Ultrasonographic Vasospasm and Outcome of Posterior Reversible Encephalopathy and Cerebral Vasoconstriction Syndromes.

PURPOSE: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are often complicated by vasospasm and ischemia. Monitoring with transcranial color-coded Doppler (TCCD) could be useful, but its role is not established. We studied the incidence of ultrasonographic vasospasm (uVSP) in PRES/RCVS and its relationship with ischemic lesions and clinical outcome. MATERIALS AND METHODS: We conducted a multicenter retrospective study of all patients with PRES/RCVS from 2008 to 2020 who underwent TCCD and magnetic resonance imaging (MRI). TCCD exams were analyzed for uVSP. Diffusion-weighted MRI was analyzed for positive lesions (DWI-positive). Functional outcome was assessed by modified Rankin scale (mRS) at 90 days. The associations with outcomes were determined by logistic regression. RESULTS: We included 80 patients (mean age of 46 (standard deviation, 17) years; 66% females; 41 with PRES, 28 with RCVS and 11 with overlap phenotype). uVSP was detected in 25 (31%) patients. DWI-positive lesions were more often detected in uVSP-positive than uVSP-negative patients (36% vs. 15%; adjusted odds ratio [aOR] 4.05 [95% CI 1.06 - 15.5], P=0.04). DWI-positive lesions were independently associated with worse functional prognosis (mRS 2-6, 43% vs. 10%; aOR, 10 [95% CI 2.6 - 43], P<0.01). Having additional uVSP further increased the odds of a worse outcome (P interaction=0.03). CONCLUSION: Ultrasonographic vasospasm was detected in a third of patients with PRES/RCVS and was associated with brain ischemic lesions. TCCD bedside monitoring can help to stratify patients at risk for cerebral ischemia, a strong predictor of functional outcome.

Signatures of natural selection in a foundation tree along Mediterranean climatic gradients.

Temperature and precipitation regimes are rapidly changing, resulting in forest dieback and extinction events, particularly in Mediterranean-type climates (MTC). Forest management that enhance forests' resilience is urgently required, however adaptation to climates in heterogeneous landscapes with multiple selection pressures is complex. For widespread trees in MTC we hypothesized that: patterns of local adaptation are associated with climate; precipitation is a stronger factor of adaptation than temperature; functionally related genes show similar signatures of adaptation; and adaptive variants are independently sorting across the landscape. We sampled 28 populations across the geographic distribution of Eucalyptus marginata (jarrah), in South-west Western Australia, and obtained 13,534 independent single nucleotide polymorphic (SNP) markers across the genome. Three genotype-association analyses that employ different ways of correcting population structure were used to identify putatively adapted SNPs associated with independent climate variables. While overall levels of population differentiation were low (FST  = 0.04), environmental association analyses found a total of 2336 unique SNPs associated with temperature and precipitation variables, with 1440 SNPs annotated to genic regions. Considerable allelic turnover was identified for SNPs associated with temperature seasonality and mean precipitation of the warmest quarter, suggesting that both temperature and precipitation are important factors in adaptation. SNPs with similar gene functions had analogous allelic turnover along climate gradients, while SNPs among temperature and precipitation variables had uncorrelated patterns of adaptation. These contrasting patterns provide evidence that there may be standing genomic variation adapted to current climate gradients, providing the basis for adaptive management strategies to bolster forest resilience in the future.

Posterior Circulation Stroke: Coma (More Than Time) is Brain.

