A modeled time-varying density function for the incubation period of AIDS

Building on the Weibull distribution, we develop a modeled time-varying density function of the incubation time between exposure to HIV infection and full-blown AIDS. This approach leads to a series of cohort-specific density functions that take into account the increasing impact of new therapies such as zidovudine (AZT). The resulting modeled density functions are studied in detail, particularly with regard to their modes and medians. The mode is sensitive to changes in the period incubation time distribution, with even a possibility of a bimodal distribution for certain combinations of the parameters that determine the rate at which the period median incubation time changes. An important substantive result is that when a period median incubation period slowly increases to some leveling off value, say m(x _c ), then it is surprisingly early on that cohorts of infected individuals have a median incubation period very close to that ultimate value m(x _c ).     

Correlation analysis for the incubation period of prion disease

Previous studies have shown that genetic quantitative trait loci (QTL), strain barriers, inoculation dose and inoculation method modulate the incubation period of prion diseases. We examined the relationship between a diverse set of physical, genetic and immunological characteristics and the incubation period of prion disease using correlation analyses. We found that incubation period was highly correlated with brain weight. In addition, mean corpuscular volume and cell size were strongly correlated with incubation period, indicating that the physical magnitude of prion-infected organs or individual cells may be important in determining the incubation period. Given the same prion inoculation dose, animals with a lower brain weight, mean corpuscular volume or cell size may experience more virulent disease, as the effective concentration of abnormal prion, which might regulate the attachment rate of prions to aggregates, is increased with smaller capacity of brains and cells. This is partly consistent with previous theoretical modeling. The strong correlations between incubation period and physical properties of the brain and cells in this study suggest that the mechanism underlying prion disease pathology may be physical, indicating that the incubation process is governed by simple chemical stoichiometry.     

Correlation analysis for the incubation period of prion disease

Previous studies have shown that genetic quantitative trait loci (QTL), strain barriers, inoculation dose and inoculation method modulate the incubation period of prion diseases. We examined the relationship between a diverse set of physical, genetic and immunological characteristics and the incubation period of prion disease using correlation analyses. We found that incubation period was highly correlated with brain weight. In addition, mean corpuscular volume and cell size were strongly correlated with incubation period, indicating that the physical magnitude of prion-infected organs or individual cells may be important in determining the incubation period. Given the same prion inoculation dose, animals with a lower brain weight, mean corpuscular volume or cell size may experience more virulent disease, as the effective concentration of abnormal prion, which might regulate the attachment rate of prions to aggregates, is increased with smaller capacity of brains and cells. This is partly consistent with previous theoretical modeling. The strong correlations between incubation period and physical properties of the brain and cells in this study suggest that the mechanism underlying prion disease pathology may be physical, indicating that the incubation process is governed by simple chemical stoichiometry.     

Visualizing clinical evidence: citation networks for the incubation periods of respiratory viral infections

Simply by repetition, medical facts can become enshrined as truth even when there is little empirical evidence supporting them. We present an intuitive and clear visual design for tracking the citation history of a particular scientific fact over time. We apply this method to data from a previously published literature review on the incubation period of nine respiratory viral infections. The resulting citation networks reveal that the conventional wisdom about the incubation period for these diseases was based on a small fraction of available data and in one case, on no retrievable empirical evidence. Overall, 50% of all incubation period statements did not provide a source for their estimate and 65% of original sources for incubation period data were not incorporated into subsequent publications. More standardized and widely available methods for visualizing these histories of medical evidence are needed to ensure that conventional wisdom cannot stray too far from empirically supported knowledge.     

Estimation of the incubation period of influenza A (H1N1-2009) among imported cases: addressing censoring using outbreak data at the origin of importation

Empirical estimates of the incubation period of influenza A (H1N1-2009) have been limited. We estimated the incubation period among confirmed imported cases who traveled to Japan from Hawaii during the early phase of the 2009 pandemic (n=72). We addressed censoring and employed an infection-age structured argument to explicitly model the daily frequency of illness onset after departure. We assumed uniform and exponential distributions for the frequency of exposure in Hawaii, and the hazard rate of infection for the latter assumption was retrieved, in Hawaii, from local outbreak data. The maximum likelihood estimates of the median incubation period range from 1.43 to 1.64 days according to different modeling assumptions, consistent with a published estimate based on a New York school outbreak. The likelihood values of the different modeling assumptions do not differ greatly from each other, although models with the exponential assumption yield slightly shorter incubation periods than those with the uniform exposure assumption. Differences between our proposed approach and a published method for doubly interval-censored analysis highlight the importance of accounting for the dependence of the frequency of exposure on the survival function of incubating individuals among imported cases. A truncation of the density function of the incubation period due to an absence of illness onset during the exposure period also needs to be considered. When the data generating process is similar to that among imported cases, and when the incubation period is close to or shorter than the length of exposure, accounting for these aspects is critical for long exposure times.     

The effect of the incubation period on the result of MPN enumerations of nitrite-oxidizing bacteria: theoretical considerations

Abstract A computer model based on Monod- and Haldane-kinetics was used to estimate the minimum incubation period required for MPN enumerations of nitrite-oxidizing bacteria. The minimum incubation period was defined as the time needed for one cell, present in the tubes inoculated with the highest dilutions, to grow into a population that oxidized all the nitrite present at the start of the incubation. Kinetic parameters used in the model were derived from literature data and applied in different combinations. The results show that the minimum incubation period may increase with decreasing initial nitrite concentrations in the incubation medium. They also show that the opposite trend, i.e. increasing minimum incubation periods with increasing nitrite concentration periods with increasing nitrite concentration, can be explained by introducing a term for substrate inhibition in the model. A MPN enumeration result obtained with samples from a waterlogged peat bog soil could only partly be explained by the model if only one set of parameters was used. This indicates that the community of nitrite-oxidizing bacteria in this soil is composed of at least two types of nitrite-oxidizing bacteria, with different kinetic parameters of nitrite oxidation and growth.     

Low genetic variance in the duration of the incubation period in a collared flycatcher (Ficedula albicollis) population

The avian incubation period is associated with high energetic costs and mortality risks suggesting that there should be strong selection to reduce the duration to the minimum required for normal offspring development. Although there is much variation in the duration of the incubation period across species, there is also variation within species. It is necessary to estimate to what extent this variation is genetically determined if we want to predict the evolutionary potential of this trait. Here we use a long-term study of collared flycatchers to examine the genetic basis of variation in incubation duration. We demonstrate limited genetic variance as reflected in the low and nonsignificant additive genetic variance, with a corresponding heritability of 0.04 and coefficient of additive genetic variance of 2.16. Any selection acting on incubation duration will therefore be inefficient. To our knowledge, this is the first time heritability of incubation duration has been estimated in a natural bird population.     

Development and metabolism of chicken embryos in the embryogenesis under acoustic stimulation

Acoustic influence on the metabolic process in the last days of incubation of embryos of domestic chicken was found. It was shown that the changes that appear under the influence of acoustic signals lead to a decrease in incubation time. As a result of acoustic hyperstimulation, gaseous exchange and growth of the embryo continue to follow a power dependence characteristic of an earlier period of embryogenesis, i.e., the depression typical of these processes in the end of incubation is arrested. In acoustically stimulated embryos, a tendency toward a decrease in the total energy expenses on growth and metabolism is observed in the period from 17 days of incubation up to hatching, but the daily expenses on energetic exchange and growth are higher under acoustic influence than in the control group.     

Critical period in the work of the form-inducing apparatus of the lens in chick embryos, detected after chloramphenicol application

The inhibitor of protein synthesis chloramphenicol (2 mg/egg) was applied to elucidate the critical period in the chicken lens development. Chloramphenicol injected before incubation and at 24, 30 and 48 h of incubation did not prevent the formation of parts in the lens-inducing apparatus (the optic vesicle, and the presumptive lens ectoderm), but the injection at the stage of 24--30 h of incubation resulted, in many survived for 5--7 days of incubation, in lack of the lens. Therefore, it is possible to speak about a disturbance in the activity of the inducing apparatus during the period of determination, or about a critical period of the lens development.     

Effects of stimuli emanating from the nest on the reproductive cycle in the ring dove. III: building in the postlaying period and effects on the success of the cycle.

