Disease transmission and mass gatherings: a case study on meningococcal infection during Hajj.

BACKGROUND: Mass gatherings can not only trigger major outbreaks on-site but also facilitate global spread of infectious pathogens. Hajj is one of the largest mass gathering events worldwide where over two million pilgrims from all over the world gather annually creating intense congestion. METHODS: We developed a meta-population model to represent the transmission dynamics of Neisseria meningitidis and the impact of Hajj pilgrimage on the risk of invasive meningococcal disease (IMD) for pilgrims population, local population at the Hajj site and country of origin of Hajj pilgrims. This model was calibrated using data on IMD over 17 years (1995-2011) and further used to simulate potential changes in vaccine policy and endemic conditions. RESULTS: The effect of increased density of contacts during Hajj was estimated to generate a 78-fold increase in disease transmission that impacts not only pilgrims but also the local population. Quadrivalent ACWY vaccination was found to be very effective in reducing the risk of outbreak during Hajj. Hajj has more limited impact on IMD transmission and exportation in the pilgrim countries of origin, although not negligible given the size of the population considered. CONCLUSION: The analysis performed highlighted the amplifying effect of mass gathering on N. meningitidis transmission and confirm vaccination as a very effective preventive measure to mitigate outbreak risks.

Impact of influenza vaccine-modified infectivity on attack rate, case fatality ratio and mortality.

Generally, vaccines are designed to provide protection against infection (susceptibility), disease (symptoms and transmissibility), and/or complications. In a recent study of influenza vaccination, it was observed that vaccinated yet infected individuals experienced increased transmission levels. In this paper, using a mathematical model of infection and transmission, we study the impact of vaccine-modified effects, including susceptibility and infectivity, on important epidemiological outcomes of an immunization program. The balance between vaccine-modified susceptibility, infectivity and recovery needed in preventing an influenza outbreak, or in mitigating the health outcomes of the outbreak is studied using the SIRV-type of disease transmission model. We also investigate the impact of influenza vaccination program on the infection risk of vaccinated and non-vaccinated individuals.

With-in host dynamics of L. monocytogenes and thresholds for distinct infection scenarios.

The case fatality and illness rates associated with L. monocytogenes continue to pose a serious public health burden despite the significant efforts and control protocol administered by private and public sectors. Due to the advance in surveillance and improvement in detection methodology, the knowledge of sources, transmission routes, growth potential in food process units and storage, effect of pH and temperature are well understood. However, the with-in host growth and transmission mechanisms of L. monocytogenes, particularly within the human host, remain unclear, largely due to the limited access to scientific experimentation on the human population. In order to provide insight towards the human immune response to the infection caused by L. monocytogenes, we develop a with-in host mathematical model. The model explains, in terms of biological parameters, the states of asymptomatic infection, mild infection and systemic infection leading to listeriosis. The activation and proliferation of T-cells are found to be critical for the susceptibility of the infection. Utilizing stability analysis and numerical simulation, the ranges of the critical parameters relative to infection states are established. Bifurcation analysis shows the impact of the differences of these parameters on the dynamics of the model. Finally, we present model applications in regards to predicting the risk potential of listeriosis relative to the susceptible human population.

Survival and predictive modeling of Listeria monocytogenes under simulated human gastric conditions in the presence of bovine milk products.