BACKGROUND AND PURPOSE: Contrary to anterior circulation, the legitimacy of endovascular treatment in posterior circulation stroke is still being questioned. Finding reliable prognostic factors and determining how patient selection should be done has become top priority. METHODS: Observational and retrospective study from two Portuguese hospitals, including all consecutive patients with posterior circulation occlusions who underwent thrombectomy between January 1st 2015 and December 31st 2019. RESULTS: Out of a total of 126 patients, the median age was 74 (IQR 61-80) and 39.7% were female. A good clinical outcome (mRS ≤2) was associated with a lower incidence of coma (24,2% vs 66,7%, p < 0,001) and of sudden onset coma (3% vs 18%,=0,04), a lower NIHSS at admission (14 vs 19, p < 0,001), a higher pc-ASPECTS at admission (10 vs 9, p < 0,001) and at 24 h (8 vs 6, p < 0,001) and a higher BATMAN score (7 vs 6, p = 0,017). Differences in the times of symptom-onset-to-recanalization (496 vs 536, p = 0,19) and symptom-onset-to-coma (130 vs 195, p = 0,52) were not remarkable. When excluding NIHSS and pc-ASPECTS at 24 h, coma (p = 0,003; OR=0,22; 95% CI: 0,08-0,59) and the pc-ASPECTS at admission (p = 0,037; OR=1,63; 95% CI: 1,03-2,57) become independent predictors of good outcome. CONCLUSIONS: In strokes from the posterior circulation, coma, more than time, appears to be an important prognostic factor. The BATMAN and the pc-ASPECTS scores were also associated with clinical outcome and coma.

How do pigs deal with dietary phosphorus deficiency?

Feeding strategies for growing monogastric livestock (particularly pigs) must focus on maximising animal performance, while attempting to reduce environmental P load. Achieving these goals requires a comprehensive understanding of how different P feeding strategies affect animal responses and an ability to predict P retention. Although along with Ca, P is the most researched macromineral in pig nutrition, knowledge gaps still exist in relation to: (1) the effects of P feed content on feed intake (FI); (2) the impact of P intake on body composition; (3) the distribution of absorbed P to pools within the body. Here, we address these knowledge gaps by gathering empirical evidence on the effects of P-deficient feeds and by developing a predictive, mechanistic model of P utilisation and retention incorporating this evidence. Based on our statistical analyses of published literature data, we found: (1) no change in FI response in pigs given lower P feed contents; (2) the body ash-protein relationship to be dependent upon feed composition, with the isometric relationship only holding for pigs given balanced feeds and (3) the priority to be given towards P retention in soft tissue over P retention in bones. Subsequent results of the mechanistic model of P retention indicated that a potential reduction in P feeding recommendations could be possible without compromising average daily gain; however, such a reduction would impact P deposition in bones. Our study enhances our current knowledge of P utilisation and by extension excretion and could contribute towards developing more accurate P feeding guidelines.

The Social Platform: Profiling FHIR to Support Community-Dwelling Older Adults.

The care networks of community-dwelling older adults require cooperation between different actors, including health and social caregivers, assistant providers, care receivers, and their informal caregivers (e.g. relatives or friends), across time, space, and organizational boundaries. In this context, the project Social Cooperation for Integrated Assisted Living (SOCIAL) aims at the development of a platform of services to support the care networks of community-dwelling older adults. Therefore, the study reported in this article assess the adequacy of the Fast Healthcare Interoperability Resources (FHIR) to guarantee the interoperability of the relevant information related to the assisted persons of the SOCIAL platform, which are mainly older adults that need care and assistance services.

Do not neglect calcium: a systematic review and meta-analysis (meta-regression) of its digestibility and utilisation in growing and finishing pigs.

Ca digestibility and utilisation in growing pigs are not well understood, and are usually neglected in diet formulation. This has implications not only for the accurate determination of its requirements but also for its interactions with other nutrients. A systematic review and meta-analysis (meta-regression) of published trials was carried out to quantify factors affecting Ca absorption and utilisation, and to derive an estimate of Ca endogenous excretion. The analysis was carried out on the data from forty studies, corresponding to 201 treatments performed on 1204 pigs. The results indicated that although Ca absorption and retention (g/kg of body weight per d) increased with increasing Ca intake (P<0·001), non-phytate-P intake (P<0·001) and exogenous phytase supplementation (P<0·001), these values decreased with increasing phytate-P intake (P<0·05). Interactions between exogenous phytase and Ca intake, indicating reduced efficacy of this enzyme (P<0·001), and between phytate-P intake and exogenous phytase, counteracting the direct negative effect of phytate-P (P<0·05) on Ca absorption and retention, were also detected. There were no effects of animal-related characteristics, such as pig genotype in Ca absorption and retention. The large amount of variance explained in Ca absorption (90 %) and retention (91 %) supported our choice of independent variables. Endogenous Ca losses obtained via linear regression were 239 mg/kg of DM intake (95 % CI 114, 364). These outcomes advance the current understanding of Ca digestibility and utilisation, and should contribute towards establishing requirements for digestible Ca. Consequently, pig diets will be more correctly formulated if digestible Ca values are used in estimating requirements for Ca.

