Adaptation to experimental alterations of the operational sex ratio in populations of Drosophila melanogaster.

Theory predicts that males adapt to sperm competition by increasing their investment in testis mass to transfer larger ejaculates. Experimental and comparative data support this prediction. Nevertheless, the relative importance of sperm competition in testis size evolution remains elusive, because experiments vary only sperm competition whereas comparative approaches confound it with other variables, in particular male mating rate. We addressed the relative importance of sperm competition and male mating rate by taking an experimental evolution approach. We subjected populations of Drosophila melanogaster to sex ratios of 1:1, 4:1, and 10:1 (female:male). Female bias decreased sperm competition but increased male mating rate and sperm depletion. After 28 generations of evolution, males from the 10:1 treatment had larger testes than males from other treatments. Thus, testis size evolved in response to mating rate and sperm depletion, not sperm competition. Furthermore, our experiment demonstrated that drift associated with sex ratio distortion limits adaptation; testis size only evolved in populations in which the effect of sex ratio bias on the effective population size had been compensated by increasing the numerical size. We discuss these results with respect to reproductive evolution, genetic drift in natural and experimental populations, and consequences of natural sex ratio distortion.

Local Competition, Inbreeding, and the Evolution of Sex-Biased Dispersal.

Using game theory, we developed a kin-selection model to investigate the consequences of local competition and inbreeding depression on the evolution of natal dispersal. Mating systems have the potential to favor strong sex biases in dispersal because sex differences in potential reproductive success affect the balance between local resource competition and local mate competition. No bias is expected when local competition equally affects males and females, as happens in monogamous systems and also in polygynous or promiscuous ones as long as female fitness is limited by extrinsic factors (breeding resources). In contrast, a male-biased dispersal is predicted when local mate competition exceeds local resource competition, as happens under polygyny/promiscuity when female fitness is limited by intrinsic factors (maximal rate of processing resources rather than resources themselves). This bias is reinforced by among-sex interactions: female philopatry enhances breeding opportunities for related males, while male dispersal decreases the chances that related females will inbreed. These results meet empirical patterns in mammals: polygynous/promiscuous species usually display a male-biased dispersal, while both sexes disperse in monogamous species. A parallel is drawn with sex-ratio theory, which also predicts biases toward the sex that suffers less from local competition. Optimal sex ratios and optimal sex-specific dispersal show mutual dependence, which argues for the development of coevolution models.

Optimal management of elderly patients with glioblastoma.

Median age at diagnosis in patients with glioblastoma (GB) is slowly increasing with an aging population in Western countries, and was 64years in 2006. The number of patients age 65 and older with GB will double in 2030 compared with 2000. Survival in this older cohort of patients is significantly less than seen in younger patients. This may in part be related to more aggressive biology of tumor, reduced use of standard management approaches, increased toxicity of available therapies, and increased presence of comorbidities in this older patient population. Limited data do support the use of more extensive resection in these patients. Randomized data support the use of post-operative radiotherapy (RT) versus supportive care, but do not demonstrate a benefit for the use of the standard 6weeks course of RT over hypofractionated RT given over 3weeks. Preliminary data of randomized studies raise the possibility of temozolomide alone as an option for these patients. The use of 6weeks of RT with concurrent and adjuvant temozolomide has been associated with reasonably good survival in several uncontrolled small series of selected older patients; however, this better outcome may be related to the selection of better prognosis patients rather than the specific therapy utilized. The current National Cancer Institute of Canada (NCIC) and European Organization for Research and Treatment of Cancer (EORTC) CE.6/26062/22061 randomized study of short course RT with or without concurrent and adjuvant temozolomide will help determine the optimal therapy for this older cohort with currently available therapies.

Optimal robust estimates using the Hellinger distance

Optimal robust M-estimates of a multidimensional parameter are described using Hampel's infinitesimal approach. The optimal estimates are derived by minimizing a measure of efficiency under the model, subject to a bounded measure of infinitesimal robustness. To this purpose we define measures of efficiency and infinitesimal sensitivity based on the Hellinger distance.We show that these two measures coincide with similar ones defined by Yohai using the Kullback-Leibler divergence, and therefore the corresponding optimal estimates coincide too.We also give an example where we fit a negative binomial distribution to a real dataset of "days of stay in hospital" using the optimal robust estimates.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE: To identify the optimal CD4 cell count at which cART should be initiated. DESIGN: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING: HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS: 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS: Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations: CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION: Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Predicting optimal lengths of random knots

