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Early-onset dementia (EOD) is defined as any type of dementia with an onset before the age of 65. Despite its profound impact on patients and their families, EOD has garnered less attention when compared to late-onset dementia (LOD), often resulting in its underestimation. In comparison to LOD, EOD commonly manifests with atypical and heterogeneous symptoms, encompassing mainly non-memory problems, ranging from language and executive impairments to behavioral-led dysfunction. Despite the importance of accurate data to organize appropriate healthcare, evidence regarding EOD patients in Portugal is lacking.
Objectives
The primary aims of this study include identifying the causes for hospitalization in EOD patients, diagnosed with dementia either as a primary or secondary diagnosis, and comparing them with inpatients aged 65 and older (LOD). Additionally, the study aims to analyze key hospitalization outcomes for both groups, including length of stay, in-hospital mortality, and readmissions. As a secondary aim, this study seeks to describe subtypes of EOD.
Methods
A retrospective observational study will be conducted following the RECORD statement. Data will be retrieved from an administrative database that gathers de-identified routinely collected hospitalization data from all Portuguese mainland public hospitals. Hospitalization episodes of inpatients younger than 65 years old, with a primary or secondary diagnosis of dementia (ascertained by ICD-9-CM codes 290.0-290.4, 294.0-294.2, 331.0, 331.1, and 331.82), will be extracted. Comparison patients will be selected by propensity score-matching from inpatients over 65 years with a dementia ICD-9-CM code (in any position), matched for Charlson Comorbidity Index (CCI).
Results
Descriptive and analytical statistics will be conducted to describe and characterize both group of inpatients. Variables such as age at admission, sex, place of residence, causes and type of admission, psychiatric comorbidities, length of stay (LoS), destination after discharge, readmissions, in-hospital mortality and hospital charges will be analyzed.
Conclusions
With this nationwide analysis of EOD hospitalizations, we aim to reveal critical aspects of this condition, including common causes of admission, diagnostic features and health outcomes, allowing for appropriate medical interventions and support tailored to the specific needs of this clinical group.
To determine risk factors for the development of long coronavirus disease 2019 (COVID-19) in healthcare personnel (HCP).
Methods:
We conducted a case–control study among HCP who had confirmed symptomatic COVID-19 working in a Brazilian healthcare system between March 1, 2020, and July 15, 2022. Cases were defined as those having long COVID according to the Centers for Disease Control and Prevention definition. Controls were defined as HCP who had documented COVID-19 but did not develop long COVID. Multiple logistic regression was used to assess the association between exposure variables and long COVID during 180 days of follow-up.
Results:
Of 7,051 HCP diagnosed with COVID-19, 1,933 (27.4%) who developed long COVID were compared to 5,118 (72.6%) who did not. The majority of those with long COVID (51.8%) had 3 or more symptoms. Factors associated with the development of long COVID were female sex (OR, 1.21; 95% CI, 1.05–1.39), age (OR, 1.01; 95% CI, 1.00–1.02), and 2 or more SARS-CoV-2 infections (OR, 1.27; 95% CI, 1.07–1.50). Those infected with the SARS-CoV-2 δ (delta) variant (OR, 0.30; 95% CI, 0.17–0.50) or the SARS-CoV-2 o (omicron) variant (OR, 0.49; 95% CI, 0.30–0.78), and those receiving 4 COVID-19 vaccine doses prior to infection (OR, 0.05; 95% CI, 0.01–0.19) were significantly less likely to develop long COVID.
Conclusions:
Long COVID can be prevalent among HCP. Acquiring >1 SARS-CoV-2 infection was a major risk factor for long COVID, while maintenance of immunity via vaccination was highly protective.
