Modeling Respiratory Syncytial Virus Adult Vaccination in the United States With a Dynamic Transmission Model.

BACKGROUND: Respiratory syncytial virus (RSV) is shown to cause substantial morbidity, hospitalization, and mortality in infants and older adults. Population-level modeling of RSV allows to estimate the full burden of disease and the potential epidemiological impact of novel prophylactics. METHODS: We modeled the RSV epidemiology in the United States across all ages using a deterministic compartmental transmission model. Population-level symptomatic RSV acute respiratory tract infection (ARI) cases were projected across different natural history scenarios with and without vaccination of adults aged ≥60 years. The impact of vaccine efficacy against ARIs, infectiousness and vaccine coverage on ARI incidence were assessed. The impact on medical attendance, hospitalization, complications, death, and other outcomes was also derived. RESULTS: Without a vaccine, we project 17.5-22.6 million symptomatic RSV ARI cases annually in adults aged ≥18 years in the US, with 3.6-4.8 million/year occurring in adults aged ≥60 years. Modeling indicates that up to 2.0 million symptomatic RSV-ARI cases could be prevented annually in ≥60-year-olds with a hypothetical vaccine (70% vaccine efficacy against symptomatic ARI and 60% vaccine coverage) and that up to 0.69 million/year could be prevented in the nonvaccinated population, assuming 50% vaccine impact on infectiousness. CONCLUSIONS: The model provides estimated burden of RSV in the US across all age groups, with substantial burden projected specifically in older adults. Vaccination of adults aged ≥60 years could significantly reduce the burden of disease in this population, with additional indirect effect in adults aged <60 years due to reduced transmissibility.

Landscape-level validation of allometric relationships for carbon stock estimation reveals bias driven by soil type.

Mitigation of climate change depends on accurate estimation and mapping of terrestrial carbon stocks, particularly in carbon dense tropical forests. Allometric equations can be used to robustly estimate biomass of tropical trees, but often require tree height, which is frequently unknown. Researchers and practitioners must, therefore, decide whether to directly measure a subset of tree heights to develop diameter : height (D:H) equations or rely on previously published generic equations. To date, studies comparing the two approaches have been spatially restricted and/or not randomly allocated across the landscape of interest, making the implications of deciding whether or not to measure tree heights difficult to determine. To address this issue, we use inventory data from a systematic-random forest inventory across Gabon (102 forest sites; 42,627 trees, including 7,036 height-measured trees). Using plot-specific models of D:H as a benchmark, we compare the performance of a suite of locally fitted and commonly used generic models (parameterized national, georegional, and pantropical equations) across a variety of scales, and assess which abiotic, anthropogenic, and topographical covariates contribute the most to bias in height estimation. We reveal marked spatial structure in the magnitude and direction of bias in tree height estimation using all generic models, due at least in part to soil type, which compounded to substantial error in site-level AGB estimates (of up to 38% or 150 Mg/ha). However, two generic pantropical models (Chave 2014; Feldpausch 2012) converged to within 2.5% of mean AGB at the landscape scale. Our results suggest that some (not all) pantropical equations can extrapolate AGB across large spatial scales with minimal bias in estimated mean AGB. However, extreme caution must be taken when interpreting the AGB estimates from generic models at the site-level as they fail to capture substantial spatial variation in D:H relationships, which could lead to dramatic under- or over-estimation of site-level carbon stocks. Validated allometric models derived at site- or soil-type-levels may be the best way to reduce such biases arising from landscape-level heterogeneity in D:H model fit in the Afrotropics.

Spatio-temporal patterns of leptospirosis in Thailand: is flooding a risk factor?

We studied the temporal and spatial patterns of leptospirosis, its association with flooding and animal census data in Thailand. Flood data from 2010 to 2012 were extracted from spatial information taken from satellite images. The incidence rate ratio (IRR) was used to determine the relationship between spatio-temporal flooding patterns and the number of human leptospirosis cases. In addition, the area of flood coverage, duration of waterlogging, time lags between flood events, and a number of potential animal reservoirs were considered in a sub-analysis. There was no significant temporal trend of leptospirosis over the study period. Statistical analysis showed an inconsistent relationship between IRR and flooding across years and regions. Spatially, leptospirosis occurred repeatedly and predominantly in northeastern Thailand. Our findings suggest that flooding is less influential in leptospirosis transmission than previously assumed. High incidence of the disease in the northeastern region is explained by the fact that agriculture and animal farming are important economic activities in this area. The periodic rise and fall of reported leptospirosis cases over time might be explained by seasonal exposure from rice farming activities performed during the rainy season when flood events often occur. We conclude that leptospirosis remains an occupational disease in Thailand.

A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.

Analysis of sintered polymer scaffolds using concomitant synchrotron computed tomography and in situ mechanical testing.

The mechanical behaviour of polymer scaffolds plays a vital role in their successful use in bone tissue engineering. The present study utilised novel sintered polymer scaffolds prepared using temperature-sensitive poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) particles. The microstructure of these scaffolds was monitored under compressive strain by image-guided failure assessment (IGFA), which combined synchrotron radiation computed tomography (SR CT) and in situ micro-compression. Three-dimensional CT data sets of scaffolds subjected to a strain rate of 0.01%/s illustrated particle movement within the scaffolds with no deformation or cracking. When compressed using a higher strain rate of 0.02%/s particle movement was more pronounced and cracks between sintered particles were observed. The results from this study demonstrate that IGFA based on simultaneous SR CT imaging and micro-compression testing is a useful tool for assessing structural and mechanical scaffold properties, leading to further insight into structure-function relationships in scaffolds for bone tissue engineering applications.

The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients.

OBJECTIVES: This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA). METHODS: Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR. RESULTS: For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from <400 to ≥3200. The median half-life of R. typhi IgM was 126 days (interquartile range 36-204 days) and IgG was 177 days (interquartile range 134-355 days). Overall median patient titres for R. typhi IgM and IgG were significantly different (p < 0.0001) and at each temporal sample collection point (range p < 0.0001 to p 0.0411). Using Bayesian latent class model analysis, the optimal diagnostic cut-off reciprocal IFA titer on patient admission for IgM was 800 (78.6%, 95% CI 71.6%-85.2% sensitivity; 89.9%, 95% CI 62.5%-100% specificity), and for IFA IgG 1600 (77.3%; 95% CI 68.2%-87.6% sensitivity; 99%, 95% CI 95%-100% specificity). CONCLUSIONS: This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.

Characterisation and evaluation of the regenerative capacity of Stro-4+ enriched bone marrow mesenchymal stromal cells using bovine extracellular matrix hydrogel and a novel biocompatible melt electro-written medical-grade polycaprolactone scaffold.

Many skeletal tissue regenerative strategies centre around the multifunctional properties of bone marrow derived stromal cells (BMSC) or mesenchymal stem/stromal cells (MSC)/bone marrow derived skeletal stem cells (SSC). Specific identification of these particular stem cells has been inconclusive. However, enriching these heterogeneous bone marrow cell populations with characterised skeletal progenitor markers has been a contributing factor in successful skeletal bone regeneration and repair strategies. In the current studies we have isolated, characterised and enriched ovine bone marrow mesenchymal stromal cells (oBMSCs) using a specific antibody, Stro-4, examined their multipotential differentiation capacity and, in translational studies combined Stro-4+ oBMSCs with a bovine extracellular matrix (bECM) hydrogel and a biocompatible melt electro-written medical-grade polycaprolactone scaffold, and tested their bone regenerative capacity in a small in vivo, highly vascularised, chick chorioallantoic membrane (CAM) model and a preclinical, critical-sized ovine segmental tibial defect model. Proliferation rates and CFU-F formation were similar between unselected and Stro-4+ oBMSCs. Col1A1, Col2A1, mSOX-9, PPARG gene expression were upregulated in respective osteogenic, chondrogenic and adipogenic culture conditions compared to basal conditions with no significant difference between Stro-4+ and unselected oBMSCs. In contrast, proteoglycan expression, alkaline phosphatase activity and adipogenesis were significantly upregulated in the Stro-4+ cells. Furthermore, with extended cultures, the oBMSCs had a predisposition to maintain a strong chondrogenic phenotype. In the CAM model Stro-4+ oBMSCs/bECM hydrogel was able to induce bone formation at a femur fracture site compared to bECM hydrogel and control blank defect alone. Translational studies in a critical-sized ovine tibial defect showed autograft samples contained significantly more bone, (4250.63 mm3, SD = 1485.57) than blank (1045.29 mm3, SD = 219.68) ECM-hydrogel (1152.58 mm3, SD = 191.95) and Stro-4+/ECM-hydrogel (1127.95 mm3, SD = 166.44) groups. Stro-4+ oBMSCs demonstrated a potential to aid bone repair in vitro and in a small in vivo bone defect model using select scaffolds. However, critically, translation to a large related preclinical model demonstrated the complexities of bringing small scale reported stem-cell material therapies to a clinically relevant model and thus facilitate progression to the clinic.

Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity.

Repeated measures data for rotavirus infection in children within 14 day care centres (DCCs) in the Oxfordshire area, UK, are used to explore aspects of rotavirus transmission and immunity. A biologically realistic model for the transmission of infection is presented as a set of probability models suitable for application to the data. Two transition events are modelled separately: incidence and recovery. The complexity of the underlying mechanistic model is reflected in the choice of the fixed variables in the probability models. Parameter estimation was carried out using a Bayesian Markov chain Monte Carlo method. We use the parameter estimates obtained to build a profile of the natural history of rotavirus reinfection in an individual child. We infer that rotavirus transmission in children in DCCs is dependent on the DCC prevalence, with symptomatic infection of longer duration, but no more infectious per day of infectious period, than asymptomatic infection. There was evidence that a recent previous infection reduces the risk of disease and, to a lesser extent, reinfection, but not duration of infection. The results provide evidence that partial immunity to rotavirus infection develops over several time scales.

Understanding the transmission dynamics of respiratory syncytial virus using multiple time series and nested models.

The nature and role of re-infection and partial immunity are likely to be important determinants of the transmission dynamics of human respiratory syncytial virus (hRSV). We propose a single model structure that captures four possible host responses to infection and subsequent reinfection: partial susceptibility, altered infection duration, reduced infectiousness and temporary immunity (which might be partial). The magnitude of these responses is determined by four homotopy parameters, and by setting some of these parameters to extreme values we generate a set of eight nested, deterministic transmission models. In order to investigate hRSV transmission dynamics, we applied these models to incidence data from eight international locations. Seasonality is included as cyclic variation in transmission. Parameters associated with the natural history of the infection were assumed to be independent of geographic location, while others, such as those associated with seasonality, were assumed location specific. Models incorporating either of the two extreme assumptions for immunity (none or solid and lifelong) were unable to reproduce the observed dynamics. Model fits with either waning or partial immunity to disease or both were visually comparable. The best fitting structure was a lifelong partial immunity to both disease and infection. Observed patterns were reproduced by stochastic simulations using the parameter values estimated from the deterministic models.

Towards quantifying the role of hydrogen bonding within amphiphile self-association and resultant aggregate formation.

Herein, we present a series of five tetrabutylammonium (TBA) sulfonate-urea amphiphilic salts. In solution these amphiphilic salts have been shown to form a variety of self-associated species. The proportion and type of which are both solvent and concentration dependent. In DMSO-d6 a variety of NMR experiments provide evidence towards the formation of mainly dimeric over larger aggregate species. Increasing the percentage of water was shown to increase the concentration of the larger aggregates over dimers in solution. A correlation was established between critical micelle concentration (CMC) values obtained in a 1 : 19 EtOH : H2O mixture, dimeric self-association constants obtained in a DMSO-d6 - 0.5% H2O and the results of simple semi-empirical PM6 computational modelling methods. This approach begins to quantify the role of hydrogen bonding in amphiphile self-association and the effects it imparts on surfactant properties. This consequently provides preliminary evidence that these properties maybe predicted by simple low level computational modelling techniques.

The transmission and control of mastitis in dairy cows: a theoretical approach.

A multi-species model that incorporates the transmission of both major and minor mastitis pathogens as well as the interaction between them via coinfection of a quarter is fitted to data from seven dairy herds. The results suggest that major and minor pathogens can interact, on occasion, in a counter-intuitive way with implications for the control of clinical mastitis. The key finding is that delaying culling of cows with major pathogen infections for more than 100 days post infection could result in a higher prevalence of major pathogen infections, whereas early culling would reduce the levels. A theoretical exploration of current and proposed control strategies is carried out, informed by parameters estimated from the model and data. The results at each stage suggest of areas of further research such as: field-testing of the hypotheses presented; the exploration of a stochastic formulation of the model; analysis of the raw repeated measures data; application of control theory to determine the most effective combination of control strategies; inclusion of economic factors into the modelling framework.

Coproduction of Regan isoenzyme and carcinoembryonic antigen in HCT-8 cells.

The presence of the Regan isoenzyme of alkaline phosphatase was demonstrated in the carcinoembryonic antigen-producing human cell line HCT-8 Biochemical, histochemical, immunologic, and electrophoretic methods were used as criteria for the identification and characterization of this isoenzyme.

The release of high-molecular-weight alkaline phosphatase and leucine aminopeptidase into the media of cultured human cells.

Using exclusion from Sepharose 4B as our criterion, we have found a high-molecular-weight form of alkaline phosphatase and of leucine aminopeptidase which are released into the culture media by the FL amnion cell line. A low-molecular-weight form of leucine aminopeptidase is also found to contribute to the total levels of this enzyme in the media. The levels of these enzymes increased during the growth cycle of the culture, paralleling the increase in cell density, suggesting that the two events may be related. This phenomen in culture suggests a possible explanation for the appearance of similar enzyme forms in patient serum and fluids originating from diseased tissue.

Forced exercise increases muscle mass in EAE despite early onset of disability.

We aimed to determine whether 10 days of treadmill exercise can increase skeletal muscle mass and intramuscular concentrations of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE). Forty female Lewis rats were randomly assigned to either EAE sedentary (EAE-Sed), EAE exercise (EAE-Ex), Control sedentary (Con-Sed) and Control exercise (Con-Ex). Exercising animals completed a 10 day forced exercising training program. Hind limb skeletal muscles were excised and weighed with soleus muscle used for BDNF and NGF quantification. Statistical analysis was done using a one-way analysis of variance. Disability was more pronounced in the EAE-Ex group than in the EAE-Sed group. Exercising animals (EAE-Ex and Con-Ex) had significantly greater bilateral EDL, plantaris and gastrocnemius muscle mass compared to their sedentary animals (p=0.01). The EAE-Ex group had significantly higher NGF concentrations (1.98+/-0.3 pg/mg) compared to Con-Ex (0.96+/-0.07 pg/mg, p=0.003) and Con-Sed (1.2+/-0.2 pg/mg, p=0.04) groups. The main effect of exercise represented a significantly lower BDNF concentrations in the soleus of exercising animals compared to sedentary animals (p=0.03). Our study provides preliminary evidence that exercise increases skeletal muscle mass despite the early onset of disability in EAE animals.

Microparasite population dynamics and continuous immunity.

A mathematical model is presented for the transmission of a microparasite where the hosts occupy one of two states, uninfected or infected. In each state, the hosts are distributed over a continuous range of immunity. The immune levels vary within hosts due to the processes of waning of immunity (when uninfected), and increasing immunity (when infected), eventually resulting in recovery. Immunity level also influences the host's ability to infect or be infected. Thus the proposed model incorporates both inter- and intra-host dynamics. It is shown from equilibrium results that this model is a general form of the susceptible-infected-resistant (SIR) and susceptible-infected-susceptible (SIS) family of models, a development that is useful for exploring multistrain pathogen transmission and use of vaccines which confer temporary protection.

The clinical efficacy assessment program of the American College of Physicians.

The experience of the American College of Physicians (ACP) in evaluating the clinical literature and publishing clinical guidelines spans more than a decade. The ACP uses an evidence-based method for the development of clinical practice guidelines for diagnostic technologies and treatments. The approach of the Clinical Efficacy Assessment Program (CEAP) involves collation, methodologic review, and analysis of the clinical literature. The process focuses on the safety, contraindications, efficacy, limitations, and cost of diagnostic technologies or treatments. To ensure a balanced perspective of the evidence, methodologic and content experts cooperate to prepare a summary paper. Strengths of this evidence-based approach include: (1) focus on the needs of practicing internists; (2) identification of all pertinent clinical literature; (3) integration of expert opinion when literature is inadequate; (4) recommendations based on high-quality scientific evidence; (5) preparation of conservative guidelines when evidence is lacking; and (6) reevaluation of past guidelines as new evidence becomes available. Limitations of the process include: (1) access only to published research; (2) use of criteria for scientific quality that are not standardized across projects; (3) published recommendations based on small numbers of high-quality research products; (4) compromise with expert opinion when evidence is limited; and (5) ad hoc management of conflict between experts when scientific evidence is sparse. The process produces credible recommendations that may improve physician knowledge and acceptance of practice guidelines.

