Respiratory syncytial virus causes more hospitalizations and deaths in equatorial Brazil than influenza (including during the 2009 pandemic).

Despite numerous studies evaluating influenza and Respiratory Syncytial Virus (RSV), there is still a lack of knowledge about them, especially in tropical countries. We compared the relative importance of respiratory viruses by examining their spatiotemporal patterns, age-specific hospitalization data and mortality data for 2007-2012 obtained from official sources. The data were aggregated into "respiratory infection seasonal zones" formed combining states that had similar seasonal patterns of pneumonia and influenza (P&I). Equatorial-North where P&I peaks in the middle of the year, Equatorial-South where P&I peaks in the first semester and coincides with the rainy-season, Subtropical where P&I peaks are clearly concentrated in the winter season, and Tropical Midwest and South-East where P&I peaks are a transition between the South-Equatorial and the Sub-tropical. Our analyses indicate that RSV has higher impact than influenza in equatorial region of Brazil, which was particularly evident during the circulation of the 2009pdm strain, and suggests that seasonal influenza may have a lower impact in Equatorial Brazil (and perhaps in other tropical regions of the world) than previously considered. Accordingly, we suggest that the broad assumption that influenza is the main cause of viral respiratory hospitalizations and death in equatorial regions be questioned with greater emphasis in future studies.

Comparison of malaria incidence rates and socioeconomic-environmental factors between the states of Acre and Rondônia: a spatio-temporal modelling study.

BACKGROUND: Plasmodium falciparum malaria is a threat to public health, but Plasmodium vivax malaria is most prevalent in Latin America, where the incidence rate has been increasing since 2016, particularly in Venezuela and Brazil. The Brazilian Amazon reported 193,000 cases in 2017, which were mostly confirmed as P. vivax (~ 90%). Herein, the relationships among malaria incidence rates and the proportion of accumulated deforestation were contrasted using data from the states of Acre and Rondônia in the south-western Brazilian Amazon. The main purpose is to test the hypothesis that the observed difference in incidence rates is associated with the proportion of accumulated deforestation. METHODS: An ecological study using spatial and temporal models for mapping and modelling malaria risk was performed. The municipalities of Acre and Rondônia were the spatial units of analysis, whereas month and year were the temporal units. The number of reported malaria cases from 2009 until 2015 were used to calculate the incidence rate per 1000 people at risk. Accumulated deforestation was calculated using publicly available satellite images. Geographically weighted regression was applied to provide a local model of the spatial heterogeneity of incidence rates. Time-series dynamic regression was applied to test the correlation of incidence rates and accumulated deforestation, adjusted by climate and socioeconomic factors. RESULTS: The malaria incidence rate declined in Rondônia but remained stable in Acre. There was a high and positive correlation between the decline in malaria and higher proportions of accumulated deforestation in Rondônia. Geographically weighted regression showed a complex relationship. As deforestation increased, malaria incidence also increased in Acre, while as deforestation increased, malaria incidence decreased in Rondônia. Time-series dynamic regression showed a positive association between malaria incidence and precipitation and accumulated deforestation, whereas the association was negative with the human development index in the westernmost areas of Acre. CONCLUSION: Landscape modification caused by accumulated deforestation is an important driver of malaria incidence in the Brazilian Amazon. However, this relationship is not linearly correlated because it depends on the overall proportion of the land covered by forest. For regions that are partially degraded, forest cover becomes a less representative component in the landscape, causing the abovementioned non-linear relationship. In such a scenario, accumulated deforestation can lead to a decline in malaria incidence.

Environmental drivers of the spatiotemporal dynamics of respiratory syncytial virus in the United States.

