Staged HIV transmission and treatment in a dynamic model with long-term partnerships.

The transmission dynamics of HIV are closely tied to the duration and overlap of sexual partnerships. We develop an autonomous population model that can account for the possibilities of an infection from either a casual sexual partner or a long-term partner who was either infected at the start of the partnership or has been newly infected since the onset of the partnership. The impact of the long-term partnerships on the rate of infection is captured by calculating the expected values of the rate of infection from these extended contacts. The model includes three stages of infectiousness: acute, chronic, and virally suppressed. We calculate HIV incidence and the fraction of new infections attributed to casual contacts and long-term partnerships allowing for variability in condom usage, the effect of achieving and maintaining viral suppression, and early intervention by beginning HAART during the acute phase of infection. We present our results using data on MSM HIV transmission from the CDC in the U.S. While the acute stage is the most infectious, the majority of the new infections will be transmitted by long-term partners in the chronic stage when condom use is infrequent as is common in long-term relationships. Time series analysis of the solution, as well as parameter sensitivity analysis, are used to determine effective intervention strategies.

Using social media listening to understand barriers to genomic medicine for those living with Ehlers-Danlos syndromes and hypermobility spectrum disorders.

INTRODUCTION: Technological improvements alone have not led to the integration of genomic medicine across a broad range of diseases and populations. For genomic medicine to be successfully implemented across specialties and conditions, the challenges patients and caregivers experience need to be identified using a multi-faceted understanding of the context in which these obstacles occur and how they are experienced. Individuals affected by rare conditions, like Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD), express numerous challenges with accessing genomic medicine. Many patients living with rare diseases seek information and find comfort in online health communities. METHODS: Social media conversations facilitated through online health communities are windows into patients' and caregivers' authentic experiences. To date, no other study has examined genomic medicine barriers by analysing the content of social media posts, yet the novel methodological approach of social media listening permits the analysis of virtual, organic conversations about lived experiences. RESULTS/CONCLUSIONS: Using a modified social-ecological model, this study found that social-structural and interpersonal barriers most frequently impede access to genomic medicine for patients and caregivers living with EDS and HSD. PATIENT OR PUBLIC CONTRIBUTION: Data were retrieved through social media conversations facilitated through publicly accessible health communities through Inspire, an online health community. Social media listening permits the analysis of virtual, organic conversations about lived experiences.

The role of curvature feedback in the energetics and dynamics of lamprey swimming: A closed-loop model.

Like other animals, lampreys have a central pattern generator (CPG) circuit that activates muscles for locomotion and also adjusts the activity to respond to sensory inputs from the environment. Such a feedback system is crucial for responding appropriately to unexpected perturbations, but it is also active during normal unperturbed steady swimming and influences the baseline swimming pattern. In this study, we investigate different functional forms of body curvature-based sensory feedback and evaluate their effects on steady swimming energetics and kinematics, since little is known experimentally about the functional form of curvature feedback. The distributed CPG is modeled as chains of coupled oscillators. Pairs of phase oscillators represent the left and right sides of segments along the lamprey body. These activate muscles that flex the body and move the lamprey through a fluid environment, which is simulated using a full Navier-Stokes model. The emergent curvature of the body then serves as an input to the CPG oscillators, closing the loop. We consider two forms of feedback, each consistent with experimental results on lamprey proprioceptive sensory receptors. The first, referred to as directional feedback, excites or inhibits the oscillators on the same side, depending on the sign of a chosen gain parameter, and has the opposite effect on oscillators on the opposite side. We find that directional feedback does not affect beat frequency, but does change the duration of muscle activity. The second feedback model, referred to as magnitude feedback, provides a symmetric excitatory or inhibitory effect to oscillators on both sides. This model tends to increase beat frequency and reduces the energetic cost to the lamprey when the gain is high and positive. With both types of feedback, the body curvature has a similar magnitude. Thus, these results indicate that the same magnitude of curvature-based feedback on the CPG with different functional forms can cause distinct differences in swimming performance.

Patient-Reported Outcomes in Online Communications on Statins, Memory, and Cognition: Qualitative Analysis Using Online Communities.

