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How much surplus capacity is required to maintain low waiting times?

Random fluctuations in demand make it impossible to see all patients in a very short time scale unless capacity exceeds the mean demand. We describe a model to estimate the capacity levels required as a function of mean demand. Random fluctuations were assumed to follow a Poisson distribution. A Monte Carlo analysis was used to model variations in length of waiting times. To see patients without a waiting list the capacity must exceed mean demand by an amount proportional to the square root of the mean; if capacity equals mean demand, then actual demand will exceed capacity almost half the time. The smaller the mean demand, the greater the percentage increase in capacity that is required. Thus, subdivision of numbers, for subspecialization or fast-tracking, demands greater overall capacity. When multiple serial steps are required, each step must have spare capacity if a waiting list is to be avoided. When capacity is only slightly greater than mean demand, random fluctuations mean that targets can be met for long stretches of time, but these are interspersed with periods when the waiting list rises substantially. Allowing a small waiting time (2-4 weeks) considerably reduces the excess capacity required. Targets such as the 2-week wait for cancer referrals can be achieved only if resource levels are set to give considerably more patient slots per week than mean demand. The level of spare capacity required depends on the level of demand and the maximum waiting time permitted. Without surplus capacity, waiting targets cannot be met. To meet the 2-week waiting target, capacity must exceed mean demand by two patient slots per week for 99% success, or by one slot per week for 90% success.

Efficiency, Organizational↗

Non-Markovian stochastic processes: colored noise.

We survey classical non-Markovian processes driven by thermal equilibrium or nonequilibrium (nonthermal) colored noise. Examples of colored noise are presented. For processes driven by thermal equilibrium noise, the fluctuation-dissipation relation holds. In consequence, the system has to be described by a generalized (integro-differential) Langevin equation with a restriction on the damping integral kernel: Its form depends on the correlation function of noise. For processes driven by nonequilibrium noise, there is no such a restriction: They are considered to be described by stochastic differential (Ito- or Langevin-type) equations with an independent noise term. For the latter, we review methods of analysis of one-dimensional systems driven by Ornstein-Uhlenbeck noise.

Artifacts↗

Dynamical model of long-term synaptic plasticity.

Long-term synaptic plasticity leading to enhancement in synaptic efficacy (long-term potentiation, LTP) or decrease in synaptic efficacy (long-term depression, LTD) is widely regarded as underlying learning and memory in nervous systems. LTP and LTD at excitatory neuronal synapses are observed to be induced by precise timing of pre- and postsynaptic events. Modification of synaptic transmission in long-term plasticity is a complex process involving many pathways; for example, it is also known that both forms of synaptic plasticity can be induced by various time courses of Ca(2+) introduction into the postsynaptic cell. We present a phenomenological description of a two-component process for synaptic plasticity. Our dynamical model reproduces the spike time-dependent plasticity of excitatory synapses as a function of relative timing between pre- and postsynaptic events, as observed in recent experiments. The model accounts for LTP and LTD when the postsynaptic cell is voltage clamped and depolarized (LTP) or hyperpolarized (LTD) and no postsynaptic action potentials are evoked. We are also able to connect our model with the Bienenstock, Cooper, and Munro rule. We give model predictions for changes in synaptic strength when periodic spike trains of varying frequency and Poisson distributed spike trains with varying average frequency are presented pre- and postsynaptically. When the frequency of spike presentation exceeds approximately 30-40 Hz, only LTP is induced.

Long-Term Potentiation↗

Single-molecule spectroscopy of the beta(2) adrenergic receptor: observation of conformational substates in a membrane protein.