Epidemics of respiratory syncytial virus (RSV) are known to occur in wintertime in temperate countries including the United States, but there is a limited understanding of the importance of climatic drivers in determining the seasonality of RSV. In the United States, RSV activity is highly spatially structured, with seasonal peaks beginning in Florida in November through December and ending in the upper Midwest in February-March, and prolonged disease activity in the southeastern US. Using data on both age-specific hospitalizations and laboratory reports of RSV in the US, and employing a combination of statistical and mechanistic epidemic modeling, we examined the association between environmental variables and state-specific measures of RSV seasonality. Temperature, vapor pressure, precipitation, and potential evapotranspiration (PET) were significantly associated with the timing of RSV activity across states in univariate exploratory analyses. The amplitude and timing of seasonality in the transmission rate was significantly correlated with seasonal fluctuations in PET, and negatively correlated with mean vapor pressure, minimum temperature, and precipitation. States with low mean vapor pressure and the largest seasonal variation in PET tended to experience biennial patterns of RSV activity, with alternating years of "early-big" and "late-small" epidemics. Our model for the transmission dynamics of RSV was able to replicate these biennial transitions at higher amplitudes of seasonality in the transmission rate. This successfully connects environmental drivers to the epidemic dynamics of RSV; however, it does not fully explain why RSV activity begins in Florida, one of the warmest states, when RSV is a winter-seasonal pathogen. Understanding and predicting the seasonality of RSV is essential in determining the optimal timing of immunoprophylaxis.

The spatiotemporal characteristics of influenza A and B in the WHO European Region: can one define influenza transmission zones in Europe?

We aimed to assess the epidemiology and spatiotemporal patterns of influenza in the World Health Organization (WHO) European Region and evaluate the validity of partitioning the Region into five influenza transmission zones (ITZs) as proposed by the WHO. We used the FluNet database and included over 650,000 influenza cases from 2000 to 2015. We analysed the data by country and season (from July to the following June). We calculated the median proportion of cases caused by each virus type in a season, compared the timing of the primary peak between countries and used a range of cluster analysis methods to assess the degree of overlap between the WHO-defined and data-driven ITZs. Influenza A and B caused, respectively, a median of 83% and 17% cases in a season. There was a significant west-to-east and non-significant (p = 0.10) south-to-north gradient in the timing of influenza activity. Typically, influenza peaked in February and March; influenza A earlier than influenza B. Most countries in the WHO European Region would fit into two ITZs: 'Western Europe' and 'Eastern Europe'; countries bordering Asia may be better placed into extra-European ITZs. Our findings have implications for the presentation of surveillance data and prevention and control measures in this large WHO Region.

Environmental predictors of seasonal influenza epidemics across temperate and tropical climates.

Human influenza infections exhibit a strong seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low specific humidity conditions facilitate the airborne survival and transmission of the influenza virus in temperate regions, resulting in annual winter epidemics. However, this relationship is unlikely to account for the epidemiology of influenza in tropical and subtropical regions where epidemics often occur during the rainy season or transmit year-round without a well-defined season. We assessed the role of specific humidity and other local climatic variables on influenza virus seasonality by modeling epidemiological and climatic information from 78 study sites sampled globally. We substantiated that there are two types of environmental conditions associated with seasonal influenza epidemics: "cold-dry" and "humid-rainy". For sites where monthly average specific humidity or temperature decreases below thresholds of approximately 11-12 g/kg and 18-21°C during the year, influenza activity peaks during the cold-dry season (i.e., winter) when specific humidity and temperature are at minimal levels. For sites where specific humidity and temperature do not decrease below these thresholds, seasonal influenza activity is more likely to peak in months when average precipitation totals are maximal and greater than 150 mm per month. These findings provide a simple climate-based model rooted in empirical data that accounts for the diversity of seasonal influenza patterns observed across temperate, subtropical and tropical climates.

Influence of pneumococcal vaccines and respiratory syncytial virus on alveolar pneumonia, Israel.

