Antiviral drugs dispensed during the 2009 influenza pandemic generally failed to contain transmission. This poses the question of whether preparedness for a future pandemic should include plans to ...use antiviral drugs to mitigate transmission.Simulations using a standard transmission model that allows for infected arrivals and delayed vaccination show that attempts to contain transmission require relatively few antiviral doses. In contrast, persistent use of antiviral drugs when the reproduction number remains above 1 use very many doses and are unlikely to reduce the eventual attack rate appreciably unless the stockpile is very large. A second model, in which the community has a household structure, shows that the effectiveness of a strategy of dispensing antiviral drugs to infected households decreases rapidly with time delays in dispensing the antivirals. Using characteristics of past pandemics it is estimated that at least 80% of primary household cases must present upon show of symptoms to have a chance of containing transmission by dispensing antiviral drugs to households. To determine data needs, household outbreaks were simulated with 50% receiving antiviral drugs early and 50% receiving antiviral drugs late. A test to compare the size of household outbreaks indicates that at least 100-200 household outbreaks need to be monitored to find evidence that antiviral drugs can mitigate transmission of the newly emerged virus.Use of antiviral drugs in an early attempt to contain transmission should be part of preparedness plans for a future influenza pandemic. Data on the incidence of the first 350 cases and the eventual attack rates of the first 200 hundred household outbreaks should be used to estimate the initial reproduction number R and the effectiveness of antiviral drugs to mitigate transmission. Use of antiviral drugs to mitigate general transmission should cease if these estimates indicate that containment of transmission is unlikely.
Engineered living microtissues such as cellular spheroids and organoids have enormous potential for the study and regeneration of tissues and organs. Microtissues are typically engineered via ...self‐assembly of adherent cells into cellular spheroids, which are characterized by little to no cell–material interactions. Consequently, 3D microtissue models currently lack structural biomechanical and biochemical control over their internal microenvironment resulting in suboptimal functional performance such as limited stem cell differentiation potential. Here, this work report on stimuli‐responsive cell‐adhesive micromaterials (SCMs) that can self‐assemble with cells into 3D living composite microtissues through integrin binding, even under serum‐free conditions. It is demonstrated that SCMs homogeneously distribute within engineered microtissues and act as biomechanically and biochemically tunable designer materials that can alter the composite tissue microenvironment on demand. Specifically, cell behavior is controlled based on the size, stiffness, number ratio, and biofunctionalization of SCMs in a temporal manner via orthogonal secondary crosslinking strategies. Photo‐based mechanical tuning of SCMs reveals early onset stiffness‐controlled lineage commitment of differentiating stem cell spheroids. In contrast to conventional encapsulation of stem cell spheroids within bulk hydrogel, incorporating cell‐sized SCMs within stem cell spheroids uniquely provides biomechanical cues throughout the composite microtissues’ volume, which is demonstrated to be essential for osteogenic differentiation.
Cellular spheroids are used to mimic native tissues but only offer poor control over their internal microenvironment. Here, stimuli‐responsive cell‐adhesive micromaterials (SCMs) that interact and self‐assemble with cells into 3D living composite tissues are developed. The behavior of stem cell spheroids, including their lineage commitment, is controlled from within by tuning cell–material interactions via the amount, size, and temporal stiffness of SCMs.
The grading of radiological severity in clinical trials in tuberculosis (TB) remains unstandardised. The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) ...severity and predicting response to treatment in adults with smear-positive pulmonary TB.
At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive pulmonary TB. Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score. The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later at the same site. Relationships between the CXR score and other measures of TB severity were examined.
The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present. As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p<0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each). In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately than did the proportion of lung affected alone. In both data sets, CXR scores decreased over time (p<0.001).
This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.
Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated ...calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, generating oxygen using CPO is mediated via the generation of toxic levels of hydrogen peroxide (H2O2). The incorporation of antioxidants, such as catalases, can potentially reduce H2O2 levels. However, the formulation in which catalases can most effectively scavenge H2O2 within oxygen generating biomaterials has remained unexplored. In this study, three distinct catalase incorporation methods are compared based on their ability to decrease H2O2 levels. Specifically, catalase is incorporated within HOGMPs, or absorbed onto HOGMPs, or freely laden into the hydrogel entrapping HOGMPs and compared with control without catalase. Supplementation of free catalase in an HOGMP‐laden hydrogel significantly decreases H2O2 levels reflecting a higher cellular viability and metabolic activity of all the groups. An HOGMP/catalase‐laden hydrogel precursor solution containing cells is used as an oxygenating bioink allowing improved viability of printed constructs under severe hypoxic conditions. The combination of HOGMPs with a catalase‐laden hydrogel has the potential to decrease peroxide toxicity of oxygen generating tissues.
Hydrophobic oxygen (O2) generating microparticles, based on solid peroxides, are shown to facilitate the survival of engineered living tissues. However, oxygen is generated via the production of hydrogen peroxide (H2O2). Here we incorporate catalase, an H2O2 scavenger, via three distinct methods. The addition of unbound catalase to an oxygen‐generating hydrogel significantly reduces H2O2 toxicity, improves printability, and increases cellular viability.
In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health ...decision making.
The time delay between the start of an influenza pandemic and its subsequent initiation in other countries is highly relevant to preparedness planning. We quantify the distribution of this random ...time in terms of the separate components of this delay, and assess how the delay may be extended by non-pharmaceutical interventions.