Nest-building as a functional activity is shown to continue well into the incubation period of the ring dove (Streptopelia risoria), its intensity depending on the state of the nest. The presence of a nest has profound consequences on breeding success: pairs with no nests did not incubate well and did not hatch their eggs. Pre-laying disruption of the nest or of the usual roles of the male and female had no effect on incubation as long as a nest was present when the eggs were laid. It is concluded that the presence of a nest is necessary for the proper establishment of incubation. The possible role of the nest in incubation is discussed.     

Development and metabolism of chicken embryos in the prenatal period under acoustic stimulation

Acoustic influence on the metabolic process in the last days of incubation of embryos of domestic chicken was found. It was shown that the changes that appear under the influence of acoustic signals lead to a decrease in incubation time. As a result of acoustic hyperstimulation, gaseous exchange and growth of the embryo continue to follow a power dependence characteristic of an earlier period of embryogenesis, i.e., the depression typical of these processes in the end of incubation is arrested. In acoustically stimulated embryos, a tendency toward a decrease in the total energy expenses on growth and metabolism is observed in the period from 17 days of incubation up to hatching, but the daily expenses on energetic exchange and growth are higher under acoustic influence than in the control group.     

The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrP(Sc), is an essential component of the infectious agent, the strain-specific relationship between PrP(Sc) properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrP(Sc) from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrP(Sc) in neurons and glia. We found that short incubation period strains were characterized by more efficient PrP(Sc) amplification and higher PrP(Sc) conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrP(Sc) in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrP(Sc) did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrP(Sc) in neurons.     

The use of R2A medium and the spread plate method for the enumeration of heterotrophic bacteria in drinking water

The pour plate method with yeast extract agar and a 3 d incubation period is the standard method in the UK for the enumeration of heterotrophic bacteria in drinking water. We have compared the standard method with other procedures using the spread plate technique, R2A medium and a longer incubation period. The R2A spread plate method with a 7 d incubation period gave an average estimate of bacterial numbers 520 times greater than for the standard method. This alternative method is recommended for obtaining a more accurate estimate of heterotrophic bacterial populations in drinking water.     

Association between the Severity of Influenza A(H7N9) Virus Infections and Length of the Incubation Period

Background

In early 2013, a novel avian-origin influenza A(H7N9) virus emerged in China, and has caused sporadic human infections. The incubation period is the delay from infection until onset of symptoms, and varies from person to person. Few previous studies have examined whether the duration of the incubation period correlates with subsequent disease severity.

Methods and Findings

We analyzed data of period of exposure on 395 human cases of laboratory-confirmed influenza A(H7N9) virus infection in China in a Bayesian framework using a Weibull distribution. We found a longer incubation period for the 173 fatal cases with a mean of 3.7 days (95% credibility interval, CrI: 3.4–4.1), compared to a mean of 3.3 days (95% CrI: 2.9–3.6) for the 222 non-fatal cases, and the difference in means was marginally significant at 0.47 days (95% CrI: -0.04, 0.99). There was a statistically significant correlation between a longer incubation period and an increased risk of death after adjustment for age, sex, geographical location and underlying medical conditions (adjusted odds ratio 1.70 per day increase in incubation period; 95% credibility interval 1.47–1.97).

Conclusions

We found a significant association between a longer incubation period and a greater risk of death among human H7N9 cases. The underlying biological mechanisms leading to this association deserve further exploration.     

The Strain-Encoded Relationship between PrPSc Replication,Stability and Processing in Neurons is Predictive of the Incubation Period of Disease

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrP^Sc, is an essential component of the infectious agent, the strain-specific relationship between PrP^Sc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrP^Sc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrP^Sc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrP^Sc amplification and higher PrP^Sc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrP^Sc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrP^Sc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrP^Sc in neurons.     

Nonparametric estimation of the incubation period of AIDS based on a prevalent cohort with unknown infection times.

