Patients with Moderate-to-Severe Atopic Dermatitis Maintain Stable Response with No or Minimal Fluctuations with 1 Year of Lebrikizumab Treatment.

INTRODUCTION: Lebrikizumab is a novel monoclonal antibody with established efficacy in patients with moderate-to-severe atopic dermatitis (AD) in multiple Phase 3 trials. One of the ultimate treatment goals for patients with moderate-to-severe AD is to achieve stable disease control without concern for planning future life events. METHODS: In ADvocate1 and ADvocate2, lebrikizumab-treated patients meeting the protocol-defined response criteria at Week 16 were re-randomized 2:2:1 to receive lebrikizumab every 2 weeks (Q2W), lebrikizumab every 4 weeks (Q4W), or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. In this post hoc analysis, we evaluated the proportions of patients with no or minimal fluctuations of efficacy during the 36-week maintenance period and plotted individual patient trajectories. We defined no or minimal fluctuations as achieving and maintaining the defined endpoint (≥ 75% improvement in the Eczema Area and Severity Index [EASI 75], ≥ 90% improvement in EASI, Pruritus Numeric Rating Scale [NRS] ≥ 4-point improvement, or Pruritus NRS ≥ 3-point improvement) for ≥ 80% of the study visits. If patients used rescue medication, discontinued treatment, or transferred to the escape arm, data collected at or after the event were imputed as non-response. RESULTS: The proportions of lebrikizumab responders who maintained EASI 75 with no or minimal fluctuations were 70.8% (lebrikizumab Q2W), 71.2% (lebrikizumab Q4W), and 60.0% (lebrikizumab withdrawal). Of the patients with baseline Pruritus NRS ≥ 4 and who achieved ≥ 4-point improvement at Week 16, 66.1% (lebrikizumab Q2W), 62.7% (lebrikizumab Q4W), and 55.2% (lebrikizumab withdrawal) maintained ≥ 4-point Pruritus NRS improvement with no or minimal fluctuations. CONCLUSIONS: Patients who met the response criteria at Week 16 and continued treatment with lebrikizumab Q2W or Q4W demonstrated a stable response with no or minimal fluctuations of efficacy in measures of skin and itch up to Week 52. CLINICAL TRIAL REGISTRATION: NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Atopic dermatitis, also known as atopic eczema (or just eczema), is a common skin disease that causes itchy, dry skin. Patients with eczema are often unsure of when disease flares will happen, even while receiving treatment. In two global studies, ADvocate1 and ADvocate2, lebrikizumab improved the signs and symptoms of moderate-to-severe eczema after 16 weeks of treatment. Most of these patients also saw improvement up to 52 weeks. We wanted to know if patients continued to feel better between Week 16 and Week 52. Patients who responded to lebrikizumab after 16 weeks were given lebrikizumab every 2 weeks, lebrikizumab every 4 weeks, or placebo every 2 weeks. We tested how many patients experienced stable response to therapy, which we said was maintaining the same level of improvement on skin signs and itch symptoms for at least 80% of study visits from Week 16 to Week 52. In patients treated with lebrikizumab every 2 weeks or every 4 weeks, we saw that about seven of every ten patients maintained a stable response in skin improvement and about six of every ten patients maintained stable response in itch symptoms. In patients who stopped lebrikizumab therapy, six out of every ten patients maintained a stable skin improvement and more than five of every ten patients maintained a stable improvement in itch symptoms. In ADvocate1 and ADvocate2, most lebrikizumab-treated patients showed a stable response over time on skin and itch with dosing every 2 weeks or every 4 weeks.

Asymmetric Counteranion-Directed Electrocatalysis for Enantioselective Control of Radical Cation.

The control of enantioselectivity in radical cation reactions presents long-standing challenges, despite a few successful examples. We introduce a novel strategy of asymmetric counteranion-directed electrocatalysis to address enantioselectivity in radical cation chemistry. This concept has been successfully demonstrated in two reactions: an asymmetric dehydrogenative indole-phenol [3 + 2] coupling and an atroposelective C-H/N-H dehydrogenative coupling. These reactions have enabled the synthesis of benzofuroindolines and C-N axially chiral indoles with high yields and excellent enantiomeric excesses. Detailed mechanistic studies confirmed a radical-radical coupling mechanism. Moreover, density functional theory (DFT) calculations supported the indole radical cation as the pivotal intermediate, rather than a neutral indolyl radical, shedding new light on the underlying processes driving these reactions.