The recent development of new offshore projects in pre-salt deepwater fields has placed offshore loading operations as the main production outflow alternative, increasing the operational complexity and risks. Numerous dangerous situations are associated with oil offloading, such as the messenger line transfer during the mooring stage. Nowadays, this critical task is realized by launching a thin messenger cable using the pneumatic line throwing apparatus. This is a complex and slow process since the operation usually occurs with the ship opposite to the wind. This work proposes a hybrid flight methodology based on computer vision and sensor fusion techniques for autonomous unmanned aerial vehicles (UAVs). The UAV takes off from an oil rig and precisely reaches a specific point in the shuttle tanker without using expensive positioning devices and augmenting UAV’s orientation (yaw) precision since the compass can suffer from severe interference due to naval metallic structures near the vehicle. The proposed framework was tested in a realistic simulated environment considering several practical operational constraints. The results demonstrated both the robustness and efficiency of the methodology.
This study evaluated the effect of roughage:concentrate (R:C) ratio associated with a variable particle size of physically effective neutral detergent fibre (peNDF8) in the forage (Tifton-85 hay) on the performance, carcass traits and meat quality of lambs. Seventy-two 4-month-old, non-castrated Santa Ines male lambs (23.5 ± 2.32 kg BW) were distributed in a completely randomized design, in a 2 × 2 factorial arrangement [two peNDF8 hay particle sizes (13 and 6 mm) and two R:C ratios (700:300 and 500:500 g/kg DM total)]. DMI, DM, NFC and TDN digestibility's, N-intake and N-faecal excretion were affected by the R:C ratio (P < 0.05). However, the N-retained was not affected by the studied variables (P > 0.05). It was observed an interaction (P < 0.05) between the peNDF8 and R:C ratios for final BW, average daily gain (ADG), colour parameters and pH 24 h. The lower roughage ratio provided greater (P < 0.05) concentrations of C14:1, C16:1–cis9, C18:1–cis9, ΣMUFA, Σn–6:Σn–3 and hypocholesterolemic/hypercholesterolemic index, enzymatic activity Δ9desaturase-C16 and -C18. Lambs fed a lower roughage diet had improved performance and feed efficiency, however, presented reduced polyunsaturated fatty acids (PUFA) concentrations in the meat, especially Σn–3 family. Higher roughage diet and larger peNDF8 particle size improved the concentrations of PUFA while decreased Σn–6:Σn–3 ratio in meat. Larger peNDF8 particle size associated with higher roughage proportion, have reduced animal performance however, it increased protein concentration, a* and C* colour parameter without affecting fatty acids profile of Longissimus lumborum muscle.
Unlike well-known global patterns of plant species richness along altitudinal gradients, in the mountainous areas of the Brazilian Caatinga, species richness and diversity reach their maxima near mountain tops. The causes of this unusual pattern are not well understood, and in particular the role of edaphic factors on plant community assembly along these gradients has not been investigated. Our goal was to assess the role of edaphic factors (fertility and soil texture) on plant community composition and structure on two mountains of the Brazilian semi-arid region. In 71 plots (Bodocongó site, twenty-one 200-m2 plots, 401–680 m asl; Arara site, fifty 100-m2 plots, 487–660 m asl) we recorded 3114 individuals representing 61 plant species; in addition, at each plot we collected composite soil samples from 0–20 cm depth. Significant altitude-related changes were observed both for community structure and composition, and edaphic variables. A canonical correspondence analysis allowed the distinction of two groups of plots according to species abundances, indicating a preferential habitat distribution of species depending both on altitude and soil variables. Although soil fertility was lowest at the highest altitudes, these areas had high richness and diversity. Conversely, the more fertile foothills were characterized by the dominance of generalist pioneer species. Despite the relatively short altitudinal range that characterizes the studied mountains, this study elucidates the role of edaphic factors on the floristic composition and species richness patterns on the mountains of the Brazilian semi-arid region.
Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
Methods:
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
Results:
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
Conclusion:
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
Sensory processing is the individual's ability to receive, process and integrate sensory information from the environment and body movement in the central nervous system, in order to produce adaptive responses. Sensory processing disorders (SPD) are associated to difficulties in regulating emotions and behaviours as well as motor abilities in response to sensory stimulation that lead to impairment in development and functioning. It is estimated that SPD affect 5–16% of school-aged children. Although these diseases constitute a primary diagnostic category in the Diagnostic Classification of Mental Health and Development Disorders of Infancy and Early Childhood: DC0-3, they have not yet been validated by the Diagnostic and Statistical Manual of Mental Disorders-DSM. In the latest edition of DSM, SPD were only included as one of the diagnostic criteria of autism-spectrum disorders. However, several studies have suggested that SPD may present themselves solely or coexist with other clinical conditions.
Objective
The aim of this study was to review systematically the relationship between SPD and psychopathology.
Methodology
Articles indexed in the Pubmed database were analyzed.
Results/conclusion
Although sensory processing problems are well known to occur in association with autism, their relationship with other mental disorders is not a well studied area. Some studies have related them with ADHD, behavioural disorders and learning disorders. Some studies also comproved that SPD are a valid diagnosis and that there are individuals with SPD who do not meet the criteria for other known disorder. One study found an abnormal white matter microstructure in children with SPD. Despite these findings SPD need to be further studied.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
The current study was carried out to examine the effect of cottonseed processing and chitosan supplementation on lamb performance, digestibility and nitrogen digestion. Eighty uncastrated Santa Inês lambs (23 ± 2.2 kg average weight, 4 months old) were distributed in a completely randomized design in a 2 × 2 factorial arrangement that consisted of two cottonseed processing forms (whole or ground) and two chitosan levels (0 or 136 mg/kg live weight). Higher dry matter and organic matter apparent digestibility coefficient (ADC) was achieved with the diets containing the whole cottonseed. Ether extract ADC was higher in the animals fed the chitosan-containing diet. There was an interaction effect on the ADC of neutral detergent fibre corrected for ash and protein, which increased with chitosan inclusion associated with the whole cottonseed. The lambs that received the treatment containing the whole cottonseed showed higher microbial protein synthesis. Chitosan addition increased nitrogen retention. The animals fed chitosan-containing diets showed higher microbial protein synthesis. There was an interaction effect on microbial protein synthesis. Whole cottonseed associated with chitosan in lamb diets increases ether extract ADC and microbial protein synthesis.
Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years.
Methods
The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis.
Results
At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (−10.215 to −0.337) and (−4.731 to −0.605) respectively).
Conclusions
Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.
This study aimed to evaluate the transcriptional changes occurring in isolated perfused mammary alveolar tissue in response to inoculation with S. agalactiae and to identify the most affected biological functions and pathways after 3 h. Four udders taken at slaughter from cows with healthy mammary gland were perfused ex situ with warmed and gassed Tyrode's solution. Mammary alveolar tissue samples were taken from the left fore and rear quarters (IQ-inoculated quarters) before inoculation (hour 0) and at 3 h post inoculation (hpi) and at the same times from control right fore and rear quarters (not inoculated: NIQ). A total of 1756 differentially expressed genes (DEGs) were identified between IQ and NIQ at 3 hpi using edgeR package. Within this set of DEGs, 952 were up regulated and mainly involved with innate immune response and inflammatory response, e.g., CD14, CCL5, TLR2, IL-8, SAA3, as well as in transcriptional regulation such as FOS, STAT3 and NFKBIA. Genes down-regulated (804) included those involved with lipid synthesis e.g., APOC2, SCD, FABP3 and FABP4. The most affected pathways were chemokine signaling, Wnt signaling and complement and coagulation cascades, which likely reflects the early stage response of mammary tissue to S. agalactiae infection. No significant gene expression changes were detected by RNA-Seq in the others contrasts. Real time-PCR confirmed the increase in mRNA abundance of immune-related genes: TLR2, TLR4, IL-1β, and IL-10 at 3 hpi between IQ and NIQ. The expression profiles of Casp1 and Bax for any contrasts were unaffected whereas Bcl2 was increased in IQ, which suggests no induction of apoptosis during the first hours after infection. Results provided novel information regarding the early functional pathways and gene network that orchestrate innate immune responses to S. agalactiae infection. This knowledge could contribute to new strategies to enhance resistance to this disease, such as genomic selection.
