Risk-based Control Strategies Research Articles

One Health-based management for sustainably mitigating tetracycline-resistant Aeromonas hydrophila-induced health risk

Aeromonas hydrophila has ability to spread tetracycline resistance (tetR) under stresses of oxytetracycline (OTC), one of the most important antibiotics in aquaculture industry. Even though environmental reservoir of Aeromonas allows it to be at interfaces across One Health components, a robust modelling framework for rigorously assessing health risks is currently lacking. We proposed a One Health-based approach and leveraged recent advances in quantitative microbial risk assessment appraised by available dataset to interpret interactions at the human–animal–environment interfaces in various exposure scenarios. The dose–response models were constructed considering the effects on mortality for aquaculture species and tetR genes transfer for humans. A scenario-specific risk assessment on pond species-associated A. hydrophila infection and human gut-associated tetR genes transfer was examined. Risk-based control strategies were involved to test their effectiveness. We showed that farmed shrimp exposed to tetracycline-resistant A. hydrophila in OTC-contaminated water experienced higher infection risk (relative risk: 1.25–1.34). The tetR genes transfer risk for farmers in shrimp ponds (∼2 × 10−4) and swimmers in coastal areas (∼4 × 10−6) during autumn exceeded acceptable risk (10−6). This cautionary finding underscores the importance of accounting for monitoring, assessing, and mitigating occupational health hazards among workers in shrimp farming sectors within future One Health-based strategies for managing water infection risks. We recommend that OTC emission rate together with A. hydrophila concentration should be reduced by up to 70–99% to protect human, farmed shrimp, and environmental health. Our predictive framework can be adopted for other systems and be used as a “risk detector” for assessing tetR-related health risks that invoke potential risk management on addressing sustainable mitigation on offsetting residual OTC emission and tetR genes spread in a species–human–environmental health system.

Probabilistic machine learning for enhanced chiller sequencing: A risk-based control strategy

Multiple-chiller systems are widely adopted in large buildings due to their high flexibility and efficiency in providing cooling capacity. A reliable and robust chiller sequencing control strategy is crucial to ensure the energy efficiency and stability of the multiple-chiller systems. However, conventional chiller sequencing control strategies are usually based on real-time measured cooling load without considering the cooling load changes in the following hours. Conventional rule-based strategy may result in unnecessary switching on and off, leading to energy waste and impairing system stability. Therefore, this study proposes a robust chiller sequencing control strategy that utilizes probabilistic cooling load predictions. 1h-ahead probabilistic cooling load prediction in the form of the normal distribution is made using natural gradient boosting (NGBoost). Compared to conventional machine learning algorithms, NGBoost can predict not only the future cooling load but also the uncertainty of the predicted cooling load, which enables the load prediction to handle the uncertainties associated with the data/measurements adequately. A novel risk-based sequencing strategy is developed based on the probabilistic cooling load predictions. The data experiment shows that the proposed strategy can significantly improve the stability and reliability of the chiller plant by reducing the total switching number by up to 43.6 %.

Analysis of Livestock Mobility and Implications for the Risk of Foot-and-Mouth Disease Virus Spread in Iran

Foot-and-mouth disease (FMD) is endemic in Iran and associated with a large impact on the livestock industry. Livestock mobility is recognized as one of the most important risk factors for FMD and other infectious livestock diseases’ introduction and dissemination. The description of temporal and spatial aspects of livestock mobility networks in Iran provides insights into FMD epidemiology. It also assists in the formulation of recommendations to mitigate the risk of animal disease transmission through livestock movements. This study is the first spatiotemporal description of official/registered cattle, sheep, goat, and camel movements in Iran, using records related to the period from March 2020 to August 2021 extracted from the Iran Veterinary Organization (IVO) Quarantine system. It shows that the static networks drawn by the movements of small ruminants, cattle, and camels to farms or slaughterhouses are complex and highlights the predominance of a few provinces and towns. In particular, the results show that Razavi Khorasan and West Azerbaijan provinces, major provinces for the Iranian livestock sector, are provinces where significant volumes of small ruminants and cattle are moved (from, to, or within) and, therefore, should be prioritized for targeted and timely risk reduction interventions. This study produces some of the necessary inputs for the risk assessment of FMD and similar transboundary animal diseases (TADs) spread within Iran, which is needed to regularly update the national risk-based control strategy for FMD and other TADs.