Single-molecule studies of the conformations of the intact beta(2) adrenergic receptor were performed in solution. Photon bursts from the fluorescently tagged adrenergic receptor in a micelle were recorded. A photon-burst algorithm and a Poisson time filter were implemented to characterize single molecules diffusing across the probe volume of a confocal microscope. The effects of molecular diffusion and photon number fluctuations were deconvoluted by assuming that Poisson distributions characterize the molecular occupation and photon numbers. Photon-burst size histograms were constructed, from which the source intensity distributions were extracted. Different conformations of the beta(2) adrenergic receptor cause quenching of the bound fluorophore to different extents and hence produce different photon-burst sizes. An analysis of the photon-burst histograms shows that there are at least two distinct substates for the native adrenergic membrane receptor. This behavior is in contrast to one peak observed for the dye molecule, rhodamine 6G. We test the reliability and robustness of the substate number determination by investigating the application of different binning criteria. Conformational changes associated with agonist binding result in a marked change in the distribution of photon-burst sizes. These studies provide insight into the conformational heterogeneity of G protein-coupled receptors in the presence and absence of a bound agonist.

Animals↗

Ultrasensitive detection and identification of fluorescent molecules by FCS: impact for immunobiology.

An experimental application of fluorescence correlation spectroscopy is presented for the detection and identification of fluorophores and auto-Abs in solution. The recording time is between 2 and 60 sec. Because the actual number of molecules in the unit volume (confocal detection volume of about 1 fl) is integer or zero, the fluorescence generated by the molecules is discontinuous when single-molecule sensitivity is achieved. We first show that the observable probability, N, to find a single fluorescent molecule in the very tiny space element of the unit volume is Poisson-distributed below a critical bulk concentration c*. The measured probability means we have traced, for example, 5 x 10(10) fluorophore molecules per ml of bulk solution. The probability is related to the average frequency, C, that the volume of detection contains a single fluorescent molecule and to the concentration, c, of the bulk solution. The analytical sensitivity of an assay is calculated from the average frequency C. In the Goodpasture experiment, we determined as analytical sensitivity a probability of 99.1% of identifying one single immune complex. Under these conditions, a single molecule event is proven. There exist no instrumental assumptions of our approach on which the experiment itself, the theoretical background, or the conclusion are based. Our results open up a broad field for analytics and diagnostics in solution, especially in immunology.

Anti-Glomerular Basement Membrane Disease↗

Mode of action of a supernatant activity from T-cell cultures that nonspecifically stimulates the humoral immune response.

The mode of action of "allogeneic supernatant" (the culture supernatant of a 24-hr mixedlymphocyte reaction), has been studied. This factor stimulates the response of spleen cell cultures depleted in thymus-derived lymphoid cells (T-cells) to antigens that elicit a thymus-dependent response. We used a limiting dilution analysis, in which the frequency and size of response of individual bone-marrow-derived lymphoid cells (B-cells) could be measured. In confirmation of other reports, the occurrence of B-cells responding to antigen under different conditions was shown to follow a Poisson distribution in mouse spleen cell suspensions. Allogeneic supernatant increased responses to thymus-dependent antigens, both by increasing the frequency of B-cells whose response is initiated and by increasing the numbers of antibody-forming cells obtained from each responding B-cell. Two fractions were obtained by dialysis of the supernatant. The nondialyzable fraction contained factors able to increase both the frequency of B-cells responding to sheep erythrocytes, and the size of the responding unit. The dialysate contained factors that were only able to increase the numbers of antibody-forming cells obtained per responding B-cell from B-cells whose response had already been initiated by antigen-specific T-cells. Since the nondialyzable factors were active in the absence of detectable functional T-cells, it was concluded that these factors, produced by T-cells, might represent one mechanism whereby T-cells cooperate with B-cells in the initiation or development of a humoral immune response.

Animals↗

Model for the incidence of embryonal cancers: application to retinoblastoma.

The two-mutation theory of cancer initiation hypothesizes that some cancers originate after two successive mutations, of which the second mutation is always somatic and the first mutation may be germinal (hereditary cases) or somatic (nonhereditary cases). A quantitative model using the Poisson distribution is developed for ages at diagnosis for hereditary and nonhereditary cases. This model relates age-specific incidence data explicitly to the number of divisions of embryonal cells and to rates of somatic mutations per cell division. A good fit is obtained when the model is applied to data on ages at diagnosis for one such embryonal tumor, retinoblastoma.

Age Factors↗

Influence of alkyltransferase activity and chromosomal locus on mutational hotspots in Chinese hamster ovary cells.

High-density mutational spectra have been established for exon 3 of the gene encoding adenine phosphoribosyltransferase (APRT) of the Chinese hamster ovary (CHO) cell line derivative D422 and closely related and/or modified lines by using the mutagen ethyl methanesulfonate (EMS). The total number of selectable sites (GC-->AT transitions yielding a selectable APRT- phenotype) was estimated at 31 based on our own accumulated data base of 136 sequenced exon 3 mutations and on literature reports. D422 and two other APRT hemizygous lines each yielded very similar spectra and showed two populations of mutable sites: (i) 24 "baseline" sites that followed the Poisson distribution and therefore were equally susceptible to mutation and (ii) two hotspots, one comprising a cluster at nucleotides 1293-1309 and the other at nucleotide 1365. Collectively, the latter sites were about 10-fold more frequently mutated than the others. CHO cells are mer- as they lack the repair enzyme O6-methylguanidine methyltransferase (EC 2.1.1.63). In modified repair-proficient CHO cells, the distribution of mutations among all of the 31 sites was random, with only 3 of the 19 GC-->AT transitions in the above hotspots. To determine whether the distribution was locus-dependent, two independent lines carrying single copies of transfected APRT genes were generated from a derivative of D422 carrying a deletion in the endogenous APRT gene. Nucleotides 1293-1309 were again no longer preferentially mutated, but the site at nucleotide 1365 was still a hotspot. We conclude that mutational spectra in mer- cells are at least in part locus dependent and that some sequences are particularly susceptible to EMS mutagenesis and perhaps also to methyltransferase repair.

Adenine Phosphoribosyltransferase↗

Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation.

We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with alpha-particles. However, because cells that are irradiated by alpha-particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of unirradiated cells in the surviving population. The calculated expected proportions of irradiated and nonirradiated cells indicate that the number of clonogenic cells transmitting chromosomal instability is greater than the number expected to be hit and survive. To investigate further this discrepancy, we studied the effects of interposing a grid between the cells and the alpha-particle source so that the surviving population consists predominantly of untraversed stem cells. Comparison with the same irradiation conditions without the grid reveals that the same level of instability is induced. The data confirm that alpha-particles induce chromosomal instability but instability is demonstrated in the progeny of nonirradiated stem cells and must be due to unexpected interactions between irradiated and nonirradiated cells. This untargeted effect has important implications for mechanistic studies of radiation action and for assessment of radiation risk.

Abnormalities, Radiation-Induced↗

Modelling inter-ward migration in Hereford and Worcester: the importance of housing growth and tenure.

"In this paper, we use the 1991 Special Migration Statistics to analyse inter-ward flows in the British county of Hereford and Worcester. New modelling techniques...based on the Poisson distribution are used in this research which partially overcome the under-dispersion problem resulting from modelling zero and very small flows.... Analysis at this scale provides the potential for more detailed generalization about migration processes such as suburbanization, counterurbanization, intra-urban mobility, rural depopulation and the relationship between housing and demographic change at the local level. Unlike migration flows over long distances, which are often employment related, these flows are primarily motivated by residential requirements and housing type and growth are identified as key variables in the interpretation of these migration patterns."

Demography↗

Mixed model for analyzing geographic variability in mortality rates.

"A mixed model is proposed for the analysis of geographic variability in mortality rates. In addition to demographic parameters and random geographic parameters, the model includes additional random-effects parameters to adjust for extra-Poisson variability. The model uses a gamma-Poisson distribution with a random scale parameter having an inverse gamma prior. An empirical Bayes approach is used to estimate relative risks for geographic regions and annual rates for demographic groups within each region. Lung cancer in Missouri is used to motivate and illustrate the procedure."

