Contrast-specific propensity scores for causal inference with multiple interventions.

Existing methods that use propensity scores for heterogeneous treatment effect estimation on non-experimental data do not readily extend to the case of more than two treatment options. In this work, we develop a new propensity score-based method for heterogeneous treatment effect estimation when there are three or more treatment options, and prove that it generates unbiased estimates. We demonstrate our method on a real patient registry of patients in Singapore with diabetic dyslipidemia. On this dataset, our method generates heterogeneous treatment recommendations for patients among three options: Statins, fibrates, and non-pharmacological treatment to control patients' lipid ratios (total cholesterol divided by high-density lipoprotein level). In our numerical study, our proposed method generated more stable estimates compared to a benchmark method based on a multi-dimensional propensity score.

Analysis of gut microbiota metabolites of platycodin D and activity verification.

As the main saponin component of Platycodon grandiflorum A.DC, Platycodin D has been reported to have an anti-obesity effect. Due to poor oral absorption, the intestinal microflora usually transforms saponins into potential bioactive substances. In this study, we profiled the metabolic changes of platycodin D by incubating it with intestinal microflora extracted from mice feces subjected to either a standard control diet or a high-fat diet. A UPLC-LTQ-Orbitrap-MS method was used for rapid analysis of the metabolic profile of platycodin D. A total of 10 compounds were identified 9 of which were assessed to be metabolized by intestinal microflora. Dehydroxylation and deglycosylation were the major metabolic process of platycodin D. The metabolic profile of platycodin D biotransformed by intestinal microflora was elucidated based on the metabolite information. Platycodin D and its metabolites had anti-inflammatory effects in LPS-stimulated RAW 264.7 cells. Only platycodin D could alleviate lipid accumulation in FFA-treated HepG2 cells.

Widening rural-urban gap in life expectancy in China since COVID-19.

INTRODUCTION: Disparities in life expectancy between rural and urban populations are well established but how it varies with epidemics and pandemics remains poorly understood. We aimed to quantify the rural-urban differences in the mortality burden of COVID-19 and to contribute to understanding the disparity trends in life expectancy between 1987 and 2021 in China. METHODS: We used monthly death counts from death registration systems. Rural-urban gap estimation and decomposition were carried out using period life tables to calculate life expectancy, the Arriaga decomposition technique to break down into age-specific and cause-specific mortality, and the Lee-Carter forecasts to estimate the expected gap. RESULTS: The rural-urban gap increased to 22.7 months (95% credible interval (CI) 19.6 to 25.8) in 2020 and further to 23.7 months (95% CI 19.6 to 26.7) in 2021, and was larger than expected under the continuation of the prepandemic trends. Compared with that in the recent 2003 SARS-CoV-2 epidemic and the 2009 influenza epidemic, excess rural-urban gaps in the COVID-19 pandemic changed from urban disadvantage to rural disadvantage, and the contributions shifted toward old age groups and circulatory diseases. Variations in the rural-urban gap since 1987 were positively correlated with the rural-urban disparity in public health expenditures, especially among ages <60 (p values <0.005). CONCLUSIONS: Our findings identified a widening rural-urban gap in life expectancy since COVID-19, and a shifting trend towards old ages and circulatory diseases, disrupting the diminishing trend of the gap over 35 years. The findings highlight the unequal impact of the pandemic on different communities in terms of mortality burdens.

Malignant pleural mesothelioma with constrictive pericarditis as the first manifestation: A case report.

Pleural mesothelioma (PM) with pericardial involvement is extremely rare. We now report a rare case of malignant PM with constrictive pericarditis as the first presentation. A 59-year-old male diagnosed with constrictive pericarditis underwent pericardiectomy and pericardial pathology revealed mesothelial hyperplasia. Eight months after surgery, the patient was admitted to the hospital with chest tightness and wheezing for 5 days. Computed tomography scan of the chest showed a left lung expansion insufficiency, limited bilateral pleural thickening, pericardial thickening with a small amount of pericardial effusion, and multiple enlarged lymph nodes in the mediastinum, bilateral supraclavicular fossa, bilateral cervical roots, and right axilla. The pleural malignancy should be possibly considered. Pathology after pleural puncture showed malignant PM. Pathology after left supraclavicular lymph node puncture biopsy showed metastatic malignant mesothelioma. The diagnosis of this patient was clear. Although malignant PM rarely involves the pericardial constriction, we cannot ignore the fact that malignant PM involves the pericardium. The patient has been diagnosed with constrictive pericarditis, accompanied by pleural thickening and pleural effusion. Without other pathogenic factors, pleural biopsy should be aggressively performed in patients with constrictive pericarditis to determine the cause.

