Peak Mortality Research Articles

Genetic characterization of heterologous Edwardsiella piscicida isolates from diverse fish hosts and virulence assessment in a Chinook salmon Oncorhynchus tshawytscha model.

Edwardsiella piscicida is an emergent global fish pathogen with a wide host range, although host associations driving genetic diversity remain unclear. This study investigated the genetic and virulence diversity of 37 E. piscicida isolates recovered from 10 fish species in North America. Multilocus sequence analysis (MLSA) was conducted using concatenated alignments of the gyrB, pgi and phoU sequences. MLSA clustered the tested isolates into six discrete clades. In light of recent disease outbreaks in cultured salmonids, the virulence of each clade was evaluated in Chinook salmon Oncorhynchus tshawytscha fingerlings following intracoelomic challenge of ~106 CFU/fish. Challenged and control fish were monitored for 21d, and microbiological and histological examination was performed on dead and surviving fish. Peak mortality occurred 3-5days post-challenge (dpc) regardless of isolate or genetic group. Edwardsiella piscicida was recovered from all moribund and dead animals. At 21 dpc, fish challenged with isolates from clades II, III and IV presented cumulative mortality ≥83.3%, whereas isolates from clade I, V and VI resulted in cumulative mortality ≤71.4%. This study suggests an underlying genetic basis for strain virulence and potential host associations. Further investigations using other fish models and variable challenge conditions are warranted.

Peripheral Nucleated Red Blood Cells and Mortality in Critically Ill Children.

The present retrospective cohort study examines whether there is an association between circulating nucleated red blood cells (nRBCs) and mortality in critically ill children. nRBCs are erythropoietic progenitor cells not found in peripheral blood of healthy adults and children beyond the neonatal period. The presence of circulating nRBCs is associated with poor prognosis in adults and neonates, though little is known about their significance in children. Admissions to both the general and cardiac pediatric intensive care unit at the Stollery Children's Hospital in Edmonton, Alberta between January 1, 2015 and December 31, 2017 were examined, and logistic regression was performed to ascertain the association between the peak absolute nRBC counts and in-hospital mortality in critically ill children. A total of 2065 admissions were included. The number of admissions with detectable nRBCs was 386 (prevalence: 13.9%), and the number of deaths was 93 (mortality: 4.5%). A statistically significant association was found between the absolute value of nRBC peak and intensive care unit mortality (odds ratio=1.37; 95% confidence interval: 1.13-1.67; P=0.002) as well as hospital mortality (odds ratio=1.38; 95% confidence interval: 1.12-1.70; P=0.003) independent of the Pediatric Index of Mortality 3 score (PIM3). This result warrants more attention to nRBC values and their potential clinical use.

Peak Exercise Ventilation And Mortality In Apparently Healthy Men And Women

Peak Exercise Ventilation And Mortality In Apparently Healthy Men And Women

Patterns of vertebrate road-kills in a pre-Saharan Tunisian area

Understanding spatio-temporal patterns of animal-vehicle collisions is a crucial step for the implementation of efficient mitigation measures of this worldwide threat against biodiversity. In this study we investigated vertebrate road-kills in a pre-Saharan area in southern Tunisia. In particular, we assessed how road mortality varied according to land cover and season. From February 2019 to January 2020, a road section crossing three land cover types (desert, oasis and urban areas) was monitored twice a week for the survey of road-killed vertebrates. There was about one animal killed per 10 km and per day. Birds were the vertebrate class most affected by road-kills. Mammals constituted a non-negligible part of recorded road-kills and were mainly represented by stray cats and dogs. The highest rate of vertebrate road-kill was recorded in oases, which was expected given the higher abundance of animals in these densely-vegetated areas compared to desert and urban areas. The peak road mortality was recorded in spring and early summer for birds, but in winter for mammals. In sum, our results reveal that vertebrate classes have different patterns of road mortality in the area studied. They also stress the need for urgent mitigation measures, especially inside oases.