BACKGROUND: In drug development clinical trials, there is a need for balance between restricting variables by setting eligibility criteria and representing the broader patient population that may use a product once it is approved. Similarly, although recent policy initiatives focusing on the inclusion of historically underrepresented groups are being implemented, barriers still remain. These limitations of clinical trials may mask potential product benefits and side effects. To bridge these gaps, online communication in health communities may serve as an additional population signal for drug side effects. OBJECTIVE: The aim of this study was to employ a nontraditional dataset to identify drug side-effect signals. The study was designed to apply both natural language processing (NLP) technology and hands-on linguistic analysis to a set of online posts from known statin users to (1) identify any underlying crossover between the use of statins and impairment of memory or cognition and (2) obtain patient lexicon in their descriptions of experiences with statin medications and memory changes. METHODS: Researchers utilized user-generated content on Inspire, looking at over 11 million posts across Inspire. Posts were written by patients and caregivers belonging to a variety of communities on Inspire. After identifying these posts, researchers used NLP and hands-on linguistic analysis to draw and expand upon correlations among statin use, memory, and cognition. RESULTS: NLP analysis of posts identified statistical correlations between statin users and the discussion of memory impairment, which were not observed in control groups. NLP found that, out of all members on Inspire, 3.1% had posted about memory or cognition. In a control group of those who had posted about TNF inhibitors, 6.2% had also posted about memory and cognition. In comparison, of all those who had posted about a statin medication, 22.6% (P<.001) also posted about memory and cognition. Furthermore, linguistic analysis of a sample of posts provided themes and context to these statistical findings. By looking at posts from statin users about memory, four key themes were found and described in detail in the data: memory loss, aphasia, cognitive impairment, and emotional change. CONCLUSIONS: Correlations from this study point to a need for further research on the impact of statins on memory and cognition. Furthermore, when using nontraditional datasets, such as online communities, NLP and linguistic methodologies broaden the population for identifying side-effect signals. For side effects such as those on memory and cognition, where self-reporting may be unreliable, these methods can provide another avenue to inform patients, providers, and the Food and Drug Administration.

Characterization of the encoding properties of intraspinal mechanosensory neurons in the lamprey.

Proprioceptive sensory inputs are an integral part of the closed-loop system of locomotion. In the lamprey, a model organism for vertebrate locomotion, such sensory inputs come from intraspinal mechanosensory cells called "edge cells". These edge cells synapse directly onto interneurons in the spinal central pattern generator (CPG) circuit and allow the CPG to adjust the motor output according to how the body is bending. However, the encoding properties of the edge cells have never been fully characterized. To identify these properties and better understand edge cells' role in locomotion, we isolated spinal cords of silver lampreys (Ichthyomyzon unicuspis) and recorded extracellularly from the lateral tracts where edge cell axons are located. We identified cells that responded to mechanical stimuli and used standard spike sorting algorithms to identify separate units, then examined how the cells respond to bending rate and bending angle. Although some cells respond to the bending angle, as was previously known, the strongest and most common responses were to bending velocity. These encoding properties will help us better understand how lampreys and other basal vertebrates adapt their locomotor rhythms to different water flow patterns, perturbations, or other unexpected changes in their environments.

Blow-spun chitosan/PEG/PLGA nanofibers as a novel tissue engineering scaffold with antibacterial properties.

Blow spinning is continuing to gain attention in tissue engineering, as the resultant nanofibrous structures can be used to create a biomimetic environment. In this study, blow spinning was used to construct nanofiber scaffolds with up to 10 % chitosan and poly(DL-lactide-co-glycolide) in the absence or presence of poly(ethylene glycol). Scanning electron microscopy demonstrated that nanofibers were distributed randomly to form three-dimensional mats. With respect to chitosan concentration, the average fiber diameter did not differ statistically in either the absence or presence of poly(ethylene glycol). In poly(ethylene glycol)-formulations, the average fiber diameter ranged from (981.9 ± 611.3) nm to (1139.2 ± 814.2) nm. In vitro cellular metabolic activity and proliferation studies using keratinized rat squamous epithelial cells (RL-65) showed that cytocompatibility was not compromised with the addition of poly(ethylene glycol). The cell responses at lower (1 and 2.5 %) chitosan concentrations were not significantly different from the groups without chitosan or no scaffold when cultivated for 3, 6, or 9 days. However, >15 % reduction in cellular responses were observed at 10 % chitosan. In presence of poly(ethylene glycol), nearly a 1-log incremental reduction in the number of colony forming units of Streptococcus mutans occurred as the chitosan concentration increased from 0-1 to 2.5 %. Bacterial preparations tested with poly(ethylene glycol) and 5 or 10 % chitosan were not significantly different than the positive kill control. Taken together, the most favorable conditions for attaining cytocompatibility and maintaining antibacterial functionality existed in poly(ethylene glycol)/poly(DL-lactide-co-glycolide) blow-spun scaffolds with integrated 1 or 2.5 % chitosan.