In a thermally fluctuating long linear polymeric chain in a solution, the ends, from time to time, approach each other. At such an instance, the chain can be regarded as closed and thus will form a knot or rather a virtual knot. Several earlier studies of random knotting demonstrated that simpler knots show a higher occurrence for shorter random walks than do more complex knots. However, up to now there have been no rules that could be used to predict the optimal length of a random walk, i.e. the length for which a given knot reaches its highest occurrence. Using numerical simulations, we show here that a power law accurately describes the relation between the optimal lengths of random walks leading to the formation of different knots and the previously characterized lengths of ideal knots of a corresponding type.

Urinary analysis of four testosterone metabolites and pregnanediol by gas chromatography-combustion-isotope ratio mass spectrometry after oral administrations of testosterone.

The most frequently used method to demonstrate testosterone abuse is the determination of the testosterone and epitestosterone concentration ratio (T/E ratio) in urine. Nevertheless, it is known that factors other than testosterone administration may increase the T/E ratio. In the last years, the determination of the carbon isotope ratio has proven to be the most promising method to help discriminate between naturally elevated T/E ratios and those reflecting T use. In this paper, an excretion study following oral administration of 40 mg testosterone undecanoate initially and 13 h later is presented. Four testosterone metabolites (androsterone, etiocholanolone, 5 alpha-androstanediol, and 5 beta-androstanediol) together with an endogenous reference (5 beta-pregnanediol) were extracted from the urines and the delta(13)C/(12)C ratio of each compound was analyzed by gas chromatography-combustion-isotope ratio mass spectrometry. The results show similar maximum delta(13)C-value variations (parts per thousand difference of delta(13)C/(12)C ratio from the isotope ratio standard) for the T metabolites and concomitant changes of the T/E ratios after administration of the first and the second dose of T. Whereas the T/E ratios as well as the androsterone, etiocholanolone and 5 alpha-androstanediol delta(13)C-values returned to the baseline 15 h after the second T administration, a decrease of the 5 beta-androstanediol delta-values could be detected for over 40 h. This suggests that measurements of 5 beta-androstanediol delta-values allow the detection of a testosterone ingestion over a longer post-administration period than other T metabolites delta(13)C-values or than the usual T/E ratio approach.

Performance of blood pressure-to-height ratio at a single screening visit for the identification of hypertension in children.

BACKGROUND: The diagnosis of hypertension in children is difficult because of the multiple sex-, age-, and height-specific thresholds to define elevated blood pressure (BP). Blood pressure-to-height ratio (BPHR) has been proposed to facilitate the identification of elevated BP in children. OBJECTIVE: We assessed the performance of BPHR at a single screening visit to identify children with hypertension that is sustained elevated BP. METHOD: In a school-based study conducted in Switzerland, BP was measured at up to three visits in 5207 children. Children had hypertension if BP was elevated at the three visits. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the identification of hypertension were assessed for different thresholds of BPHR. The ability of BPHR at a single screening visit to discriminate children with and without hypertension was evaluated with receiver operating characteristic (ROC) curve analyses. RESULTS: The prevalence of systolic/diastolic hypertension was 2.2%. Systolic BPHR had a better performance to identify hypertension compared with diastolic BPHR (area under the ROC curve: 0.95 vs. 0.84). The highest performance was obtained with a systolic BPHR threshold set at 0.80 mmHg/cm (sensitivity: 98%; specificity: 85%; PPV: 12%; and NPV: 100%) and a diastolic BPHR threshold set at 0.45 mmHg/cm (sensitivity: 79%; specificity: 70%; PPV: 5%; and NPV: 99%). The PPV was higher among tall or overweight children. CONCLUSION: BPHR at a single screening visit had a high performance to identify hypertension in children, although the low prevalence of hypertension led to a low PPV.

Autumnal vs spring hatching in the fairy shrimp Siphonophanes grubii (Dybowski) (Crustacea, Anostraca): diversified bet-hedging strategy ?