Estimation of the incubation period distribution of human immunodeficiency virus based on prevalent cohorts of subjects, already infected at the time of recruitment, is complicated by the absence of information on the original times of infection. Here, we overcome this difficulty by using a prior distribution for the infection times, based on external data. Our estimate is nonparametric, but uses smoothness assumptions to avoid instability. The method is illustrated on two prevalent cohorts from San Francisco, separately and combined. The estimates produced agree with other published estimates of the incubation period distribution.     

The effect of the virus-serum incubation period upon vaccinia virus serum neutralization titers

Rabbit and human vaccinia virus immune sera were titrated by the plaque reduction serum neutralization (SN) method. Titers determined following a 2-h, 37 degree C virus-serum incubation period were not significantly different from those determined following an 18-h incubation period (2-h, 37 degree C incubation followed by a 16-h, 4 degree C period). However, control virus plaque counts decreased significantly after the longer incubation period. Numerous factors affecting SN titer estimation are reviewed. Standardization of SN test conditions may be useful in comparative potency evaluation of vaccinia-vectored recombinant DNA viral vaccines.     

Experimental reduction of incubation temperature affects both nestling and adult blue tits Cyanistes caeruleus

Incubation was for a long time considered to be a period of decreased activity and low cost for parents. It was therefore ignored as a potential factor affecting life‐history trade‐offs in birds. Lately this view has started to change, and studies now show that there might be considerable costs connected to incubation. We experimentally reduced the nest temperature during incubation in blue tits Cyanistes caeruleus, thus increasing the energetic cost of incubation, to test the importance of incubation as a component of reproductive costs and for nestling quality. While most other studies use brood size manipulation to manipulate reproductive costs, we were able to separate treatment effects acting during the incubation period from those acting on later reproductive performance by applying a cross‐foster design. We were also able to isolate the effects of decreased incubation temperature on the nestlings from treatment effects acting on incubating females. We found no experimental effect on the length of the incubation period or on hatching success. The lower temperature during incubation, however, caused lower growth rates in nestlings and reduced chick rearing capacity in adults. We conclude that incubation is a costly period, with the potential to affect both the trade‐off between current and future reproduction and the one between parental effort and offspring quality within the current breeding attempt.     

Effect of pre-incubation with different concentrations of LH-RH on subsequent LH release caused by supramaximally active amounts of LH-RH; role of LH-RH-induced protein synthesis.

Anterior pituitary glands from intact diestrous female rats were incubated for two consecutive periods of 3 hours. During the first period various submaximally active amounts of luteinizing hormone-releasing hormone (LH-RH) were added to the media, whereas during the second period a supramaximally active concentration of LH-RH was present. When during the second incubation period protein synthesis was inhibited by cycloheximide, the amount of luteinizing hormone (LH) released during that period was positively correlated to the concentration of LH present during the first incubation period. This relationship was not seen when cycloheximide was absent, or when cycloheximide was present throughout both periods. Total LH was not affected by LH-RH; thus no effect of LH-RH on LH synthesis was observed. It is concluded that the amounts of protein synthesized by the pituitary glands in response to the different amounts of LH-RH during the first incubation period can constitute a limiting factor for the response to the supramaximally active amount of LH-RH added during the second incubation period.     

Determination of the spread of HIV from the AIDS incidence history

The relation between the incidence of HIV in the general population, the number of AIDS cases, and the incubation period for the disease is examined. The number of AIDS cases can be expressed in terms of a convolution integral over the incubation period distribution and the temporal history of HIV incidence. In order to determine the level of HIV incidence it is necessary to invert the convolution. In this manner, it is possible to determine the spread of HIV up to the present time from knowledge of the AIDS incidence history and the incubation period. We describe the inversion of the convolution in terms of a Laplace transform technique that is applicable for any given incubation period distribution. Substantial simplifications in the technique are found in the case of an Erlang distribution for the probability density. The spread of HIV infections in the United States is charted through 1988 using AIDS incidence data that are corrected for both the revised AIDS case definition and reporting time delays. The results are consistent with current estimates of the HIV incidence in the United States and show no evidence of saturation in the rate of new infections. Indeed, the rate of new infections still appears to be climbing as of that date. While the technique is unable to predict the future course of the epidemic, it may provide a useful benchmark for comparison with mathematical models of the epidemic. The techniques are conceptually applicable to diseases other than AIDS.