Rethinking online health information: How about personalization?

Dr. Howard Koh, Former Assistant Secretary of Health and Human Services (HHS explained, "While [health literacy] may not necessarily attract headlines, it is absolutely at the core of everything we do as health care ... professionals." Yet making health information that is searched for on the Internet accessible means not only reducingjargon but also reducing volume. Personalization is one answer that Medivizor, a start-up featured in Forbes, has developed to answer the need. Hospitals and providers partner with Medivizor to improve the health literacy of patients, enhancing engagement and collaborative decision-making.

Roles of GABAA and GABAB receptors in regulating thalamic activity by the zona incerta: a computational study.

The posterior thalamic nucleus (PO) is a higher order nucleus heavily implicated in the processing of somatosensory information. We have previously shown in rodent models that activity in PO is tightly regulated by inhibitory inputs from a GABAergic nucleus known as the zona incerta (ZI). The level of incertal inhibition varies under both physiological and pathological conditions, leading to concomitant changes in PO activity. These changes are causally linked to variety of phenomena from altered sensory perception to pathological pain. ZI regulation of PO is mediated by GABAA and GABAB receptors (GABAAR and GABABR) that differ in their binding kinetics and their electrophysiological properties, suggesting that each may have distinct roles in incerto-thalamic regulation. We developed a computational model to test this hypothesis. We created a two-cell Hodgkin-Huxley model representing PO and ZI with kinetically realistic GABAAR- and GABABR-mediated synapses. We simulated spontaneous and evoked firing in PO and observed how these activities were affected by inhibition mediated by each receptor type. Our model predicts that spontaneous PO activity is preferentially regulated by GABABR-mediated mechanisms, while evoked activity is preferentially regulated by GABAAR. Our model also predicts that modulation of ZI firing rate and synaptic GABA concentrations is an effective means to regulate the incerto-thalamic circuit. The coupling of distinct functions to GABAAR and GABABR presents an opportunity for the development of therapeutics, as particular aspects of incerto-thalamic regulation can be targeted by manipulating the corresponding receptor class. Thus these findings may provide interventions for pathologies of sensory processing.

Effect of parity on productivity and sustainability of Lotka-Volterra food chains: bounded orbits in food chains.

Hairston, Slobodkin, and Smith conjectured that top down forces act on food chains, which opposed the previously accepted theory that bottom up forces exclusively dictate the dynamics of populations. We model food chains using the Lotka-Volterra predation model and derive sustainability constants which determine which species will persist or go extinct. Further, we show that the productivity of a sustainable food chain with even trophic levels is predator regulated, or top down, while a sustainable food chain with odd trophic levels is resource limited, which is bottom up, which is consistent with current ecological theory.

Breakthrough Symptoms Remain an Unmet Need in Symptomatic Patients With Neuroendocrine Tumors and Carcinoid Syndrome.

OBJECTIVES: The aims of the study were to assess the effects of breakthrough carcinoid syndrome symptoms on well-being in neuroendocrine tumor (NET) patients insufficiently controlled on long-acting somatostatin analog (SSA) and to assess patient experience with treatment options, physician communication, and disease information sources. METHODS: This study surveyed US NET patients from 2 online communities, experiencing at least one symptom, by utilizing a 64-item questionnaire. RESULTS: One hundred patients participated: 73% female, 75% age 56 to 75 years, and 93% White. Primary tumor distribution was as follows: gastrointestinal NET (n = 55), pancreatic NET (n = 33), lung NET (n = 11), and other NET (n = 13). All patients were actively treated with one long-acting SSA and experiencing breakthrough symptoms: diarrhea, flushing, or other (13% experienced one, 30% two, 57% greater than two). More than one third of treated patients experienced carcinoid-related symptoms daily. Sixty percent of respondents reported not having short-acting "rescue" treatment available, impacting well-being though anxiety or depression (45%), trouble exercising (65%), sleeping (57%), employment (54%), and maintaining friendships (43%). CONCLUSIONS: Breakthrough symptoms remain an unmet need, even in treated patients with NETs. Though still relying on physicians, NET patients are now also using the Internet. Improved awareness of optimal SSA use may improve syndrome control.