Epidemics in markets with trade friction and imperfect transactions.

Market trade-routes can support infectious-disease transmission, impacting biological populations and even disrupting trade that conduces the disease. Epidemiological models increasingly account for reductions in infectious contact, such as risk-aversion behaviour in response to pathogen outbreaks. However, responses in market dynamics clearly differ from simple risk aversion, as are driven by other motivation and conditioned by "friction" constraints (a term we borrow from labour economics). Consequently, the propagation of epidemics in markets of, for example livestock, is frictional due to time and cost limitations in the production and exchange of potentially infectious goods. Here we develop a coupled economic-epidemiological model where transient and long-term market dynamics are determined by trade friction and agent adaptation, and can influence disease transmission. The market model is parameterised from datasets on French cattle and pig exchange networks. We show that, when trade is the dominant route of transmission, market friction can be a significantly stronger determinant of epidemics than risk-aversion behaviour. In particular, there is a critical level of friction above which epidemics do not occur, which suggests some epidemics may not be sustained in highly frictional markets. In addition, friction may allow for greater delay in removal of infected agents that still mitigates the epidemic and its impacts. We suggest that policy for minimising contagion in markets could be adjusted to the level of market friction, by adjusting the urgency of intervention or by increasing friction through incentivisation of larger-volume less-frequent transactions that would have limited effect on overall trade flow. Our results are robust to model specificities and can hold in the presence of non-trade disease-transmission routes.

Multiparametric analysis from dynamic susceptibility contrast-enhanced perfusion MRI to evaluate malignant brain tumors.

BACKGROUND AND PURPOSE: Dynamic susceptibility contrast-enhanced (DSC) MR perfusion is a valuable technique for distinguishing brain tumors. Diagnostic potential of measurable parameters derived from preload leakage-corrected-DSC-MRI remains somewhat underexplored. This study aimed to evaluate these parameters for differentiating primary CNS lymphoma (PCNSL), glioblastoma, and metastasis. METHODS: Thirty-nine patients with pathologically proven PCNSL (n = 14), glioblastoma (n = 14), and metastasis (n = 11) were analyzed. Five DSC parameters-relative CBV (rCBV), percentage of signal recovery (PSR), downward slope (DS), upward slope (US), and first-pass slope ratio-were derived from tumor-enhancing areas. Diagnostic performance was assessed using receiver operating characteristic curve analysis. RESULTS: RCBV was higher in metastasis (4.58; interquartile range [IQR]: 2.54) and glioblastoma (3.98; IQR: 1.87), compared with PCNSL (1.46; IQR: 0.29; p = .00006 for both). rCBV better distinguished metastasis and glioblastoma from PCNSL, with an area under the curve (AUC) of 0.97 and 0.99, respectively. PSR was higher in PCNSL (88.11; IQR: 21.21) than metastases (58.30; IQR: 22.28; p = .0002), while glioblastoma (74.54; IQR: 21.23) presented almost significant trend-level differences compared to the others (p≈.05). AUCs were 0.79 (PCNSL vs. glioblastoma), 0.91 (PCNSL vs. metastasis), and 0.78 (glioblastoma vs. metastasis). DS and US parameters were statistically significant between glioblastoma (-109.92; IQR: 152.71 and 59.06; IQR: 52.87) and PCNSL (-47.36; IQR: 44.30 and 21.68; IQR: 16.85), presenting AUCs of 0.86 and 0.87. CONCLUSION: Metastasis and glioblastoma can be better differentiated from PCNSL through rCBV. PSR demonstrated higher differential performance compared to the other parameters and seemed useful, allowing a proper distinction among all, particularly between metastasis and glioblastoma, where rCBV failed. Finally, DS and US were only helpful in differentiating glioblastoma from PCNSL.