The model constructed for this time delay accounts for: (i) epidemic growth in the source region, (ii) the delay until an infected individual from the source region seeks to travel to an at-risk country, (iii) the chance that infected travelers are detected by screening at exit and entry borders, (iv) the possibility of in-flight transmission, (v) the chance that an infected arrival might not initiate an epidemic, and (vi) the delay until infection in the at-risk country gathers momentum. Efforts that reduce the disease reproduction number in the source region below two and severe travel restrictions are most effective for delaying a local epidemic, and under favourable circumstances, could add several months to the delay. On the other hand, the model predicts that border screening for symptomatic infection, wearing a protective mask during travel, promoting early presentation of cases arising among arriving passengers and moderate reduction in travel volumes increase the delay only by a matter of days or weeks. Elevated in-flight transmission reduces the delay only minimally.
The delay until an epidemic of pandemic strain influenza is imported into an at-risk country is largely determined by the course of the epidemic in the source region and the number of travelers attempting to enter the at-risk country, and is little affected by non-pharmaceutical interventions targeting these travelers. Short of preventing international travel altogether, eradicating a nascent pandemic in the source region appears to be the only reliable method of preventing country-to-country spread of a pandemic strain of influenza.
3D Bioprinting
In article number 2102697 by Jeroen Leijten, Su Ryon Shin, and co‐workers, mitigating the toxic effects from solid peroxides in self‐oxygenating living tissues is achieved by ...catalase‐mediated hydrolysis of hydrogen peroxide.
Background: Foodborne illness is a significant public health issue in most countries, including Australia. We examined the association between temperature and salmonellosis notifications, and ...compared these associations for 5 Australian cities. Methods: Log-linear models describing monthly salmonellosis notifications in terms of calendar time and monthly average temperatures were fitted over the period 1991 to 2001 for each city. We used a negative binomial chance model to accommodate overdispersion in the counts. Results: The long-term trend showed an increase in salmonellosis notifications in each of the 5 cities. There was a positive association between monthly salmonellosis notifications and mean monthly temperature of the previous month in every city. Seasonal patterns in salmonellosis notifications were fully explained by changes in temperature. Discussion: The strength of the association, the consistency across 5 cities, and a plausible biologic pathway suggest that higher ambient temperatures are a cause of higher salmonellosis notifications. The lag of 1 month suggests that temperature might be more influential earlier in the production process rather than at the food preparation stage. This knowledge can help to guide policy on food preparation and distribution. It also suggests a basis for an early warning system for increased risk from salmonellosis, and raises yet another possible health problem with global warming.
Current estimates of antiviral effectiveness for influenza are based on the existing strains of the virus. Should a pandemic strain emerge, strain-specific estimates will be required as early as ...possible to ensure that antiviral stockpiles are used optimally and to compare the benefits of using antivirals as prophylaxis or to treat cases. We present a method to measure antiviral effectiveness using early pandemic data on household outbreak sizes, including households that are provided with antivirals for prophylaxis and those provided with antivirals for treatment only. We can assess whether antiviral drugs have a significant impact on susceptibility or on infectivity with the data from approximately 200 to 500 households with a primary case. Fewer households will suffice if the data can be collected before case numbers become high, and estimates are more precise if the study includes data from prophylaxed households and households where no antivirals are provided. Rates of asymptomatic infection and the level of transmissibility of the virus do not affect the accuracy of these estimates greatly, but the pattern of infectivity in the individual strongly influences the estimate of the effect of antivirals on infectivity. An accurate characterization of the infectiousness profile-informed by strain-specific data-is essential for measuring antiviral effectiveness.
Objective: To estimate the prevalence of heart failure (HF) and left ventricular (LV) systolic dysfunction in a population‐based sample of older Australians.
Design, setting and participants: A ...cross‐sectional survey of 2000 randomly selected residents of Canberra, aged 60–86 years, conducted between February 2002 and June 2003. Participants were assessed by history, physical examination by a cardiologist, and echocardiography.
Main outcome measures: Age‐ and sex‐specific prevalence rates of clinical HF and LV systolic dysfunction (defined as LV ejection fraction ≤ 50%).
Results: Of 1846 people eligible for our study, 1388 (75%) agreed to participate and 1275 completed all investigations (mean age, 69.4 years; 50% men). In the study sample, 72 subjects (5.6%; 95% CI, 4.4%–7.1%) had clinical HF that had been previously diagnosed and was confirmed by our assessment. A further 0.6% (95% CI, 0.3%–1.2%) had undiagnosed clinical HF (ie, evidence of structural heart disease and symptoms/signs of cardiac insufficiency without a previous diagnosis of clinical HF). Thus, the overall prevalence of clinical HF in the sample was 6.3% (95% CI, 5.0%–7.7%). Clinical HF increased in prevalence with advancing age (a 4.4‐fold increase from the 60–64‐years age group to the 80–86‐years age group; P < 0.0001). Of the 75 subjects (5.9%; 95% CI, 4.7%–7.3%) with LV systolic dysfunction, 44 (59%) were in the preclinical stage of disease.
Conclusion: Diagnosed HF cases represent the “tip of the iceberg” for the national burden of HF and LV systolic dysfunction. Clinically identifiable HF cases can remain undiagnosed, and the majority of people with LV systolic dysfunction are in a preclinical stage of the disease.
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