Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population.

BACKGROUND: LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting IL-13 in patients with uncontrolled asthma. Failure to demonstrate efficacy may have been related to patient selection in those trials. OBJECTIVE: To assess the efficacy in a well-defined subpopulation of patients with elevated blood eosinophil counts and a minimum number of prior asthma exacerbations. We performed an additional analysis in a subpopulation of patients with elevated FeNO and prior exacerbations. METHODS: Adult (LI and LII) and adolescent patients (aged 12-17 years weighing ≥40 kg, ACOUSTICS) with uncontrolled asthma received lebrikizumab (125 mg, n = 832; or 37.5 mg, n = 829) or placebo (n = 833) subcutaneously every 4 weeks. Post hoc analysis of the annualized adjusted exacerbation rate (AER) was performed in a subpopulation of patients with baseline blood eosinophils of 300 cells/µL or greater and history of one or more exacerbations. In this subpopulation, there were 227 patients in the placebo group, 222 in the lebrikizumab 37.5-mg group, and 217 in the lebrikizumab 125-mg group. We summarized safety in patients who received at least one dose of lebrikizumab using adverse events. RESULTS: Lebrikizumab significantly reduced AER compared with placebo in adults (AER reduction: 125 mg [38%]; and 37.5 mg [41%]) and adolescents (AER reduction:125 mg [59%]; 37.5 mg [64%]) with baseline blood eosinophils of 300 cells/µL or greater and one or more exacerbations. Most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. CONCLUSION: Lebrikizumab significantly reduced asthma exacerbations in a subpopulation of patients with elevated blood eosinophils, elevated FeNO, and a history of asthma exacerbation.

Hybrid grey assisted whale optimization based machine learning for the COVID-19 prediction.

Recently, COVID-19 (coronavirus) has been a huge influence on the socio and economic field. COVID-19 cases are seriously increasing day-day and also don't identified proper vaccine for COVID-19. Hence, COVID-19 is fast spreading virus and it causes more deaths. In order to address this, the work has proposed a machine learning (ML) scheme for the prediction of COVID-19 positive, negative, and deceased instances. Initially, the data is pre-processed by eliminating redundant and missing values. Then, the features are selected using hybrid grey assisted whale optimization algorithm (H-GAWOA). Finally, the classifier ANFIS (adaptive network-based fuzzy inference systems) is used for investigating the confirmed, survival and death rate of COVID-19. The performance is analysed on John Hopkins University dataset and the performances like MSE, RMSE, MAPE, and R2 are measured. In all the comparisons, the MSE value is very less for the proposed model. Particularly, in the deceased cases prediction, the MSE value is 0.00 for the proposed H-GAWOA-ANFIS. Finally, it is proved that the suggested model is able to generate the better results when contrast to the other approaches.

Quantum Metric Unveils Defect Freezing in Non-Hermitian Systems.

Non-Hermiticity in quantum Hamiltonians leads to nonunitary time evolution and possibly complex energy eigenvalues, which can lead to a rich phenomenology with no Hermitian counterpart. In this work, we study the dynamics of an exactly solvable non-Hermitian system, hosting both PT-symmetric and PT-broken modes subject to a linear quench. Employing a fully consistent framework, in which the Hilbert space is endowed with a nontrivial dynamical metric, we analyze the dynamics of the generated defects. In contrast to Hermitian systems, our study reveals that PT-broken time evolution leads to defect freezing and hence the violation of adiabaticity. This physics necessitates the so-called metric framework, as it is missed by the oft used approach of normalizing quantities by the time-dependent norm of the state. Our results are relevant for a wide class of experimental systems.

ECC Status, CRAFT Categorization and OHRQoL Assessment in 3-6-year-old Children: A Cross-sectional Study.

Introduction: Early Childhood Caries (ECC) can affect the health and quality of life of the children. Assessing a patient's risk of developing caries is an important aspect of caries management; however, can assessing the caries risk predict the impact of ECC on the OHRQoL? Few Indian studies have reported association between caries status, risk, and the impact on OHRQoL. Aim: To assess the association between dental caries status, risk assessment, and OHRQoL in 3-6-year-old children. Methodology: A total of 50 healthy children were recruited in a cross-sectional study. Parents filled the ECOHIS questionnaire. Caries status, risk, and OHRQoL were measured as dmft-pufa, CRAFT (Caries Risk Assessment for Treatment- an indigenous tool) and ECOHIS scores, respectively. Results: Moderate correlation was seen between dmft and ECOHIS scores (r = 0.496, p < 0.01), and pufa and ECOHIS scores (r = 0.408, p < 0.05). More number of subjects with higher scores of ECOHIS were in the high-risk category of CRAFT (p < 0.05). Conclusion: Caries status, risk and OHRQoL were associated in 3-6-year-old children. Thus, caries risk assessment may predict poor OHRQoL. How to cite this article: Iyer CR, Jawdekar AM. ECC Status, CRAFT Categorization and OHRQoL Assessment in 3-6-year-old Children: A Cross-sectional Study. Int J Clin Pediatr Dent 2023;16(2):199-204.

Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit. METHODS: Adolescent patients (N = 206) (≥ 12 to < 18 years old, weighing ≥ 40 kg) with moderate-to-severe AD received subcutaneous lebrikizumab 500 mg loading doses at baseline and Week 2, followed by 250 mg every 2 weeks (Q2W) thereafter. Safety was monitored using reported AEs, AEs leading to treatment discontinuation, vital signs, growth assessments, and laboratory testing. Efficacy analyses included Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Body Surface Area (BSA), (Children's) Dermatology Life Quality Index ((C)DLQI), and Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, and PROMIS Depression. RESULTS: 172 patients completed the treatment period. Low frequencies of SAEs (n = 5, 2.4%) and AEs leading to treatment discontinuation (n = 5, 2.4%) were reported. Overall, 134 patients (65%) reported at least one treatment-emergent AE (TEAE), most being mild or moderate in severity. In total, 62.6% achieved IGA (0,1) with ≥ 2-point improvement from baseline and 81.9% achieved EASI-75 by Week 52. The EASI mean percentage improvement from baseline to Week 52 was 86.0%. Mean BSA at baseline was 45.4%, decreasing to 8.4% by Week 52. Improvements in mean change from baseline (CFB) to Week 52 were observed in DLQI (baseline 12.3; CFB - 8.9), CDLQI (baseline 10.1; CFB - 6.5), PROMIS Anxiety (baseline 51.5; CFB - 6.3), and PROMIS Depression (baseline 49.3; CFB - 3.4) scores. CONCLUSIONS: Lebrikizumab 250 mg Q2W had a safety profile consistent with previous trials and significantly improved AD symptoms and quality of life, with meaningful responses at Week 16 increasing by Week 52. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04250350.

Atopic dermatitis is a chronic relapsing inflammatory skin disease that affects up to 15% of adolescents worldwide, with up to 50% suffering from moderate-to-severe disease. Signs and symptoms include dry, cracked skin; redness; itching; and painful lesions, which can negatively affect quality of life and lead to complications, including skin infections. Adolescents also report increased rates of anxiety and stress. Lebrikizumab is a novel monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, the key cytokine in atopic dermatitis, blocking the downstream effects of IL-13 with high potency. Lebrikizumab has been shown previously to improve symptoms of atopic dermatitis, including itch, skin clearance, and quality of life in ADvocate1, ADvocate2 and ADhere. The ADore study aimed to evaluate the safety and efficacy of lebrikizumab in adolescents with moderate-to-severe atopic dermatitis. Investigators recruited patients ≥ 12 to < 18 years old, weighing ≥ 40 kg, from Australia, Canada, Poland, and the US who were diagnosed with moderate-to-severe atopic dermatitis. These patients received a loading dose of 500 mg of lebrikizumab at Weeks 0 and 2, followed by 250 mg every 2 weeks for 52 weeks. The safety profile of lebrikizumab was consistent with previously published reports, with mostly mild or moderate adverse events, which did not lead to treatment discontinuation. Lebrikizumab improved skin clearance; 62.6% of patients had clear or almost clear skin by the end of the trial. Lebrikizumab also improved the patients' quality of life. These safety and efficacy results support lebrikizumab's role in treating adolescents with moderate-to-severe atopic dermatitis. Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study (MP4 44681 KB).

Safety of Lebrikizumab in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: An Integrated Analysis of Eight Clinical Trials.