Uporedna studija o proceni rizika elementarnih nečistoća u Montelukast tabletama za žvakanje i filmom obloženim tabletama

It is well documented that elemental impurities (EIs) are critical in the field of pharmaceutical development since they could affect the quality, efficacy and safety of the finished dosage form (FDF). The responsibility of pharmaceutical manufacturers is to demonstrate via assessment approach, risk-based control strategy and/or required data analysis that the FDFs are compliant with ICH Q3D (R2). The aim of this research is to conduct a comprehensive comparative EIs risk assessment study of three different Montelukast dosage forms produced as chewable tablets (4 mg and 5 mg) and film-coated tablets 10 mg. The inductively coupled plasma-mass spectrometry (ICP-MS) system was used for the determination of EIs in samples of Montelukast sodium as the active pharmaceutical ingredient (API), placebos for all FDFs, and FDFs. Moreover, the analyses were also conducted on three batches from all three studied FDFs. Based on ICH Q3D (R2) guidelines, the tested products for EIs Class 1 and Class 2A showed that EIs levels in the API and placebos are well below the ICH Option 1 oral and parenteral limits. For the examined batches of each FDF strength (total of 9), none of the EI exceeds their concentration limits.

Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants.

Since the first approval of the anti-CD3 recombinant monoclonal antibody (mAb), muromonab-CD3, a mouse antibody for the prevention of transplant rejection, by the US Food and Drug Administration (FDA) in 1986, mAb therapeutics have become increasingly important to medical care. A wealth of information about mAbs regarding their structure, stability, post-translation modifications, and the relationship between modification and function has been reported. Yet, substantial resources are still required throughout development and commercialization to have appropriate control strategies to maintain consistent product quality, safety, and efficacy. A typical feature of mAbs is charge heterogeneity, which stems from a variety of modifications, including modifications that are common to many mAbs or unique to a specific molecule or process. Charge heterogeneity is highly sensitive to process changes and thus a good indicator of a robust process. It is a high-risk quality attribute that could potentially fail the specification and comparability required for batch disposition. Failure to meet product specifications or comparability can substantially affect clinical development timelines. To mitigate these risks, the general rule is to maintain a comparable charge profile when process changes are inevitably introduced during development and even after commercialization. Otherwise, new peaks or varied levels of acidic and basic species must be justified based on scientific knowledge and clinical experience for a specific molecule. Here, we summarize the current understanding of mAb charge variants and outline risk-based control strategies to support process development and ultimately commercialization.

Impact of mass vaccination on the spatiotemporal dynamics of FMD outbreaks in India, 2008-2016.

Foot-and-mouth disease (FMD) is endemic in India, where circulation of serotypes O, A and Asia1 is frequent. Here, we provide an epidemiological assessment of the ongoing mass vaccination programs in regard to post-vaccination monitoring and outbreak occurrence. The objective of this study was assessing the contribution of mass vaccination campaigns in reducing the risk of FMD in India from 2008 to 2016 by evaluating sero-monitoring data and modelling the spatiotemporal dynamics of reported outbreaks. Through analyzing antibody titre data from>1 million animals sampled as part of pre- and post-vaccination monitoring, we show that the percent of animals with inferred immunological protection (based on ELISA) was highly variable across states but generally increased through time. In addition, the number of outbreaks in a state was negatively correlated with the percent of animals with inferred protection. We then analyzed the distribution of reported FMD outbreaks across states using a Bayesian space-time model. This approach provides better acuity to disentangle the effect of mass vaccination programs on outbreak occurrence, while accounting for other factors that contribute to spatiotemporal variability in outbreak counts, notably proximity to international borders and inherent spatiotemporal correlations in incidence. This model demonstrated a ∼50% reduction in the risk of outbreaks in states that were part of the vaccination program. In addition, after controlling for spatial autocorrelation in the data, states that had international borders experienced heightened risk of FMD outbreaks. These findings help inform risk-based control strategies for India as the country progresses towards reducing reported clinical disease.

A Risk-Based Approach for Managing Aquaculture Used Oxytetracycline-Induced TetR in Surface Water Across Taiwan Regions.

