High Heritability Is Compatible with the Broad Distribution of Set Point Viral Load in HIV Carriers.

Set point viral load in HIV patients ranges over several orders of magnitude and is a key determinant of disease progression in HIV. A number of recent studies have reported high heritability of set point viral load implying that viral genetic factors contribute substantially to the overall variation in viral load. The high heritability is surprising given the diversity of host factors associated with controlling viral infection. Here we develop an analytical model that describes the temporal changes of the distribution of set point viral load as a function of heritability. This model shows that high heritability is the most parsimonious explanation for the observed variance of set point viral load. Our results thus not only reinforce the credibility of previous estimates of heritability but also shed new light onto mechanisms of viral pathogenesis

Physiological and clinical consequences of relief of right ventricular outflow tract obstruction late after repair of congenital heart defects.

BACKGROUND: Right ventricular outflow tract obstruction (RVOTO) is a common problem after repair of congenital heart disease. Percutaneous pulmonary valve implantation (PPVI) can treat this condition without consequent pulmonary regurgitation or cardiopulmonary bypass. Our aim was to investigate the clinical and physiological response to relieving RVOTO. METHODS AND RESULTS: We studied 18 patients who underwent PPVI for RVOTO (72% male, median age 20 years) from a total of 93 who had this procedure for various indications. All had a right ventricular outflow tract (RVOT) gradient >50 mm Hg on echocardiography without important pulmonary regurgitation (less than mild or regurgitant fraction <10% on magnetic resonance imaging [MRI]). Cardiopulmonary exercise testing, tissue Doppler echocardiography, and MRI were performed before and within 50 days of PPVI. PPVI reduced RVOT gradient (51.4 to 21.7 mm Hg, P<0.001) and right ventricular systolic pressure (72.8 to 47.3 mm Hg, P<0.001) at catheterization. Symptoms and aerobic (25.7 to 28.9 mL.kg(-1).min(-1), P=0.002) and anaerobic (14.4 to 16.2 mL.kg(-1).min(-1), P=0.002) exercise capacity improved. Myocardial systolic velocity improved acutely (tricuspid 4.8 to 5.3 cm/s, P=0.05; mitral 4.7 to 5.5 cm/s, P=0.01), whereas isovolumic acceleration was unchanged. The tricuspid annular velocity was not maintained on intermediate follow-up. Right ventricular end-diastolic volume (99.9 to 89.7 mL/m2, P<0.001) fell, whereas effective stroke volume (43.7 to 48.3 mL/m2, P=0.06) and ejection fraction (48.0% to 56.8%, P=0.01) increased. Left ventricular end-diastolic volume (72.5 to 77.4 mL/m2, P=0.145), stroke volume (45.3 to 50.6 mL/m2, P=0.02), and ejection fraction (62.6% to 65.8%, P=0.03) increased. CONCLUSIONS: PPVI relieves RVOTO, which leads to an early improvement in biventricular performance. Furthermore, it reduces symptoms and improves exercise tolerance. These findings have important implications for the management of this increasingly common condition

The competition dynamics of resistant and sensitive infections

Antimicrobial resistance is a major health problem with complex dynamics. Resistance may occur in an area because treated infections mutated and developed resistance, and the proportion of infections in a population may then increase. We developed a novel and flexible model that captures several features of resistance dynamics and competition. The model is able to account for many antimicrobials and thus can generally explore competition dynamics and their impact on pathogens and bacteria. Unlike simpler models, our nested model allows the population of resistant pathogen to smoothly increase or decrease. Time dependent dynamics are incorporated into difference equations which examines the effects of 12 parameters. This enables us to explicitly include three key competition dynamics: the transmission cost of resistance that occurs between hosts, the fitness cost of resistance that occurs within untreated hosts, and the release of this competition (from the fitness cost) that occurs once a host is treated. For malaria, our results suggest that without competitive release, drug resistance does not emerge. However, once emerged, competitive release has little effect, and the best way to mitigate the spread is to ensure that treatment is very effective

Short-term activity cycles impede information transmission in ant colonies.

