Fetal Tachyarrhythmia - Part I: Diagnosis

Fetal tachycardia, first recognized in 1930 by Hyman et al1, is a condition occurring in approximately 0.4-0.6% of all pregnancies2. A subset of these cases with more sustained periods of tachycardia is clinically relevant. The necessity of therapeutic intervention in this condition is still a matter of discussion focused on the natural history of the disease. The spectrum of opinions varies from non-intervention3,4,5 based on a number of cases in which the tachycardia subsided spontaneously6, to aggressive pharmacotherapeutic intervention7,8 based on reports of deterioration of the fetal condition ultimately ending in significant neurological morbidity9,10,11, or fetal demise12,13,14. Prenatal treatment through indirect, maternally administered drug therapy seems to be the preference of most centers15,16,17,18,19,20,21. This matter will be discussed further in Fetal Tachyarrhythmia, Part II, Treatment

Fetal Tachyarrhythmia - Part II: Treatment

The decision to initiate pharmacological intervention in case of fetal tachycardia depends on several factors and must be weighed against possible maternal and/or fetal adverse effects inherent to the use of antiarrhythmics. First, the seriousness of the fetal condition must be recognized. Many studies have shown that in case of fetal tachycardia, there is a significant predisposition to congestive heart failure and subsequent development of fetal hydrops and even sudden cardiac death1,2,3 Secondly, predictors of congestive heart failure have been suggested in several studies, such as the percentage of time that the tachycardia is present, the gestational age at which the tachycardia occurs4, the ventricular rate5 and the site of origin of the tachycardia6. However, the sensitivity of these predictors is low and they are therefore clinically not very useful. In addition, hemodynamic compromise may occur in less than 24 - 48 hours as has been shown in the fetal lamb7 and in tachycardic fetuses8,9. On the other hand, spontaneous resolution of the tachycardia has also been described10. Thirdly, transplacental management of fetuses with tricuspid regurgitation11, congestive heart failure or fetal hydrops is difficult12,13, probably as a result of limited transplacental transfer of the antiarrhythmic drug14,15. In case of fetal hydrops, conversion rates are decreased and time to conversion is increased13. Treatment of sustained fetal tachycardia is therefore to be preferred above expectant management, although some centers oppose this regimen and suggest that in cases with (intermittent) fetal SVT not complicated by congestive heart failure or fetal hydrops, conservative management and close surveillance might be a reasonable alternative16,17,18

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Optimal Use of Vitamin D When Treating Osteoporosis

Inadequate serum 25-hydroxyvitamin D (25[OH]D) concentrations are associated with muscle weakness, decreased physical performance, and increased propensity in falls and fractures. This paper discusses several aspects with regard to vitamin D status and supplementation when treating patients with osteoporosis in relation to risks and prevention of falls and fractures. Based on evidence from literature, adequate supplementation with at least 700 IU of vitamin D, preferably cholecalciferol, is required for improving physical function and prevention of falls and fractures. Additional calcium supplementation may be considered when dietary calcium intake is below 700 mg/day. For optimal bone mineral density response in patients treated with antiresorptive or anabolic therapy, adequate vitamin D and calcium supplementation is also necessary. Monitoring of 25(OH)D levels during follow-up and adjustment of vitamin D supplementation should be considered to reach and maintain adequate serum 25(OH)D levels of at least 50 nmol/L, preferably greater than 75 nmol/L in all patients

Stellar models with Schwarzschild and non-Schwarzschild vacuum exteriors

A striking characteristic of non-Schwarzschild vacuum exteriors is that they contain not only the total gravitational mass of the source, but also an {\it arbitrary} constant. In this work, we show that the constants appearing in the "temporal Schwarzschild", "spatial Schwarzschild" and "Reissner-Nordstr{\"o}m-like" exteriors are not arbitrary but are completely determined by star's parameters, like the equation of state and the gravitational potential. Consequently, in the braneworld scenario the gravitational field outside of a star is no longer determined by the total mass alone, but also depends on the details of the internal structure of the source. We show that the general relativistic upper bound on the gravitational potential $M/R < 4/9$, for perfect fluid stars, is significantly increased in these exteriors. Namely, $M/R < 1/2$, $M/R < 2/3$ and $M/R < 1$ for the temporal Schwarzschild, spatial Schwarzschild and Reissner-Nordstr{\"o}m-like exteriors, respectively. Regarding the surface gravitational redshift, we find that the general relativistic Schwarzschild exterior as well as the braneworld spatial Schwarzschild exterior lead to the same upper bound, viz., $Z < 2$. However, when the external spacetime is the temporal Schwarzschild metric or the Reissner-Nordstr{\"o}m-like exterior there is no such constraint: $Z < \infty$. This infinite difference in the limiting value of $Z$ is because for these exteriors the effective pressure at the surface is negative. The results of our work are potentially observable and can be used to test the theory.Comment: 19 pages, 3 figures and caption