Refractive changes at extreme altitude after radial keratotomy.

PURPOSE: We studied the effects of altitude on four corneas that had undergone radial keratotomy and four normal corneas exposed to increasing elevation during a high-altitude excursion. METHODS: We measured visual acuity, cycloplegic refraction, keratometry, and intraocular pressure at sea level and after 24-hour exposure to 12,000 and 17,000 ft. RESULTS: We observed a significant increase in spherical equivalence (hyperopic shift) in radial keratotomy eyes exposed to altitude as compared to controls (P < .0001). The average change in spherical equivalent cycloplegic refraction from sea level to 12,000 ft was 1.03 +/- 0.16 diopters and from sea level to 17,000 ft was 1.94 +/- 0.26 diopters. We also observed a significant decrease in keratometry values at altitude as compared with control corneas (P < .0001). The average change in keratometry from sea level to 12,000 ft was 0.59 +/- 0.19 diopter and from sea level to 17,000 ft was 1.75 +/- 0.27 diopters. CONCLUSIONS: Although the specific origin of these changes is open to question, we hypothesize that hypoxic corneal expansion in the area of the radial keratotomy incisions may lead to central corneal flattening and a hyperopic shift in refractive error. The cornea that has undergone radial keratotomy appears to adjust constantly to changing environmental oxygen concentration, producing a new refractive error over a period of 24 hours or more. Additional study is required to identify with certainty the specific origin of the hyperopic shift at high altitude.

Detection of signals having expected and unexpected temporal structures.

Two experiments used a variant of the 'probe-signal' method [Greenberg and Larkin, J. Acoust. Soc. Am. 44 (1968) 1513-1523] to examine the effect of expectedness on the detection of signals having fixed frequencies but uncertain temporal structures. Expectedness was manipulated by presenting one signal on 75% of the trials and the other on only 25% of trials. Experiment 1 measured sensitivity (d') to 4000-Hz sinusoidal signals having durations of 10 ms and 295 ms. The results confirmed the finding by Wright and Dai [J. Acoust. Soc. Am. 95 (1994) 931-938] that sensitivity was poorer when the duration of the signal was unexpected. The second experiment used two signals having the same overall duration: six 10-ms 4000-Hz tone pulses with a 0-ms inter-pulse interval, and two 10-ms 4000-Hz pulses separated by 40 ms. Again, sensitivity was lower when the temporal structure of the signal was unexpected. It is argued that this finding is inconsistent with 'long time constant' models of temporal integration, but can be accounted for by assuming that subjects combine information from a number of short 'looks' at the signal, with the number and temporal location of these looks being influenced by its expected temporal structure.

Patient transfer from nursing home to emergency department: outcomes and policy implications.

OBJECTIVE: To describe the process and outcomes of nursing home (NH) residents transferred to hospital EDs. METHODS: This was a prospective, observational study conducted at 2 Midwestern community teaching hospitals during a 12-month period. All elder patients (> 64 years of age) transferred to hospital EDs from regional NHs were eligible for the study. Hospital records were used to abstract relevant descriptive and clinical data. Need for ambulance use was graded prospectively using 3 categories of urgency developed in other studies. Transfers were considered "appropriate" based on outcome measures or if the problem necessitated diagnostic and/or therapeutic procedures not available in the NH. Transfer documentation was evaluated using a standardized 18-item checklist. RESULTS: A total of 709 consecutive NH patients made 1,012 ED visits. Their mean age was 83.4 years (range 65-100); 76% were female. The majority of patients (94%) were transferred by ambulance. Ambulance transfer was classified as emergent (16% of patients), urgent (45%), or routine (39%). There were 319 (45%) patients subsequently admitted to the hospital. Approximately 77% (546/709) of the NH transfers were considered appropriate by the emergency physician (EP). Sixty-seven patients (10%) were transferred without any documentation. For those patients with transfer documentation, 6 common discrepancies were identified. CONCLUSION: Although the majority of NH transfers in this population were appropriate, many patients were transferred without adequate documentation for the EP.