Americas↗

Age patterns of marital fertility: revising the Coale-Trussell method.

"This article revises the Coale-Trussell method for analyzing data from the World Fertility Survey by proposing and testing alternative log-linear and log-multiplicative models. The models, in one form or another, represent the structural constraint underlying the Coale-Trussell method on the variation in the age pattern of human fertility. With a Poisson distribution assumption for the number of births, several parameters of the models are simultaneously estimated via maximum likelihood. It is shown that the new approach can be adopted whenever fertility limitation is compared across multiple populations or subpopulations."

Age Factors↗

Reaction kinetics for the development of radiation-induced chromosome aberrations.

The formation of chromosome aberrations from DNA double-strand breaks (dsb) following ionizing irradiation of cells is analysed using a stochastic, continuous-time Markov chain formalism. A restitution/complete exchange model is proposed which incorporates kinetic competition between dsb restitution and chromosome exchange; it applies primarily to those dsb whose broken ends are held in close proximity by proteins. Some additional pathways for damage evolution are also considered. The calculations are compared in detail to the experiments on dicentric yield and variance in human lymphocytes following acute low-LET irradiation summarized by Lloyd and Edwards (1983) and Lloyd et al. (1987). It was found that dicentric formation by pairwise dsb interactions can lead to a dicentric yield/dose curve with a significant linear component even if one-track action is neglected. In other words a dicentric formation rate quadratic in the dsb number does not automatically imply a dicentric yield quadratic in the dose. However, the data indicate that at least in some experiments there could have been a significant one-track contribution to the dicentric yield in addition to the intertrack contributions analysed in the present paper. From the data the order of magnitude of the dsb interaction rate constant is estimated to be at most approximately 3 x 10(-3) exchanges per dsb pair per hour. It was found that for the reaction pathways considered, a initial Poisson distribution of dsb leads to an underdispersed distribution of dicentrics; the amount of underdispersion is strongly model-dependent and the variance data are consistent with the restitution/complete exchange model. Finally, a general mathematical theorem on Markov models is presented. It implies that assays performed after repair and exchange are completed cannot determine absolute repair or exchange rates, only their ratio (which may depend on lesion number).

Chromosome Aberrations↗

Linear quadratic model of radiocurability on multicellular spheroids of human lung adenocarcinoma LCT1 and mouse fibrosarcoma FSA.

The LCT1 cells derived from a human lung adenocarcinoma and the FSA cells from a mouse fibrosarcoma were found to form spheroids. The cure-dose relationship of spheroids and the survival curves of their component cells were analysed by using a linear-quadratic model for cell survival and a Poisson distribution for cure. The analysis resulted in three conclusions: (1) the double minus logarithm of cure probability was linearly related to radiation dose, (2) the critical cell number was constant at any given cure probability, and (3) cellular radiosensitivity was also constant. The experiments seem to meet these conditions for each of two kinds of spheroids. Control doses (50%) were 20 Gy for LCT1 spheroids and 21 Gy for FSA spheroids, both 400 microns in diameter. The analysis showed that the lower cellular radiosensitivity and the higher number of clonogenic cells made LCT1 spheroids more radioresistant than FSA spheroids and that the higher critical number of 130 cells made the LCT1 spheroids more sensitive than the FSA spheroids with 18 such cells. The overall radiocurability of spheroids was a result of these three opposing effects, indicating that the critical cell number can be one important factor in determining the radiocurability of multicellular systems.

Adenocarcinoma↗

Inactivation of individual mammalian cells by single alpha-particles.