Understanding vaccine hesitancy with PCV13 in children: Results of a survey in Shanghai, China.

A questionnaire survey for parents of children under 5 years of age was conducted to analyze vaccine hesitancy with the 13-valent pneumococcal conjugate vaccine (PCV13) in Shanghai, China. A total of 892 valid questionnaires were collected. Descriptive statistical methods, Chi-square test and effect size of Cohen were used. Among participants, 421 (48.8%) had children who had been vaccinated with PCV13 before the survey while 227 (26.73%) planned vaccination with PCV13 in the future. The main reasons for not receiving vaccination were the fear of adverse reactions (79, 26.7%), beyond vaccination age (69, 23.3%), and no need to vaccinate (44, 14.9%). Reducing vaccine hesitancy and increasing vaccination willingness can be achieved through health interventions, lower vaccine prices, and the adjustment of vaccination strategies.

Electrosynthesis of 2-Substituted Benzoxazoles via Intramolecular Shono-Type Oxidative Coupling of Glycine Derivatives.

Herein, an atom-economical and eco-friendly electrochemical oxidation/cyclization of glycine derivatives through intramolecular Shono-type oxidative coupling is disclosed, leading to a variety of 2-substituted benzoxazoles in 51-85% yields. This oxidative cyclization proceeded in transition metal- and oxidant-free conditions and generated H2 as only a byproduct. Additionally, gram-scale reactions and a broad substrate scope demonstrated the synthetic usefulness of this protocol.

Hospitalization costs for children with pneumonia in Shanghai, China from 2019 to 2020.

Pneumonia is the leading cause of death in children under 5 years of age worldwide. In this study, we primarily analyzed the hospitalization costs for children diagnosed with pneumonia in one of the leading public hospitals in Shanghai, China. Furthermore, factors affecting the hospitalization costs for children with pneumonia were evaluated. Data on case diagnosis, hospitalization time, age and various hospitalization expenses were collected. Total hospitalization expense for the 149 cases was $177,750, with an average total cost of $1,193 per person and an average out-of-pocket cost of $642. The highest per capita expenses included fees for laboratory diagnosis ($418), general medical service ($235), western medicine ($253), and antibacterial drugs ($158). The leading diagnosis was bronchopneumonia, with 68 (46%) cases, an average hospital stays of 7.4 days, and average hospitalization expenses of $1,068. Considering the high burden of pneumonia in children, hospitals and governments must make more reasonable use of limited resources of the medical system. At the same time, various types of medical insurance should be added into the children's medical security system, encourage vaccination with pneumonia vaccines (13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine), and ensure that more children benefit from the vaccine by including it in the national immunization program.

Varicella outbreaks in schools and kindergartens in Shanghai, China from 2011 to 2020.

BACKGROUND: Varicella is a contagious disease caused by varicella-zoster virus and varicella vaccine (VarV) is the most effective way to prevent and control varicella. Despite high VarV coverage there were still varicella outbreaks in schools and kindergartens. We aim to analyze the epidemiological characteristics of varicella outbreaks in Huangpu District, Shanghai, China from 2011 to 2020. METHODS: For varicella outbreaks, case information and vaccination history were collected. Mann-Kendall test and descriptive methods were used to analyzed the trend and epidemiological catachrestic of varicella outbreaks. RESULTS: A total of 57 varicella outbreaks were reported from 2011 to 2020, including 30 outbreaks (52.6%) in primary schools. The results of the Mann-Kendall trend test (z = 1.97, p = 0.049) showed an upward trend in the number of cases during the study period, but the trend change was not statistically significant. Emergency vaccination was carried out in 42 (73.7%) outbreaks which influenced the duration of the epidemic (F = 4.53, p = 0.0379). A total of 573 varicella cases were reported, including 357 cases (62.3%) who had received at least one dose of varicella vaccine. CONCLUSIONS: The number of varicella outbreaks has not changed significantly in the decade from 2011 to 2020. The strategy of varicella vaccination, the development and application of varicella vaccine, and the control measures after the occurrence of varicella outbreaks need to be optimized. In addition to vaccination, as a disease transmitted by contact, quarantine measures, good personal hygiene, environmental disinfection, and ventilation are also important.