Listeria monocytogenes is an opportunistic foodborne pathogen which has been implicated in many outbreaks of foodborne diseases. This study evaluated the effects of gastric acidity and gastric digestion time of adults, L. monocytogenes strain and food type on the survival of L. monocytogenes under simulated stomach conditions of adults in in vitro gastric models with dynamic pH changes occurring throughout the exposure. Individual strains as well as a cocktail of L. monocytogenes, inoculated at 8 log CFU/mL in filtered bovine milk products, 0 % milk, 2 % milk, 2 % chocolate milk and 3.25 % milk, were introduced to the gastric models for 2 h. The survival of L. monocytogenes depended on a combination of factors, including gastric acidity and gastric digestion time of adults, L. monocytogenes strain, food type and recovery method (P < 0.05). The survival rates of L. monocytogenes inoculated in 2 % milk after a 2-h exposure to simulated gastric fluids with pH values of 1.5, 2.0 and 3.0 were 0.003 to 0.040 %, 22.7 to 43.4 % and 16.6 to 27.2 %, respectively. Fluid milk containing a higher milk fat content (3.25 % vs 0 % milk) protected L. monocytogenes from being inactivated when they were exposed to the human stomach model with a gastric acidity of pH 2.0. Compared to 0 % and 3.25 % milk, L. monocytogenes survived the best in 2 % chocolate milk, which appears to be due to the presence of milk fat (2 %) and the additional nutrients that are present in chocolate milk. A predictive mathematical model was developed that captured the population of the strains of L. monocytogenes under the in vitro conditions. This study advances our understanding of the behaviour of L. monocytogenes under various human gastric conditions and provides key parameters that can affect the survival of L. monocytogenes in the stomachs of adults. The mathematical models developed in this study can be used as a supplementary tool to help predict the survival of L. monocytogenes under similar scenarios and for relevant risk-assessment studies.

Selective autophagy and Golgi quality control in <i>Drosophila</i>.

The LIR motif-docking site (LDS) of Atg8/LC3 proteins is essential for the binding of LC3-interacting region (LIR)-containing proteins and their subsequent degradation by macroautophagy/autophagy. In our recent study, we created a mutated LDS site in Atg8a, the <i>Drosophila</i> homolog of Atg8/LC3 and found that LDS mutants accumulate known autophagy substrates and have reduced lifespan. We also conducted quantitative proteomics analyses and identified several proteins that are enriched in the LDS mutants, including Gmap (Golgi microtubule-associated protein). Gmap contains a LIR motif and accumulates in LDS mutants. We showed that Gmap and Atg8a interact in a LIR-LDS dependent manner and that the Golgi size and morphology are altered in Atg8a-LDS and Gmap-LIR motif mutants. Our findings highlight a role for Gmap in the regulation of Golgiphagy.

GMAP is an Atg8a-interacting protein that regulates Golgi turnover in Drosophila.

Selective autophagy receptors and adapters contain short linear motifs called LIR motifs (LC3-interacting region), which are required for the interaction with the Atg8-family proteins. LIR motifs bind to the hydrophobic pockets of the LIR motif docking site (LDS) of the respective Atg8-family proteins. The physiological significance of LDS docking sites has not been clarified in vivo. Here, we show that Atg8a-LDS mutant Drosophila flies accumulate autophagy substrates and have reduced lifespan. Using quantitative proteomics to identify the proteins that accumulate in Atg8a-LDS mutants, we identify the cis-Golgi protein GMAP (Golgi microtubule-associated protein) as a LIR motif-containing protein that interacts with Atg8a. GMAP LIR mutant flies exhibit accumulation of Golgi markers and elongated Golgi morphology. Our data suggest that GMAP mediates the turnover of Golgi by selective autophagy to regulate its morphology and size via its LIR motif-mediated interaction with Atg8a.

Estimating social contacts in mass gatherings for disease outbreak prevention and management: case of Hajj pilgrimage.

BACKGROUND: Most mass gathering events have been suspended due to the SARS-CoV-2 pandemic. However, with vaccination rollout, whether and how to organize some of these mass gathering events arises as part of the pandemic recovery discussions, and this calls for decision support tools. The Hajj, one of the world's largest religious gatherings, was substantively scaled down in 2020 and 2021 and it is still unclear how it will take place in 2022 and subsequent years. Simulating disease transmission dynamics during the Hajj season under different conditions can provide some insights for better decision-making. Most disease risk assessment models require data on the number and nature of possible close contacts between individuals. METHODS: We sought to use integrated agent-based modeling and discrete events simulation techniques to capture risky contacts among the pilgrims and assess different scenarios in one of the Hajj major sites, namely Masjid-Al-Haram. RESULTS: The simulation results showed that a plethora of risky contacts may occur during the rituals. Also, as the total number of pilgrims increases at each site, the number of risky contacts increases, and physical distancing measures may be challenging to maintain beyond a certain number of pilgrims in the site. CONCLUSIONS: This study presented a simulation tool that can be relevant for the risk assessment of a variety of (respiratory) infectious diseases, in addition to COVID-19 in the Hajj season. This tool can be expanded to include other contributing elements of disease transmission to quantify the risk of the mass gathering events.