Peak oxygen pulse and mortality risk in healthy women and men: The Ball State Adult Fitness Longitudinal Lifestyle Study (BALL ST)

Peak oxygen pulse (O2 pulsepeak) may have predictive utility for health outcomes yet, presently, has only been examined in men and only using a single baseline measure. PurposeThe primary aim of this investigation was to evaluate the relationship between O2 pulsepeak and all-cause mortality in apparently healthy women and men. A secondary aim was to explore the relationship between longitudinal changes to O2 pulsepeak and mortality. MethodsThe sample included 3877 participants (43% women) for the primary aim and 759 participants (32% women) who performed two cardiopulmonary exercise tests ≥1 year apart for the secondary aim. Cox proportional hazard models were performed to determine the relationship between O2 pulsepeak and mortality. Prognostic peak oxygen consumption (VO2peak) and O2 pulsepeak models were compared using the concordance index and Akaike information criterion (AIC). ResultsIn the assessment from baseline, there were 730 deaths over a 24.7 ± 11.8 year follow-up period. For men, a single measure of O2 pulsepeak was inversely associated with risk for mortality (P < 0.05). However, the concordance index and AIC indicated lower discrimination compared to VO2peak models and O2 pulsepeak did not provide complementary benefit to VO2peak models. For women, O2 pulsepeak was not associated with mortality risk. In the longitudinal analysis, there were 168 deaths over a follow-up of 20.1 ± 11.4 years. Changes to O2 pulsepeak were not significantly related to mortality in either sex. ConclusionsWithin an apparently healthy cohort, a single assessment of O2 pulsepeak is related to all-cause mortality in men but not women. Further, longitudinal changes to O2 pulsepeak are not predictive of mortality in either sex. These findings suggest O2 pulsepeak may have limited prognostic utility in healthy individuals, particularly within healthy women.

Changing readiness to mitigate SARS-CoV-2 steered long-term epidemic and social trajectories

Societal responses crucially shape the course of a pandemic, but are difficult to predict. Mitigation measures such as social distancing are here assumed to minimize a utility function that consists of two conflicting sub-targets, the disease related mortality and the multifaceted consequences of mitigation. The relative weight of the two sub-targets defines the mitigation readiness H, which entails the political, social, and psychological aspects of decision making. The dynamics of social and behavioral mitigation thus follows an adaptive rule, which in turn is mediated by a non-adaptive dynamics of H. This framework for social dynamics is integrated into an epidemiological model and applied to the ongoing SARS-CoV-2 pandemic. Unperturbed simulations accurately reproduce diverse epidemic and mitigation trajectories from 2020 to 2021, reported from 11 European countries, Iran, and 8 US states. High regional variability in the severity and duration of the spring lockdown and in peak mortality rates of the first SARS-CoV-2 wave can be explained by differences in the reconstructed readiness H. A ubiquitous temporal decrease of H has greatly intensified second and third waves and slowed down their decay. The unprecedented skill of the model suggests that the combination of an adaptive and a non-adaptive rule may constitute a more fundamental mode in social dynamics. Its implementation in an epidemic context can produce realistic long-term scenarios relevant for strategic planning, such as on the feasibility of a zero-infection target or on the evolutionary arms race between mutations of SARS-CoV-2 and social responses.

Peak Systolic Blood Pressure During the Exercise Test: Reference Values by Sex and Age and Association With Mortality.

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Covid-19 Social Distancing Interventions by Statutory Mandate and Their Observational Correlation to Mortality in the United States and Europe.

PurposeEvaluate the correlation between statutory social distancing interventions and Covid-19 mortality independently in both the United States and Europe. The study is presented as a potential methodology to evaluate the effectiveness of statutory social distancing policy.Patients and MethodsTwenty-seven states in the United States and, separately, 12 European countries were selected which had clearly defined and dated establishment of statewide or national mandates for social distancing measures from the Institute for Health Metrics and Evaluation (IHME) data. Mandated social distancing measures considered in this study include: School closures, Prohibition on mass gatherings, business closures, stay at home orders, severe travel restrictions, and closure of non-essential businesses. The state/country Covid-19 peak mortality rate (PMR) was defined as the initial averaged normalized maximum during which social distancing mandates were in effect. Mandate-days were defined as the total days legislative mandates were in place to the PMR.ResultsThe normalized peak mortality rate in the US and in Europe did not demonstrate a statistically significant correlation to the total mandate days (R-squared=0.053, p=0.246, R-squared=2.4E-06, p=0.996). A significant correlation was found between normalized mortality rate and state/country population density (R-squared=0.524, p=0.00002,R-squared=0.397, p=0.0281).DiscussionThe analysis appears to suggest no mandate effective reduction in Covid-19 mortality rate to its defined initial peak when interpreting their mean-effect. A strong correlation to population density suggests human interaction frequency does affect the peak mortality rate.