Intake, digestibility, nitrogen (N) balance, microbial protein synthesis, weight gain, yields of the main commercial cuts and carcass morphometric measurements were evaluated in lambs fed diets containing different levels of chitosan. Sixty Santa Inês crossbred sheep with an average body weight (BW) of 24 ± 2.2 kg were assigned to three treatments (diets containing 0, 136 or 272 mg chitosan/kg BW) in a completely randomized design. There was no effect of chitosan on dry matter (DM) intake. Ingested and retained N showed a quadratic response, with the highest values estimated at the chitosan levels of 142 and 152 mg/kg BW, respectively. Similar to N balance, microbial protein synthesis showed the same quadratic response, in which the level of 136 mg/kg BW resulted in higher synthesis when compared with the other levels. No effect of chitosan was detected on average daily gain, final weight, or carcass variables (hot carcass weight, cold carcass weight, yield of commercial cuts and morphometric measurements of the carcass). Conformation, visceral fat content and fatness of carcasses were also not altered by the use of chitosan. Chitosan improves the digestibility of DM, crude protein and neutral detergent fibre, and increases N balance and microbial protein synthesis but does not change the production performance of feedlot lambs.
Many economic losses occur in the poultry industry due to leg fragility. Knowing the genomic regions that influence traits associated with the growth and composition of the leg’s bone can help to improve the selection process leading to increased leg resistance to fracture. The present study aimed to map quantitative trait loci (QTL) for mineral composition and morphometric traits of the tibia in 478 animals from an F2 broiler × layer cross. The measurement of weight, length and width of Tibia was carried out at 42 days of age. Ash, dry matter, levels of calcium (Ca), phosphorus (P), magnesium (Mg), Zinc (Zn) and Calcium:Phosphorus (Ca:P) ratio were also recorded. The population was genotyped for 128 microsatellite markers and one single nucleotide polymorphism, covering 2630 cM of the chicken genome. A likelihood ratio test was performed to find QTLs. Additive and dominance effects of the QTLs were included in the model. In the chromosomes 2 (GGA2), 6 (GGA6), 8 (GGA8), 24 (GGA24) and 26 (GGA26) some suggestive QTLs (P<0.00276) were mapped for tibia weight (GGA2 and GGA26), ash percentage (GGA2 and GGA6), dry matter percentage (GGA2), Ca (GGA8 and GGA24) and Ca:P ratio (GGA8), many of which are close to genes already identified as good candidates for those traits. The suggestive QTL on GGA2 has a pleiotropic effect on ash percentage, dry matter and bone weight, whereas in the GGA8 there seems to be two QTLs, one for Ca and another for Ca:P ratio. Thus, this study identified at least five genomic regions, in different chromosomes, that can be targeted for further research to identify potential mutations influencing the development and composition of leg bones in Gallus gallus.
Tuberculosis (TB) is still a major public health problem in many countries, including Brazil. Primary health care (PHC) services are a set of important services with infrastructure and resources to diagnose, treat, and cure several diseases, including the TB.
Aim
The aim of this study is to analyse aspects of the facility infrastructure of Brazilian PHC, regarding the control and treatment of TB from a countrywide perspective.
Methods
This is a cross-sectional study based on PHC services. Data were collected from 38,812 health centres and were assessed by means of the National Program for Improving Access and Quality Primary Care. The outcome was obtained by the presence and availability of the following infrastructure items: air circulation in the consultation room, refrigerator, individual protective equipment, plastic jar for sputum examination, and TB notification form of the primary care information system. Poisson regression was used to calculate the prevalence ratio.