Postlicensure surveillance of pneumonia incidence can be used to estimate whether pneumococcal conjugate vaccines (PCVs) affect incidence. We used Poisson regression models that control for baseline seasonality to determine the impact of PCVs and the possible effects of variations in virus activity in Israel on these surveillance estimates. PCV was associated with significant declines in radiologically confirmed alveolar pneumonia (RCAP) among patients <6 months, 6-17 months, and 18-35 months of age (-31% [95% CI -51% to -15%], -41% [95% CI -52 to -32%], and -34% [95% CI -42% to -25%], respectively). Respiratory syncytial virus (RSV) activity was associated with strong increases in RCAP incidence, with up to 44% of cases attributable to RSV among infants <6 months of age and lower but significant impacts in older children. Seasonal variations, particularly in RSV activity, masked the impact of 7-valent PCVs, especially for young children in the first 2 years after vaccine introduction.

Characterization of regional influenza seasonality patterns in China and implications for vaccination strategies: spatio-temporal modeling of surveillance data.

BACKGROUND: The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs. METHODS AND FINDINGS: We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005-2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%-151%] in the north versus 37% [95% CI 27%-47%] in the south, p<0.0001). Epidemics peaked in January-February in Northern China (latitude ≥33°N) and April-June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January-February and June-August (periodicity ratio >0.6 in provinces located within 27.4°N-31.3°N, slope of latitudinal gradient with latitude -0.016 [95% CI -0.025 to -0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces. CONCLUSIONS: Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4-6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics. Please see later in the article for the Editors' Summary.

Shift in the timing of respiratory syncytial virus circulation in a subtropical megalopolis: implications for immunoprophylaxis.

Respiratory syncytial virus (RSV) is the most common cause of severe respiratory infections worldwide, and an important cause of childhood bronchiolitis, pneumonia, and mortality. Although prevention of RSV infection by immunoprophylaxis with palivizumab has proved effective, a precise understanding of the timing of RSV outbreaks is necessary to ensure that infants are protected when RSV is circulating. In this study a consistent shift in the seasonal patterns of RSV circulation in southeast Brazil (São Paulo) is reported based on the analysis of 15 years of viral surveillance. Surveillance was conducted from 1996 to 2010 and involved the collection of samples from children with symptoms of acute respiratory infection. Putative changes in school terms, in the proportion of RSV genotypes infecting children and in the seasonal dynamics of several climatic parameters during the period were also investigated. The results revealed a progression in the timing of RSV seasons, with a shift in the onset and peak of RSV epidemics from 2007 onwards. Although lower rainfall and temperatures were associated with the onset of outbreaks, there was no evidence of changes in climate, school terms or in the relative proportion of genotypes in the period analyzed. These findings have direct implications for improving the prophylactic use of palivizumab, and stress the importance of fine tuning prophylaxis with recent surveillance data. In the case of São Paulo, palivizumab prophylaxis should be initiated earlier than suggested currently. Similar adjustments may be necessary in other regions.

EPIPOI: a user-friendly analytical tool for the extraction and visualization of temporal parameters from epidemiological time series.

BACKGROUND: There is an increasing need for processing and understanding relevant information generated by the systematic collection of public health data over time. However, the analysis of those time series usually requires advanced modeling techniques, which are not necessarily mastered by staff, technicians and researchers working on public health and epidemiology. Here a user-friendly tool, EPIPOI, is presented that facilitates the exploration and extraction of parameters describing trends, seasonality and anomalies that characterize epidemiological processes. It also enables the inspection of those parameters across geographic regions. Although the visual exploration and extraction of relevant parameters from time series data is crucial in epidemiological research, until now it had been largely restricted to specialists. METHODS: EPIPOI is freely available software developed in Matlab (The Mathworks Inc) that runs both on PC and Mac computers. Its friendly interface guides users intuitively through useful comparative analyses including the comparison of spatial patterns in temporal parameters. RESULTS: EPIPOI is able to handle complex analyses in an accessible way. A prototype has already been used to assist researchers in a variety of contexts from didactic use in public health workshops to the main analytical tool in published research. CONCLUSIONS: EPIPOI can assist public health officials and students to explore time series data using a broad range of sophisticated analytical and visualization tools. It also provides an analytical environment where even advanced users can benefit by enabling a higher degree of control over model assumptions, such as those associated with detecting disease outbreaks and pandemics.