Performance Evaluation of Kuroiler and Sasso Chicken Breeds Reared under On-farm and On-station Management Conditions in Tanzania

A study was conducted to evaluate the effect of management, breed, and their interaction on growth performance, egg production, and survivability under on-station and on-farm management conditions in Tanzania. A total of 1200 chicks, 600 for each breed, Kuroiler, and Sasso of mixed sexes were used. Birds under on-station management were confined and fed commercial ration throughout the experiment while those under on-farm management were allowed to semi-scavenge and supplemented with available feeds in the household. Brooding was carried out on-station for six weeks. Thereafter, birds were sub-divided for on-station and on-farm evaluation where data on body weight, egg production traits, and survival rate were taken at different ages from week 6 up to 52. The General Linear Models procedure fitting management, breed, and interaction between management and breed was used to analyze the data. Results show that management conditions had a significant influence on the performance of the breeds. Birds reared on-station performed better in all traits measured than those reared on-farm. The general effect of the breed was significant only for hen-day egg production (HDEP %) and hen-housed egg production (HHEP) in favour of Sasso chickens. Similarly, Sasso was more efficient at converting feed to live body weight. Interactions between management and breed were observed for all traits except peak egg production rate and mortality rate. While Sasso performance was better than that of Kuroiler on body weight, age at first egg, HDEP, age at peak egg production, and HHEP under the on-station management system, their performance in these traits were similar under the on-farm management except for body weight and age at first egg where Kuroiler was superior to Sasso. The survivability was also higher for Kuroiler than for Sasso under both management systems. It is concluded that genotype by environment (GxE) interaction had significant effects on the performance of the two breeds thus, a need to consider such effect when promoting them for either on-station or on-farm rearing.

The Association between Healthcare Resources, Non-Communicable Diseases, and COVID-19 Mortality: An Ecological Study of 162 Countries

Background: To provide an overview of the worldwide association between hospital beds, the burden of non-communicable diseases (NCDs), and COVID-19 mortality.Methods: We extracted data regarding COVID-19 deaths and cases from the Our World in Data as of November 21, 2020. We also obtained the following data:1) NCDs disability-adjusted life years (DALYs), health-adjusted life expectancy, and the health access and quality index from the Global Burden of Disease study; 2) the number of hospital beds, physicians, nurses and midwives per population, and out-of-pocket payments from the WHO website; 3) income levels and population density from the World Bank database. Using the principal component approach and a multilevel generalised linear model, we examined these variables’ independent associations with COVID-19 mortality rate ratio (MRR).Findings: During the study period, 17.62 COVID-19 deaths per 100,000 population were reported globally (1.20 in low-, 13.43 in lower-middle-, 14.14 in upper-middle-, and 46.72 in high-income countries). Median age increased COVID-19 mortality. Hospital beds were associated with reduced COVID-19 mortality (MRR=0.62; 95% CI: 0.59, 0.64) globally. During COVID-19 peak periods, despite a decreasing trend in COVID-19 MRR with increasing beds in high-income countries, the odds of mortality remained high even within the highest percentile of hospital beds (MRR=2.99 for 20th - 40th and 1.51 for >60 th bed percentile, respectively). On the contrary, in middle-income countries, we observed an inverse association between the number of hospital beds and COVID-19 mortality in both periods. NCD DALYs were associated with increased COVID-19 deaths, particularly during peak mortality periods in high-income countries. Death-to-case ratio increased by approximately two times during the peak vs non-peak mortality periods.Interpretations: COVID-19 is a syndemic interacting with non-communicable diseases and not only a pandemic. A comprehensive national healthcare plan against COVID-19 spread should include adequate measures to protect vulnerable patients with pre-existing chronic conditions.Funding: None.Declaration of Interests: The authors declare no conflicts of interest to disclose.

