A methodology for estimating SARS-CoV-2 importation risk by air travel into Canada between July and November 2021.

BACKGROUND: Estimating rates of disease importation by travellers is a key activity to assess both the risk to a country from an infectious disease emerging elsewhere in the world and the effectiveness of border measures. We describe a model used to estimate the number of travellers infected with SARS-CoV-2 into Canadian airports in 2021, and assess the impact of pre-departure testing requirements on importation risk. METHODS: A mathematical model estimated the number of essential and non-essential air travellers infected with SARS-CoV-2, with the latter requiring a negative pre-departure test result. The number of travellers arriving infected (i.e. imported cases) depended on air travel volumes, SARS-CoV-2 exposure risk in the departure country, prior infection or vaccine acquired immunity, and, for non-essential travellers, screening from pre-departure molecular testing. Importation risk was estimated weekly from July to November 2021 as the number of imported cases and percent positivity (PP; i.e. imported cases normalised by travel volume). The impact of pre-departure testing was assessed by comparing three scenarios: baseline (pre-departure testing of all non-essential travellers; most probable importation risk given the pre-departure testing requirements), counterfactual scenario 1 (no pre-departure testing of fully vaccinated non-essential travellers), and counterfactual scenario 2 (no pre-departure testing of non-essential travellers). RESULTS: In the baseline scenario, weekly imported cases and PP varied over time, ranging from 145 to 539 cases and 0.15 to 0.28%, respectively. Most cases arrived from the USA, Mexico, the United Kingdom, and France. While modelling suggested that essential travellers had a higher weekly PP (0.37 - 0.65%) than non-essential travellers (0.12 - 0.24%), they contributed fewer weekly cases (62 - 154) than non-essential travellers (84 - 398 per week) given their lower travel volume. Pre-departure testing was estimated to reduce imported cases by one third (counterfactual scenario 1) to one half (counterfactual scenario 2). CONCLUSIONS: The model results highlighted the weekly variation in importation by traveller group (e.g., reason for travel and country of departure) and enabled a framework for measuring the impact of pre-departure testing requirements. Quantifying the contributors of importation risk through mathematical simulation can support the design of appropriate public health policy on border measures.

Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. METHODS: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models. RESULTS: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37). CONCLUSIONS: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality. LAY SUMMARY: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

Could a rabies incursion spread in the northern Australian dingo population? Development of a spatial stochastic simulation model.

Australia, home to the iconic dingo, is currently free from canine rabies. However northern Australia, including Indigenous communities with large free-roaming domestic dog populations, is at increased risk of rabies incursion from nearby Indonesia. We developed a novel agent-based stochastic spatial rabies spread model to evaluate the potential spread of rabies within the dingo population of the Northern Peninsula Area (NPA) region of northern Australia. The model incorporated spatio-temporal features specific to this host-environment system, including landscape heterogeneity, demographic fluctuations, dispersal movements and dingo ecological parameters-such as home range size and density-derived from NPA field studies. Rabies spread between dingo packs in nearly 60% of simulations. In such situations rabies would affect a median of 22 dingoes (approximately 14% of the population; 2.5-97.5 percentiles: 2-101 dingoes) within the study area which covered 1,131 km2, and spread 0.52 km/week for 191 days. Larger outbreaks occurred in scenarios in which an incursion was introduced during the dry season (vs. wet season), and close to communities (vs. areas with high risk of interaction between dingoes and hunting community dogs). Sensitivity analyses revealed that home range size and duration of infectious clinical period contributed most to the variance of outputs. Although conditions in the NPA would most likely not support a sustained propagation of the disease in the dingo population, due to the predicted number of infected dingoes following a rabies incursion and the proximity of Indigenous communities to dingo habitat, we conclude that the risk for human transmission could be substantial.

Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro.