Outcomes of mechanical thrombectomy in anticoagulated patients with acute distal and medium vessel stroke.

BACKGROUND: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. METHODS: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. RESULTS: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p < 0.001) and had a higher prevalence of atrial fibrillation (77% vs 26%; p < 0.001). Their baseline National Institutes of Health Stroke Scale (NIHSS) scores were also higher (median 12 vs 9; p = 0.002). Before propensity score matching (PSM), anticoagulated patients had similar rates of favorable 90-day outcomes (mRS 0-1: 30% vs 37%, p = 0.1; mRS 0-2: 47% vs 50%, p = 0.41) but higher mortality (26% vs 17%, p = 0.008). After PSM, there were no significant differences in outcomes between the two groups. CONCLUSION: Anticoagulated patients undergoing MT for AIS due to DMVO did not show significant differences in 90-day mRS outcomes, reperfusion, or hemorrhage compared to non-anticoagulated patients after adjustment for covariates.

Landscape epidemiology and control of pathogens with cryptic and long-distance dispersal: sudden oak death in northern Californian forests.

Exotic pathogens and pests threaten ecosystem service, biodiversity, and crop security globally. If an invasive agent can disperse asymptomatically over long distances, multiple spatial and temporal scales interplay, making identification of effective strategies to regulate, monitor, and control disease extremely difficult. The management of outbreaks is also challenged by limited data on the actual area infested and the dynamics of spatial spread, due to financial, technological, or social constraints. We examine principles of landscape epidemiology important in designing policy to prevent or slow invasion by such organisms, and use Phytophthora ramorum, the cause of sudden oak death, to illustrate how shortfalls in their understanding can render management applications inappropriate. This pathogen has invaded forests in coastal California, USA, and an isolated but fast-growing epidemic focus in northern California (Humboldt County) has the potential for extensive spread. The risk of spread is enhanced by the pathogen's generalist nature and survival. Additionally, the extent of cryptic infection is unknown due to limited surveying resources and access to private land. Here, we use an epidemiological model for transmission in heterogeneous landscapes and Bayesian Markov-chain-Monte-Carlo inference to estimate dispersal and life-cycle parameters of P. ramorum and forecast the distribution of infection and speed of the epidemic front in Humboldt County. We assess the viability of management options for containing the pathogen's northern spread and local impacts. Implementing a stand-alone host-free "barrier" had limited efficacy due to long-distance dispersal, but combining curative with preventive treatments ahead of the front reduced local damage and contained spread. While the large size of this focus makes effective control expensive, early synchronous treatment in newly-identified disease foci should be more cost-effective. We show how the successful management of forest ecosystems depends on estimating the spatial scales of invasion and treatment of pathogens and pests with cryptic long-distance dispersal.

Diffusion-weighted imaging of the liver: usefulness of ADC values in the differential diagnosis of focal lesions and effect of ROI methods on ADC measurements.