BACKGROUND: Lebrikizumab is a monoclonal antibody that binds with high affinity to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. OBJECTIVES: To report integrated safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis from phase 2 and 3 studies. METHODS: Five double-blind, randomized placebo-controlled studies; one randomized open-label study; one adolescent open-label, single-arm study; and one long-term safety study were summarized in two datasets: (1) placebo-controlled week 0-16 (All-PC Week 0-16) in patients who received lebrikizumab 250 mg every 2 weeks (LEBQ2W) versus placebo and (2) patients who received any dose of lebrikizumab at any time during the studies (All-LEB). Exposure-adjusted incidence rates (IR)/100 patient-years (PY) are provided. RESULTS: A total of 1720 patients received lebrikizumab (1637.0 PY exposure). In All-PC Week 0-16, the frequency of treatment-emergent adverse events (TEAEs) was similar between treatment groups; most events were nonserious and mild or moderate in severity. The most frequently reported TEAEs were atopic dermatitis (placebo) and conjunctivitis (LEBQ2W). Frequencies of conjunctivitis cluster were 2.5% (placebo) and 8.5% (LEBQ2W), and all events were mild or moderate (All-LEB 10.6%, IR, 12.2). Frequencies of injection site reactions were 1.5% (placebo) and 2.6% (LEBQ2W; All-LEB 3.1%, IR, 3.3). Frequencies of adverse events leading to treatment discontinuation were 1.4% (placebo) and 2.3% (LEBQ2W; All-LEB 4.2%, IR, 4.5). CONCLUSION: The safety profile for lebrikizumab consisted of TEAEs that were mostly nonserious, mild or moderate in severity, and did not lead to treatment discontinuation. The safety profile was similar in both adults and adolescents. CLINICALTRIALS: GOV: NCT02465606, NCT02340234, NCT03443024, NCT04146363, NCT04178967, NCT04250337, NCT04250350, NCT04392154 Safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis: an integrated analysis of eight clinical trials (MP4 34165 KB).

Atopic dermatitis (AD) is a common chronic (persistent) skin disease that occurs in up to 7% of adults and approximately 20% of children. Lebrikizumab is a monoclonal antibody that goes against interleukin-13, which is overexpressed in patients with AD. Lebrikizumab is given by injection and is being studied to treat AD. It has been tested in several studies in both adults and adolescents (patients age ≥ 12 ­ < 18 years). In some of those studies, patients used lebrikizumab by itself, and in other studies patients used lebrikizumab in combination with low-to-moderate strength topical (rubbed on the skin) corticosteroid medicines. We examined the safety of lebrikizumab by combining the data from eight of those studies and analyzing the data in two datasets. The first dataset compared the safety of lebrikizumab 250 mg injected every 2 weeks with placebo (no drug in the injection) in four 16-week studies in which neither patient nor physician knew whether lebrikizumab or placebo was being injected. The second dataset included four additional studies and examined the safety of lebrikizumab in all patients receiving at least 1 injection of lebrikizumab at any dose. A total of 1720 patients took lebrikizumab. In the first dataset the frequency of adverse events was similar between lebrikizumab and placebo, and most events that did occur were mild or moderate in severity and were not serious. The most common adverse event in patients treated with placebo was atopic dermatitis, and in patients treated with lebrikizumab it was conjunctivitis. Frequencies of adverse events in the conjunctivitis cluster, which included a search for the terms of conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, and giant papillary conjunctivitis, were 2.5% in placebo and 8.5% in lebrikizumab, and all events were mild or moderate. Frequencies of injection site reactions were 1.5% in placebo and 2.6% in lebrikizumab, and frequencies of adverse events that led to patients stopping treatment were 1.4% in placebo and 2.3% in lebrikizumab. In the second dataset, the rate of these adverse events did not increase with longer duration of lebrikizumab. The safety profile for lebrikizumab consisted of adverse events that were mostly nonserious, mild or moderate in severity, and did not lead to stopping treatment. The safety profile was similar in both adults and adolescents.

Association of CTG Diagnosis of Intrapartum Fetal Distress and Immediate Postpartum Acidemia in Foetal Umbilical Artery.

Background: Intrapartum fetal hypoxia which is one of the leading causes of neonatal morbidity and mortality is a preventable cause. Over the past years, many methods have been employed to diagnose fetal distress, a sign of fetal hypoxia, among these, cardiotocography (CTG) is the most widely used method. Diagnosis of fetal distress based on CTG can have high inter and intraobserver variation leading to either delayed or inessential intervention henceforth increasing maternal morbidity and mortality. Fetal cord arterial blood pH is an objective method to diagnose intrapartum fetal hypoxia, hence by observing the incidence of acidemia in cord blood pH among those newborns born through cesarean section (CS) in view of non-reassuring CTG can help make a judicious decision. Methods: In this single institutional observational study, patients admitted for safe confinement were subjected to CTG in the latent and active phases of labor. Non-Reassuring traces were further classified based on NICE guideline CG190. The cord blood of these neonates born through CS in view of non-reassuring CTG was drawn and sent for ABG analysis. Results: Among the 87 neonates delivered through CS in view of fetal distress, 19.5% had acidosis. Among those with pathological traces, 16(28.6%) had acidosis and one (100%) which was categorized as the need for urgent intervention showed acidosis. This result showed a statistically significant association (p value-0.003). No statistically significant association was obtained when variation in baseline characters of CTG when taken independently. Conclusions: In our study, neonatal acidemia which is the objective evidence of fetal distress was seen in 19.5% of our study population who underwent cesarean in view of non-reassuring CTG. Among these, acidemia was significantly associated with pathological CTG trace compared to suspicious trace. We also observed that abnormal FHR features when taken independently showed no significant association with acidosis. Acidosis among newborns certainly increased the requirement for active resuscitation and additional hospital stay. Hence, we conclude that by recognizing specific fetal heart rate patterns associated with acidosis in a fetus, a more judicious decision can be made, thereby preventing both delayed as well as inessential intervention.

Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials.

BACKGROUND: Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. OBJECTIVES: To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). METHODS: Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. RESULTS: After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. CONCLUSIONS: After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data.

Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial (ADhere).

Importance: Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials. Objective: To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD. Design, Setting, and Participants: The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO). Interventions: Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks [Q2W] thereafter) or PBO Q2W in combination with TCS for 16 weeks. Main Outcomes and Measures: Efficacy analyses at week 16 included proportions of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs). Results: The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 [4.8%]), headache (7 [4.8%]), hypertension (4 [2.8%]), injection site reactions (4 [2.8%]), and herpes infection (5 [3.4%]) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%). Conclusions and Relevance: In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04250337.

QoS Analysis for Cloud-Based IoT Data Using Multicriteria-Based Optimization Approach.

This work explains why and how QoS modeling has been used within a multicriteria optimization approach. The parameters and metrics defined are intended to provide a broader and, at the same time, more precise analysis of the issues highlighted in the work dedicated to placement algorithms in the cloud. In order to find the optimal solution to a placement problem which is impractical in polynomial time, as in more particular cases, meta-heuristics more or less approaching the optimal solution are used in order to obtain a satisfactory solution. First, a model by a genetic algorithm is proposed. This genetic algorithm dedicated to the problem of placing virtual machines in the cloud has been implemented in two different versions. The former only considers elementary services, while the latter uses compound services. These two versions of the genetic algorithm are presented, and also, two greedy algorithms, round-robin and best-fit sorted, were used in order to allow a comparison with the genetic algorithm. The characteristics of these two algorithms are presented.

Dissipation-Engineered Family of Nearly Dark States in Many-Body Cavity-Atom Systems.

Three-level atomic systems coupled to light have the capacity to host dark states. We study a system of V-shaped three-level atoms coherently coupled to the two quadratures of a dissipative cavity. The interplay between the atomic level structure and dissipation makes the phase diagram of the open system drastically different from the closed one. In particular, it leads to the stabilization of a continuous family of dark and nearly dark excited many-body states with inverted atomic populations as the steady states. The multistability of these states can be probed via their distinct fluctuations and excitation spectra, as well as the system's Liouvillian dynamics which are highly sensitive to ramp protocols. Our model can be implemented experimentally by encoding the two higher-energy modes in orthogonal density-modulated states in a bosonic quantum gas. This implementation offers prospects for potential applications like the realization of quantum optical random walks and microscopy with subwavelength spatial resolution.

Observing Dynamical Currents in a Non-Hermitian Momentum Lattice.

We report on the experimental realization and detection of dynamical currents in a spin-textured lattice in momentum space. Collective tunneling is implemented via cavity-assisted Raman scattering of photons by a spinor Bose-Einstein condensate into an optical cavity. The photon field inducing the tunneling processes is subject to cavity dissipation, resulting in effective directional dynamics in a non-Hermitian setting. We observe that the individual tunneling events are superradiant in nature and locally resolve them in the lattice by performing real-time, frequency-resolved measurements of the leaking cavity field. The results can be extended to a regime exhibiting a cascade of currents and simultaneous coherences between multiple lattice sites, where numerical simulations provide further understanding of the dynamics. Our observations showcase dynamical tunneling in momentum-space lattices and provide prospects to realize dynamical gauge fields in driven-dissipative settings.

Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling.

The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-ß. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-ß signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

Clinical features and surgical outcomes of complications of proliferative diabetic retinopathy in young adults with type 1 diabetes mellitus versus type 2 diabetes mellitus - A comparative observational study.

