Patterns of smallpox mortality in London, England, over three centuries.

Smallpox is unique among infectious diseases in the degree to which it devastated human populations, its long history of control interventions, and the fact that it has been successfully eradicated. Mortality from smallpox in London, England was carefully documented, weekly, for nearly 300 years, providing a rare and valuable source for the study of ecology and evolution of infectious disease. We describe and analyze smallpox mortality in London from 1664 to 1930. We digitized the weekly records published in the London Bills of Mortality (LBoM) and the Registrar General's Weekly Returns (RGWRs). We annotated the resulting time series with a sequence of historical events that might have influenced smallpox dynamics in London. We present a spectral analysis that reveals how periodicities in reported smallpox mortality changed over decades and centuries; many of these changes in epidemic patterns are correlated with changes in control interventions and public health policies. We also examine how the seasonality of reported smallpox mortality changed from the 17th to 20th centuries in London.

Fast estimation of time-varying infectious disease transmission rates.

Compartmental epidemic models have been used extensively to study the historical spread of infectious diseases and to inform strategies for future control. A critical parameter of any such model is the transmission rate. Temporal variation in the transmission rate has a profound influence on disease spread. For this reason, estimation of time-varying transmission rates is an important step in identifying mechanisms that underlie patterns in observed disease incidence and mortality. Here, we present and test fast methods for reconstructing transmission rates from time series of reported incidence. Using simulated data, we quantify the sensitivity of these methods to parameters of the data-generating process and to mis-specification of input parameters by the user. We show that sensitivity to the user's estimate of the initial number of susceptible individuals-considered to be a major limitation of similar methods-can be eliminated by an efficient, "peak-to-peak" iterative technique, which we propose. The method of transmission rate estimation that we advocate is extremely fast, for even the longest infectious disease time series that exist. It can be used independently or as a fast way to obtain better starting conditions for computationally expensive methods, such as iterated filtering and generalized profiling.

Quality of care: international comparisons of Canadian provinces.

There is increasing interest in comparing Canada's health system internationally to enhance accountability, promote benchmarking and increase mutual learning. The Canadian Institute for Health Information (CIHI) developed an interactive web display using data from the Organization for Economic Co-operation and Development, CIHI and Statistics Canada.

Assessing primary healthcare using pan- Canadian indicators of health and health system performance.

Updated primary healthcare (PHC) indicators are now available for use across Canada. The Canadian Institute for Health Information identified and updated two sets of priority indicators - a policy set to meet the needs of policy makers and a provider set to meet the needs of providers of PHC at the practice and organization levels. A total of 51 indicator definitions were updated to ensure that they are measurable and operational, align with clinical practice guidelines and available data sources and reflect important dimensions of PHC performance in Canada.

Estimating surge in COVID-19 cases, hospital resources and PPE demand with the interactive and locally-informed COVID-19 Health System Capacity Planning Tool.

Introduction: The COVID-19 pandemic revealed an urgent need for analytic tools to help health system leaders plan for surges in hospital capacity. Our objective was to develop a practical and locally informed Tool to help explore the effects of public health interventions on SARS-CoV-2 transmission and create scenarios to project potential surges in hospital admissions and resource demand. Methods: Our Excel-based Tool uses a modified S(usceptible)-E(xposed)-I(nfected)-R(emoved) model with vaccination to simulate the potential spread of COVID-19 cases in the community and subsequent demand for hospitalizations, intensive care unit beds, ventilators, health care workers, and personal protective equipment. With over 40+ customizable parameters, planners can adapt the Tool to their jurisdiction and changes in the pandemic. Results: We showcase the Tool using data for Ontario, Canada. Using healthcare utilization data to fit hospitalizations and ICU cases, we illustrate how public health interventions influenced the COVID-19 reproduction number and case counts. We also demonstrate the Tool's ability to project a potential epidemic trajectory and subsequent demand for hospital resources. Using local data, we built three planning scenarios for Ontario for a 3-month period. Our worst-case scenario accurately projected the surge in critical care demand that overwhelmed hospital capacity in Ontario during Spring 2021. Conclusions: Our Tool can help different levels of health authorities plan their response to the pandemic. The main differentiators between this Tool and other existing tools include its ease of use, ability to build scenarios, and that it provides immediate outcomes that are ready to share with executive decision makers. The Tool is used by provincial health ministries, public health departments, and hospitals to make operational decisions and communicate possible scenarios to the public. The Tool provides educational value for the healthcare community and can be adapted for existing and emerging diseases.

A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules.

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta). In the canonical WNT pathway, the negative regulator Axin forms a complex with beta-catenin and GSK-3beta, resulting in beta-catenin degradation. Inhibition of GSK-3beta by DVL increases beta-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3beta through a transcription- and beta-catenin-independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3beta-mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3beta, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

Control of the Transdermal Delivery Process of Active Substances of the Phytocomplex during Phonophoresis in Model Experiments.

