Prediction of HIV transmission cluster growth with statewide surveillance data

Background:Prediction of HIV transmission cluster growth may help guide public health action. We developed a predictive model for cluster growth in North Carolina (NC) using routine HIV surveillance data.Methods:We identified putative transmission clusters with ≥2 members through pairwise genetic distances ≤1.5% from HIV-1 pol sequences sampled November 2010-December 2017 in NC. Clusters established by a baseline of January 2015 with any sequences sampled within 2 years before baseline were assessed for growth (new diagnoses) over 18 months. We developed a predictive model for cluster growth incorporating demographic, clinical, temporal, and contact tracing characteristics of baseline cluster members. We internally and temporally externally validated the final model in the periods January 2015-June 2016 and July 2016-December 2017.Results:Cluster growth was predicted by larger baseline cluster size, shorter time between diagnosis and HIV care entry, younger age, shorter time since the most recent HIV diagnosis, higher proportion with no named contacts, and higher proportion with HIV viremia. The model showed areas under the receiver-operating characteristic curves of 0.82 and 0.83 in the internal and temporal external validation samples.Conclusions:The predictive model developed and validated here is a novel means of identifying HIV transmission clusters that may benefit from targeted HIV control resources. © 2018 Wolters Kluwer Health, Inc. All rights reserved

Mycoplasma genitalium Infection in Women Attending a Sexually Transmitted Infection Clinic: Diagnostic Specimen Type, Coinfections, and Predictors

In female sexually transmitted infection (STI) clinic attendees, Mycoplasma genitalium (MG) was more frequently detected using vaginal (53/73) versus endocervical (43/73) specimens. In women without other STIs, MG detection (N=44) was associated with age≤ 22 years (odds ratio (OR) 2.53, P=0.006) and clinical evidence of cervicitis (OR 2.11, P=0.03)

Distance to testing sites and its association with timing of HIV diagnosis *

Early HIV diagnosis enables prompt treatment initiation, thereby contributing to decreased morbidity, mortality, and transmission. We aimed to describe the association between distance from residence to testing sites and HIV disease stage at diagnosis. Using HIV surveillance data, we identified all new HIV diagnoses made at publicly-funded testing sites in central North Carolina during 2005-2013. Early-stage HIV was defined as acute HIV (antibody-negative test with a positive HIV RNA) or recent HIV (normalized optical density <0.8 on the BED assay for non-AIDS cases); remaining diagnoses were considered post-early-stage HIV. Street distance between residence at diagnosis and 1) the closest testing site and 2) the diagnosis site was dichotomized at 5 miles. We fit log-binomial models using generalized estimating equations to estimate prevalence ratios (PR) and robust 95% CI for post-early-stage diagnoses by distance. Models were adjusted for race/ethnicity and testing period. Most of the 3028 new diagnoses were black (N=2144; 70.8%), men who have sex with men (N=1685; 55.7%), and post-early-stage HIV diagnoses (N=2010; 66.4%). Overall, 1145 (37.8%) cases traveled <5 miles for a diagnosis. Among cases traveling ≥5 miles for a diagnosis, 1273 (67.6%) lived <5 miles from a different site. Residing ≥5 miles from a testing site was not associated with post-early-stage HIV (adjusted PR, 95% CI: 0.98, 0.92-1.04), but traveling ≥5 miles for a diagnosis was associated with higher post-early HIV prevalence (1.07, 1.02-1.13). Most of the elevated prevalence observed in cases traveling ≥5 miles for a diagnosis occurred among those living <5 miles from a different site (1.09, 1.03-1.16). Modest increases in post-early-stage HIV diagnosis were apparent among persons living near a site, but choosing to travel longer distances to test. Understanding reasons for increased travel distances could improve accessibility and acceptability of HIV services and increase early diagnosis rates

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Assessing the Conformational Equilibrium of Carboxylic Acid via Quantum Mechanical and Molecular Dynamics Studies on Acetic Acid.

Accurate hydrogen placement in molecular modeling is crucial for studying the interactions and dynamics of biomolecular systems. The carboxyl functional group is a prototypical example of a functional group that requires protonation during structure preparation. To our knowledge, when in their neutral form, carboxylic acids are typically protonated in the syn conformation by default in classical molecular modeling packages, with no consideration of alternative conformations, though we are not aware of any careful examination of this topic. Here, we investigate the general belief that carboxylic acids should always be protonated in the syn conformation. We calculate and compare the relative energetic stabilities of syn and anti acetic acid using ab initio quantum mechanical calculations and atomistic molecular dynamics simulations. We focus on the carboxyl torsional potential and configurations of microhydrated acetic acid from molecular dynamics simulations, probing the effects of solvent, force field (GAFF vs GAFF2), and partial charge assignment of acetic acid. We show that while the syn conformation is the preferred state, the anti state may in some cases also be present under normal NPT conditions in solution

Benchmark assessment of molecular geometries and energies from small molecule force fields.