What do the numbers say? - Introduction of the WHO ICD-PM classification and fetuses-at risk approach in perinatal audit, South India

Objective: In India, despite a reduction in perinatal mortality rate from 2014 to 2019, still birth rate is still the same at the national average of 4/1000 live births. As yet there is no nation-wide audit in India except for facility based audits. Hence the need for a simplified yet effective audit process exists. The aim of this study was to perform a qualitative perinatal audit and devise methods for future audits. Methods: We conducted a one year audit for all perinatal deaths using WHO ICD PM and 3-delay classification. Gestational age (GA) specific mortality was calculated for significant underlying factors using fetuses-at risk approach. Results: We recorded a perinatal mortality rate of 6.1/1000 births among booked cases and 21.32/1000 births among referred cases. Fetal growth restriction was the most common antenatal condition, accounting to 33.3% of antepartum deaths. Prematurity accounted to 52% of neonatal deaths. Phase 2 delay with delayed referrals in severe pre-eclampsia and Phase 1 delay with late visit (&gt; 24 h) to hospital after experiencing absent fetal movements were the most common identifiable delays. Hypertension stood out to be the single most common risk-factor. GA specific mortalities, calculated using fetuses-at risk approach, show a peak mortality rate at 30 weeks, 37 weeks and 38 weeks in pregnancies with early-onset preeclampsia, severe fetal growth restriction and medically treated gestational diabetes respectively. Conclusion: The audit identified significant contributing factors to the mortality. ICD-PM and 3-delay classification was simpler and easier to apply with wide areas of opportunities for secondary analysis.

Impact of Relaxing Covid-19 Social Distancing Measures on Rural North Wales: A Simulation Analysis.

Background: Social distancing policies aimed to limit Covid-19 across the UK were gradually relaxed between May and August 2020, as peak incidences passed. Population density is an important driver of national incidence rates; however peak incidences in rural regions may lag national figures by several weeks. We aimed to forecast the timing of peak Covid-19 mortality rate in rural North Wales.Methods: Covid-19 related mortality data up to 7/5/2020 were obtained from Public Health Wales and the UK Government. Sigmoidal growth functions were fitted by non-linear least squares and model averaging used to extrapolate mortality to 24/8/2020. The dates of peak mortality incidences for North Wales, Wales and the UK; and the percentage of predicted mortality at 24/8/2020 were calculated.Results: The peak daily death rates in Wales and the UK were estimated to have occurred on the 14/04/2020 and 15/04/2020, respectively. For North Wales, this occurred on the 07/05/2020, corresponding to the date of analysis. The number of deaths reported in North Wales on 07/05/2020 represents 33% of the number predicted to occur by 24/08/2020, compared with 74 and 62% for Wales and the UK, respectively.Conclusion: Policies governing the movement of people in the gradual release from lockdown are likely to impact significantly on areas–principally rural in nature–where cases of Covid-19, deaths and immunity are likely to be much lower than in populated areas. This is particularly difficult to manage across jurisdictions, such as between England and Wales, and in popular holiday destinations.

COVID-19 and Overall Mortality Inequities in the Surge in Death Rates by Zip Code Characteristics: Massachusetts, January 1 to May 19, 2020

