Optimal execution and speculation with trade signals

We propose a price impact model where changes in prices are purely driven by the order flow in the market. The stochastic price impact of market orders and the arrival rates of limit and market orders are functions of the market liquidity process which reflects the balance of the demand and supply of liquidity. Limit and market orders mutually excite each other so that liquidity is mean reverting. We use the theory of Meyer-$\sigma$-fields to introduce a short-term signal process from which a trader learns about imminent changes in order flow. In this setting, we examine an optimal execution problem and derive the Hamilton--Jacobi--Bellman (HJB) equation for the value function. The HJB equation is solved numerically and we illustrate how the trader uses the signal to enhance the performance of execution problems and to execute speculative strategies

Neurologic phenotypes associated with COL4A1/2 mutations

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall

No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia

Background!#!X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns.!##!Methods!#!Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features.!##!Results!#!The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes.!##!Conclusions!#!We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors

Glutamatergic synaptic input to glioma cells drives brain tumour progression

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications

Characteristics of deaths associated with kratom use.

BACKGROUND: Kratom (Mitragyna speciosa Korth) use has increased in Western countries, with a rising number of associated deaths. There is growing debate about the involvement of kratom in these events. AIMS: This study details the characteristics of such fatalities and provides a 'state-of-the-art' review. METHODS: UK cases were identified from mortality registers by searching with the terms 'kratom', 'mitragynine', etc. Databases and online media were searched using these terms and 'death', 'fatal*', 'overdose', 'poisoning', etc. to identify additional cases; details were obtained from relevant officials. Case characteristics were extracted into an Excel spreadsheet, and analysed employing descriptive statistics and thematic analysis. RESULTS: Typical case characteristics (n = 156): male (80%), mean age 32.3 years, White (100%), drug abuse history (95%); reasons for use included self-medication, recreation, relaxation, bodybuilding, and avoiding positive drug tests. Mitragynine alone was identified/implicated in 23% of cases. Poly substance use was common (87%), typically controlled/recreational drugs, therapeutic drugs, and alcohol. Death cause(s) included toxic effects of kratom ± other substances; underlying health issues. CONCLUSIONS: These findings add substantially to the knowledge base on kratom-associated deaths; these need systematic, accurate recording. Kratom's safety profile remains only partially understood; toxic and fatal levels require quantification

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies

Figure 5

Figure 5. Family pedigrees from published cases. Fig.5a. COL4A2 c. 2399 G>A; p. G800E. Ref. Ha et al., 2016. Fig.5b. COL4A2 c. 3455 G>A; p. G1152D. Ref. Yoneda et al., 2012. Fig.5c. COL4A1 c. 1249G>C; p.G417R. Ref. Giorgio et al., 2015. Fig.5d. COL4A1 c.3796G>C; p.G1266R. Ref. Shah et al., 2012. Fig.5e: COL4A1 c.2662G>C; p.G888R. Ref. Giorgio et al., 2015. Fig.5f: COL4A1 p.G562E. Ref. Vahedi et al., 2003 and Vahedi et al., 2007. Fig.5g.: COL4A1 p. G749S. Ref. Gasparini et al., 2006. Fig.5h: COL4A1 c.3389G>A; p.G1130D. Ref. Breedved et al. 2006 Fig.5i: COL4A1 c.2159G>A. Ref. Tonduti et al., 2012. Fig.5j: COL4A1 c.3715G>A; p.G1239R. Ref. Takenouchi et al., 2015. Fig.5k: COL4A1 c. 2645G>A. Ref. Shah et al., 2012. Fig.5l: COL4A1 c.1973 G>A. Ref. Livingston et al., 2011. Fig.5m: COL4A1 c.4031G>C; p.G1344A. Ref. Leung et al., 2012. Fig.5n: COL4A2 c.3455G>A; p.G1152D. Ref. Yoneda et al., 2012. Fig.5o: COL4A1 c.2085del; p. G696fs. Ref. Lemmens et al., 2013. wt/m: wild-type/mutated

Additional material

Table 1 summarizes the methods of identification of COL4A1/2 mutations in the cohort of new patients. Table 2 reports the phenotypes of previously-published patients with COL4A1/2 mutations and epilepsy. Tables 3a/b describes the clinical, EEG and brain MRI data of the new cohort of patients with COL4A1/2 mutations. Additional Method describes immunohistochemistry performed from consented surplus resected tissue from 1 case