Polyphenisms, as opposed to polymorphism, refers to coexistence of several distinct phenotypes having a common genotype. Polyphenism can be selected for in unpredictable environments. Here we document and anlyse a case of siphenism in the north-European fairy shrinp Siphonophanes grubii (Dybowski), in relation to the temporary and unpredictable nature of its habitat. The active part of this species'life cycle usually consists of a single, short-lived, spring cohort. Here we report field observations on autumnal hatching and on a long-lived, overwintering cohort; we show that the winter cohort runs the risk of total failure, due to the pond freezing entirely or drying up during winter. If, however, environmental conditions allow winter survival, animals reach a larger size, reproduce for a longer time, and display higher fecundity, than do animals from the spring cohort. Laboratory experiments support the theory that these differences are purely phenotypic and dependent on temperatur. Using an analytical model adapted from Cohen (1966), we propose that the coexistence of both a winter and a spring cohort in the same ponds can be interpreted as a diversified bet-hedging strategy.

Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'?

OBJECTIVES: Hypoglycaemia (glucose <2.2 mmol/l) is a defining feature of severe malaria, but the significance of other levels of blood glucose has not previously been studied in children with severe malaria. METHODS: A prospective study of 437 consecutive children with presumed severe malaria was conducted in Mali. We defined hypoglycaemia as <2.2 mmol/l, low glycaemia as 2.2-4.4 mmol/l and hyperglycaemia as >8.3 mmol/l. Associations between glycaemia and case fatality were analysed for 418 children using logistic regression models and a receiver operator curve (ROC). RESULTS: There was a significant difference between blood glucose levels in children who died (median 4.6 mmol/l) and survivors (median 7.6 mmol/l, P < 0.001). Case fatality declined from 61.5% of the hypoglycaemic children to 46.2% of those with low glycaemia, 13.4% of those with normal glycaemia and 7.6% of those with hyperglycaemia (P < 0.001). Logistic regression showed an adjusted odds ratio (AOR) of 0.75 (0.64-0.88) for case fatality per 1 mmol/l increase in baseline blood glucose. Compared to a normal blood glucose, hypoglycaemia and low glycaemia both significantly increased the odds of death (AOR 11.87, 2.10-67.00; and 5.21, 1.86-14.63, respectively), whereas hyperglycaemia reduced the odds of death (AOR 0.34, 0.13-0.91). The ROC [area under the curve at 0.753 (95% CI 0.684-0.820)] indicated that glycaemia had a moderate predictive value for death and identified an optimal threshold at glycaemia <6.1 mmol/l, (sensitivity 64.5% and specificity 75.1%). CONCLUSIONS: If there is a threshold of blood glucose which defines a worse prognosis, it is at a higher level than the current definition of 2.2 mmol/l.

Optimal public rationing and price response

We study optimal public rationing of an indivisible good and private sector price responses. Consumers differ in their wealth and costs of provisions. Due to a limited budget, some consumers must be rationed. Public rationing determines the characteristics of consumers who seek supply from the private sector, where a firm sets prices based on consumers' cost information and in response to the rationing rule. We consider two information regimes. In the first, the public supplier rations consumers according to their wealth information. In equilibrium, the public supplier must ration both rich and poor consumers. Supplying all poor consumers would leave only rich consumers in the private market, and the firm would react by setting a high price. Rationing some poor consumers is optimal, and implements price reduction in the private market. In the second information regime, the public supplier rations consumers according to consumers' wealth and cost information. In equilibrium, consumers are allocated the good if and only if their costs are below a threshold. Wealth information is not used. Rationing based on cost results in higher equilibrium total consumer surplus than rationing based on wealth. [Authors]

On the use of the likelihood ratio for forensic evaluation: response to Fenton et al.

This letter to the Editor comments on the article When 'neutral' evidence still has probative value (with implications from the Barry George Case) by N. Fenton et al. [[1], 2014].

Detection of Optimal Models in Parameter Space with Support Vector Machines

The paper proposes an approach aimed at detecting optimal model parameter combinations to achieve the most representative description of uncertainty in the model performance. A classification problem is posed to find the regions of good fitting models according to the values of a cost function. Support Vector Machine (SVM) classification in the parameter space is applied to decide if a forward model simulation is to be computed for a particular generated model. SVM is particularly designed to tackle classification problems in high-dimensional space in a non-parametric and non-linear way. SVM decision boundaries determine the regions that are subject to the largest uncertainty in the cost function classification, and, therefore, provide guidelines for further iterative exploration of the model space. The proposed approach is illustrated by a synthetic example of fluid flow through porous media, which features highly variable response due to the parameter values' combination.