An agent-based simulator for the gastrointestinal pathway of Listeria monocytogenes.

We developed an agent-based gastric simulator for a human host to illustrate the within host survival mechanisms of Listeria monocytogenes. The simulator incorporates the gastric physiology and digestion processes that are critical for pathogen survival in the stomach. Mathematical formulations for the pH dynamics, stomach emptying time, and survival probability in the presence of gastric acid are integrated in the simulator to evaluate the portion of ingested bacteria that survives in the stomach and reaches the small intestine. The parameters are estimated using in vitro data relevant to the human stomach and L. monocytogenes. The simulator predicts that 5%-29% of ingested bacteria can survive a human stomach and reach the small intestine. In the absence of extensive scientific experiments, which are not feasible on the grounds of ethical and safety concerns, this simulator may provide a supplementary tool to evaluate pathogen survival and subsequent infection, especially with regards to the ingestion of small doses.

Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

There is a heavy burden associated with influenza including all-cause hospitalization as well as severe cardiovascular and cardiorespiratory events. Influenza associated cardiac events have been linked to multiple biological pathways in a human host. To study the contribution of influenza virus infection to cardiovascular thrombotic events, we develop a dynamic model which incorporates some key elements of the host immune response, inflammatory response, and blood coagulation. We formulate these biological systems and integrate them into a cohesive modelling framework to show how blood clotting may be connected to influenza virus infection. With blood clot formation inside an artery resulting from influenza virus infection as the primary outcome of this integrated model, we demonstrate how blood clot severity may depend on circulating prothrombin levels. We also utilize our model to leverage clinical data to inform the threshold level of the inflammatory cytokine TNFα which initiates tissue factor induction and subsequent blood clotting. Our model provides a tool to explore how individual biological components contribute to blood clotting events in the presence of influenza infection, to identify individuals at risk of clotting based on their circulating prothrombin levels, and to guide the development of future vaccines to optimally interact with the immune system.

Advancing risk assessment: mechanistic dose-response modelling of Listeria monocytogenes infection in human populations.

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose-response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose-response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose-response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen-host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose-response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen-immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose-response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

Incidences of malignancy in chronic burn scar ulcers: experience from Bangladesh.

Malignant transformation on any scar tissue is known as Marjolin's ulcer. Most cases of Marjolin's ulcer reported so far occur in post-burn scars but not all ulcers that occur in post-burn scar are malignant. One hundred and forty cases of chronic non-healing ulcers in post-burn scar were included in this prospective observational study. The study was conducted in the Department of Burn and Plastic Surgery Unit of Dhaka Medical College Hospital. Mean age of the patients was 40.63±18.44 with a range from 12 to 75 years. Two third of the patients were male. All patients underwent excision biopsy and coverage with either split thickness skin graft or flap. Histopathological analysis of the resected specimen revealed malignancy in 46 cases and pseudoepitheliomatous hyperplasia in four cases and verruca plantaris in one case. The rest of the cases were chronic non-healing benign ulcers. All 46 cases of Marjolin's ulcer were squamous cell carcinoma with a mean latency period of 26.73 years. The commonest site of chronic ulcer was in the lower extremities (n-80, 57%), and malignancy was also found to be more common there (n-18). The most common type of burn was flame burn (68.57%). The Marjolin's ulcers were significantly larger in size than benign ulcers, and were mostly exophytic or ulcerative in appearance whereas benign ulcers were mostly flat. A non-healing ulcer in a post-burn scar should be addressed promptly because of its potential to develop into a malignant ulcer. Emphasis should be given to early surgical treatment of deep partial to full thickness burns to prevent scar formation, particularly over joints, and thus reduce the risk of development of Marjolin's ulcer.