Developmental Gerontology and Active Population Aging in China.

Population aging is an irreversible process in the development of modern society, which brings challenges to comprehensive modernized social governance. Population aging is a "dualistic" development issue that not only leads to aging of the labor force structure but also creates new demographic dividends. This study describes the core thoughts of developmental gerontology (DG), which provides new insight into the relationship between active aging and comprehensive governance for modernized society. The development of DG will provide a feasible and sustainable path to integrate and coordinate the relationship between population aging, society, and economy.

Correlation of ABO blood groups with treatment response and efficacy in infants with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide.

OBJECTIVE: Not all infants with persistent pulmonary hypertension of the newborn (PPHN) respond to inhaled nitric oxide (iNO) therapy, as it is known to improve oxygenation in only 50% to 60% of cases. In this study, we investigated whether ABO blood groups were a relevant factor affecting the improvement of oxygenation by nitric oxide (NO) therapy in infants with PPHN. METHODS: This study was a retrospective, multicenter, and cohort-controlled trial that involved 37 medical units. Infants with PPHN who met the inclusion criteria and were treated with NO (a vasodilator) alone from July 1, 2015, to June 30, 2020, were selected and assigned into three groups: blood type A, blood type B, and blood type O (there were only 7 cases of blood type AB, with a small number of cases, and therefore, blood type AB was excluded for further analysis). The response to iNO therapy was defined as an increase in the ratio of the partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) > 20% from the basal value after treatment. Oxygenation was assessed mainly based on the two values, oxygenation index (OI) and PaO2/FiO2. The correlation of ABO blood groups with responses to iNO therapy and their influence on the efficacy of iNO therapy was analyzed based on the collected data. RESULTS: The highest proportion of infants with PPHN who eventually responded to iNO therapy was infants with blood type O. Infants with blood type O more readily responded to iNO therapy than infants with blood type B. Oxygenation after iNO treatment group was optimal in the blood type O group and was the worst in the blood type A group among the three groups. Infants with blood type O showed better efficacy than those with blood types A and B. CONCLUSION: ABO blood groups are correlated with responses to iNO therapy in infants with PPHN, and different blood groups also affect the efficacy of NO therapy in infants with PPHN. Specifically, infants with blood type O have a better response and experience the best efficacy to iNO therapy.

Modeling Posttreatment Prognosis of Skin Lesions in Patients With Psoriasis in China.

Importance: Understanding the posttreatment prognosis of skin lesions in patients with psoriasis is essential for improving patients' treatment satisfaction. Objectives: To model the prognosis of skin lesions for patients with psoriasis after 3 types of therapy. Design, Setting, and Participants: This prospective cohort study included patients with psoriasis who visited a dermatologist and were enrolled in the platform of the Psoriasis Standardized Diagnosis and Treatment Center in China from August 2020 to December 2021. Interventions: Biologic, traditional, and systemic therapy for psoriasis. Main Outcomes and Measures: Skin lesions were measured by the Investigator's Global Assessment (IGA) scale subsumed into 4 stages of severity (IGA 0/1, IGA 2, IGA 3, and IGA 4), with higher scores indicating higher severity. The matching method was used to balance baseline covariates between patients receiving each of the 3 treatments. Transition probabilities from IGA scores at baseline to 0 to 1 month and 1 to 12 months were estimated. Results: A total of 8767 patients were included in the final analysis (median age, 38.6 years [IQR, 28.7-52.8 years]; 5809 [66.3%] male). Across the 3 therapies, as the follow-up duration increased, the probability of improvement transition into a less severe IGA stage (from IGA 4 to IGA 0/1) increased from 0.19 (95% CI, 0.18-0.21) in 0 to 1 month to 0.36 (95% CI, 0.34-0.37) in 1 to 12 months. Biologic therapy was associated with greater improvement transitions for severe conditions, with transition probabilities from IGA 4 to IGA 0/1 increasing by 0.06 (95% CI, 0.02-0.09) vs traditional therapy and by 0.06 (95% CI, 0.03-0.09) vs systemic therapy in 0 to 1 month and by 0.08 (95% CI, 0.04-0.12) vs traditional therapy and 0.11 (95% CI, 0.07-0.14) vs systemic therapy in 1 to 12 months. Conclusions and Relevance: This cohort study modeling psoriasis prognosis provided a complete prognosis of skin lesions, and biologic therapy was associated with improved prognosis of moderate to severe psoriasis compared with traditional and systemic therapies. The study provides insight on using transition diagrams to assess psoriasis prognosis and to communicate with patients in clinical practice.