Objectives. To address evidence gaps in COVID-19 mortality inequities resulting from inadequate race/ethnicity data and no socioeconomic data.Methods. We analyzed age-standardized death rates in Massachusetts by weekly time intervals, comparing rates for January 1 to May 19, 2020, with the corresponding historical average for 2015 to 2019 stratified by zip code social metrics.Results. At the surge peak (week 16, April 15-21), mortality rate ratios (comparing 2020 vs 2015-2019) were 2.2 (95% confidence interval [CI] = 1.4, 3.5) and 2.7 (95% CI = 1.4, 5.5) for the lowest and highest zip code tabulation area (ZCTA) poverty categories, respectively, with the 2020 peak mortality rate 1.1 (95% CI = 1.0, 1.3) times higher in the highest than the lowest poverty ZCTA. Similarly, rate ratios were significantly elevated for the highest versus lowest quintiles with respect to household crowding (1.7; 95% CI = 1.0, 2.9), racialized economic segregation (3.1; 95% CI = 1.8, 5.3), and percentage population of color (1.8; 95% CI = 1.6, 2.0).Conclusions. The COVID-19 mortality surge exhibited large inequities.Public Health Implications. Using zip code social metrics can guide equity-oriented COVID-19 prevention and mitigation efforts.

Response strategies for COVID-19 epidemics in African settings: a mathematical modelling study

BackgroundThe health impact of COVID-19 may differ in African settings as compared to countries in Europe or China due to demographic, epidemiological, environmental and socio-economic factors. We evaluated strategies to reduce SARS-CoV-2 burden in African countries, so as to support decisions that balance minimising mortality, protecting health services and safeguarding livelihoods.MethodsWe used a Susceptible-Exposed-Infectious-Recovered mathematical model, stratified by age, to predict the evolution of COVID-19 epidemics in three countries representing a range of age distributions in Africa (from oldest to youngest average age: Mauritius, Nigeria and Niger), under various effectiveness assumptions for combinations of different non-pharmaceutical interventions: self-isolation of symptomatic people, physical distancing and ‘shielding’ (physical isolation) of the high-risk population. We adapted model parameters to better represent uncertainty about what might be expected in African populations, in particular by shifting the distribution of severity risk towards younger ages and increasing the case-fatality ratio. We also present sensitivity analyses for key model parameters subject to uncertainty.ResultsWe predicted median symptomatic attack rates over the first 12 months of 23% (Niger) to 42% (Mauritius), peaking at 2–4 months, if epidemics were unmitigated. Self-isolation while symptomatic had a maximum impact of about 30% on reducing severe cases, while the impact of physical distancing varied widely depending on percent contact reduction and R0. The effect of shielding high-risk people, e.g. by rehousing them in physical isolation, was sensitive mainly to residual contact with low-risk people, and to a lesser extent to contact among shielded individuals. Mitigation strategies incorporating self-isolation of symptomatic individuals, moderate physical distancing and high uptake of shielding reduced predicted peak bed demand and mortality by around 50%. Lockdowns delayed epidemics by about 3 months. Estimates were sensitive to differences in age-specific social mixing patterns, as published in the literature, and assumptions on transmissibility, infectiousness of asymptomatic cases and risk of severe disease or death by age.ConclusionsIn African settings, as elsewhere, current evidence suggests large COVID-19 epidemics are expected. However, African countries have fewer means to suppress transmission and manage cases. We found that self-isolation of symptomatic persons and general physical distancing are unlikely to avert very large epidemics, unless distancing takes the form of stringent lockdown measures. However, both interventions help to mitigate the epidemic. Shielding of high-risk individuals can reduce health service demand and, even more markedly, mortality if it features high uptake and low contact of shielded and unshielded people, with no increase in contact among shielded people. Strategies combining self-isolation, moderate physical distancing and shielding could achieve substantial reductions in mortality in African countries. Temporary lockdowns, where socioeconomically acceptable, can help gain crucial time for planning and expanding health service capacity.

Analysis on long-term trend of mortality and years of life lost of breast cancer in women in Tianjin, 1999-2017