OBJECT: By measuring the apparent diffusion coefficient (ADC) of liver parenchyma and focal hepatic lesions (FHL) we proposed to investigate the utility of ADC in the differential diagnosis of hepatic disease and to determine the influence of region of interest (ROI) characteristics in those measurements. MATERIALS AND METHODS: Ninety-three patients with at least one supracentimetric FHL, or parenchymal abnormality, were retrospectively evaluated. Diagnosis was based on histopathologic data or, alternatively, on a combination of consensus between imaging methods and 24 months of follow-up. Ninety lesions were evaluated with respiratory-triggered diffusion-weighted imaging (b values: 50 and 700 s/mm(2)): 14 hepatocellular carcinomas, 18 metastases, 10 focal nodular hyperplasias, four adenomas, 30 hemangiomas and 14 cysts. ADC of hepatic parenchyma was measured by placing ROIs in four different segments, and in FHLs by using three circular 1 cm(2) ROIs and one ROI encompassing the full lesion. Data was statistically analyzed (p < 0.05 considered significant), and a receiver operating characteristic curve was assessed to evaluate the accuracy for the diagnosis of malignancy. RESULTS: Our measurements showed that parenchyma ADC was significantly higher in segment II and that ADCs of malignant lesions were significantly lower than those of benign lesions (p < 0.001). There was significant overlap between benign solid lesions and malignant lesions and the area under the curve for malignancy was 0.939 (sensitivity 89.7 %, specificity 90.6 %), using a cutoff of 1.43 × 10(-3) mm(2)/s. No significant difference was found between ROIs of different characteristics. CONCLUSION: ADC measurements can help to characterize FHLs and differentiate normal from pathological parenchyma. Any ROI above 1 cm(2) can provide accurate ADC measurements in homogenous lesions.

Germination temperature sensitivity differs between co-occurring tree species and climate origins resulting in contrasting vulnerability to global warming.

Climate change is shifting temperatures from historical patterns, globally impacting forest composition and resilience. Seed germination is temperature-sensitive, making the persistence of populations and colonization of available habitats vulnerable to warming. This study assessed germination response to temperature in foundation trees in south-western Australia's Mediterranean-type climate forests (Eucalyptus marginata (jarrah) and Corymbia calophylla (marri)) to estimate the thermal niche and vulnerability among populations. Seeds from the species' entire distribution were collected from 12 co-occurring populations. Germination thermal niche was investigated using a thermal gradient plate (5-40°C). Five constant temperatures between 9 and 33°C were used to test how the germination niche (1) differs between species, (2) varies among populations, and (3) relates to the climate of origin. Germination response differed among species; jarrah had a lower optimal temperature and thermal limit than marri (T o 15.3°C, 21.2°C; ED50 23.4°C, 31°C, respectively). The thermal limit for germination differed among populations within both species, yet only marri showed evidence for adaptation to thermal origins. While marri has the capacity for germination at higher thermal temperatures, jarrah is more vulnerable to global warming exceeding safety margins. This discrepancy is predicted to alter species distributions and forest composition in the future.

Free and Modified Mycotoxins in Organic and Conventional Oats (Avena sativa L.) Grown in Scotland.

Small grain cereals are frequently infected with mycotoxigenic Fusarium fungi. Oats have a particularly high risk of contamination with type A trichothecene mycotoxins; their glucoside conjugates have also been reported. Agronomy practices, cereal variety and weather conditions have been suggested to play a role in Fusarium infection in oats. The current study investigates concentrations of free and conjugated Fusarium mycotoxins in organic and conventional oats grown in Scotland. In 2019, 33 milling oat samples (12 organic, 21 conventional) were collected from farmers across Scotland, together with sample questionnaires. Samples were analysed for 12 mycotoxins (type A trichothecenes T-2-toxin, HT-2-toxin, diacetoxyscirpenol; type B trichothecenes deoxynivalenol, nivalenol; zearalenone and their respective glucosides) using LC-MS/MS. The prevalence of type A trichothecenes T-2/HT-2 was very high (100% of conventional oats, 83% of organic oats), whereas type B trichothecenes were less prevalent, and zearalenone was rarely found. T-2-glucoside and deoxynivalenol-glucoside were the most prevalent conjugated mycotoxins (36 and 33%), and co-occurrence between type A and B trichothecenes were frequently observed (66% of samples). Organic oats were contaminated at significantly lower average concentrations than conventional oats, whereas the effect of weather parameters were not statistically significant. Our results clearly indicate that free and conjugated T-2- and HT-2-toxins pose a major risk to Scottish oat production and that organic production and crop rotation offer potential mitigation strategies.