Prediction of risk for secondary lower respiratory tract fungal infection during the acute exacerbation phase of COPD.

INTRODUCTION: We aimed to investigate the risk factors for secondary lower respiratory tract fungal infection during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODOLOGY: A total of 466 AECOPD patients diagnosed from March 2019 to November 2020 were divided into infection (n = 48) and non-infection (n = 418) groups. The risk factors for lower respiratory tract fungal infection were screened by logistic regression analysis, and a nomogram prediction model was established. The discriminability was validated by area under the receiver operating characteristic curve (AUC) and C-index, calibration was validated by GiViTI calibration belt and Hosmer-Lemeshow test, and clinical validity was assessed by decision curve analysis (DCA) curve. RESULTS: Thirty fungi strains were detected, including 18 strains of Candida albicans. Pulmonary heart disease, hypoalbuminemia, use of antibiotics within 3 months before admission, use time of antibiotics ≥ 14 d, invasive operation, blood glucose ≥ 11.10 mmol/L at admission, and procalcitonin (PCT) ≥ 0.5 ng/mL when diagnosed as fungal infection independent risk factors (p < 0.05). AUC was 0.891, indicating high discriminability of the model. The threshold probability in the DCA curve was set to 31.3%, suggesting that the model had clinical validity. CONCLUSIONS: We identified the independent risk factors for lower respiratory tract fungal infection in AECOPD patients. The established model has high discriminability and calibration. Immediate intervention is beneficial when the predicted risk exceeds 31.3%.

Defining estimands in clinical trials: A unified procedure.

The ICH E9 (R1) addendum proposes five strategies to define estimands by addressing intercurrent events. However, mathematical forms of these targeted quantities are lacking, which might lead to discordance between statisticians who estimate these quantities and clinicians, drug sponsors, and regulators who interpret them. To improve the concordance, we provide a unified four-step procedure for constructing the mathematical estimands. We apply the procedure for each strategy to derive the mathematical estimands and compare the five strategies in practical interpretations, data collection, and analytical methods. Finally, we show that the procedure can help ease tasks of defining estimands in settings with multiple types of intercurrent events using two real clinical trials.

The clinical role of serum cell division control 42 in coronary heart disease.

Cell division control 42 (CDC42) regulates blood lipids, atherosclerosis, T cell differentiation and inflammation, which is involved in the process of coronary heart disease (CHD). This study aimed to evaluate the CDC42 level and its correlation with clinical features, the T-helper 17 (Th17)/regulatory-T (Treg) cell ratio and prognosis in CHD patients. In total, 210 CHD patients, 20 healthy controls and 20 disease controls were enrolled. Serum CDC42 levels of all participants were measured by enzyme-linked immunosorbent assay. In CHD patients, Th17 and Treg cells were discovered by flow cytometry; CHD patients were followed-up for a median of 16.9 months (range of 2.5-38.2 months). CDC42 level was lowest in CHD patients (median (interquartile range (IQR)): 402.5 (287.3-599.0) pg/mL), moderate in disease controls (median (IQR): 543.5 (413.0-676.3) pg/mL) and highest in healthy controls (median (IQR): 668.0 (506.5-841.3) pg/mL) (p < .001). Moreover, in CHD patients, lower CDC42 level was related to more prevalent diabetes mellitus (p = .021), and higher levels of C-reactive protein (p = .001), Gensini score (p = .006), Th17 cells (p = .001) and Th17/Treg ratio (p < .001) but was associated with lower Treg cells (p = .018). Furthermore, CDC42 low level [below the median level (402.5 pg/mL) of CDC42 in CHD patients] was correlated with higher accumulating major adverse cardiovascular event (MACE) risk (p = .029), while no correlation was found between the quartile of CDC42 level and accumulating MACE risk in CHD patients (p = .102). The serum CDC42 level is decreased and its low level is related to higher Th17/Treg ratio and increased accumulating MACE risk in CHD patients.

Influenza's Plummeting During the COVID-19 Pandemic: The Roles of Mask-Wearing, Mobility Change, and SARS-CoV-2 Interference.