Objective: To analyze the trends of mortality and years of life lost (YLL) of breast cancer in women in Tianjin and provide references for the development of intervention strategies. Methods: The crude mortality rate, standard mortality rate, cumulative rate (0-74 years old) and truncated rate (35-64 years old) of breast cancer in women in Tianjin from 1999 to 2017 were calculated. The annual percentage change of the mortality rate and YLL rate were analyzed by Joinpoint regression. Results: From 1999 to 2017, a total of 8 356 deaths of breast cancer were reported in Tianjin, resulting in a YLL of 262 835.53 person-years. The average crude mortality rate was 9.15/100 000. The average age standardized rate(ASR) (World) was 6.14/100 000. The ratio of ASR (World) between urban and rural areas was 1.73∶1. The peak mortality ratio of age groups between urban area and rural area was 3.13∶1. From 1999 to 2017, both the crude mortality rate and ASR of breast cancer in Tianjin had rising trends. In 2017, the crude mortality rate and the ASR of breast cancer increased by 113.7% and 44.4% respectively compared with 1999. The increase of urban mortality mainly came from elderly group aged ≥75 years, and the mortality of young age groups in rural area showed an fast increases, which was most obvious in age group 45-59 years (average annual percentage change=3.6%, P<0.01). Conclusions: The mortality rate of breast cancer and disease burden in women in Tianjin are still in rapid increase. We should continue to implement the prevention and control strategies such as lifestyle intervention and screening of key groups. More attention need to be paid to the increase of breast cancer incidence in rural area.

Flight of the Mountain Pine Beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae: Scolytinae), in Suburban Cheyenne, Wyoming, USA during Summer 2011

The mountain pine beetle (MPB), Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae: Scolytinae), is a major tree-killing bark beetle that attacks primarily ponderosa pine, Pinus ponderosa Lawson & C. Lawson, and lodgepole pine, Pinus contorta Douglas ex Loudon (Pinaceae), among other pines, across the western coniferous forests of North America (Negron and Fettig 2014). A continental-scale outbreak of MPB occurred from the late 1990s through the mid- to late 2010s, ranging from the southern Rockies north to British Columbia (Jarvis and Kulakowski 2015; Negron and Fettig 2014). In northern Colorado and southern Wyoming, most of the mortality occurred among lodgepole pine but mortality also occurred among ponderosa pine, whitebark pine, Pinus albicaulis Engelm., and limber pine, Pinus flexilis James. Elevated populations of mountain pine beetles across Wyoming reached their highest levels from 2007-2010. Peak mortality in 2009 affected approximately 500,000 ha. A decade later, populations had markedly declined, with tree mortality occurring on < 200 ha by 2017 (DeSantis 2017).

Accounting for Global COVID-19 Diffusion Patterns, January-April 2020.

Key factors in modeling a pandemic and guiding policy-making include mortality rates associated with infections; the ability of government policies, medical systems, and society to adapt to the changing dynamics of a pandemic; and institutional and demographic characteristics affecting citizens’ perceptions and behavioral responses to stringent policies. This paper traces the cross-country associations between COVID-19 mortality, policy interventions aimed at limiting social contact, and their interactions with institutional and demographic characteristics. We document that, with a lag, more stringent pandemic policies were associated with lower mortality growth rates. The association between stricter pandemic policies and lower future mortality growth is more pronounced in countries with a greater proportion of the elderly population and urban population, greater democratic freedoms, and larger international travel flows. Countries with greater policy stringency in place prior to the first death realized lower peak mortality rates and exhibited lower durations to the first mortality peak. In contrast, countries with higher initial mobility saw higher peak mortality rates in the first phase of the pandemic, and countries with a larger elderly population, a greater share of employees in vulnerable occupations, and a higher level of democracy took longer to reach their peak mortalities. Our results suggest that policy interventions are effective at slowing the geometric pattern of mortality growth, reducing the peak mortality, and shortening the duration to the first peak. We also shed light on the importance of institutional and demographic characteristics in guiding policy-making for future waves of the pandemic.

Analysing Covid-19 Epidemic Trajectories: are Countries Flattening the Curve?