PURPOSE: To measure clonogenic death of Chinese hamster V79 cells following exposure to a defined number of 4.3 MeV alpha-particles (track-averaged LET = 105 keV/micron). MATERIALS AND METHODS: Cells were irradiated at the radiobiological facility installed at the TTT-3 Tandem accelerator in Naples by using a 'Biostack' approach, which allows the positions of incident tracks relative to cells to be carefully determined. Subcellular structure was identified by fluorescence microscopy, while tracks were visualized by LR-115 solid state nuclear track detectors. RESULTS: Particle hits in the cytoplasm did not significantly affect cell survival, yet survival probability decreased exponentially as a function of the number of nuclear traversals. Measured probability of surviving to exactly one 4.3 MeV alpha-particle traversal in the cell nucleus was 0.67 +/- 0.10. Inactivation cross-section was substantially higher than expected from conventional survival curves. However, folding of the data with Poisson statistics showed that survival level expected if a mean of one alpha-particle goes through a nucleus is higher than the measured value after exactly one particle traversal. CONCLUSIONS: V79 cells have about 67% probability to survive a single alpha-particle traversal in the cell nucleus. Single-particle survival curves are consistent with conventional dose-survival relationships, once Poisson distribution of traversals is taken into account.

Alpha Particles↗

The relationship of herpes simplex virus latency associated transcript expression to genome copy number: a quantitative study using laser capture microdissection.

To investigate the quantitative relationship of latent herpes simplex virus (HSV) genomes to the expression of latency associated transcripts (LATs) we used a combination of laser capture microdissection (LCM), polymerase chain reaction (PCR), and quantitative real-time PCR to determine the number of HSV genomes in individual neurons of the mouse trigeminal ganglion (TG) during viral latency. Both LAT-positive and LAT-negative neurons detected by in situ hybridization (ISH) and lifted by LCM contained HSV genomes detected by PCR for HSV ICP47. The number of genomes/cell determined by real-time PCR with probes for HSV UL44 following LCM demonstrated a Poisson distribution with a predicted mean count of 178 genomes/LAT-positive neuron, and 68 genomes/LAT-negative neuron. The range was similar between the LAT-positive and LAT-negative neurons, and there was a substantial overlap in the distributions. These results suggest that the expression of LATs in an amount that is detectable by ISH does not depend only on the number of HSV genomes in the cell, and by implication suggests that neuron-specific factors play a role in the regulation of LAT expression during latency.

Animals↗

Powder mixing.

The factors affecting powder mixing are reviewed. Methods of analyzing a random mix are discussed (indices, the Poisson distribution, and analyses of variance [ANOVA]). The influence of particle size, shape, and density are described, along with scale of scrutiny and sampling. Segregation and agglomeration are major problems in powder mixing, and their prevention and minimization are therefore paramount. Ordered mixing reduces segregation, but also introduces other problems. Regulating the particle size of the drug and altering particle shape minimizes segregation and agglomeration.

Algorithms↗

Recognition of polymorphic H-2 domains by T lymphocytes. I. Functional role of different H-2 domains for the generation of alloreactive cytotoxic T lymphocytes and determination of precursor frequencies.

In the present communication, the repertoire of alloreactive cytotoxic T lymphocytes (CTL) clones was quantitatively investigated by limiting dilution analysis and by target inhibition with a panel of monoclonal antibodies (mAb). These mAb have previously been shown to define two distinct alloantigenic domains, A and B, on the H-2Kk molecule. The Poisson distribution analysis of H-2Kk-specific CTL clones generated in a limiting dilution system revealed three CTL populations with different precursor frequencies. The high frequent population is suppressed by an unknown suppressive mechanism that allows less frequent CTL populations to become visible. Target inhibition studies with a panel of Kk-specific mAb showed that these CTL populations differ not only in their precursor frequency but also in their specificity for different H-2 epitopes on the Kk molecule. Thus clones of the high frequency population are almost exclusively specific for determinants within domain A. In contrast, the low frequency population displays predominant specificity for determinants of domain B, while the population with medium frequency is blocked equally well by mAb against either domains A or B. Each mAb blocked only a fraction of clones indicating that each CTL subpopulation may consist of a large number of clonotypes with specificity for different H-2 epitopes. The data suggest that CTL recognize basically the same polymorphic domains on the H-2Kk molecule defined by antibodies, and they show that regulatory mechanisms determine the expressed repertoire in CTL populations.

Animals↗