Seasonal influenza activity typically peaks in the winter months but plummeted globally during the current coronavirus disease 2019 (COVID-19) pandemic. Unraveling lessons from influenza's unprecedented low profile is critical in informing preparedness for incoming influenza seasons. Here, we explored a country-specific inference model to estimate the effects of mask-wearing, mobility changes (international and domestic), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interference in China, England, and the United States. We found that a one-week increase in mask-wearing intervention had a percent reduction of 11.3%-35.2% in influenza activity in these areas. The one-week mobility mitigation had smaller effects for the international (1.7%-6.5%) and the domestic community (1.6%-2.8%). In 2020-2021, the mask-wearing intervention alone could decline percent positivity by 13.3-19.8. The mobility change alone could reduce percent positivity by 5.2-14.0, of which 79.8%-98.2% were attributed to the deflected international travel. Only in 2019-2020, SARS-CoV-2 interference had statistically significant effects. There was a reduction in percent positivity of 7.6 (2.4-14.4) and 10.2 (7.2-13.6) in northern China and England, respectively. Our results have implications for understanding how influenza evolves under non-pharmaceutical interventions and other respiratory diseases and will inform health policy and the design of tailored public health measures.

Serum Anion Gap Level Predicts All-Cause Mortality in Septic Patients: A Retrospective Study Based on the MIMIC III Database.

PURPOSE: Sepsis is a significant threat in the intensive care unit (ICU) worldwide because it has high morbidity and mortality rates. Early recognition and diagnosis of sepsis are essential for the prevention of adverse outcomes. The present study aimed to quantitatively assess the association between serum anion gap (AG) levels and 30- and 90-day all-cause mortality among sepsis patients. METHODS: Clinical data of patients diagnosed with sepsis were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association between serum AG levels and all-cause mortality. A receiver operating characteristic (ROC) curve was drawn to quantify the efficacy of using the serum AG level to predict all-cause mortality. RESULTS: A total of 3811 patients were included in the study. The Kaplan-Meier curves showed that patients with higher serum AG levels had a shorter survival time than those with lower levels. Serum AG levels were found to be highly effective in predicting all-cause mortality secondary to sepsis (30-day: AUROC = 0.703; 90-day: AUROC = 0.696). The Cox regression model further indicated that the serum AG level was an independent risk factor for 30- and 90-day mortality in sepsis (HR 3.44, 95% CI 2.97-3.99 for 30-day; HR 3.17, 95% CI 2.76-3.65 for 90-day, P < 0.001 for both). CONCLUSIONS: High serum AG may be considered as an alternative parameter for predicting the death risk in sepsis when other variables are not immediately available. Prospective large-scale studies are needed to support its predictive value in the clinic.

A real-world study of interleukin-6 receptor blockade in patients with neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease that can cause permanent neurological disabilities. However, the interleukin-6 (IL-6) signaling pathway is a promising therapeutic target for relapse prevention. Therefore, this study evaluated the long-term effectiveness of tocilizumab, a humanized anti-IL-6 receptor antibody, for NMOSD. We enrolled 65 patients with NMOSD who received regular intravenous administration of tocilizumab (8 mg/kg) between October 2017 and January 2022. Then, we retrospectively collected data on the clinical characteristics and baseline glial fibrillary acidic protein (GFAP) and neurofilament light chain levels. The primary outcome was the annualized relapse rate (ARR). Risk factors were assessed using a multivariable logistic regression model. During the median follow-up of 34.1 (interquartile range: 25.5-39.3) months, 23% (15/65) of patients relapsed during tocilizumab treatment, but the median ARR decreased from 1.9 (range 0.12-6.29) to 0.1 (range 0-1.43, p < 0.0001). A prolonged infusion interval (> 4 weeks, odds ratio [OR]: 10.7, 95% confidence interval [CI]: 1.6-71.4, p = 0.014) and a baseline plasma GFAP level of > 220 pg/mL (OR: 20.6, 95% CI 3.3-129.4, p = 0.001) were risk factors for future relapses. During treatment, the median Expanded Disability Status Scale score significantly decreased in aquaporin-4 antibody-positive and -negative patients, but the pain did not considerably improve. There were no severe safety concerns. Tocilizumab treatment significantly reduced the relapse rate in patients with NMOSD. However, prolonged infusion intervals and high baseline plasma GFAP levels may increase the relapse risk during tocilizumab therapy.

EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/ß-catenin and TGF-ß/Smad2/3 signal pathways.