COVID-19 Vaccine Hesitancy and Acceptance Among Individuals With Cancer, Autoimmune Diseases, or Other Serious Comorbid Conditions: Cross-sectional, Internet-Based Survey.

BACKGROUND: Individuals with comorbid conditions have been disproportionately affected by COVID-19. Since regulatory trials of COVID-19 vaccines excluded those with immunocompromising conditions, few patients with cancer and autoimmune diseases were enrolled. With limited vaccine safety data available, vulnerable populations may have conflicted vaccine attitudes. OBJECTIVE: We assessed the prevalence and independent predictors of COVID-19 vaccine hesitancy and acceptance among individuals with serious comorbidities and assessed self-reported side effects among those who had been vaccinated. METHODS: We conducted a cross-sectional, 55-item, online survey, fielded January 15, 2021 through February 22, 2021, among a random sample of members of Inspire, an online health community of over 2.2 million individuals with comorbid conditions. Multivariable regression analysis was utilized to determine factors independently associated with vaccine hesitancy and acceptance. RESULTS: Of the 996,500 members of the Inspire health community invited to participate, responses were received from 21,943 individuals (2.2%). Respondents resided in 123 countries (United States: 16,277/21,943, 74.2%), had a median age range of 56-65 years, were highly educated (college or postgraduate degree: 10,198/17,298, 58.9%), and had diverse political leanings. All respondents self-reported at least one comorbidity: cancer, 27.3% (5459/19,980); autoimmune diseases, 23.2% (4946/21,294); chronic lung diseases: 35.4% (7544/21,294). COVID-19 vaccine hesitancy was identified in 18.6% (3960/21,294), with 10.3% (2190/21,294) declaring that they would not, 3.5% (742/21,294) stating that they probably would not, and 4.8% (1028/21,294) not sure whether they would agree to be vaccinated. Hesitancy was expressed by the following patients: cancer, 13.4% (731/5459); autoimmune diseases, 19.4% (962/4947); chronic lung diseases: 17.8% (1344/7544). Positive predictors of vaccine acceptance included routine influenza vaccination (odds ratio [OR] 1.53), trust in responsible vaccine development (OR 14.04), residing in the United States (OR 1.31), and never smoked (OR 1.06). Hesitancy increased with a history of prior COVID-19 (OR 0.86), conservative political leaning (OR 0.93), younger age (OR 0.83), and lower education level (OR 0.90). One-quarter (5501/21,294, 25.8%) had received at least one COVID-19 vaccine injection, and 6.5% (1390/21,294) completed a 2-dose series. Following the first injection, 69.0% (3796/5501) self-reported local reactions, and 40.0% (2200/5501) self-reported systemic reactions, which increased following the second injection to 77.0% (1070/1390) and 67.0% (931/1390), respectively. CONCLUSIONS: In this survey of individuals with serious comorbid conditions, significant vaccine hesitancy remained. Assumptions that the most vulnerable would automatically accept COVID-19 vaccination are erroneous and thus call for health care team members to initiate discussions focusing on the impact of the vaccine on an individual's underlying condition. Early self-reported side effect experiences among those who had already been vaccinated, as expressed by our population, should be reassuring and might be utilized to alleviate vaccine fears. Health care-related social media forums that rapidly disseminate accurate information about the COVID-19 vaccine may play an important role.

Entrainment ranges of forced phase oscillators.