Rhythmical activity patterns are ubiquitous in nature. We study an oscillatory biological system: collective activity cycles in ant colonies. Ant colonies have become model systems for research on biological networks because the interactions between the component parts are visible to the naked eye, and because the time-ordered contact network formed by these interactions serves as the substrate for the distribution of information and other resources throughout the colony. To understand how the collective activity cycles influence the contact network transport properties, we used an automated tracking system to record the movement of all the individuals within nine different ant colonies. From these trajectories we extracted over two million ant-to-ant interactions. Time-series analysis of the temporal fluctuations of the overall colony interaction and movement rates revealed that both the period and amplitude of the activity cycles exhibit a diurnal cycle, in which daytime cycles are faster and of greater amplitude than night cycles. Using epidemiology-derived models of transmission over networks, we compared the transmission properties of the observed periodic contact networks with those of synthetic aperiodic networks. These simulations revealed that contrary to some predictions, regularly-oscillating contact networks should impede information transmission. Further, we provide a mechanistic explanation for this effect, and present evidence in support of it

Percutaneous pulmonary valve implantation in humans - Results in 59 consecutive patients

Background - Right ventricular outflow tract (RVOT) reconstruction with valved conduits in infancy and childhood leads to reintervention for pulmonary regurgitation and stenosis in later life.Methods and Results - Patients with pulmonary regurgitation with or without stenosis after repair of congenital heart disease had percutaneous pulmonary valve implantation (PPVI). Mortality, hemodynamic improvement, freedom from explantation, and subjective and objective changes in exercise tolerance were end points. PPVI was performed successfully in 58 patients, 32 male, with a median age of 16 years and median weight of 56 kg. The majority had a variant of tetralogy of Fallot (n = 36), or transposition of the great arteries, ventricular septal defect with pulmonary stenosis (n = 8). The right ventricular (RV) pressure (64.4 +/- 17.2 to 50.4 +/- 14 mm Hg, P < 0.001), RVOT gradient (33 +/- 24.6 to 19.5 +/- 15.3, P < 0.001), and pulmonary regurgitation ( PR) (grade 2 of greater before, none greater than grade 2 after, P < 0.001) decreased significantly after PPVI. MRI showed significant reduction in PR fraction (21 +/- 13% versus 3 +/- 4%, P < 0.001) and in RV end-diastolic volume (EDV) (94 +/- 28 versus 82 +/- 24 mL (.) beat(-1) (.) m(-2), P < 0.001) and a significant increase in left ventricular EDV ( 64 +/- 12 versus 71 +/- 13 mL (.) beat(-1.) m(-2), P = 0.005) and effective RV stroke volume ( 37 +/- 7 versus 42 +/- 9 mL (.) beat(-1) (.) m(-2), P = 0.006) in 28 patients (age 19 +/- 8 years). A further 16 subjects, on metabolic exercise testing, showed significant improvement in V(O2)max (26 +/- 7 versus 29 +/- 6 mL (.) kg(-1) (.) min(-1), P < 0.001). There was no mortality.Conclusions - PPVI is feasible at low risk, with quantifiable improvement in MRI-defined ventricular parameters and pulmonary regurgitation, and results in subjective and objective improvement in exercise capacity

Adherence to the paediatric immunisation schedule in England

Both adequate coverage and adherence to paediatric immunisation schedules are required for optimal protection against vaccine preventable diseases. We studied the timeliness of routine paediatric vaccinations according to the NHS's immunisation schedule and potential factors of schedule adherence. Immunisation data was obtained from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We collected vaccine types, doses, and dates for all routine paediatric vaccines between 2008 and 2018: DTaP/IPV/Hib/HepB, DTaP/IPV/Hib, DTaP/IPV, dTaP/IPV, Td/IPV, MMR, PCV, MenB, MenC, MenACWY, Hib/MenC, RV, HPV. Adherence to the immunisation schedule was calculated for each vaccine and dose. Differences in adherence between genders, NHS regions, and IMD quintiles were analysed. Our study included 6'257'828 vaccinations in 1'005'827 children. Seventy-five percent of first doses were administered within one (for vaccines scheduled in the first year of life) or two months (for vaccines scheduled later in life) following the recommended age, 19% too late and 6% too early. About half of the subsequent doses were given timely. The time between first and second doses was too short for 36% of vaccinations while 13% of second doses were administered too long after the first dose. Third doses were administered timely for 45%, too short for 37%, and too long for 18% of vaccinations. Differences in immunisation schedule adherence between girls and boys were negligible, except for HPV, and differences between the four main NHS regions were small. Overall, immunisation schedule adherence improved slightly with decreasing deprivation according to the Index of Multiple Deprivation. Efforts are required to improve the timeliness of paediatric vaccinations and to assure adequate protection against vaccine preventable diseases. We propose developing a compound measure combining coverage and adherence to provide a better indication of the protection against vaccine preventable diseases in a community