Predicting in-hospital length of stay: a two-stage modeling approach to account for highly skewed data.

BACKGROUND: In the early stages of the COVID-19 pandemic our institution was interested in forecasting how long surgical patients receiving elective procedures would spend in the hospital. Initial examination of our models indicated that, due to the skewed nature of the length of stay, accurate prediction was challenging and we instead opted for a simpler classification model. In this work we perform a deeper examination of predicting in-hospital length of stay. METHODS: We used electronic health record data on length of stay from 42,209 elective surgeries. We compare different loss-functions (mean squared error, mean absolute error, mean relative error), algorithms (LASSO, Random Forests, multilayer perceptron) and data transformations (log and truncation). We also assess the performance of two stage hybrid classification-regression approach. RESULTS: Our results show that while it is possible to accurately predict short length of stays, predicting longer length of stay is extremely challenging. As such, we opt for a two-stage model that first classifies patients into long versus short length of stays and then a second stage that fits a regresssor among those predicted to have a short length of stay. DISCUSSION: The results indicate both the challenges and considerations necessary to applying machine-learning methods to skewed outcomes. CONCLUSIONS: Two-stage models allow those developing clinical decision support tools to explicitly acknowledge where they can and cannot make accurate predictions.

Epidemiological characteristics and trends of Bacillus Calmette-Guérin lymphadenitis in Shanghai, China from 2010 to 2019.

Although the administration of the Bacillus Calmette-Guérin (BCG) vaccine is generally safe, lymphadenitis, the most common complication of BCG vaccination, can occur. Here, we describe the epidemiological characteristics and incidence trends of BCG lymphadenitis in Shanghai, China, among a population with a high burden of tuberculosis. A total of 56 cases of adverse events following immunization (AEFI) after BCG vaccination were reported in Shanghai, including 51 cases of BCG lymphadenitis (91.07%), from 2010 to 2019. The general incidence of BCG lymphadenitis was 173 per 1,000,000 doses in Shanghai from 2010 to 2019. A nonsignificant increase of 58.81% per year was observed between 2010 and 2012 (t = 0.93; p = .40), followed by a significant decline of 28.00% per year from 2012 to 2019 (t = -4.27; p < .01). Seven batches of BCG vaccines triggered three or more BCG lymphadenitis cases, for 27 (52.94%) cases in total. We identified two patients with immunodeficiency of chronic granulomatous disease, one of whom died four years later after BCG vaccination and another of whom was still being treated after two transplants. The average total care cost of the 47 recovered cases was 11,336 RMB (range: 2,637-33,861 RMB). Due to the high burden of BCG lymphadenitis, especially in children with immunodeficiency, it is suggested that government departments should strengthen healthcare provider training, assign specific nurses to perform BCG vaccination, monitor vaccinated individuals actively and timely detect abnormal signals so as to reduce the incidence of BCG lymphadenitis.

Model-Free Reinforcement Learning by Embedding an Auxiliary System for Optimal Control of Nonlinear Systems.

In this article, a novel integral reinforcement learning (IRL) algorithm is proposed to solve the optimal control problem for continuous-time nonlinear systems with unknown dynamics. The main challenging issue in learning is how to reject the oscillation caused by the externally added probing noise. This article challenges the issue by embedding an auxiliary trajectory that is designed as an exciting signal to learn the optimal solution. First, the auxiliary trajectory is used to decompose the state trajectory of the controlled system. Then, by using the decoupled trajectories, a model-free policy iteration (PI) algorithm is developed, where the policy evaluation step and the policy improvement step are alternated until convergence to the optimal solution. It is noted that an appropriate external input is introduced at the policy improvement step to eliminate the requirement of the input-to-state dynamics. Finally, the algorithm is implemented on the actor-critic structure. The output weights of the critic neural network (NN) and the actor NN are updated sequentially by the least-squares methods. The convergence of the algorithm and the stability of the closed-loop system are guaranteed. Two examples are given to show the effectiveness of the proposed algorithm.

