Counting function fluctuations and extreme value threshold in multifractal patterns: the case study of an ideal 1/f1/f noise

To understand the sample-to-sample fluctuations in disorder-generated multifractal patterns we investigate analytically as well as numerically the statistics of high values of the simplest model - the ideal periodic $1/f$ Gaussian noise. By employing the thermodynamic formalism we predict the characteristic scale and the precise scaling form of the distribution of number of points above a given level. We demonstrate that the powerlaw forward tail of the probability density, with exponent controlled by the level, results in an important difference between the mean and the typical values of the counting function. This can be further used to determine the typical threshold $x_m$ of extreme values in the pattern which turns out to be given by $x_m^{(typ)}=2-c\ln{\ln{M}}/\ln{M}$ with $c=3/2$. Such observation provides a rather compelling explanation of the mechanism behind universality of $c$. Revealed mechanisms are conjectured to retain their qualitative validity for a broad class of disorder-generated multifractal fields. In particular, we predict that the typical value of the maximum $p_{max}$ of intensity is to be given by $-\ln{p_{max}} = \alpha_{-}\ln{M} + \frac{3}{2f'(\alpha_{-})}\ln{\ln{M}} + O(1)$, where $f(\alpha)$ is the corresponding singularity spectrum vanishing at $\alpha=\alpha_{-}>0$. For the $1/f$ noise we also derive exact as well as well-controlled approximate formulas for the mean and the variance of the counting function without recourse to the thermodynamic formalism.Comment: 28 pages; 7 figures, published version with a few misprints corrected, editing done and references adde

Ixekizumab Citrate-Free Formulation : Results from Two Clinical Trials

Introduction: Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. Methods: Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh. Results: Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was − 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC, AUC, and C between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable. Conclusion: Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation. Trail Registration: ClinicalTrials.gov identifier NCT03848403, NCT04259346

Long-term Risk of Neuropsychiatric Disease after Exposure to Infection in Utero

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Ovine Fetal Thymus Response to Lipopolysaccharide-Induced Chorioamnionitis and Antenatal Corticosteroids

RATIONALE: Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development. METHODS: Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term = 150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated. RESULTS: Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes. CONCLUSION: Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus

Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes

Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies

The Impact of Increased Awareness of Acute Kidney Injury in the Neonatal Intensive Care Unit on Acute Kidney Injury Incidence and Reporting: Results of a Retrospective Cohort Study

Objective: To evaluate the impact of nephrology integration in the NICU on acute kidney injury (AKI) incidence, provider reporting, and nephrology referral. Study design: Cohort study in a single-center NICU from January 2012 to December 2017 (n = 1464). We assessed the impact of clinical practice changes including neonatal-nephrology rounds on the incidence of AKI. Results: AKI occurred in 318 neonates (22%). AKI occurred less frequently in those admitted after clinical practice changes (P < 0.001). After multivariable adjustment, clinical practice changes were associated with reduced odds of AKI (adjusted odds ratio, 0.31; 95% CI 0.22-0.44, P < 0.001). Provider reporting of AKI improved (P < 0.001) and more neonates were referred for nephrology follow-up (P < 0.001). Conclusions: Increased nephrology integration in the NICU was associated with decreased AKI incidence. While recognition of AKI improved, AKI remained poorly reported and nephrology AKI follow-up did not routinely occur. This study supports the importance of increased nephrology involvement in the NICU

Salinity tolerance in cotton

Cotton is the chief crop and main pillar of textile industry. Its fiber and seed have significant economic importance. However, salinity interferes with the normal growth functioning and results in halted growth and declined yield of fiber and seed. Salinity effects are more obvious at early growth stages of cotton, limiting final yield. Salt decreases boll formation per plant which ultimately gives decreased fiber yield and poor lint quality. Salinity is a global issue increasing every year due to uncontrolled measures and improper land management. Application of saline irrigation water is adding increments to already existing salts and deteriorating the productive soil. Arid regions are totally dependent upon rain for growth of cotton. Salt problem is more in arid regions due least availability of moisture and water for flushing salts from cotton root zone. Moreover, higher temperature favors excessive evaporation under arid conditions and leaving salt on the upper surface of soil. Salts at the surface soil impede cotton seed germination. In this chapter, we discussed formation of saline soils and their sources which deter cotton growth. Physiological changes, oxidative stress caused due to salinity, role of molecular transporters involved in detoxification and specific gene expression is also illuminated. © Springer Nature Singapore Pte Ltd. 2020. All rights reserved