Oxytetracycline (OTC), one of the most important antibiotics in aquaculture industry, has been linked to emergence of antibiotic resistant genes in the aquatic environment. Given rapid growth of the aquaculture industry and unregulated use of antibiotics, it is necessary to implement measures to mitigate the impact of antibiotic resistance risk on environmental and human health. However, there is a lack of quantitative models to properly assess risk of antibiotic resistance associated with environmentally relevant antibiotic residues. To address this issue, here we developed a computational framework to assess antibiotic resistance risk posed by low-concentration OTC in aquaculture ponds and rivers across Taiwan regions. To this end, estimated amount of aquaculture used OTC as a crucial input parameter was incorporated into a multimedia fugacity model to predict environmental concentrations of OTC in surface water/sediment. A pharmacodynamic-based dose–response model was used to characterize the OTC concentration–antibiotic resistance relationships. The risk of antibiotic resistance selection in an aquatic environment could be assessed based on a probabilistic risk model. We also established a control measure model to manage the risks of substantial OTC-induced antibiotic resistance impacts. We found that OTC residues were likely to pose a high risk of tetracycline resistance (tetR) genes selection in aquaculture ponds among all the study basins, whereas risk of tetR genes selection in rivers experienced a variably changing fashion. We also showed that it was extremely difficult to moderate the tetR genes selection rates to less than 10% increase in aquaculture ponds situated at northeastern river basins in that the minimum reductions on OTC emission rates during spring, summer, and autumn were greater than 90%. On the other hand, water concentrations of OTC during spring and summer in southwestern rivers should be prioritized to be severely limited by reducing 67 and 25% of OTC emission rate, respectively. Overall, incorporating a computational fugacity model into a risk assessment framework can identify relative higher risk regions to provide the risk-based control strategies for public health decision-making and development of robust quantitative methods to zero-in on environment with high risk of tetR genes selection in relation to aquaculture-used pharmaceutical residues.

Evaluation of China\u2019s Hubei control strategy for COVID-19 epidemic: an observational study

BackgroundTo fight against COVID-19, many policymakers are wavering on stricter public health interventions. Examining the different strategies both in and out of China’s Hubei province, which contained the epidemic in late February 2020, could yield valuable guidance for the management of future pandemics. This study assessed the response process and estimated the time-varying effects of the Hubei control strategy. Analysis of these strategies provides insights for the design and implementation of future policy interventions.MethodsWe retrospectively compared the spread and control of COVID-19 between China’s Hubei (excluding Wuhan) and non-Hubei areas using data that includes case reports, human mobility, and public health interventions from 1 January to 29 February 2020. Static and dynamic risk assessment models were developed to statistically investigate the effects of the Hubei control strategy on the virus case growth after adjusting importation risk and policy response timing with the non-Hubei strategy as a control.ResultsThe analysis detected much higher but differential importation risk in Hubei. The response timing largely coincided with the importation risk in non-Hubei areas, but Hubei areas showed an opposite pattern. Rather than a specific intervention assessment, a comprehensive comparison showed that the Hubei control strategy implemented severe interventions characterized by unprecedentedly strict and ‘monitored’ self-quarantine at home, while the non-Hubei strategy included physical distancing measures to reduce contact among individuals within or between populations. In contrast with the non-Hubei control strategy, the Hubei strategy showed a much higher, non-linear and gradually diminishing protective effect with at least 3 times fewer cases.ConclusionsA risk-based control strategy was crucial to the design of an effective response to the COVID-19 outbreak. Our study demonstrates that the stricter Hubei strategy achieves a stronger controlling effect compared to other strategies. These findings highlight the health benefits and policy impacts of precise and differentiated strategies informed by constant monitoring of outbreak risk.

Assessing Lung and Skin Cancer Risks for Steel and Iron Manufacturing Industry Workers Exposed to Polycyclic Aromatic Hydrocarbons