Findings
Of the 38,812 evaluated centres, only 1628 (4.2%) presented a positive result regarding the outcome. Primary health centres, among all types of centres, presented the highest quality of facility infrastructure for TB control. Centres with large workloads, as well as those that presented a list of offered services and a welcoming consulting room, also presented the highest quality infrastructure. The present study shows that major improvements should be made to the infrastructure to reach a satisfactory TB control in Brazil.
The goal of this study was to analyse the spatial pattern of tuberculosis (TB) mortality using different approaches, namely: mortality rates (MR), spatial relative risks (RR) and Bayesian rates (Global and Local) and their association with human development index (HDI), Global and its three dimensions: education, longevity and income. An ecological study was developed in Curitiba, Brazil based on data from Mortality Information System (2008–2014). Spatial scan statistics were used to compute RR and identify high-risk clusters. Bivariate Local Indicator of Spatial Associations was used to assess associations. MR ranged between 0 and 25.24/100.000 with a mean (standard deviation) of 1.07 (2.66). Corresponding values for spatial RR were 0–27.46, 1.2 (2.99) and for Bayesian rates (Global and Local) were 0.49–1.66, 0.90 (0.19) and 0–6.59, 0.98 (0.80). High-risk clusters were identified for all variables, except for HDI-income and Global Bayesian rate. Significant negative spatial relations were found between MR and income; between RR and HDI global, longevity and income; and Bayesian rates with all variables. Some areas presented different patterns: low social development/low risk and high risk/high development. These results demonstrate that social development variables should be considered, in mortality due TB.
Polymorphisms in the growth hormone (GH) and IGF type-1 (IGF1) genes have been associated with the economic traits in farm animals, including BW of some sheep breeds. However, it remains unknown if these polymorphisms also affect carcass traits in sheep. Thus, we aimed to identify polymorphisms in the GH and IGF1 genes in Santa Ines sheep in order to describe their allelic and genotypic frequencies as well as to test the hypotheses that they are associated with the carcass traits. Fragments of 4550 bp (IGF1) and 1194 bp (GH) were sequenced in up to 191 lambs. In all, 18 polymorphisms were identified in the IGF1 and 21 in the GH gene. The IGF1 polymorphisms rs430457475, rs412470350, rs409110739 and rs400113576 showed an additive effect on the internal carcass length (−0.9265±0.4223), rump girth (−2.9285±1.1473), rib yield (−1.0003±0.4588) and neck weight (−0.0567±0.0278), respectively. In addition, the polymorphisms rs58957314 in the GH affected the rib weight (−0.4380±0.1272) and rib yield (−2.2680±0.6970), loin weight (−0.1893±0.0516) and loin yield (−0.9423±0.3259), palette weight (−0.2265±0.0779) and palette yield (−0.9424±0.4184), leg weight (−0.3960±0.1375), neck weight (−0.0851±0.0394) and carcass finishing score (−0.1700±0.0839). These results allow us to conclude that there are polymorphisms in the IGF1 and GH genes associated with carcass traits in Santa Ines sheep, which can provide important information for marker-assisted selection.