PURPOSE: To evaluate the clinical profile, visual outcomes, and complications among young adult patients with type 1 diabetes mellitus (insulin-dependent DM-T1DM) in comparison with patients with type 2 diabetes mellitus (T2DM) undergoing vitrectomy for complications of proliferative diabetic retinopathy (PDR).. METHODS: A retrospective review of patients between 18 and 45 years with T1DM undergoing vitrectomy for complications of PDR between June 2017 and June 2019, with a minimum follow-up of 12 months. Consecutive patients between 30 and 45 years with type 2 diabetes (non-insulin-dependent DM-T2DM) who underwent vitrectomy for the same indications were retrospectively enrolled as the control group. RESULTS: There were 42 eyes (28 patients) in the T1DM group and 58 eyes (47 patients) in the T2DM group. The average age at operation was 35.9 ± 6.88 years and 39.8 ± 3.03 years, respectively (P < 0.001). At the end of follow-up, the mean logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 1.53 ± 0.55 to 1.30 ± 0.93 (P value 0.07) in the T1DM group and from 1.59 ± 0.46 to 1.00 ± 0.78 in the T2DM group (P = 0.0001). The rate of the primary and final reattachment was 76.2% and 88.1% in the T1DM group and 84.5% and 96.6% in the T2DM group. Preoperative macular tractional retinal detachment (MTRD) and neovascular glaucoma (NVG) in both the groups, chronic kidney disease (CKD) and lack of preoperative Pan retinal photocoagulation (PRP) in the T1DM group, hypertension (HTN) and, resurgery in the T2DM group, were risk factors for poor vision at the final follow-up. CONCLUSION: The visual and anatomic outcomes were poorer in the T1DM patients which could be due to the longer duration of diabetes with worse glycemic control, associated comorbidities like CKD, and a higher incidence of MTRD.

Co-infection of Newcastle disease virus genotype XIII with low pathogenic avian influenza exacerbates clinical outcome of Newcastle disease in vaccinated layer poultry flocks.

Newcastle disease (ND) and avian influenza (AI) are economically important infectious diseases of poultry. Sometime, concomitant secondary viral/or bacterial infections significantly alters the pathobiology of ND and AI in poultry. As of now, the disease patterns and dynamics of co-infections caused by ND virus (NDV, genotype XIII) and Low Pathogenic AI viruses (LPAI, H9N2) are explicitly elusive. Thus, we examined the clinicopathological disease conditions due to these two economically important viruses to understand the complex disease outcomes by virus-virus interactions in vaccinated flocks. The findings of clinicopathological and molecular investigations carried on 37 commercial ND vaccinated poultry flocks revealed simultaneous circulation of NDV and AIV in same flock/bird. Further, molecular characterization of hemagglutinin (HA) and neuraminidase (NA) genes confirmed that all the identified AIVs were of low pathogenicity H9N2 subtype and fusion (F) gene analysis of detected NDVs belong to NDV class II, genotype XIII, a virulent type. The NDV and H9N2 alone or co-infected flocks (NDV + LPAI) exhibit clinical signs and lesions similar to that of virulent NDV except the degree of severity, which was higher in H9N2-NDV co-infected flocks. Additionally, avian pathogenic E. coli and mycoplasma infections were detected in majority of the ailing/dead birds from the co-infected flocks during progression of the clinical disease. Overall, the findings highlight the multi-factorial disease complexity in commercial poultry and suggest the importance of NDV genotype XIII in intensifying the clinical disease in vaccinated birds.

Quantum Transducer Using a Parametric Driven-Dissipative Phase Transition.

We study a dissipative Kerr resonator subject to both single- and two-photon detuned drives. Beyond a critical detuning threshold, the Kerr resonator exhibits a semiclassical first-order dissipative phase transition between two different steady states that are characterized by a π phase switch of the cavity field. This transition is shown to persist deep into the quantum limit of low photon numbers. Remarkably, the detuning frequency at which this transition occurs depends almost linearly on the amplitude of the single-photon drive. Based on this phase-switching feature, we devise a sensitive quantum transducer that translates the observed frequency of the parametric quantum phase transition to the detected single-photon amplitude signal. The effects of noise and temperature on the corresponding sensing protocol are addressed, and a realistic circuit-QED implementation is discussed.

Classical Many-Body Time Crystals.

Discrete time crystals are a many-body state of matter where the extensive system's dynamics are slower than the forces acting on it. Nowadays, there is a growing debate regarding the specific properties required to demonstrate such a many-body state, alongside several experimental realizations. In this work, we provide a simple and pedagogical framework by which to obtain many-body time crystals using parametrically coupled resonators. In our analysis, we use classical period-doubling bifurcation theory and present a clear distinction between single-mode time-translation symmetry breaking and a situation where an extensive number of degrees of freedom undergo the transition. We experimentally demonstrate this paradigm using coupled mechanical oscillators, thus providing a clear route for time crystal realizations in real materials.