Unidentified drugs in traditional medications causing toxic epidermal necrolysis: a developing country experience.

BACKGROUND: Drugs are by far the most common cause of toxic epidermal necrolysis (TEN), but unidentified drugs and chemicals present in herbal and traditional medications may also be responsible for this reaction, which manifests as widespread epidermal detachment of the skin and mucous membrane. In contexts in which a subject has used an herbal or traditional medication, it is very difficult to diagnose the condition, identify the offending agent, and prevent the disease from recurring. METHODS: This prospective study was conducted at a tertiary burn center between July 2004 and October 2012. All patients were referred to this unit by the local department of medicine at least one week after the eruption of vesicles. On arrival, all patients demonstrated a severe form of disease with features of sepsis and electrolyte imbalance (SCORTEN scores of ≥4). All non-fatal cases were followed to observe long-term sequelae and recurrences. RESULTS: About 34% of patients had developed the condition after ingesting traditional herbal medications and were unable to identify the responsible drug by name. Nineteen (66%) of the 29 patients referred to the unit with TEN died within the first week after being transferred. Nine patients achieved complete recovery, and one developed corneal haziness and alopecia. One patient experienced recurrence within three months but recovered. CONCLUSIONS: Illiteracy and financial vulnerability were major factors in driving patients towards the use of traditional medications, which were often prepared and preserved improperly. Mortality and other complications could be reduced by the prompt recognition of the condition, immediate withdrawal of the culprit drug, and quick referral to proper care.

Zinc, manganese, calcium, copper, and cadmium level in scalp hair samples of schizophrenic patients.

The purpose of the study was to determine the concentration of trace elements present in scalp hair sample of schizophrenic patients and to find out the relationship between trace elements level and nutritional status or socioeconomic factors. The study was conducted among 30 schizophrenic male patients and 30 healthy male volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University by random sampling. Hair trace element concentrations were determined by flame atomic absorption spectroscopy and analyzed by independent t test, Pearson's correlation analysis, regression analysis, and analysis of variance (ANOVA). Mn, Zn, Ca, Cu, and Cd concentrations of schizophrenic patients were 3.8 +/- 2.31 microg/gm, 171.6 +/- 59.04 microg/gm, 396.23 +/- 157.83 microg/gm, 15.40 +/- 5.68 microg/gm, and 1.14 +/- 0.89 microg/gm of hair sample, while those of control subjects were 4.4 +/- 2.32 microg/gm, 199.16 +/- 27.85 microg/gm, 620.9 +/- 181.55 microg/gm, 12.23 +/- 4.56 microg/gm, and 0.47 +/- 0.32 microg/gm of hair sample, respectively. The hair concentration of Zn and Ca decreased significantly (p = 0.024; p = 0.000, respectively) and the concentration of Cu and Cd increased significantly (p = 0.021; p = 0.000, respectively) in schizophrenic patients while the concentration of Mn (p = 0.321) remain unchanged. Socioeconomic data reveals that most of the patients were poor, middle-aged and divorced. Mean body mass indices (BMIs) of the control group (22.26 +/- 1.91 kg/m(2)) and the patient group (20.42 +/- 3.16 kg/m(2)) were within the normal range (18.5-25.0 kg/m(2)). Pearson's correlation analysis suggested that only Ca concentration of patients had a significant positive correlation with the BMI (r = 0.597; p = 0.000) which was further justified from the regression analysis (R (2) = 44%; t = 3.59; p = 0.002) and one-way ANOVA test (F = 3.62; p = 0.015). A significant decrease in the hair concentration of Zn and Ca as well as a significant increase in the hair concentration of Cu and Cd in schizophrenic patients than that of its control group was observed which may provide prognostic tool for the diagnosis and treatment of this disease. However, further work with larger population is suggested to examine the exact correlation between trace element level and the degree of disorder.