In the vertebrate spinal cord, a neural circuit called the central pattern generator produces the basic locomotory rhythm. Short and long distance intersegmental connections serve to maintain coordination along the length of the body. As a way of examining the influence of such connections, we consider a model of a chain of coupled phase oscillators in which one oscillator receives a periodic forcing stimulus. For a certain range of forcing frequencies, the chain will match the stimulus frequency, a phenomenon called entrainment. Motivated by recent experiments in lampreys, we derive analytical expressions for the range of forcing frequencies that entrain the chain, and how that range depends on the forcing location. For short intersegmental connections, in which an oscillator is connected only to its nearest neighbors, we describe two ways in which entrainment is lost: internally, in which oscillators within the chain no longer oscillate at the same frequency; and externally, in which the the chain no longer has the same frequency as the forcing. By analyzing chains in which every oscillator is connected to every other oscillator (i.e., all-to-all connections), we show that the presence of connections with lengths greater than one do not necessarily change the entrainment ranges based on the nearest-neighbor model. We derive a criterion for the ratio of connection strengths under which the connections of length greater than one do not change the entrainment ranges produced in the nearest-neighbor model, provided entrainment is lost externally. However, when this criterion holds, the range of entrained frequencies is a monotonic function of forcing location, unlike experimental results, in which entrainment ranges are larger near the middle of the chain than at the ends. Numerically, we show that similar non-monotonic entrainment ranges are possible if the ratio criterion does not hold, suggesting that in the lamprey central pattern generator, intersegmental connection strengths are not a simple function of the connection length.

On the derivation and tuning of phase oscillator models for lamprey central pattern generators.

Using phase response curves and averaging theory, we derive phase oscillator models for the lamprey central pattern generator from two biophysically-based segmental models. The first one relies on network dynamics within a segment to produce the rhythm, while the second contains bursting cells. We study intersegmental coordination and show that the former class of models shows more robust behavior over the animal's range of swimming frequencies. The network-based model can also easily produce approximately constant phase lags along the spinal cord, as observed experimentally. Precise control of phase lags in the network-based model is obtained by varying the relative strengths of its six different connection types with distance in a phase model with separate coupling functions for each connection type. The phase model also describes the effect of randomized connections, accurately predicting how quickly random network-based models approach the determinisitic model as the number of connections increases.

Entrainment Ranges for Chains of Forced Neural and Phase Oscillators.

Sensory input to the lamprey central pattern generator (CPG) for locomotion is known to have a significant role in modulating lamprey swimming. Lamprey CPGs are known to have the ability to entrain to a bending stimulus, that is, in the presence of a rhythmic signal, the CPG will change its frequency to match the stimulus frequency. Bending experiments in which the lamprey spinal cord has been removed and mechanically bent back and forth at a single point have been used to determine the range of frequencies that can entrain the CPG rhythm. First, we model the lamprey locomotor CPG as a chain of neural oscillators with three classes of neurons and sinusoidal forcing representing edge cell input. We derive a phase model using the connections described in the neural model. This results in a simpler model yet maintains some properties of the neural model. For both the neural model and the derived phase model, entrainment ranges are computed for forcing at different points along the chain while varying both intersegmental coupling strength and the coupling strength between the forcer and chain. Entrainment ranges for chains with nonuniform intersegmental coupling asymmetry are larger when forcing is applied to the middle of the chain than when it is applied to either end, a result that is qualitatively similar to the experimental results. In the limit of weak coupling in the chain, the entrainment results of the neural model approach the entrainment results for the derived phase model. Both biological experiments and the robustness of non-monotonic entrainment ranges as a function of the forcing position across different classes of CPG models with nonuniform asymmetric coupling suggest that a specific property of the intersegmental coupling of the CPG is key to entrainment.

Development and Assessment of Modules to Integrate Quantitative Skills in Introductory Biology Courses.

Redesigning undergraduate biology courses to integrate quantitative reasoning and skill development is critical to prepare students for careers in modern medicine and scientific research. In this paper, we report on the development, implementation, and assessment of stand-alone modules that integrate quantitative reasoning into introductory biology courses. Modules are designed to improve skills in quantitative numeracy, interpreting data sets using visual tools, and making inferences about biological phenomena using mathematical/statistical models. We also examine demographic/background data that predict student improvement in these skills through exposure to these modules. We carried out pre/postassessment tests across four semesters and used student interviews in one semester to examine how students at different levels approached quantitative problems. We found that students improved in all skills in most semesters, although there was variation in the degree of improvement among skills from semester to semester. One demographic variable, transfer status, stood out as a major predictor of the degree to which students improved (transfer students achieved much lower gains every semester, despite the fact that pretest scores in each focus area were similar between transfer and nontransfer students). We propose that increased exposure to quantitative skill development in biology courses is effective at building competency in quantitative reasoning.