ABSTRACT Conducting both inhalatory and dermal samplings are crucial for chemicals, such as polycyclic aromatic hydrocarbons (PAHs), which are known with chronic dermal and inhalatory health effects. The present study is the first one set out for conducting both PAH inhalatory and dermal exposure assessments simultaneously for electric arc furnace (EAF) workers in an iron and steelmaking industry. The results were further used to assess the health risks posed on workers. Finally, risk-based control strategies were suggested. Three similar exposure groups (SEGs) of the melting, ladling, and casting were selected for conducting personal samplings. A total of 15 and 120 samples were collected for assessing workers’ inhalatory and dermal PAH exposures, respectively. Results show that the inhalatory gas-phase PAH exposure levels (2.17 × 104–1.52 × 105 ng m–3) were consistently higher than that of particle-phase (2.73 × 103–6.76 × 103 ng m–3) in all selected exposure groups. The mean inhalatory exposure concentrations of the melting and casting workers (2.84 × 104–3.32 × 104 ng m–3) were higher, but ladling workers (1.58 × 105 ng m–3) were lower, than the time-weighted average permissible exposure level (PEL-TWA) regulated in Taiwan (1.00 × 105 ng m–3). The estimated lifetime excessive lung cancer risks for the latter (2.09 × 10–3) were lower than that of the former (3.43 × 10-3–8.84 × 10–3), they were all higher than the significant risk (10–3) defined by the US Supreme Court. The mean whole-body total PAH dermal exposure levels were 2.84 × 105–7.45 × 105 ng day–1, and those body surfaces uncovered by clothes were found with higher exposure levels. Since the estimated lifetime excessive skin cancer risks (7.74 × 10–5–1.62 × 10–4) were lower than of the lung cancer risk, which indicates that the control of workers' inhalatory exposures is more important than that of dermal exposures. The installation of effective ventilation systems and the use of proper personal respiratory protection equipment are recommended for the abatement of risks posed on workers associated with PAH exposures.

Demonstrating Pharmaceutical Quality System Effectiveness and Driving Continual Improvement: Evidence-Based Risk Reduction.

Product knowledge grows and evolves during the life of a product. In order to maintain a state of control and deliver product with consistent quality throughout its commercial life, continuous improvement and product lifecycle management become essential. The practical link between product and process knowledge, risk-based control strategies, and continual improvement and innovation can be made stronger through evidence-based risk reduction. This paper introduces the concept of evidence-based risk reduction within the continual improvement framework. It presents how regulatory relief and flexibility in post-approval change management and overall product lifecycle management can likely only be achieved via (1) effective application of science and risk-based concepts and (2) demonstrated effectiveness of the pharmaceutical quality system in assuring a state of control.

Using social network analysis to inform disease control interventions

Contact patterns between individuals are an important determinant for the spread of infectious diseases in populations. Social network analysis (SNA) describes contact patterns and thus indicates how infectious pathogens may be transmitted. Here we explore network characteristics that may inform the development of disease control programes.This study applies SNA methods to describe a livestock movement network of 180 farms in New Zealand from 2006 to 2010. We found that the number of contacts was overall consistent from year to year, while the choice of trading partners tended to vary. This livestock movement network illustrated how a small number of farms central to the network could play a potentially dominant role for the spread of infection in this population. However, fragmentation of the network could easily be achieved by “removing” a small proportion of farms serving as bridges between otherwise isolated clusters, thus decreasing the probability of large epidemics.This is the first example of a comprehensive analysis of pastoral livestock movements in New Zealand. We conclude that, for our system, recording and exploiting livestock movements can contribute towards risk-based control strategies to prevent and monitor the introduction and the spread of infectious diseases in animal populations.

Development of advanced host cell protein enrichment and detection strategies to enable process relevant spike challenge studies.

An orthogonal chromatography methodology for the enrichment of host cell protein (HCP) species relative to monoclonal antibody (mAb) products was developed and applied for the successful enrichment of HCP from post-Protein A process pools for seven different mAb products. An advanced two-dimensional liquid chromatography/mass spectrometry platform (2D-LC/MS(E) ) was utilized to demonstrate that the HCP enriched material was representative, in terms of species content, to pre-enriched process pools. The HCP enrichment methodology was scaled up for two different mAb products, and this process relevant enriched HCP material was used to conduct advanced spike challenge studies to demonstrate the utility of the approach for the understanding of (1) quantitative HCP clearance, (2) individual species clearance, and (3) species clearance redundancy across polishing chromatography steps. The combined ability to enrich process relevant HCP, detect individual HCP species with 2D-LC/MS(E) technology, and conduct advanced challenge studies with process relevant material surmounts prior limitations to high integrity process challenge study implementation, and facilitates significant process understanding for development of risk-based control strategies and strategic process design. This also demonstrates implementation of a foundational strategy for conducting spike-challenge studies using process-relevant impurities isolated from processes of interest using orthogonal approaches.

