Markov population process. We derive exact expressions for the likelihood of a given genealogy conditional on the history of the underlying population process. These lead to a nonlinear filtering equation which can be used to design efficient Monte Carlo inference algorithms. We demonstrate these calculations with several examples. Existing full-information approaches for phylodynamic inference are special cases of the theory.

The contribution of host cell-directed vs. parasite-directed immunity to the disease and dynamics of malaria infections.

Hosts defend themselves against pathogens by mounting an immune response. Fully understanding the immune response as a driver of host disease and pathogen evolution requires a quantitative account of its impact on parasite population dynamics. Here, we use a data-driven modeling approach to quantify the birth and death processes underlying the dynamics of infections of the rodent malaria parasite, Plasmodium chabaudi, and the red blood cells (RBCs) it targets. We decompose the immune response into 3 components, each with a distinct effect on parasite and RBC vital rates, and quantify the relative contribution of each component to host disease and parasite density. Our analysis suggests that these components are deployed in a coordinated fashion to realize distinct resource-directed defense strategies that complement the killing of parasitized cells. Early in the infection, the host deploys a strategy reminiscent of siege and scorched-earth tactics, in which it both destroys RBCs and restricts their supply. Late in the infection, a "juvenilization" strategy, in which turnover of RBCs is accelerated, allows the host to recover from anemia while holding parasite proliferation at bay. By quantifying the impact of immunity on both parasite fitness and host disease, we reveal that phenomena often interpreted as immunopathology may in fact be beneficial to the host. Finally, we show that, across mice, the components of the host response are consistently related to each other, even when infections take qualitatively different trajectories. This suggests the existence of simple rules that govern the immune system's deployment.

The impact of infection-derived immunity on disease dynamics.

When modeling infectious diseases, it is common to assume that infection-derived immunity is either (1) non-existent or (2) perfect and lifelong. However there are many diseases in which infection-derived immunity is known to be present but imperfect. There are various ways in which infection-derived immunity can fail, which can ultimately impact the probability that an individual be reinfected by the same pathogen, as well as the long-run population-level prevalence of the pathogen. Here we discuss seven different models of imperfect infection-derived immunity, including waning, leaky and all-or-nothing immunity. For each model we derive the probability that an infected individual becomes reinfected during their lifetime, given that the system is at endemic equilibrium. This can be thought of as the impact that each of these infection-derived immunity failures have on reinfection. This measure is useful because it provides us with a way to compare different modes of failure of infection-derived immunity.

Differential and enhanced response to climate forcing in diarrheal disease due to rotavirus across a megacity of the developing world.

The role of climate forcing in the population dynamics of infectious diseases has typically been revealed via retrospective analyses of incidence records aggregated across space and, in particular, over whole cities. Here, we focus on the transmission dynamics of rotavirus, the main diarrheal disease in infants and young children, within the megacity of Dhaka, Bangladesh. We identify two zones, the densely urbanized core and the more rural periphery, that respond differentially to flooding. Moreover, disease seasonality differs substantially between these regions, spanning variation comparable to the variation from tropical to temperate regions. By combining process-based models with an extensive disease surveillance record, we show that the response to climate forcing is mainly seasonal in the core, where a more endemic transmission resulting from an asymptomatic reservoir facilitates the response to the monsoons. The force of infection in this monsoon peak can be an order of magnitude larger than the force of infection in the more epidemic periphery, which exhibits little or no postmonsoon outbreak in a pattern typical of nearby rural areas. A typically smaller peak during the monsoon season nevertheless shows sensitivity to interannual variability in flooding. High human density in the core is one explanation for enhanced transmission during troughs and an associated seasonal monsoon response in this diarrheal disease, which unlike cholera, has not been widely viewed as climate-sensitive. Spatial demographic, socioeconomic, and environmental heterogeneity can create reservoirs of infection and enhance the sensitivity of disease systems to climate forcing, especially in the populated cities of the developing world.

Quinone-based fluorophores for imaging biological processes.

Quinones are privileged chemical structures playing crucial roles as redox and alkylating agents in a wide range of processes in cells. The broad functional array of quinones has prompted the development of new chemical approaches, including C-H bond activation and asymmetric reactions, to generate probes for examining their activity by means of fluorescence imaging. This tutorial review covers recent advances in the design, synthesis and applications of quinone-based fluorescent agents for visualizing specific processes in multiple biological systems, from cells to tissues and complex organisms in vivo.

Unraveling the Transmission Ecology of Polio.

Sustained and coordinated vaccination efforts have brought polio eradication within reach. Anticipating the eradication of wild poliovirus (WPV) and the subsequent challenges in preventing its re-emergence, we look to the past to identify why polio rose to epidemic levels in the mid-20th century, and how WPV persisted over large geographic scales. We analyzed an extensive epidemiological dataset, spanning the 1930s to the 1950s and spatially replicated across each state in the United States, to glean insight into the drivers of polio's historical expansion and the ecological mode of its persistence prior to vaccine introduction. We document a latitudinal gradient in polio's seasonality. Additionally, we fitted and validated mechanistic transmission models to data from each US state independently. The fitted models revealed that: (1) polio persistence was the product of a dynamic mosaic of source and sink populations; (2) geographic heterogeneity of seasonal transmission conditions account for the latitudinal structure of polio epidemics; (3) contrary to the prevailing "disease of development" hypothesis, our analyses demonstrate that polio's historical expansion was straightforwardly explained by demographic trends rather than improvements in sanitation and hygiene; and (4) the absence of clinical disease is not a reliable indicator of polio transmission, because widespread polio transmission was likely in the multiyear absence of clinical disease. As the world edges closer to global polio eradication and continues the strategic withdrawal of the Oral Polio Vaccine (OPV), the regular identification of, and rapid response to, these silent chains of transmission is of the utmost importance.

Clinical Insights About Onychomycosis and Its Treatment: A Consensus.

BACKGROUND: Recently, experience and knowledge have been gained using effective topical treatment for onychomycosis, a difficult-to-treat infection. METHODS: This project aims to help understand and improve patient-focused quality of care for fungal nail infections. A panel of dermatologists who treat onychomycosis convened on several occasions to review and discuss recent learnings in the treatment of onychomycosis. The panel developed and conducted a survey on diagnosis, treatment and prevention, discussed the results, and provided recommendations. RESULTS: The survey was sent out digitally to the Canadian Dermatology community. Ninety-two dermatologists completed the questionnaires, which were included in the analysis. The survey respondents and panel members agreed that the diagnosis of toe onychomycosis should be confirmed with a positive microscopic examination for fungus or a positive mycological culture when oral therapy and/or topical treatment is prescribed, except when it is not clinically feasible, in which case topical therapy could be started based on clinical presentation. The panel and survey respondents also agreed that treatment is to be based on percentage of nail involvement: less than 20%=topical efinaconazole; 20%-60%=topical efinaconazole±oral terbinafine (for greater than 3 nails); greater than 60%=oral terbinafine±topical therapy. CONCLUSIONS: The current treatment paradigm for onychomycosis may have shifted from mainly oral antifungals to topical treatment, improving patient-focused quality of care.

J Drugs Dermatol. 2018;17(3):253-262.

Inference for dynamic and latent variable models via iterated, perturbed Bayes maps.

Iterated filtering algorithms are stochastic optimization procedures for latent variable models that recursively combine parameter perturbations with latent variable reconstruction. Previously, theoretical support for these algorithms has been based on the use of conditional moments of perturbed parameters to approximate derivatives of the log likelihood function. Here, a theoretical approach is introduced based on the convergence of an iterated Bayes map. An algorithm supported by this theory displays substantial numerical improvement on the computational challenge of inferring parameters of a partially observed Markov process.

On the synthesis of quinone-based BODIPY hybrids: New insights on antitumor activity and mechanism of action in cancer cells.

Fluorescent quinone-based BODIPY hybrids were synthesised and characterised by NMR analysis and mass spectrometry. We measured their cytotoxic activity against cancer and normal cell lines, performed mechanistic studies by lipid peroxidation and determination of reduced (GSH) and oxidized (GSSG) glutathione, and imaged their subcellular localisation by confocal microscopy. Cell imaging experiments indicated that nor-ß-lapachone-based BODIPY derivatives might preferentially localise in the lysosomes of cancer cells. These results assert the potential of hybrid quinone-BODIPY derivatives as promising prototypes in the search of new potent lapachone antitumor drugs.

Time-varying, serotype-specific force of infection of dengue virus.

Infectious disease models play a key role in public health planning. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the per-capita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Dengue virus (DENV) is a mosquito-borne, multiserotype pathogen that currently infects ∼390 million people a year. Existing estimates of the DENV FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. Here, we present to our knowledge the first time-varying (daily), serotype-specific estimates of DENV FoIs using a spline-based fitting procedure designed to examine a 12-y, longitudinal DENV serological dataset from Iquitos, Peru (11,703 individuals, 38,416 samples, and 22,301 serotype-specific DENV infections from 1999 to 2010). The yearly DENV FoI varied markedly across time and serotypes (0-0.33), as did daily basic reproductive numbers (0.49-4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.

Maternal pertussis immunisation: clinical gains and epidemiological legacy.

The increase in whooping cough (pertussis) incidence in many countries with high routine vaccination coverage is alarming, with incidence in the US reaching almost 50,000 reported cases per year, reflecting incidence levels not seen since the 1950s. While the potential explanations for this resurgence remain debated, we face an urgent need to protect newborns, especially during the time window between birth and the first routine vaccination dose. Maternal immunisation has been proposed as an effective strategy for protecting neonates, who are at higher risk of severe pertussis disease and mortality. However, if maternally derived antibodies adversely affect the immunogenicity of the routine schedule, through blunting effects, we may observe a gradual degradation of herd immunity. 'Wasted' vaccines would result in an accumulation of susceptible children in the population, specifically leading to an overall increase in incidence in older age groups. In this Perspective, we discuss potential long-term epidemiological effects of maternal immunisation, as determined by possible immune interference outcomes.

Climate-driven endemic cholera is modulated by human mobility in a megacity.

Although a differential sensitivity of cholera dynamics to climate variability has been reported in the spatially heterogeneous megacity of Dhaka, Bangladesh, the specific patterns of spread of the resulting risk within the city remain unclear. We build on an established probabilistic spatial model to investigate the importance and role of human mobility in modulating spatial cholera transmission. Mobility fluxes were inferred using a straightforward and generalizable methodology that relies on mapping population density based on a high resolution urban footprint product, and a parameter-free human mobility model. In accordance with previous findings, we highlight the higher sensitivity to the El Niño Southern Oscillation (ENSO) in the highly populated urban center than in the more rural periphery. More significantly, our results show that cholera risk is largely transmitted from the climate-sensitive core to the periphery of the city, with implications for the planning of control efforts. In addition, including human mobility improves the outbreak prediction performance of the model with an 11 month lead. The interplay between climatic and human mobility factors in cholera transmission is discussed from the perspective of the rapid growth of megacities across the developing world.

The pertussis enigma: reconciling epidemiology, immunology and evolution.

Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980-2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.