Introduction: We evaluated COVID19 epidemic trajectories of different countries in terms of relative trajectory steepness and anticipated epidemic duration, in other words “flatness of the curve”. Methods: We used open-domain data on COVID-19 reported cases and deaths per country per day. A subset of 47 countries was analysed. Data were fitted with an analytical model following Gompertz equation. Uncertainty pertaining to the model forecasts was also quantified. To relate differences in epidemic trajectories of different countries to the mitigation approach taken by governments of those countries, we made use of the COVID-19 Government Response Stringency Index developed and published by Oxford University and Blavatnik School. Results: Acceptable quality fits were obtained for all the countries with R2 mostly in excess of 0.98. Uncertainty on the final Cases and/or Deaths count is typically a factor of two early in the epidemic but this quickly reduces as the epidemic progresses. Uncertainty on Epidemic Duration also reduces but less fast. Statistics on key parameters like Epidemic Duration, Epidemic Peak and Final Mortality Rate were obtained and then cross-correlated with the rigor of government measures as recorded in the Stringency Score. Most significantly, we find a clear trend of decreasing Peak Epidemic height (and to a less extent, shorter Epidemic Duration) with increased Government Stringency at the epidemic onset. We also find that Final Mortality Rate decreases with increased Stringency of Government Testing and Contact-Tracing. Conclusions: Whilst COVID-19 epidemic trajectories for most countries are similar, some countries do have flatter and less severe trajectories than others. Our analysis suggests that mitigation measures taken by a government at the very initial stage of a COVID-19 outbreak might significantly impact severity and to a less extent duration of the epidemic.

In vitro and in vivo activity of voriconazole and benznidazole combination on trypanosoma cruzi infection models

Combination therapy has been proposed as an ideal strategy to reduce drug toxicity and improve treatment efficacy in Chagas disease. Previously, we demonstrated potent in vivo anti-Trypanosoma cruzi activity of voriconazole. In this work, we aimed to study the synergistic effect of voriconazole (VCZ) and benznidazole (BZ) both in vitro and in vivo models of T. cruzi infection using the Tulahuen strain. Combining VCZ and BZ at fixed concentrations, the inhibitory concentration 50% (IC50) on amastigotes was lower than the obtained IC50 for BZ alone and the Fractional Inhibitory Concentration Index (∑FIC) suggested an in vitro additive effect on T. cruzi amastigotes inhibition at concentrations devoid of cytotoxic effects. Treatment response in the in vivo model was evaluated by comparing behavior and physical aspects, parasitemia and mortality of mice infected with Tulahuen strain. VCZ and BZ treatments alone or in combination were well tolerated. All treated animals displayed significantly lower mean peak parasitemia and mortality compared to infected non-treated controls (p< 0.05). However, VCZ + BZ combination elicited no additional benefits over BZ monotherapy. VCZ efficacy was not enhanced by combination therapy with BZ at the doses studied, requiring further and astringent non-clinical studies to establish the VCZ efficacy and eventually moving forward to clinical trials.

Transcriptome Profiling of Pacu (Piaractus mesopotamicus) Challenged With Pathogenic Aeromonas hydrophila: Inference on Immune Gene Response.

Pacu (Piaractus mesopotamicus) is a Neotropical fish of major importance for South American aquaculture. Septicemia caused by Aeromonas hydrophila bacteria is currently considered a substantial threat for pacu aquaculture that have provoked infectious disease outbreaks with high economic losses. The understanding of molecular aspects on progress of A. hydrophila infection and pacu immune response is scarce, which have limited the development of genomic selection for resistance to this infection. The present study aimed to generate information on transcriptome of pacu in face of A. hydrophila infection, and compare the transcriptomic responses between two groups of time-series belonging to a disease resistance challenge, peak mortality (HM) and mortality plateau (PM) groups of individuals. Nine RNA sequencing (RNA-Seq) libraries were prepared from liver tissue of challenged individuals, generating ∼160 million 150 bp pair-end reads. After quality trimming/cleanup, these reads were assembled de novo generating 211,259 contigs. When the expression of genes from individuals of HM group were compared to individuals from control group, a total of 4,413 differentially expressed transcripts were found (2,000 upregulated and 2,413 downregulated candidate genes). Additionally, 433 transcripts were differentially expressed when individuals from MP group were compared with those in the control group (155 upregulated and 278 downregulated candidate genes). The resulting differentially expressed transcripts were clustered into the following functional categories: cytokines and signaling, epithelial protection, antigen processing and presentation, apoptosis, phagocytosis, complement system cascades and pattern recognition receptors. The proposed results revealing relevant differential gene expression on HM and PM groups which will contribute to a better understanding of the molecular defense mechanisms during A. hydrophila infection.