Survival-extinction phase transition in a bit-string population with mutation

A bit-string model for the evolution of a population of haploid organisms, subject to competition, reproduction with mutation and selection is studied, using mean field theory and Monte Carlo simulations. We show that, depending on environmental flexibility and genetic variability, the model exhibits a phase transtion between extinction and survival. The mean-field theory describes the infinite-size limit, while simulations are used to study quasi-stationary properties.Comment: 11 pages, 5 figure

Informed Switching Strongly Decreases the Prevalence of Antibiotic Resistance in Hospital Wards

Antibiotic resistant nosocomial infections are an important cause of mortality and morbidity in hospitals. Antibiotic cycling has been proposed to contain this spread by a coordinated use of different antibiotics. Theoretical work, however, suggests that often the random deployment of drugs (“mixing”) might be the better strategy. We use an epidemiological model for a single hospital ward in order to assess the performance of cycling strategies which take into account the frequency of antibiotic resistance in the hospital ward. We assume that information on resistance frequencies stems from microbiological tests, which are performed in order to optimize individual therapy. Thus the strategy proposed here represents an optimization at population-level, which comes as a free byproduct of optimizing treatment at the individual level. We find that in most cases such an informed switching strategy outperforms both periodic cycling and mixing, despite the fact that information on the frequency of resistance is derived only from a small sub-population of patients. Furthermore we show that the success of this strategy is essentially a stochastic phenomenon taking advantage of the small population sizes in hospital wards. We find that the performance of an informed switching strategy can be improved substantially if information on resistance tests is integrated over a period of one to two weeks. Finally we argue that our findings are robust against a (moderate) preexistence of doubly resistant strains and against transmission via environmental reservoirs. Overall, our results suggest that switching between different antibiotics might be a valuable strategy in small patient populations, if the switching strategies take the frequencies of resistance alleles into account

Co-Evolution of quasispecies: B-cell mutation rates maximize viral error catastrophes

Co-evolution of two coupled quasispecies is studied, motivated by the competition between viral evolution and adapting immune response. In this co-adaptive model, besides the classical error catastrophe for high virus mutation rates, a second ``adaptation-'' catastrophe occurs, when virus mutation rates are too small to escape immune attack. Maximizing both regimes of viral error catastrophes is a possible strategy for an optimal immune response, reducing the range of allowed viral mutation rates to a minimum. From this requirement one obtains constraints on B-cell mutation rates and receptor lengths, yielding an estimate of somatic hypermutation rates in the germinal center in accordance with observation.Comment: 4 pages RevTeX including 2 figure

Antibiotic cycling versus mixing: the difficulty of using mathematical models to definitively quantify their relative merits.

Published PDF version deposited in accordance with SHERPA RoMEO guidelines.We ask the question Which antibiotic deployment protocols select best against drug-resistant microbes: mixing or periodic cycling? and demonstrate that the statistical distribution of the performances of both sets of protocols, mixing and periodic cycling, must have overlapping supports. In other words, it is a general, mathematical result that there must be mixing policies that outperform cycling policies and vice versa. As a result, we agree with the tenet of Bonhoefer et al. [1] that one should not apply the results of [2] to conclude that an antibiotic cycling policy that implements cycles of drug restriction and prioritisation on an ad-hoc basis can select against drug-resistant microbial pathogens in a clinical setting any better than random drug use. However, nor should we conclude that a random, per-patient drug-assignment protocol is the de facto optimal method for allocating antibiotics to patients in any general sense