We have used a perfusion bellows cell culture system to investigate resveratrolinduced anti-proliferation/apoptosis in a human estrogen receptor (ER)-negative breast cancer cell line (MDA-MB-231). Using an injection system to perfuse media with stilbene, we showed resveratrol (0.5 - 100 µM) to decrease cell proliferation in a concentration-dependent manner. Comparison of influx and medium efflux resveratrol concentrations revealed rapid disappearance of the stilbene, consistent with cell uptake and metabolism of the agent reported by others. Exposure of cells to 10 µM resveratrol for 4 h daily × 6 d inhibited cell proliferation by more than 60%. Variable extracellular acid-alkaline conditions (pH 6.8 - 8.6) affected basal cell proliferation rate, but did not alter anti-proliferation induced by resveratrol. Resveratrol-induced gene expression, including transcription of the most up-regulated genes and pro-apoptotic p53-dependent genes, was not affected by culture pH changes. The microarray findings in the context of induction of anti-proliferation with brief daily exposure of cells to resveratrol-and rapid disappearance of the compound in the perfusion system-are consistent with existence of an accessible initiation site for resveratrol actions on tumor cells, e.g., the cell surface receptor for resveratrol described on integrin αvß3.

Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone.

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvß3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3'-triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin ß3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin ß3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygenase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor ß1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway.

Crosstalk between integrin αvß3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells.

A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvß3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10(-7) M), T(4) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T(3)) at a supraphysiologic concentration. Neutralizing antibody to integrin αvß3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T(4) and T(3) to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T(4)>T(3)) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T(4)-induced, but not T(3)-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.

Pharmacodynamic modeling of anti-cancer activity of tetraiodothyroacetic acid in a perfused cell culture system.

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvß3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.

Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-alpha-positive and -negative breast cancer cells.

Androgens have important physiological effects in women. Not only are they the precursor hormones for estrogen biosynthesis in the ovaries and extragonadal tissues, but also act directly via androgen receptors (ARs) throughout the body. Studies of the role of androgens on breast cancer development are controversial and the mechanisms involved are not fully understood. In this report we demonstrate that a non-aromatizable androgen metabolite, dihydrotestosterone (DHT), stimulated cell proliferation in vitro of both estrogen receptor-alpha (ER-alpha)-positive MCF-7 cells and ER-alpha-negative MDA-MB-231 human breast cancer cells. A contribution of ER to the proliferative effect of DHT in MCF-7 cells was supported by actions of small interfering RNA (siRNA) ER-alpha transfection and of the specific inhibitor of ER, ICI 182,780 to block DHT-induced proliferation. A contribution of the possible conversion of DHT to androstane-3alpha, 17beta-diol was not excluded in these MCF-7 cell studies. In MDA-MB-231 cells, a novel mechanism was implicated, in that anti-integrin alphavbeta3 or an Arg-Gly-Asp (RGD) peptide targeted at a small molecule binding domain of the integrin eliminated the DHT effect on cell proliferation. Anti-integrin alphavbeta3 did not affect DHT action on MCF-7 cells. A contribution from classical androgen receptor to the DHT effect in each cell line was excluded. A proliferative DHT signal is transduced in both ER-alpha-positive and ER-alpha-negative breast cancer cells, but by discrete mechanisms.

The factors influencing transactional sex among young men and women in 12 sub-Saharan African countries.

Transactional sex may put young women and young men in sub-Saharan Africa at increased risk of contracting sexually transmitted infections (STIs), including HIV/AIDS. This behavior may also put young women at higher risk of pregnancy and childbearing. Policymakers and program managers need to know what factors put youth at increased risk. We investigated this issue using logistic regression analyses of data from male and female modules of Demographic and Health Surveys from 12 sub-Saharan African countries. We found that young men and young women are at greater risk of engaging in transactional sex than are older people. Unmarried young women and young men were significantly more likely to engage in transactional sex than married youth. Based on these results, our conclusions were that programs geared toward reducing the incidence of transactional sex or protecting men and women already in transactional sexual relationships should be aimed at both young women and young men. Due to our finding that unmarried young women and young men are more vulnerable to experiencing transactional sex, programs to prevent transactional sex should be specifically directed to this subgroup of young people.

Obtaining the apex of the unitarity triangle from B-->piK decays.

We present a method of obtaining the apex of the unitarity triangle from measurements of B-->piK decay rates alone. Electroweak penguin amplitudes are included, and are related to tree operators. Discrete ambiguities are removed by comparing solutions with independent experimental data. The theoretical uncertainty in this method is about 10%.