Productivity of mother pigs is lower, and mortality greater, in countries that still confine them in gestation crates.

Background: For decades, pig farmers have used gestation crates - small metal enclosures about two feet wide - to confine pregnant sows (female breeding pigs). Gestation crates physically restrain sows for most of their life, preventing them from walking or even turning around. Millions of females are still housed in these systems. Growing societal concern about animal welfare has been pressuring the industry for change, with recent legislation in the European Union and California restricting the use of crates. Still, the notion that gestation crates negatively affect sow welfare has been challenged by producers in regions where crates are widely used, who argue that, by facilitating health monitoring and preventing aggression, crates lead to lower sow mortality and higher piglet outputs per sow. We address these claims by comparing sow mortality and performance across countries with different housing systems. Methods: To this end, we use publicly available data from InterPig, a network of pig production economists in 17 countries that provides internationally harmonized methods for meaningful comparisons of national production data. Results: The results show that sow mortality is significantly higher, and annual pig production per sow significantly lower, in those countries where gestation crates are still the norm compared to countries in the European Union, where use of gestation crates is restricted to up to four weeks after insemination. Conclusions: Claims of higher mortality and reduced productivity per sow in crate-free systems are not substantiated by this data. This evidence should be considered in policies affecting the welfare of breeding pigs.

Pain-Track: a time-series approach for the description and analysis of the burden of pain.

OBJECTIVE: To present the Pain-Track, a novel framework for the description and analysis of the pain experience based on its temporal evolution, around which intensity and other attributes of pain (texture, anatomy), interventions and clinical symptoms can be registered. This time-series approach can provide valuable insight on the expected evolution of the pain typically associated with different medical conditions and on time-varying (risk) factors associated with the temporal dynamics of pain. RESULTS: We illustrate the use of the framework to explore hypotheses on the temporal profile of the pain associated with an acute injury (bone fracture), and the magnitude of the pain burden it represents. We also show that, by focusing on the critical dimensions of the pain experience (intensity and time), the approach can help map different conditions to a common scale directly relating to the experiences of those who endure them (time in pain), providing the basis for the quantification of the burden of pain inflicted upon individuals or populations. An electronic version for data entry and interpretation is also presented.

Laying hen mortality in different indoor housing systems: a meta-analysis of data from commercial farms in 16 countries.

Societal concern with the welfare of egg laying hens housed in conventional cages is fostering a transition towards cage-free systems in many countries. However, although cage-free facilities enable hens to move freely and express natural behaviours, concerns have also been raised over the possibility that cage-free flocks experience higher mortality, potentially compromising some aspects of their welfare. To investigate this possibility, we conducted a large meta-analysis of laying hen mortality in conventional cages, furnished cages and cage-free aviaries using data from 6040 commercial flocks and 176 million hens from 16 countries. We show that except for conventional cages, mortality gradually drops as experience with each system builds up: since 2000, each year of experience with cage-free aviaries was associated with a 0.35-0.65% average drop in cumulative mortality, with no differences in mortality between caged and cage-free systems in more recent years. As management knowledge evolves and genetics are optimized, new producers transitioning to cage-free housing may experience even faster rates of decline. Our results speak against the notion that mortality is inherently higher in cage-free production and illustrate the importance of considering the degree of maturity of production systems in any investigations of farm animal health, behaviour and welfare.

The reproduction number of seasonal influenza epidemics in Brazil, 1996-2006.

The transmission dynamics of influenza in tropical regions are poorly understood. Here we explore geographical variations in the reproduction number of influenza across equatorial, tropical and subtropical areas of Brazil, based on the analysis of weekly pneumonia and influenza (P&I) mortality time series in 27 states. The reproduction number (R) was low on average in Brazil (mean = 1.03 (95% CI 1.02-1.04), assuming a serial interval of 3 days). Estimates of the reproduction number were slightly lower for Brazil than for the USA or France (difference in mean R = 0.08, p < 0.01) and displayed less between-year variation (p < 0.001). Our findings suggest a weak gradient in the reproduction number with population size, where R increases from low population in the North to high population in the South of Brazil. Our low estimates of the reproduction number suggest that influenza population immunity could be high on average in Brazil, potentially resulting in increased viral genetic diversity and rate of emergence of new variants. Additional epidemiological and genetic studies are warranted to further characterize the dynamics of influenza in the tropics and refine our understanding of the global circulation of influenza viruses.