Risk factors for infection with Foot-and-Mouth Disease virus in a cattle population vaccinated with a non-purified vaccine in Iran

In this study, we estimated the level of Foot-and-Mouth (FMD) virus infection in a cattle-dense north-western province of Islamic Republic of Iran and analyzed putative risk factors for FMD infection. Calves (6–24 months of age) from all 17 districts of West Azerbaijan were tested for antibodies against non-structural proteins (NSP-Ab) of FMD virus. A proportional stratification with a minimum of 30 epi-units was applied for 3 different husbandry systems: villages, dairy and mixed farms. Within an epi-unit, 30 calves were sampled. For the interpretation of ELISA test results, we used the 50% inhibition (50PI) cut-off as per producer's instructions and created one at 75% inhibition (75PI) based on the lowest point of the histogram of PI results. This approach resulted in three categories of outcomes; negative (N), low-positive (LP) and high-positive (HP). A generalized mixed-effect model for binary outcomes was used for analysing putative risk factors and was run for both cut-off values.A total of 8378 calves from 202 villages, 51 dairy farms and 28 mixed farms were eligible for analysis. The percentage of calves testing positive (LP+HP) was 53.7% (95% Confidence interval (CI): 52.6%–54.8%), with 39.6% (95% CI: 38.6–40.7%) testing HP (n=3309) while 14.1% (95% CI: 13.5–15.0%) of calves tested LP (n=1188). Of 281 epi-units sampled, all calves sampled tested negative in only 2 epi-units (0.7% (95% CI: 0.1–2.5%)) and more than 25 calves tested positive in 29 epi-units (10.3% (95% CI: 7.0–14.5%)). Outcomes of regression modelling using the 50 PI cut-off indicated that, for each month increase in age, the odds of testing positive increased 1.01 times (95% CI: 1.00–1.03). The odds of calves testing NSP-positive increased 1.46 times (95% CI: 1.22–1.77) for calves residing in epi-units that had experienced clinical FMD in the 12 months preceding this study. The odds of calves owned by livestock owners who traded livestock testing positive were 1.4–1.6 times higher than those owned by persons not engaged in trading while the odds for calves testing positive in dairy herds was 1.62 (95% CI: 1.10–2.35) times higher compared with calves in villages. The results of the model using the 75 PI cut-off value resulted in comparable estimates, with the age-effect becoming more evident. These results have confirmed widespread FMD infection and were used in developing a risk-based control strategy on FMD, in line with Stage 1 of the Progressive Control Pathway for FMD (PCP-FMD).

Economy, Efficacy, and Feasibility of a Risk-Based Control Program Against Paratuberculosis

Long-term effects of paratuberculosis on within-herd prevalence and on-farm economy of implementing risk-based control strategies were compared with alternative strategies by using a herd-simulation model. Closing transmission routes is essential for effective control of paratuberculosis. However, many farmers lack the resources to carry out these procedures for all cows in the herd. When using risk-based control strategies 1) all cows are tested quarterly with a milk ELISA, 2) specific cows with a high risk of being infectious are identified, and 3) the farmer can focus only on these infectious animals to close infection routes. In this way the workload can be reduced, making these control strategies more feasible. This study evaluates potential long-term effects of the risk-based approach compared with non-risk-based strategies by simulations conducted with the herd-simulation model PTB-Simherd. Seven control strategies were simulated in herds with initial true herd prevalences of 5, 25, and 50%, respectively. The results predicted the risk-based control strategies to be very efficient and comparable to the best whole-herd strategies in reducing the within-herd prevalence of paratuberculosis with considerably less labor. If infection routes are closed efficiently, prevalence can be reduced to 10% of initial prevalence within 5 to 7 yr. Test-and-cull strategies without closing infection routes were found, by simulation, to be ineffective in reducing prevalence and were not cost-effective methods. The profitability of the various control strategies depends on hourly wages and time spent per cow/calving. Furthermore, simulations show that immediate culling of highly infectious cows is only necessary and cost-effective if infection routes from these cows are not efficiently closed. The risk-based control strategies are recommended in the Danish voluntary control program “Operation Paratuberculosis,” which was initiated in February 2006 and now includes 1,220 dairy farmers in Denmark.