Smoldering and Flame Resistant Textiles via Conformal Barrier Formation.

A durable and flexible silicone-based backcoating (halogen free) is applied to the backside of an otherwise smoldering-prone and flammable fabric. When exposed to fire, cyclic siloxanes (produced by thermal decomposition of the backcoating) diffuse through the fabric in the gas phase. The following oxidation of the cyclic siloxanes forms a highly conformal and thermally stable coating that fully embeds all individual fibers and shields them from heat and oxidation. As a result, the combustion of the fabric is prevented. This is a novel fire retardant mechanism that discloses a powerful approach towards textiles and multifunctional flexible materials with combined smoldering/flaming ignition resistance and fire-barrier properties.

Airbrushed composite polymer Zr-ACP nanofiber scaffolds with improved cell penetration for bone tissue regeneration.

Electrospun polymer nanofibers have multiple applications in the tissue engineering field despite limited cell penetration within the scaffolds and slow synthesis rates. Airbrushing, a proposed alternative to traditional electrospinning, is a technique capable of synthesizing open structure nanofiber scaffolds at high rates. In this study, three biocompatible polymers-poly-D,L-lactic acid (P-DL-LA), polycaprolactone (PCL), and poly(methyl methacrylate) (PMMA), were airbrushed to form networks for bone tissue regeneration. All three polymers were loaded with up to 20% (w/w) zirconium-modified amorphous calcium phosphate (Zr-ACP). A simple one-step mix and straightforward material deposition yielded open structure networks with well-distributed Zr-ACP. Cell penetration within the airbrushed scaffolds was found to be more than twice the cell penetration within conventional electrospun networks. The airbrushed polymer network supported cell growth and differentiation. Cells grown on the Zr-ACP in P-DL-LA fibers exhibited improved levels of osteocalcin protein with an increase in the Zr-ACP content by day 16. This airbrushing method promises to be a viable and attractive alternative to currently used electrospinning techniques in the formation of composite 3D nanofiber scaffolds for tissue engineering applications.

Analysis of SI models with multiple interacting populations using subpopulations.

Computing endemic equilibria and basic reproductive numbers for systems of differential equations describing epidemiological systems with multiple connections between subpopulations is often algebraically intractable. We present an alternative method which deconstructs the larger system into smaller subsystems and captures the interactions between the smaller systems as external forces using an approximate model. We bound the basic reproductive numbers of the full system in terms of the basic reproductive numbers of the smaller systems and use the alternate model to provide approximations for the endemic equilibrium. In addition to creating algebraically tractable reproductive numbers and endemic equilibria, we can demonstrate the influence of the interactions between subpopulations on the basic reproductive number of the full system. The focus of this paper is to provide analytical tools to help guide public health decisions with limited intervention resources.

Normal hematologic and serum clinical chemistry values for captive chimpanzees (Pan troglodytes).

In the study reported here, reference intervals for hematologic and serum clinical chemistry variables in the chimpanzee (Pan troglodytes) were developed and characterized. Data were collected longitudinally across a 10-year period for 86 subjects at the Primate Foundation of Arizona (PFA). Variables included nine standard hematologic and 25 standard serum clinical chemistry values. An analysis of variance (ANOVA) was used to test for main effects by age and sex. In addition, PFA mean and range values were compared with those published for humans and six other chimpanzee colonies. The ANOVA results suggest an age effect on hematologic (mean corpuscular hemoglobin, mean corpuscular volume, neutrophils) and serum clinical chemical (creatinine, total protein, globulin, tryglycerides, direct bilirubin, iron, (gamma-glutamyltransferase, alanine transaminase, creatine kinase) values. In addition, sex had a main effect on several variables (red blood cells, hemoglobin concentration, hematocrit, uric acid and sodium concentrations, and aspartate transminase and creatine kinase activities); values for males were greater than those for females. Further, human and chimpanzee mean and range values often were indistinguishable from one another. However, changes in human and chimpanzee values associated with age differ and suggest that hematologic and serum clinical chemistry values may be differentially affected by physical and sexual maturation in humans and chimpanzees.