Timing of daily calorie loading affects appetite and hunger responses without changes in energy metabolism in healthy subjects with obesity.

Morning loaded calorie intake in humans has been advocated as a dietary strategy to improve weight loss. This is also supported by animal studies suggesting time of eating can prevent weight gain. However, the underlying mechanisms through which timing of eating could promote weight loss in humans are unclear. In a randomized crossover trial (NCT03305237), 30 subjects with obesity/overweight underwent two 4-week calorie-restricted but isoenergetic weight loss diets, with morning loaded or evening loaded calories (45%:35%:20% versus 20%:35%:45% calories at breakfast, lunch, and dinner, respectively). We demonstrate no differences in total daily energy expenditure or resting metabolic rate related to the timing of calorie distribution, and no difference in weight loss. Participants consuming the morning loaded diet reported significantly lower hunger. Thus, morning loaded intake (big breakfast) may assist with compliance to weight loss regime through a greater suppression of appetite.

Nationwide Access to Endovascular Treatment for Acute Ischemic Stroke in Portugal.

INTRODUCTION: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. MATERIAL AND METHODS: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. RESULTS: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. DISCUSSION: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. CONCLUSION: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.

Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Discussão: A análise nacional a taxas de tratamento endovascular e tempos de atuação é comparável a outros registos internacionais. Verificaram-se heterogeneidades geográficas, com taxas de tratamento endovascular menores e maior tempo para tratamento nos distritos do sul e interior. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto.

A Novel Estimation of Unobserved Pig Growth Traits for the Purposes of Precision Feeding Methods.

Recent technological advances make it possible to deliver feeding strategies that can be tailored to the needs of individual pigs in order to optimise the allocation of nutrient resources and contribute toward reducing excess nutrient excretion. However, these efforts are currently hampered by the challenges associated with: (1) estimation of unobserved traits from the available data on bodyweight and feed consumption; and (2) characterisation of the distributions and correlations of these unobserved traits to generate accurate estimates of individual level variation among pigs. Here, alternative quantitative approaches to these challenges, based on the principles of inverse modelling and separately inferring individual level distributions within a Bayesian context were developed and incorporated in a proposed precision feeding modelling framework. The objectives were to: (i) determine the average and distribution of individual traits characterising growth potential and body composition in an empirical population of growing-finishing barrows and gilts; (ii) simulate the growth and excretion of nitrogen and phosphorus of the average pig offered either a commercial two-phase feeding plan, or a precision feeding plan with daily adjustments; and (iii) simulate the growth and excretion of nitrogen and phosphorus across the pig population under two scenarios: a two-phase feeding plan formulated to meet the nutrient requirements of the average pig or a precision feeding plan with daily adjustments for each and every animal in the population. The distributions of mature bodyweight and ratio of lipid to protein weights at maturity had median (IQR) values of 203 (47.8) kg and 2.23 (0.814) kg/kg, respectively; these estimates were obtained without any prior assumptions concerning correlations between the traits. Overall, it was found that a proposed precision feeding strategy could result in considerable reductions in excretion of nitrogen and phosphorus (average pig: 8.07 and 9.17% reduction, respectively; heterogenous pig population: 22.5 and 22.9% reduction, respectively) during the growing-finishing period from 35 to 120 kg bodyweight. This precision feeding modelling framework is anticipated to be a starting point toward more accurate estimation of individual level nutrient requirements, with the general aim of improving the economic and environmental sustainability of future pig production systems.

Bayesian, Likelihood-Free Modelling of Phenotypic Plasticity and Variability in Individuals and Populations.