Introduction: Seeking patient outcome feedback (POF), defined as obtaining information on a patients clinical course beyond ones care, is crucial to the learning process. However, the lack of POF is a major pitfall of emergency medicine. Emergency department (ED) bouncebacks, which are characterized as patients with unplanned returns to the ED after being discharged, are an important type of POF to study because they represent a potential misdiagnosis or mismanagement and can highlight areas for physician self-improvement. Currently, most hospitals do not relay details about ED bouncebacks back to the treating physician, unless a grave error occurred. This studys purpose is to provide weekly reports to all physicians in the ED on patients who have unplanned returns within 7 days of discharge from the ED, and evaluate the impact this has on the physicians practice on seeking POF. Methods: A new weekly report was distributed to physicians working at an academic hospital outlining the patients who have returned within 7 days of discharge from the ED, their new presenting complaint and final disposition. An online survey was also administered to all ED staff evaluating the amount of POF they sought pre and post report, and their attitude towards the new reports. Results: 22 responses were received, for a response rate of 85%. The majority of respondents follow the reports (73%) and actively seek POF by looking up patients charts and results(70%). Additionally, 58% state that they seek POF more often since receiving these reports, for both the bouncebacks and their other patients. Furthermore, 37% claimed that the reports helped improve the appropriateness of their referrals and 32% stated it helped increase their confidence in their clinical practice. The majority of physicians (87%) found the reports to be helpful and would like to continue receiving it. Conclusion: Weekly bounceback reports are a high-yield tool for increasing POF sought in the ED and have benefits for both the physician and the department as a whole. They can be used to not only identify patients who may have had an error in their management, but also help to improve physicians’ clinical skills by encouraging and enabling follow-up of patients they managed. Thus, bounceback reports are a valuable tool to provide to physicians and should be considered by ED Departments.
Percutaneous balloon valvuloplasty is the primary treatment for critical pulmonary valve stenosis in neonates. Thus far, a few studies have reported long-term results of this technique in neonatal critical pulmonary valve stenosis.
Methods
We carried out a retrospective study of all consecutive newborns with critical pulmonary valve stenosis subjected to percutaneous balloon valvuloplasty at a single centre, between 1994 and 2014, to assess its immediate and long-term safety and efficacy.
Results
A total of 24 neonates presented with critical pulmonary valve stenosis. The mean diameter of the pulmonary annulus was 7 mm (±1.19); 33.3% had a dysplastic pulmonary valve, and 92% were started on prostaglandin E1 treatment. Percutaneous balloon valvuloplasty was performed at a mean age of 4.0±4.3 days using, on average, a balloon-to-pulmonary annulus ratio of 1.18 mm (with a range from 0.9 to 1.43). Immediate success was achieved in 22/24 patients (92%) with a reduction in the pulmonary transvalvular peak gradient (p<0.05) and in the right ventricle/systemic pressure ratio (p<0.05). There was one death (4%) 6 days after the procedure, and 29.2% of them had transient rhythm complications. For a mean follow-up time of 8.4 years, the re-intervention rate was 42.9%. In total, 14 re-interventions were performed in nine neonates, including surgery in six. Freedom from re-intervention was 50% at 8 years and 43% at 10 and 15 years.
Conclusion
This series, to the best of our knowledge, has had the longest follow-up of neonates with critical pulmonary valve stenosis. Percutaneous balloon valvuloplasty is a safe and effective treatment, and in our study 75% of the patients were exclusively treated using this technique.
Animal health surveillance enables the detection and control of animal diseases including zoonoses. Under the EU-FP7 project RISKSUR, a survey was conducted in 11 EU Member States and Switzerland to describe active surveillance components in 2011 managed by the public or private sector and identify gaps and opportunities. Information was collected about hazard, target population, geographical focus, legal obligation, management, surveillance design, risk-based sampling, and multi-hazard surveillance. Two countries were excluded due to incompleteness of data. Most of the 664 components targeted cattle (26·7%), pigs (17·5%) or poultry (16·0%). The most common surveillance objectives were demonstrating freedom from disease (43·8%) and case detection (26·8%). Over half of components applied risk-based sampling (57·1%), but mainly focused on a single population stratum (targeted risk-based) rather than differentiating between risk levels of different strata (stratified risk-based). About a third of components were multi-hazard (37·3%). Both risk-based sampling and multi-hazard surveillance were used more frequently in privately funded components. The study identified several gaps (e.g. lack of systematic documentation, inconsistent application of terminology) and opportunities (e.g. stratified risk-based sampling). The greater flexibility provided by the new EU Animal Health Law means that systematic evaluation of surveillance alternatives will be required to optimize cost-effectiveness.