Purpose: To investigate the prognostic value and function of six-transmembrane epithelial antigen of prostate 1 (STEAP1) in osteosarcoma and determine whether EFEMP1 mediates its effects. Methods: IHC (immunohistochemistry)/ICC (immunocytochemistry) in conjunction with RT-qPCR (quantitative real-time polymerase chain reaction) were employed to assess the expression of STEAP1 in paratumoral tissues, osteosarcoma, benign fibrous dysplasia, osteosarcoma cells, normal osteoblastic hFOB cells, as well as various invasive subclones. The association of STEAP1 with outcome was examined with Kaplan-Meier graph among the osteosarcoma population. The effects of the down-regulation and up-regulation of STEAP1 on the biological behavior of osteosarcoma cells were studied through in-vitro and in-vivo functional tests. Results: Up-regulation of STEAP1 in the osteosarcoma tissues, whose correlations with the malignant osteosarcoma phenotype and the poor patient outcome were positive. In addition, STEAP1 induced the epithelial-mesenchymal transition (EMT) via the Wnt/ß-catenin and TGF-ß/Smad2/3 pathways and facilitated the osteosarcoma cell infiltration and migration. An increase or decrease in EFEMP1 expression directly promoted or inhibited the expression of STEAP1. In osteosarcoma cells overexpressing EFEMP1, STEAP1 knockdown significantly inhibited cell invasion, EMT process, and increased activity of Wnt/ß-catenin and TGF-ß/Smad2/3 signaling pathways. Although exogenous EFEMP1 could stimulate the Wnt/ß-catenin and TGF-ß/Smad2/3 pathways to promote the EMT, it had not effect on osteosarcoma cells with STEAP1 knockdown. Collectively, similar to EFEMP1, STEAP1 acted like an oncogene in the osteosarcoma progression. Conclusion: EFEMP1 enabled the Wnt/ß-catenin and TGF-ß/Smad2/3 axises initiation and EMT elicitation by targeting STEAP1, thereby facilitating the osteosarcoma cell infiltration and migration. These results are expected to contribute to the search for new targeted drugs able to effectively inhibit invasion and metastasis and improve prognosis in osteosarcoma.

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OBJECTIVES: To establish a system for regulating the gene expression of embryonic mouse cerebral cortex neural stem cells (NSCs) using in utero electroporation (IUE). METHODS: At embryonic day 14.5, the mouse cerebral cortex NSCs were electro-transfected with the pCIG plasmid injected into the ventricle of the mouse embryo. At embryonic day 16.5 or day 17.5, embryonic mouse brain tissues were collected to prepare frozen sections. Immunofluorescence staining was used to observe the proliferation, apoptosis, division, directional differentiation, migration, and maturation of NSCs. RESULTS: The differentiation of NSCs into intermediate progenitors, the proliferation and apoptosis of NSCs, and the morphological development of radial axis of radial glial cells were observed at embryonic day 16.5. The differentiation of NSCs into neurons in layers V-VI of the cerebral cortex, the migration of NSCs to the lateral cerebral cortex, the development of dendrites of migrating neurons, and the maturation of neurons were observed at embryonic day 17.5. CONCLUSIONS: The system for regulating the gene expression of embryonic mouse cerebral cortex NSCs can be established using IUE, which is useful for the study of neural development related to the proliferation, apoptosis, division, directional differentiation, migration and maturation of NSCs in the cerebral cortex.

City-Specific Effects of Lifting Mobility Restrictions - China, February-March 2020.

What is already known about this topic?: Government used mobility restrictions to help contain the first wave of coronavirus disease 2019 (COVID-19) across cities in China. The restrictions were lifted during times of non-zero incidence in response to a return to work order that went into effect on February 10, 2020. What is added by this report?: The effect of lifting mobility restrictions on COVID-19 death rate and incidence varied by city, with smaller increases or even reductions in cities with low community connectivity and small floating volume, and larger increases in cities with high community connectivity and large floating volume. Effects on recovery rates were similar across cities. What are the implications for public health practice?: City-specific mobility restriction lifting is likely to be beneficial. Two indexes, community connectivity and floating volume, can inform the design of city-specific mobility restriction lifting policies.

Data-driven integrated care pathways: Standardization of delivering patient-centered care.

Health care delivery in China is in transition from reactive and doctor-centered to preventative and patient-centered. The challenge for the reform is to account for the needs of unique individuals and local communities while ensuring efficiency and equity. This Viewpoint presents data-driven integrated care pathways as a potential solution to standardize patient-centered care delivery, highlighting five core aspects of the entire care journey for personalization by using real-time data and digital technology, and identifying three capabilities to support the uptake of data-driven design.