There is a paradigm shift from the traditional focus on the "average" individual towards the definition and analysis of trait variation within individual life-history and among individuals in populations. This is a result of increasing availability of individual phenotypic data. The shift allows the use of genetic and environment-driven variations to assess robustness to challenge, gain greater understanding of organismal biological processes, or deliver individual-targeted treatments or genetic selection. These consequences apply, in particular, to variation in ontogenetic growth. We propose an approach to parameterise mathematical models of individual traits (e.g., reaction norms, growth curves) that address two challenges: 1) Estimation of individual traits while making minimal assumptions about data distribution and correlation, addressed via Approximate Bayesian Computation (a form of nonparametric inference). We are motivated by the fact that available information on distribution of biological data is often less precise than assumed by conventional likelihood functions. 2) Scaling-up to population phenotype distributions while facilitating unbiased use of individual data; this is addressed via a probabilistic framework where population distributions build on separately-inferred individual distributions and individual-trait interpretability is preserved. The approach is tested against Bayesian likelihood-based inference, by fitting weight and energy intake growth models to animal data and normal- and skewed-distributed simulated data. i) Individual inferences were accurate and robust to changes in data distribution and sample size; in particular, median-based predictions were more robust than maximum- likelihood-based curves. These results suggest that the approach gives reliable inferences using few observations and monitoring resources. ii) At the population level, each individual contributed via a specific data distribution, and population phenotype estimates were not disproportionally influenced by outlier individuals. Indices measuring population phenotype variation can be derived for study comparisons. The approach offers an alternative for estimating trait variability in biological systems that may be reliable for various applications, for example, in genetics, health, and individualised nutrition, while using fewer assumptions and fewer empirical observations. In livestock breeding, the potentially greater accuracy of trait estimation (without specification of multitrait variance-covariance parameters) could lead to improved selection and to more decisive estimates of trait heritability.

Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis.

The broad-spectrum antiparasitic drug ivermectin was licensed for use against onchocerciasis in 1987, yet the mechanisms by which it exerts a fast decrease and long-lasting suppression of Onchocerca volvulus microfilaridermia, and inhibition of microfilarial release by female worms remain largely unknown. A better understanding of the effects of ivermectin on O volvulus microfilariae and macrofilariae is crucial to improve our ability to predict the long-term effect of treatment. We did a systematic review of individual and population-based ivermectin trials to investigate the temporal dynamics of the drug's microfilaricidal and embryostatic efficacy after administration of a single, standard dose (150 microg/kg). Meta-analyses on data from 26 microfilarial and 15 macrofilarial studies were linked by a mathematical model describing the dynamics of potentially fertile female parasites to skin microfilariae. The model predicts that after treatment, microfilaridermia would be reduced by half after 24 h, by 85% after 72 h, by 94% after 1 week, and by 98-99% after 1-2 months, the latter also corresponding to the time when the fraction of females harbouring live microfilariae is at its lowest (reduced by around 70% from its original value). Our results provide a baseline microfilarial skin repopulation curve against which to compare studies done after long-term treatment.

Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model.

Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways ("immunity functions"): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.

Estimates of the duration of the early and late stage of gambiense sleeping sickness.

BACKGROUND: The durations of untreated stage 1 (early stage, haemo-lymphatic) and stage 2 (late stage, meningo-encephalitic) human African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense are poorly quantified, but key to predicting the impact of screening on transmission. Here, we outline a method to estimate these parameters. METHODS: We first model the duration of stage 1 through survival analysis of untreated serological suspects detected during Médecins Sans Frontières interventions in Uganda and Sudan. We then deduce the duration of stage 2 based on the stage 1 to stage 2 ratio observed during active case detection in villages within the same sites. RESULTS: Survival in stage 1 appears to decay exponentially (daily rate = 0.0019; mean stage 1 duration = 526 days [95%CI 357 to 833]), possibly explaining past reports of abnormally long duration. Assuming epidemiological equilibrium, we estimate a similar duration of stage 2 (500 days [95%CI 345 to 769]), for a total of nearly three years in the absence of treatment. CONCLUSION: Robust estimates of these basic epidemiological parameters are essential to formulating a quantitative understanding of sleeping sickness dynamics, and will facilitate the evaluation of different possible control strategies.