Background: Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality of these studies relies on the quality of the force fields used to represent the systems. Methods: Focusing on small molecules of fewer than 50 heavy atoms, our aim in this work is to compare nine force fields: GAFF, GAFF2, MMFF94, MMFF94S, OPLS3e, SMIRNOFF99Frosst, and the Open Force Field Parsley, versions 1.0, 1.1, and 1.2. On a dataset comprising 22,675 molecular structures of 3,271 molecules, we analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. Results: We show that while OPLS3e performs best, the latest Open Force Field Parsley release is approaching a comparable level of accuracy in reproducing QM geometries and energetics for this set of molecules. Meanwhile, the performance of established force fields such as MMFF94S and GAFF2 is generally somewhat worse. We also find that the series of recent Open Force Field versions provide significant increases in accuracy. Conclusions: This study provides an extensive test of the performance of different molecular mechanics force fields on a diverse molecule set, and highlights two (OPLS3e and OpenFF 1.2) that perform better than the others tested on the present comparison. Our molecule set and results are available for other researchers to use in testing

Improving small molecule force fields by identifying and characterizing small molecules with inconsistent parameters

Many molecular simulation methods use force fields to help model and simulate molecules and their behavior in various environments. Force fields are sets of functions and parameters used to calculate the potential energy of a chemical system as a function of the atomic coordinates. Despite the widespread use of force fields, their inadequacies are often thought to contribute to systematic errors in molecular simulations. Furthermore, different force fields tend to give varying results on the same systems with the same simulation settings. Here, we present a pipeline for comparing the geometries of small molecule conformers. We aimed to identify molecules or chemistries that are particularly informative for future force field development because they display inconsistencies between force fields. We applied our pipeline to a subset of the eMolecules database, and highlighted molecules that appear to be parameterized inconsistently across different force fields. We then identified over-represented functional groups in these molecule sets. The molecules and moieties identified by this pipeline may be particularly helpful for future force field parameterization

Insights on small molecule binding to the Hv1 proton channel from free energy calculations with molecular dynamics simulations.

Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we computed relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We used alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model and shed light on the preferred tautomeric state of the channel blocker. This work lays the groundwork for future studies on adapting the blocker molecule for more effective inhibition of Hv1

Distance to testing sites and its association with timing of HIV diagnosis *

Early HIV diagnosis enables prompt treatment initiation, thereby contributing to decreased morbidity, mortality, and transmission. We aimed to describe the association between distance from residence to testing sites and HIV disease stage at diagnosis. Using HIV surveillance data, we identified all new HIV diagnoses made at publicly-funded testing sites in central North Carolina during 2005-2013. Early-stage HIV was defined as acute HIV (antibody-negative test with a positive HIV RNA) or recent HIV (normalized optical density <0.8 on the BED assay for non-AIDS cases); remaining diagnoses were considered post-early-stage HIV. Street distance between residence at diagnosis and 1) the closest testing site and 2) the diagnosis site was dichotomized at 5 miles. We fit log-binomial models using generalized estimating equations to estimate prevalence ratios (PR) and robust 95% CI for post-early-stage diagnoses by distance. Models were adjusted for race/ethnicity and testing period. Most of the 3028 new diagnoses were black (N=2144; 70.8%), men who have sex with men (N=1685; 55.7%), and post-early-stage HIV diagnoses (N=2010; 66.4%). Overall, 1145 (37.8%) cases traveled <5 miles for a diagnosis. Among cases traveling ≥5 miles for a diagnosis, 1273 (67.6%) lived <5 miles from a different site. Residing ≥5 miles from a testing site was not associated with post-early-stage HIV (adjusted PR, 95% CI: 0.98, 0.92-1.04), but traveling ≥5 miles for a diagnosis was associated with higher post-early HIV prevalence (1.07, 1.02-1.13). Most of the elevated prevalence observed in cases traveling ≥5 miles for a diagnosis occurred among those living <5 miles from a different site (1.09, 1.03-1.16). Modest increases in post-early-stage HIV diagnosis were apparent among persons living near a site, but choosing to travel longer distances to test. Understanding reasons for increased travel distances could improve accessibility and acceptability of HIV services and increase early diagnosis rates

Escaping Atom Types in Force Fields Using Direct Chemical Perception.

Traditional approaches to specifying a molecular mechanics force field encode all the information needed to assign force field parameters to a given molecule into a discrete set of atom types. This is equivalent to a representation consisting of a molecular graph comprising a set of vertices, which represent atoms labeled by atom type, and unlabeled edges, which represent chemical bonds. Bond stretch, angle bend, and dihedral parameters are then assigned by looking up bonded pairs, triplets, and quartets of atom types in parameter tables to assign valence terms and using the atom types themselves to assign nonbonded parameters. This approach, which we call indirect chemical perception because it operates on the intermediate graph of atom-typed nodes, creates a number of technical problems. For example, atom types must be sufficiently complex to encode all necessary information about the molecular environment, making it difficult to extend force fields encoded this way. Atom typing also results in a proliferation of redundant parameters applied to chemically equivalent classes of valence terms, needlessly increasing force field complexity. Here, we describe a new approach to assigning force field parameters via direct chemical perception. Rather than working through the intermediary of the atom-typed graph, direct chemical perception operates directly on the unmodified chemical graph of the molecule to assign parameters. In particular, parameters are assigned to each type of force field term (e.g., bond stretch, angle bend, torsion, and Lennard-Jones) based on standard chemical substructure queries implemented via the industry-standard SMARTS chemical perception language, using SMIRKS extensions that permit labeling of specific atoms within a chemical pattern. We use this to implement a new force field format, called the SMIRKS Native Open Force Field (SMIRNOFF) format. We demonstrate the power and generality of this approach using examples of specific molecules that pose problems for indirect chemical perception and construct and validate a minimalist yet very general force field, SMIRNOFF99Frosst. We find that a parameter definition file only ∼300 lines long provides coverage of all but &lt;0.02% of a 5 million molecule drug-like test set. Despite its simplicity, the accuracy of SMIRNOFF99Frosst for small molecule hydration free energies and selected properties of pure organic liquids is similar to that of the General Amber Force Field, whose specification requires thousands of parameters. This force field provides a starting point for further optimization and refitting work to follow