Two cases of disseminated BCG disease following vaccination in the same family: case reports and review of the literature in China.

Disseminated bacillus Calmette-Guérin (BCG) disease is a rare and serious adverse event following immunization (AEFI) with BCG. Here, we reported two cases of disseminated BCG disease in the same family and reviewed the literature to identify another 35 cases in China. The average age at onset was 3.7 ± 2.1 months among the 37 cases and only 21 cases (56.8%) were laboratory confirmed. Of the 37 cases, 22 were evaluated for immunodeficiency; definite immunodeficiency was observed in 16 cases (72.7%) and could not be excluded in the other six cases (27.3%). Following treatment, 20 of the 37 cases died (54.1%), one case developed sequelae (2.7%), four cases had progressive disease (10.8%), nine cases had stable disease (24.3%), and only three cases were cured (8.1%). Vaccination of infants with BCG is cost-effective and should not be stopped because of the possibility of rare disseminated BCG disease, especially in countries with high tuberculosis burdens such as China. However, infants with a family history of immunodeficiency should be vaccinated after excluding immunodeficiency-related diseases to minimize the risk of disseminated BCG disease. Furthermore, government should strengthen proactive surveillance programs to detect and treat rare AEFIs early and improve disease outcomes.

[Effects of cholesterol ester transfer protein Taq1B polymorphism on response of serum HDL-C to dietary factors in hyperlipidemia patients].

OBJECTIVE: To analyze the effects of cholesterol ester transfer protein (CETP) Taq1B polymorphism on the response of serum HDL-C to dietary factors in hyperlipidemia patients. METHODS: All 141 hyperlipidemia residents in a community in Shanghai were investigated by a 3-day diet questionnaire. The serum lipids were analyzed, and the polymorphism of CETP gene was detected by PCR-RFLP method. The correlation between dietary factors and serum HDL-C in different genotype was analyzed when considering the effects of sex, age and body mass index. RESULT: The HDL-C of hyperlipidemia patients was affected by dietary factors and CETP gene Taq1B polymorphism. The strength of the correlation between dietary factors and serum HDL-C was different among the genotype groups. The relation was shown closer in B(2)B(2) subjects than in B(1)B(1). CONCLUSION: The Taq1B CETP gene polymorphism should be a strong determinant of HDL-C in hyperlipidemia patients, and might contribute to the heterogeneity in HDL-C response to dietary intervention.

[Association of gene polymorphism at cholesterol ester transfer protein locus with obesity and response to dietary intervention in obesity].

OBJECTIVE: To study the association of gene polymorphism at cholesterol ester transfer protein (CETP) locus with obesity and response to dietary intervention in obesity. METHODS: The PCR-PFLP method was used to detect the polymorphism of CETP gene of 340 adults in Shanghai. The levels of serum lipid profile, including TG, TC, HDL and LDL were analyzed. Obesity was selected to dietary intervention. RESULTS: (1)The genotype frequencies of CETP-TaqIB B1 B1, B1 B2 and B2 B2 were 35.6%, 47.9% and 16.5% respectively, which were in agreement with Hardy-Weinberg equilibrium. There was no significant difference in the distribution of genotypes between the obesity group and control group. The result was same after several influence factors controlled. (2) The levels of HDL were significantly different among genotype groups. Subjects for the B2 B2 genotype had the highest HDL levels. The relationship was steady after adjusting several influence factors. (3)Subjects for the B1 B2 genotype had higher HDL level after intervention, which was significantly different to other genotype groups. After adjusting baseline HDL level and gender, genotype didn't effect the change in HDL. CONCLUSION: CETP-TaqIB gene polymorphism influenced serum HDL level. But this gene polymorphism at CETP locus wasn't especial in adult obesity. Baseline HDL level influenced the change in HDL response to dietary intervention in three genotype groups.