Effect of pneumococcal conjugate vaccine introduction on childhood pneumonia mortality in Brazil: a retrospective observational study.

BACKGROUND: Understanding the real-world effect of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is crucial because of the expectation that increased PCV use will substantially reduce the burden of pneumonia deaths in children younger than 5 years. However, few post-vaccine introduction studies have estimated the benefits of PCV use on childhood mortality and results have been inconsistent. Therefore, we set out to assess the effect of introduction of ten-valent pneumococcal conjugate vaccine (PCV10) on pneumonia mortality in children in Brazil. METHODS: In this retrospective observational study, we used publicly available mortality data of children aged 3-59 months in Brazil. We separated data by age group (3-11 months, 3-23 months, and 3-59 months) and stratified data by three different socioeconomic factors of Brazilian municipalities (in 2010): Human Development Index, proportion of children living in extreme poverty, and proportion of mothers with no primary education. We first examined long-term trends in childhood pneumonia mortality in Brazil (from 1980 to 2014). We then assessed the effect of PCV10-introduced in Brazil in 2010-both nationally and in municipalities stratified by socioeconomic status, with a synthetic control approach as our primary analytical method. FINDINGS: Between 1980 and 2010, a period during which Brazil's Human Development Index rose substantially, national pneumonia mortality in children younger than 5 years decreased from about 150 to 15 deaths per 100 000 children younger than 5 years. Despite rapid uptake of PCV10 after its introduction in 2010, we observed a further vaccine-associated decline of about 10% in national childhood pneumonia mortality with our primary analytical method, with a high degree of uncertainty in the estimates. We observed larger reductions in municipal childhood pneumonia mortality in all three age groups (3-11 months, 3-23 months, and 3-59 months) in municipalities with a high percentage of extreme childhood poverty and mothers with no primary education, with the largest decrease observed in children aged 3-23 months in municipalities with low maternal education (24%, 95% credible interval 7-35). INTERPRETATION: The large reduction observed from 1980 to 2010 in national pneumonia mortality in children younger than 5 years underscores that improvements in nutrition, hygiene, education, and health care have an important role in reducing pneumonia mortality. Although the PCV-associated reduction in childhood pneumonia mortality at the national level was modest, we found that PCV led to larger reductions in low-income municipalities. Similarly, large benefits might occur when PCVs are introduced in other low-income settings. FUNDING: Bill & Melinda Gates Foundation and National Institute of Allergy and Infectious Diseases.

The 1918-1919 influenza pandemic in England and Wales: spatial patterns in transmissibility and mortality impact.

Spatial variations in disease patterns of the 1918-1919 influenza pandemic remain poorly studied. We explored the association between influenza death rates, transmissibility and several geographical and demographic indicators for the autumn and winter waves of the 1918-1919 pandemic in cities, towns and rural areas of England and Wales. Average measures of transmissibility, estimated by the reproduction number, ranged between 1.3 and 1.9, depending on model assumptions and pandemic wave and showed little spatial variation. Death rates varied markedly with urbanization, with 30-40% higher rates in cities and towns compared with rural areas. In addition, death rates varied with population size across rural settings, where low population areas fared worse. By contrast, we found no association between transmissibility, death rates and indicators of population density and residential crowding. Further studies of the geographical mortality patterns associated with the 1918-1919 influenza pandemic may be useful for pandemic planning.

Temporal trends and climatic factors associated with bacterial enteric diseases in Vietnam, 1991-2001.