The Genetics of Adaptation for Eight Microvirid Bacteriophages

Theories of adaptive molecular evolution have recently experienced significant expansion, and their predictions and assumptions have begun to be subjected to rigorous empirical testing. However, these theories focus largely on predicting the first event in adaptive evolution, the fixation of a single beneficial mutation. To address long-term adaptation it is necessary to include new assumptions, but empirical data are needed for guidance. To empirically characterize the general properties of adaptive walks, eight recently isolated relatives of the single-stranded DNA (ssDNA) bacteriophage φX174 (family Microviridae) were adapted to identical selective conditions. Three of the eight genotypes were adapted in replicate, for a total of 11 adaptive walks. We measured fitness improvement and identified the genetic changes underlying the observed adaptation. Nearly all phages were evolvable; nine of the 11 lineages showed a significant increase in fitness. However, fitness plateaued quickly, and adaptation was achieved through only three substitutions on average. Parallel evolution was rampant, both across replicates of the same genotype as well as across different genotypes, yet adaptation of replicates never proceeded through the exact same set of mutations. Despite this, final fitnesses did not vary significantly among replicates. Final fitnesses did vary significantly across genotypes but not across phylogenetic groupings of genotypes. A positive correlation was found between the number of substitutions in an adaptive walk and the magnitude of fitness improvement, but no correlation was found between starting and ending fitness. These results provide an empirical framework for future adaptation theory

Imaging Features of Adult Choledochal Cysts: a Pictorial Review

Choledochal cysts are rare congenital anomalies which are principally diagnosed by disproportional dilatation of the extrahepatic bile ducts. In addition, choledochal cysts are believed to arise from the anomalous union of the common bile duct and pancreatic duct outside the duodenal wall which is also proximal to the sphincter of the Oddi mechanism. The various types of choledochal cysts have been classified on the basis of these anomalous unions (Komi classification) and their anatomical locations (Todani classification). The multidetector computed tomography with reformatted imaging, magnetic resonance cholangiopancreatography, and an endoscopic retrograde cholangiography represent the important techniques providing the anatomical resolution and detail required to properly diagnose and classify choledochal cysts and their associated abnormal features of the biliary tree, as well as their pancreaticobile duct union. This study describes the various imaging features of a choledochal cyst in adults according to the various types of anomalous unions of the pancreaticobile duct according to Komi's classification and anatomic location according to Todani's classification. Lastly, we also review and discuss the associated abnormal findings developed in biliary systems

Statistical Methodological Issues in Handling of Fatty Acid Data: Percentage or Concentration, Imputation and Indices

Basic aspects in the handling of fatty acid-data have remained largely underexposed. Of these, we aimed to address three statistical methodological issues, by quantitatively exemplifying their imminent confounding impact on analytical outcomes: (1) presenting results as relative percentages or absolute concentrations, (2) handling of missing/non-detectable values, and (3) using structural indices for data-reduction. Therefore, we reanalyzed an example dataset containing erythrocyte fatty acid-concentrations of 137 recurrently depressed patients and 73 controls. First, correlations between data presented as percentages and concentrations varied for different fatty acids, depending on their correlation with the total fatty acid-concentration. Second, multiple imputation of non-detects resulted in differences in significance compared to zero-substitution or omission of non-detects. Third, patients’ chain length-, unsaturation-, and peroxidation-indices were significantly lower compared to controls, which corresponded with patterns interpreted from individual fatty acid tests. In conclusion, results from our example dataset show that statistical methodological choices can have a significant influence on outcomes of fatty acid analysis, which emphasizes the relevance of: (1) hypothesis-based fatty acid-presentation (percentages or concentrations), (2) multiple imputation, preventing bias introduced by non-detects; and (3) the possibility of using (structural) indices, to delineate fatty acid-patterns thereby preventing multiple testing

Heterogeneous Adaptive Trajectories of Small Populations on Complex Fitness Landscapes

Background Small populations are thought to be adaptively handicapped, not only because they suffer more from deleterious mutations but also because they have limited access to new beneficial mutations, particularly those conferring large benefits. Methodology/Principal Findings Here, we test this widely held conjecture using both simulations and experiments with small and large bacterial populations evolving in either a simple or a complex nutrient environment. Consistent with expectations, we find that small populations are adaptively constrained in the simple environment; however, in the complex environment small populations not only follow more heterogeneous adaptive trajectories, but can also attain higher fitness than the large populations. Large populations are constrained to near deterministic fixation of rare large-benefit mutations. While such determinism speeds adaptation on the smooth adaptive landscape represented by the simple environment, it can limit the ability of large populations from effectively exploring the underlying topography of rugged adaptive landscapes characterized by complex environments. Conclusions Our results show that adaptive constraints often faced by small populations can be circumvented during evolution on rugged adaptive landscapes

Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems

A generic mechanism - networked buffering - is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems. \ud \u