BACKGROUND: The scientific substantiation for the selection of therapeutically significant dosage of phytocomplex in the dosage form for phonophoresis, control over the delivery of active substances into the body, and what affects this process require the study of the kinetics of phytocomplex flavonoids delivery during phonophoresis. AIM: The aim was to study the possibilities of controlling the process of transdermal delivery of phytocomplex active substances (flavonoids) during phonophoresis in vitro model experiments. METHODS: Working compositions with different concentrations of phytocomplex for phonophoresis were used. The content of flavonoids in the compositions was determined using the spectrophotometric method and was calculated equivalent to quercetin, the flavonoid prevailing in the phytocomplex. The study of the kinetics of flavonoids delivery from working compositions was carried out using Franz diffusion cells and Carbosyl-P membranes. The authors determined the main parameters of the process and established the dependence of the delivery rate of flavonoids on their initial concentration in the working composition. The authors studied the effect of dimethyl sulfoxide and the base-forming substances of the working composition on the kinetics of phytocomplex flavonoid delivery during phonophoresis. RESULTS: The authors recorded an increase in the rate of delivery of the active substances from working compositions containing dimethyl sulfoxide into the model medium by almost 1.5-2 times during the first ten minutes of the experiment (approximate duration of the phonophoresis procedure). The authors proposed technological techniques for improvement of the phonophoresis method for the phytocomplex. The possibilities of control over the process of transdermal delivery of the phytocomplex active ingredients during phonophoresis in vitro model experiments were shown. CONCLUSION: The obtained results provide information for further pharmacological studies of the nature and mechanism of the effect of phytocomplex flavonoids during phonophoresis in the rehabilitation of patients with osteoarthrosis.

WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons.

Sensory axons from dorsal root ganglia neurons are guided to spinal targets by molecules differentially expressed along the dorso-ventral axis of the neural tube. NT-3-responsive muscle afferents project ventrally, cease extending, and branch upon contact with motoneurons (MNs), their synaptic partners. We have identified WNT-3 as a candidate molecule that regulates this process. Wnt-3 is expressed by MNs of the lateral motor column at the time when MNs form synapses with sensory neurons. WNT-3 increases branching and growth cone size while inhibiting axonal extension in NT-3- but not NGF-responsive axons. Ventral spinal cord secretes factors with axonal remodeling activity for NT-3-responsive neurons. This activity is present at limb levels and is blocked by a WNT antagonist. We propose that WNT-3, expressed by MNs, acts as a retrograde signal that controls terminal arborization of muscle afferents.

Effects of the infectious period distribution on predicted transitions in childhood disease dynamics.

The population dynamics of infectious diseases occasionally undergo rapid qualitative changes, such as transitions from annual to biennial cycles or to irregular dynamics. Previous work, based on the standard seasonally forced 'susceptible-exposed-infectious-removed' (SEIR) model has found that transitions in the dynamics of many childhood diseases result from bifurcations induced by slow changes in birth and vaccination rates. However, the standard SEIR formulation assumes that the stage durations (latent and infectious periods) are exponentially distributed, whereas real distributions are narrower and centred around the mean. Much recent work has indicated that realistically distributed stage durations strongly affect the dynamical structure of seasonally forced epidemic models. We investigate whether inferences drawn from previous analyses of transitions in patterns of measles dynamics are robust to the shapes of the stage duration distributions. As an illustrative example, we analyse measles dynamics in New York City from 1928 to 1972. We find that with a fixed mean infectious period in the susceptible-infectious-removed (SIR) model, the dynamical structure and predicted transitions vary substantially as a function of the shape of the infectious period distribution. By contrast, with fixed mean latent and infectious periods in the SEIR model, the shapes of the stage duration distributions have a less dramatic effect on model dynamical structure and predicted transitions. All these results can be understood more easily by considering the distribution of the disease generation time as opposed to the distributions of individual disease stages. Numerical bifurcation analysis reveals that for a given mean generation time the dynamics of the SIR and SEIR models for measles are nearly equivalent and are insensitive to the shapes of the disease stage distributions.

Methods to stimulate national and sub-national benchmarking through international health system performance comparisons: a Canadian approach.

OBJECTIVE: This paper presents, discusses and evaluates methods used by the Canadian Institute for Health Information to present health system performance international comparisons in ways that facilitate their understanding by the public and health system policy-makers and can stimulate performance benchmarking. METHODS: We used statistical techniques to normalize the results and present them on a standardized scale facilitating understanding of results. We compared results to the OECD average, and to benchmarks. We also applied various data quality rules to ensure the validity of results. In order to evaluate the impact of the public release of these results, we used quantitative and qualitative methods and documented other types of impact. RESULTS: We were able to present results for performance indicators and dimensions at national and sub-national levels; develop performance profiles for each Canadian province; and show pan-Canadian performance patterns for specific performance indicators. The results attracted significant media attention at national level and reactions from various stakeholders. Other impacts such as requests for additional analysis and improvement in data timeliness were observed. CONCLUSIONS: The methods used seemed attractive to various audiences in the Canadian context and achieved the objectives originally defined. These methods could be refined and applied in different contexts.