Complexity is costly: A meta-analysis of parametric and non-parametric methods for short-term population forecasting

Short-term forecasts based on time series of counts or survey data are widely used in population biology to provide advice concerning the management, harvest and conservation of natural populations. A common approach to produce these forecasts uses time-series models, of different types, fit to time series of counts. Similar time-series models are used in many other disciplines, however relative to the data available in these other disciplines, population data are often unusually short and noisy and models that perform well for data from other disciplines may not be appropriate for population data. In order to study the performance of time-series forecasting models for natural animal population data, we assembled 2379 time series of vertebrate population indices from actual surveys. Our data were comprised of three vastly different types: highly variable (marine fish productivity), strongly cyclic (adult salmon counts), and small variance but long-memory (bird and mammal counts). We tested the predictive performance of 49 different forecasting models grouped into three broad classes: autoregressive time-series models, non-linear regression-type models and non-parametric time-series models. Low-dimensional parametric autoregressive models gave the most accurate forecasts across a wide range of taxa; the most accurate model was one that simply treated the most recent observation as the forecast. More complex parametric and non-parametric models performed worse, except when applied to highly cyclic species. Across taxa, certain life history characteristics were correlated with lower forecast error; specifically, we found that better forecasts were correlated with attributes of slow growing species: large maximum age and size for fishes and high trophic level for birds. © 2014 Nordic Society Oikos

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV co-infection on the pharmacokinetics of anti-tuberculosis drugs in Sub-Saharan Africa. 47 Malawian adults underwent rich pharmacokinetic sampling at 0-0.5-1-2-3-4-6-8 and 24 hours post-dose. 51% were male; mean age was 34 years. 65% were HIV-positive with a mean CD4 count of 268 cells/μL. Anti-tuberculosis drugs were administered as fixed-dose combinations (rifampicin150mg/isoniazid75mg/pyrazinamide400mg/ethambutol275mg) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampicin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analysed by non-compartmental methods and analysis of variance of log-transformed summary parameters. Pharmacokinetic parameters were: rifampicin Cmax 4.129 (2.474-5.596)μg/mL, AUC0-24 21.32 (13.57-28.60)μg/mL*h, half-life 2.45 (1.86-3.08)h; isoniazid Cmax 3.97 (2.979-4.544)μg/mL, AUC0-24 22.5 (14.75-34.59)μg/mL*h, half-life 3.93 (3.18-4.73)h.; pyrazinamide Cmax 34.21 (30.00-41.60)μg/mL, AUC0-24 386.6 (320.0-463.7)μg/mL*h, half-life 6.821 (5.71-8.042)h; ethambutol Cmax 2.278 (1.694-3.098)μg/mL, AUC0-24 20.41 (16.18-26.27)μg/mL*h, half-life 7.507 (6.517-8.696)h. Isoniazid PK data analysis suggested that around two-thirds were slow acetylators. Dose, weight and weight-adjusted dose were not significant predictors of PK exposure probably due to weight-banded dosing. In this first pharmacokinetic study of tuberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with other studies for all first line drugs except for rifampicin, for which Cmax and AUC0-24 were notably lower. Contrary to some earlier observations, HIV status did not significantly affect AUC of any of the drugs. Increasing the dose of rifampicin could be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in half-life of isoniazid of 41% (p=0.022). Possible competitive interactions between isoniazid and sulphamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further

Monoclonal antibodies and Fc-fusion protein biologic medicines: A multinational cross-sectional investigation of accessibility and affordability in Asia Pacific regions between 2010 and 2020

Background: Monoclonal antibody (mAb) and Fc-fusion protein (FcP) are highly effective therapeutic biologics. We aimed to analyse consumption and expenditure trends in 14 Asia-Pacific countries/regions (APAC) and three benchmark countries (the UK, Canada, and the US). Methods: We analysed 440 mAb and FcP biological products using the IQVIA-MIDAS global sales database. For each year between 2010 and 2020 inclusive, we used standard units (SU) sold per 1000 population and manufacture level price (standardised in 2019 US dollars) to evaluate consumption (accessibility) and expenditure (affordability). Changes of consumption and expenditure were estimated using compound annual growth rate (CAGR). Correlations between consumption, country's economic and health performance indicators were measured using Spearman correlation coefficient. Findings: Between 2010 and 2020, CAGRs of consumption in each region ranged from 7% to 34% and the CAGRs of expenditure ranged from 9% to 31%. The median consumption of biologics was extremely low in lower-middle-income economies (0·29 SU/1000 population) compared with upper-middle-income economies (1·20), high-income economies (40·94) and benchmark countries (109·55), although the median CAGRs of biologics consumption in lower-middle-income economies (31%) was greater than upper-middle-income (14%), high-income economies (13%) and benchmark countries (9%). Consumption was correlated with GDP per capita [Spearman's rank correlation coefficient (r) = 0·75, p < 0·001], health expenditure as a percentage of total (r = 0·83, p < 0·001) and medical doctors’ density (r = 0·85, p < 0·001). Interpretation: There have been significant increases in mAb and FcP biologics consumption and expenditure, however accessibility of biological medicines remains unequal and is largely correlated with country's income level. Funding: This research was funded by NHMRC Project Grant GNT1157506 and GNT1196900; Enhanced Start-up Fund for new academic staff and Internal Research Fund, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong

Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma

Background: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. Methods: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. Results: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. Conclusions: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC

Quantum Simulation of Tunneling in Small Systems

A number of quantum algorithms have been performed on small quantum computers; these include Shor's prime factorization algorithm, error correction, Grover's search algorithm and a number of analog and digital quantum simulations. Because of the number of gates and qubits necessary, however, digital quantum particle simulations remain untested. A contributing factor to the system size required is the number of ancillary qubits needed to implement matrix exponentials of the potential operator. Here, we show that a set of tunneling problems may be investigated with no ancillary qubits and a cost of one single-qubit operator per time step for the potential evolution. We show that physically interesting simulations of tunneling using 2 qubits (i.e. on 4 lattice point grids) may be performed with 40 single and two-qubit gates. Approximately 70 to 140 gates are needed to see interesting tunneling dynamics in three-qubit (8 lattice point) simulations.Comment: 4 pages, 2 figure

Preclinical and post-treatment changes in the HCC-associated serum proteome

SELDI-based proteomic profiling of body fluids is currently in widespread use for cancer biomarker discovery. We have successfully used this technology for the diagnosis of hepatocellular carcinoma (HCC) in hepatitis C patients and now report its application to serial serum samples from 37 hepatitis C patients before development of HCC, with HCC and following radiofrequency ablation of the tumour. As with alpha-fetoprotein, an accepted biomarker for HCC, we hypothesised that HCC-associated proteomic features would ‘return to normal' following successful treatment and the primary aim of our study was to test this hypothesis. Several SELDI peaks that changed significantly during HCC development were detected but they did not reverse following treatment. These data may be interpreted to suggest that the characteristic SELDI profile is not linearly related to tumour burden but may result from the progression of underlying liver disease or from the emergence of precancerous lesions. β2-Microglobulin, a protein previously reported to be markedly elevated in patients with HCV related HCC, was also the most significantly HCC associated proteomic feature (m/z 11720) in this study

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

Peer reviewedPublisher PD

Profound structural conservation of chemically cross-linked HIV-1 envelope glycoprotein experimental vaccine antigens.

Chemical cross-linking is used to stabilize protein structures with additional benefits of pathogen and toxin inactivation for vaccine use, but its use has been restricted by the potential for local or global structural distortion. This is of particular importance when the protein in question requires a high degree of structural conservation for inducing a biological outcome such as the elicitation of antibodies to conformationally sensitive epitopes. The HIV-1 envelope glycoprotein (Env) trimer is metastable and shifts between different conformational states, complicating its use as a vaccine antigen. Here we have used the hetero-bifunctional zero-length reagent 1-Ethyl-3-(3-Dimethylaminopropyl)-Carbodiimide (EDC) to cross-link two soluble Env trimers, selected well-folded trimer species using antibody affinity, and transferred this process to good manufacturing practice (GMP) for experimental medicine use. Cross-linking enhanced trimer stability to biophysical and enzyme attack. Cryo-EM analysis revealed that cross-linking retained the overall structure with root-mean-square deviations (RMSDs) between unmodified and cross-linked Env trimers of 0.4-0.5 Å. Despite this negligible distortion of global trimer structure, we identified individual inter-subunit, intra-subunit, and intra-protomer cross-links. Antigenicity and immunogenicity of the trimers were selectively modified by cross-linking, with cross-linked ConS retaining bnAb binding more consistently than ConM. Thus, the EDC cross-linking process improves trimer stability whilst maintaining protein folding, and is readily transferred to GMP, consistent with the more general use of this approach in protein-based vaccine design

Thunder lizard handstands: Manus-only sauropod trackways from the Glen Rose Formation (Lower Cretaceous, Kendall County, Texas)

Three parallel, manus-only sauropod trackways from the Coffee Hollow A-Male tracksite (Glen Rose Formation, Kendall County, Texas) were studied separately by researchers from the Heritage Museum of the Texas Hill Country and the Houston Museum of Natural Sciences. Footprint and trackway measurements generally show good agreement between the two groups’ data sets. Footprints appear to be shallowly impressed true tracks rather than undertracks. One of the Coffee Hollow trackways shows marked asymmetry in the lengths of paces that begin with the left as opposed to the right forefoot, and two of the Coffee Hollow trackways are unusually broad. The Coffee Hollow trackways differ enough from the manus portions of other Glen Rose Formation sauropod trackways to suggest that they were made by a different kind of sauropod. Greater differential pressure exerted on the substrate by the forefeet than the hindfeet probably explains the Coffee Hollow trackways, like other manus-only sauropod trackways, but the possibility that they indicate unusual locomotion cannot at present be ruled out

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms