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

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

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

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

Development of a prenatal clinical care pathway for uncomplicated gastroschisis and literature review.

BACKGROUND: Gastroschisis is an abdominal wall defect wherein the bowel is herniated into the amniotic fluid. Controversy exists regarding optimal prenatal surveillance strategies that predict fetal well-being and help guide timing of delivery. Our objective was to develop a clinical care pathway for prenatal management of uncomplicated gastroschisis at our institution. METHODS: We performed a review of literature from January 1996 to May 2017 to evaluate prenatal ultrasound (US) markers and surveillance strategies that help determine timing of delivery and optimize outcomes in fetal gastroschisis. RESULTS: A total 63 relevant articles were identified. We found that among the US markers, intraabdominal bowel dilatation, polyhydramnios, and gastric dilatation are potentially associated with postnatal complications. Prenatal surveillance strategy with monthly US starting at 28weeks of gestational age (wGA) and twice weekly non-stress testing beginning at 32wGA is recommended to optimize fetal wellbeing. Timing of delivery should be based on obstetric indications and elective preterm delivery prior to 37wGA is not indicated. CONCLUSIONS: Close prenatal surveillance of fetal gastroschisis is necessary due to the high risk for adverse outcomes including intrauterine fetal demise in the third trimester. Decisions regarding the timing of delivery should take into consideration the additional prematurity-associated morbidity

Intra- and Inter-observer Variability in Different Methods of Measuring Carpal Collapse

Introduction: Carpal collapse of wrist occurs in disorders like rheumatoid arthritis and Kienbock's disease. Three techniques have been described to measure carpal collapse. First, the carpal height ratio (CHR), measured by dividing carpal height by 3rd metacarpal length. Second, the revised carpal height ratio (RCH ratio), measured by dividing carpal height by length of capitate. Third, capitate radius distance (CR index), measured by shortest distance between distal edge of radius and the proximal edge of capitate. The index publications describe good reliability of all these but which method out of the three is best in terms of intra- and inter-observer variability is not known. The purpose of this study was to find out which method had the least inter- and intra-observer variability for determining carpal collapse. Materials and Methods: Fifty normal wrist postero-anterior radiographs were studied by three assessors who measured CHR, RCH ratio and CR index separately. The measurements were repeated after one month by all the three observers. The results were then statistically analysed. Results: The p-value was <0.001 in all the three assessors in CR index meaning that the intra-observer variability was least in CR index. For the inter-observer variability intra class coefficient of 0.9 indicated that the CR index has the least variability. Conclusion: CR index is the most reproducible method to measure carpal collapse. The method which provides accurate measurement of carpal collapse will allow better staging of carpal disorders

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Not AvailableThe study was conducted on 56 female camels for E2 and P4 profiles at different reproductive stages, viz. 35bred females (Group A) monitored after breeding once daily for 0-30 days were divided into 2 groups of pregnant (n=13) and nonpregnant (n=22) based on P4 profiles, another pregnant group (Group B) (n=8) was monitored at weekly intervals from 23rd weeks to the end of gestation; periparturient camels (Group C) were monitored at 6h intervals, while nonpregnant females (n=7) (Group D) with growing and mature follicles were monitored for E2 profiles before and after mating. The average P4 concentrations in pregnant and nonpregnant femals of group A were similar from days 0-10 after mating. They declined from day 11 onward in nonpregnant females, but continued to increase in pregnant animals (P<0.01). The average daily E2 profiles were found to be low or basal in both non-pregnant (1.32 to 8.74 pg/ml) and pregnant femals (0.69 to8.24 pg/ml). The average concentration of p4 in group B was relatively higher (5.87 to 12.07 ng/ml) between 23rd to 32nd weeks of gestation than at later stages (2.88 to 5.09 ng/ml). The average concentration of P4 trcorded in periparturient female camels og group c was around 4.0-4.5 ng/ml at 55-31 hrs prior to parturition and declined slightly to measure 3 ng/ml at parturition. It started to increase slowly and steadily after the 39th week and measured more than 50, 100, 250, 300 and 375 pg/ml at the 42nd, 45th, 47th, 49th, and 52nd weeks of gestation, respectively. It decline in periparturient females to 92.2-243 g/ml at 1-55 hrs before calving. It further declined sharply to 23.3, 5.6 and 6.6 pg/ml at 5, 11 and 17 hrs after calving. E2 profile of nonpregnent females of group D (n=7) with mature sized ovarian follicles monitored at 30 minute intervals for 2 hrs daily for 15-20 days (for E2 profiles only) revealed mostly basal levels with a few intermittent peaks, indicating the pulsatile nature its secretion. One grou of nonpregnant females, Group E (n=6) with mature follicles monitored for E2 profiles only, one day prior to and immediately after mating showed that E2 profiles are these times did not differNot Availabl

Not Available

Not AvailableThe study was conducted on 56 female camels for E2 and P4 profiles at different reproductive stages, viz. 35 bred females (Group A) monitored after breeding once daily for 0-30 days were divided into 2 groups of pregnant (n=13)and nonpregnant (n=22)based on P4 profiles, another pregnant group (Group B) (n=8)was monitored at weekly intervals from 23 rd weeks to the end of gestation; periparturient camels (Group C) were monitored at 6h intervals, while nonpregnant females (n=7) (Group D) with growing and mature follicles were monitored for E2 profiles only and the final group (Group E) (n=6)of nonpregnant females was monitored for E2 profiles before and after mating. The average P4 concentrations in pregnant and nonpregnant females of group A were similar from days 0 -10 after mating. They declined from day 11 onward in nonpregnant females, but continued to increase in pregnant animals (P<0.01). The average daily E2 profiles were found to be low or basal in both non-pregnant (1.32 to 8.74 pg/ml) and pregnant females (0.69 to 8.24 pg/ml). The average concentration of P4 in group B was relatively higher (5.87 to 12.07 ng/ml) between 23rd to 32nd weeks of gestation than at later stages (2.88 to 5.09 ng/ml). The average concentration of P4 recorded in periparturient female camels of Group C was around 4.0-4.5 ng/ml at 55-31 hrs prior to parturition and declined slightly to measure 3 ng/ml at parturition. A further decline in P4 concentration to 1.6 ng/ml occurred after expulsion of the fetus. The average concentration of E2 was low up to 38th weeks of gestation. It started to increase slowly and steadily after the 39th week and measured more than 50, 100, 250, 300 and 375 pg/ml at the 42nd, 45th, 47th, 49th and 52nd weeks of gestation, respectively. It declined in periparturient females to 92.2-243 g/ml at 1-55 hrs before calving. It further declined sharply to 23.3, 5.6 and 6.6 pg/ml at 5, 11 and 17 hrs after calving. E2 profiles of nonpregnant females of group D (n=7)with mature sized ovarian follicles monitored at 30 minute intervals for 2 hrs daily for 15-20 days (for E2 profiles only) revealed mostly basal levels with a few intermittent peaks, indicating the pulsatile nature its secretion. One group of nonpregnant females, Group E (n=6) with mature follicles monitored for E2 profiles only, one day prior to and immediately after mating showed that E2 profiles ar these times did not differNot Availabl

Synergistic spermicidal activity of neem seed extract, reetha saponins and quinine hydrochloride

In order to identify potent spermicidal agents which are free from the side effects of currently available agents, spermicidal activity of purified neem seeds extract (Praneem), reetha saponins and quinine hydrochloride was studied individually and in combination. Sander-Cramer test was used to assess the activity on human sperm. Under the test conditions, minimum effective spermicidal concentrations for Praneem, reetha saponins and quinine hydrochloride were 25%, 0.05% and 0.346%, respectively. At these concentrations, 100% of the sperm were immobilised within 20 seconds. A positive syner-gistic effect in the spermicidal activity of these components, if used in combination, was observed which implies the use of reduced concentrations of each to bring about the desired action. The selected combination formulated into a suitable dosage form is likely to offer dual benefit of a potent contraceptive and an antimicrobial preparation