Combining genomics and epidemiology to track mumps virus transmission in the United States.

Unusually large outbreaks of mumps across the United States in 2016 and 2017 raised questions about the extent of mumps circulation and the relationship between these and prior outbreaks. We paired epidemiological data from public health investigations with analysis of mumps virus whole genome sequences from 201 infected individuals, focusing on Massachusetts university communities. Our analysis suggests continuous, undetected circulation of mumps locally and nationally, including multiple independent introductions into Massachusetts and into individual communities. Despite the presence of these multiple mumps virus lineages, the genomic data show that one lineage has dominated in the US since at least 2006. Widespread transmission was surprising given high vaccination rates, but we found no genetic evidence that variants arising during this outbreak contributed to vaccine escape. Viral genomic data allowed us to reconstruct mumps transmission links not evident from epidemiological data or standard single-gene surveillance efforts and also revealed connections between apparently unrelated mumps outbreaks

dfpk : An R-package for Bayesian dose-finding designs using Pharmacokinetics (PK) for phase I clinical trials

Background and objective Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. Methods All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. Results For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. Conclusion The developed user-friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information

Prospective SPECT-CT organ dosimetry-driven radiation-absorbed dose escalation using the In-111 (111In)/yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin ®) theranostic pair in patients with lymphoma at myeloablative dose levels

PURPOSE: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin\u27s lymphoma using the theranostic pair of METHODS: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts \u3e 75,000/mm RESULTS: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of CONCLUSIONS: Patient-specific outpatien

HIV-1 Superinfection in Women Broadens and Strengthens the Neutralizing Antibody Response

Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (∼5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23–2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Learning perceptually grounded word meanings from unaligned parallel data

In order for robots to effectively understand natural language commands, they must be able to acquire meaning representations that can be mapped to perceptual features in the external world. Previous approaches to learning these grounded meaning representations require detailed annotations at training time. In this paper, we present an approach to grounded language acquisition which is capable of jointly learning a policy for following natural language commands such as “Pick up the tire pallet,” as well as a mapping between specific phrases in the language and aspects of the external world; for example the mapping between the words “the tire pallet” and a specific object in the environment. Our approach assumes a parametric form for the policy that the robot uses to choose actions in response to a natural language command that factors based on the structure of the language. We use a gradient method to optimize model parameters. Our evaluation demonstrates the effectiveness of the model on a corpus of commands given to a robotic forklift by untrained users.U.S. Army Research Laboratory (Collaborative Technology Alliance Program, Cooperative Agreement W911NF-10-2-0016)United States. Office of Naval Research (MURIs N00014-07-1-0749)United States. Army Research Office (MURI N00014-11-1-0688)United States. Defense Advanced Research Projects Agency (DARPA BOLT program under contract HR0011-11-2-0008

Limited HIV-1 superinfection in seroconverters from the CAPRISA 004 Microbicide trial.

CAPRISA, 2014.HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P=0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P<0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research

Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer

BACKGROUND: The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC). METHODS: Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients. RESULTS: Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found. CONCLUSION: Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies

Comparing breast cancer mortality rates before-and-after a change in availability of screening in different regions: Extension of the paired availability design

BACKGROUND: In recent years there has been increased interest in evaluating breast cancer screening using data from before-and-after studies in multiple geographic regions. One approach, not previously mentioned, is the paired availability design. The paired availability design was developed to evaluate the effect of medical interventions by comparing changes in outcomes before and after a change in the availability of an intervention in various locations. A simple potential outcomes model yields estimates of efficacy, the effect of receiving the intervention, as opposed to effectiveness, the effect of changing the availability of the intervention. By combining estimates of efficacy rather than effectiveness, the paired availability design avoids confounding due to different fractions of subjects receiving the interventions at different locations. The original formulation involved short-term outcomes; the challenge here is accommodating long-term outcomes. METHODS: The outcome is incident breast cancer deaths in a time period, which are breast cancer deaths that were diagnosed in the same time period. We considered the plausibility of the basic five assumptions of the paired availability design and propose a novel analysis to accommodate likely violations of the assumption of stable screening effects. RESULTS: We applied the paired availability design to data on breast cancer screening from six counties in Sweden. The estimated yearly change in incident breast cancer deaths per 100,000 persons ages 40–69 (in most counties) due to receipt of screening (among the relevant type of subject in the potential outcomes model) was -9 with 95% confidence interval (-14, -4) or (-14, -5), depending on the sensitivity analysis. CONCLUSION: In a realistic application, the extended paired availability design yielded reasonably precise confidence intervals for the effect of receiving screening on the rate of incident breast cancer death. Although the assumption of stable preferences may be questionable, its impact will be small if there is little screening in the first time period. However, estimates may be substantially confounded by improvements in systemic therapy over time. Therefore the results should be interpreted with care