OBJECTIVE: In Vietnam, shigellosis/dysentery, typhoid fever, and cholera are important enteric diseases. To better understand their epidemiology, we determined temporal trends, seasonal patterns, and climatic factors associated with high risk periods in eight regions across Vietnam. METHODS: We quantified monthly cases and incidence rates (IR) for each region from national surveillance data (1991-2001). High- and low-disease periods were defined from the highest and lowest IRs (1 SD above and below the mean) and from outbreaks from positive outliers (4 SDs higher in 1 month or 2 SDs higher in > or = 2 consecutive months). We used general linear models to compare precipitation, temperature, and humidity between high- and low-risk periods. RESULTS: Shigellosis/dysentery was widespread and increased 2.5 times during the study period, with the highest average IRs found between June and August (2.1/100,000-26.2/100,000). Typhoid fever was endemic in the Mekong River Delta and emerged in the Northwest in the mid-1990s, with peaks between April and August (0.38-8.6). Cholera was mostly epidemic along the central coast between May and November (0.07-2.7), and then decreased dramatically nationwide from 1997 onward. Significant climate differences were found only between high- and low-disease periods. We were able to define 4 shigellosis/dysentery, 14 typhoid fever, and 8 cholera outbreaks, with minimal geotemporal overlap and no significant climatic associations. CONCLUSIONS: In Vietnam, bacterial enteric diseases have distinct temporal trends and seasonal patterns. Climate plays a role in defining high- and low-disease periods, but it does not appear to be an important factor influencing outbreaks.

Cognition in an ever-changing world: climatic variability is associated with brain size in Neotropical parrots.

Research on the conditions favoring the evolution of complex cognition and its underlying neural structures has increasingly stressed the role of environmental variability. These studies suggest that the ability to learn, behave flexibly and innovate would be favored under unpredictable variations in the availability of resources, as it would enable organisms to adjust to novel conditions. Despite the growing number of studies based on the idea that larger-brained organisms would be better prepared to cope with environmental challenges, direct testing of the association between brain size and environmental variability per se remains scant. Here we focus on Neotropical parrots as our model group and test the hypothesis that if relatively larger brains were favored in climatically variable environments, larger-brained species should currently tolerate a higher degree of environmental uncertainty. Although we show that there are also other factors underlying the dynamics of brain size variation in this group, our results support the hypothesis that proportionally larger-brained species are more tolerant to climatic variability, both on a temporal and spatial scale. Additionally, they suggest that the differences in relative brain size among Neotropical parrots represent multiple, recent events in the evolutionary history of the group, and are particularly tied to an increased dependence on more open and climatically unstable habitats. As this is the first study to present evidence of the link between brain size and climatic variability in birds, our findings provide a step towards understanding the potential benefits underlying variation in brain size and the maintenance of highly enlarged brains in this and other groups.

Rotavirus vaccination takes seasonal signature of childhood diarrhea back to pre-sanitation era in Brazil.

OBJECTIVES: This study aimed to examine the previously unknown long-term spatio-temporal patterns in diarrheal morbidity and mortality across age groups and geography in Brazil under the light of evolving socioeconomic factors and interventions. METHODS: Nationwide mortality (1979-2014) and hospitalization (1998-2014) data were obtained from the Brazilian Ministry of Health. Analyses of long-term secular trends and seasonality of diarrheal morbidity and mortality were performed in EPIPOI (www.epipoi.info). RESULTS: For most states, the primary peak in mortality risk among children under 5 years occurred from December-April (summer/early autumn) from 1979-1988. From 2000-2005 (before the 2006 implementation of rotavirus vaccination), the pattern switched to June-October (winter/early spring). By 2007-2014, the peak in mortality shifted back towards summer/early autumn. A similar pattern was observed for hospitalizations. These patterns were particularly apparent in non-equatorial regions of the country. In contrast, the risk of diarrhea-related death among older children (5-19 years) did not demonstrate well-defined seasonality or spatial patterns. CONCLUSIONS: Rotavirus vaccination policies were associated with a shift in the timing of seasonal peaks in children under 5, reminiscent of the summer diarrhea period common decades prior. Additionally, young children were shown to have distinct disease patterns compared to other age groups, suggesting different etiologies.