Association between type 2 inflammatory diseases and neurodevelopmental disorders in low-birth-weight children and adolescents.

Background: Evidence of the association of certain neurodevelopmental disorder with specific type 2 inflammatory (T2) disease has been found. However, the association of various neurodevelopmental disorders with T2 diseases as a whole remains unclear in low-birth-weight (LBW) infants. Objective: To evaluate the association of type 2 inflammatory (T2) diseases with intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and learning disability (LD) in LBW children and adolescents. Methods: The study sample was derived from 2005 to 2018 National Health Interview Survey sample child files. LBW children and adolescents aged 3-17 were included. History of T2 diseases (including asthma and atopic dermatitis) and four neurodevelopmental disorders were reported by adults in families. The relationship between T2 diseases and the risk of four neurodevelopmental disorders was investigated through multiple-weighted logistic regression. Age, sex, race/ethnicity, region, highest education in family and ratio of family income to the poverty threshold were adjusted as covariates for model estimation. Subgroup analyses were conducted by age stratification (3-11 and 12-17 years), sex (male and female), and race (white and non-white). Results: 11,260 LBW children aged 3-17 years [mean age (SE), 9.73 (0.05) years] were included, in which 3,191 children had T2 diseases. History of T2 diseases was associated with an increased risk of neurodevelopmental disorders, with an OR of 1.35 (95% CI, 0.99-1.84) for ID, 1.47 (95% CI, 1.05-2.05) for ASD, 1.81 (95% CI, 1.51-2.16) for ADHD, and 1.74 (95% CI, 1.49-2.04) for LD following the adjustment of all the covariates. The correlations between T2 disorders and each of the four neurodevelopmental disorders were significantly different by sex and race (all P for interaction < 0.001), and no differences were found in age stratification (all P for interaction > 0.05). Conclusion: In a nationally representative sample of children, we found a significant association of T2 diseases with ASD, ADHD, and LD, even after adjusting for demographic baseline. We also found that the association of T2 disease with neurodevelopmental disorders differed between sex and race. Further investigation is needed to evaluate causal relationships and elucidate their potential mechanisms.

Lifestyle Behaviors and Cardiometabolic Diseases by Race and Ethnicity and Social Risk Factors Among US Young Adults, 2011 to 2018.

Background Cardiometabolic health has been worsening among young adults, but the prevalence of lifestyle risk factors and cardiometabolic diseases is unclear. Methods and Results Adults aged 18 to 44 years were included from the National Health and Nutrition Examination Survey, 2011 to 2018. Age-standardized prevalence of lifestyle risk factors and cardiometabolic diseases was estimated overall and by demographic and social risk factors. A set of multivariable logistic regressions was sequentially performed by adjusting for age, sex, social risk factors, and lifestyle factors to determine whether racial and ethnic disparities in the prevalence of cardiometabolic diseases may be attributable to differences in social risk factors and lifestyle factors. Appropriate weights were used to ensure national representativeness of the estimates. A total of 10 405 participants were analyzed (median age, 30.3 years; 50.8% women; 32.3% non-Hispanic White). The prevalence of lifestyle risk factors ranged from 16.3% for excessive drinking to 49.3% for poor diet quality. The prevalence of cardiometabolic diseases ranged from 4.3% for diabetes to 37.3% for dyslipidemia. The prevalence of having ≥2 lifestyle risk factors was 45.2% and having ≥2 cardiometabolic diseases was 22.0%. Racial and ethnic disparities in many cardiometabolic diseases persisted but were attenuated after adjusting for social risk factors and lifestyle factors. Conclusions The prevalence of lifestyle risk factors and cardiometabolic diseases was high among US young adults and varied by race and ethnicity and social risk factors. Racial and ethnic disparities in the prevalence of cardiometabolic diseases were not fully explained by differences in social risk factors and lifestyle factors.

Etoposide, dexamethasone, and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma: A randomized phase III study.

Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.

Age-specific differences in hypertension combination management and associated factors influencing treatment choice.

The current hypertension guideline emphasizes combination therapy, especially single-pill combination therapy (SPC). However, few studies compared the prevalence and factors associated with initial therapy choice across heterogeneous age groups in a current population. First, the authors consecutively identified 964 treatment naïve hypertensive patients in a large academic hospital from 01/31/2019 to 01/31/2020. All patients were grouped into (1) young aged, age < 55; (2) middle-aged, 55≤age < 65; and (3) older aged, age ≥65. The multivariable regression model examined the factors associated with the combination therapy by age group. Overall, 80 (8.3%) were young, 191 (19.8%) were middle, and 693 (71.9%) were older aged. Compared with older age, younger patients were more likely to be male, highly educated, regularly exercised, have metabolic syndrome, and less likely to have cardiovascular-related comorbidities, with a lower systolic but higher diastolic pressure. Only one in five patients used SPC, and the prevalence decreased with age. Besides hypertension grade, young patients without catheterization or echo test were less likely to receive multiple therapies, while older patients who were male with lower weight and lower risk levels were less likely to receive multiple therapies. In conclusion, combination therapy, especially SPC, was underused in the targeted hypertensive population. Our contemporary population study showed that young patients (<55) without a history of catheterization or echo examination and male older-aged (≥65) patients with low-risk classification were the population most likely to be neglected. Such information can help triage medical care resources in improving SPC use.

Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study.

BACKGROUND: The optimal treatment for older adults with diffuse large B-cell lymphoma (DLBCL) needs to be further explored due to patient comorbidities, standard immunochemotherapy intolerance, and unfavourable genetic features. We did a phase 2 trial of ibrutinib, rituximab, and lenalidomide (iR2) to evaluate the efficacy and safety in older adult patients with de novo DLBCL. METHODS: In this phase 2, single-arm study, unfit or frail patients with de novo DLBCL aged 75 years or older were enrolled at Shanghai Ruijin Hospital, Shanghai, China. During the induction phase from cycle 1 to 6, 560 mg ibrutinib was given orally daily throughout each 21-day treatment cycle, 375 mg/m2 rituximab was given intravenously on day 1, and 25 mg lenalidomide was given orally daily from day 1 to 10 in each cycle. Patients who had a complete response after induction were given another 6 cycles of lenalidomide maintenance (25 mg orally daily from day 1 to 10 every 21 days from cycle 7 to 12). The primary endpoint was complete response rate after 6 cycles or at the end of the induction treatment. This trial is registered with ClinicalTrials.gov, NCT03949062. FINDINGS: Between May 15, 2019, and May 8, 2020, a total of 30 patients were enrolled. The end of induction complete response rate was 56·7% (95% CI 37·4-74·5), and overall response rate was 66·7% (95% CI 47·2-82·7). With a median follow-up of 27·6 months (IQR 23·9-29·6), the 2-year progression-free survival rate was 53·3% (95% CI 34·3-69·1) and the 2-year overall survival rate was 66·7% (95% CI 46·9-80·5). The main grade 3-4 haematological adverse events were neutropenia (seven patients [23%]), thrombocytopenia (three patients [10%]), and anaemia (two patients [7%]). The most common grade 3-4 non-haematological adverse event was pulmonary infection (seven patients [23%]). Atrial fibrillation was observed in three (10%) patients, including one grade 2 and two grade 3. INTERPRETATION: A chemotherapy-free iR2 regimen is clinically effective and safe and warrants further investigation in phase 3 trials as first-line treatment in older adult patients with DLBCL. FUNDING: National Natural Science Foundation of China, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Clinical Research Plan of Shanghai Hospital Development Center, and Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine.

The Association of Low Molecular Weight Heparin Use and In-hospital Mortality Among Patients Hospitalized with COVID-19.

PURPOSE: To determine the association between low molecular weight heparin (LMWH) use and mortality in hospitalized COVID-19 patients. METHODS: We conducted a retrospective study of patients consecutively enrolled from two major academic hospitals exclusively for COVID-19 in Wuhan, China, from January 26, 2020, to March 26, 2020. The primary outcome was adjusted in-hospital mortality in the LMWH group compared with the non-LMWH group using the propensity score. RESULTS: Overall, 525 patients with COVID-19 enrolled with a median age of 64 years (IQR 19), and 49.33% men. Among these, 120 (22.86%) were treated with LMWH. Compared with the non-LMWH group, the LMWH group was more likely to be older and male; had a history of hypertension, diabetes, coronary heart disease (CHD), or stroke; and had more severe COVID-19 parameters such as higher inflammatory cytokines or D-dimer. Compared with non-LMWH group, LMWH group had a higher unadjusted in-hospital mortality rate (21.70% vs. 11.10%; p = 0.004), but a lower adjusted mortality risk (adjusted odds ratio [OR], 0.20; 95% CI, 0.09-0.46). A propensity score-weighting analysis demonstrated similar findings (adjusted OR, 0.18; 95% CI, 0.10-0.30). Subgroup analysis showed a significant survival benefit among those who were severely (adjusted OR, 0.07; 95% CI, 0.02-0.23) and critically ill (adjusted OR, 0.32; 95% CI, 0.15-0.65), as well as among the elderly patients' age > 65, IL-6 > 10 times upper limit level, and D-dimer > 5 times upper limit level. CONCLUSIONS: Among hospitalized COVID-19 patients, LMWH use was associated with lower all-cause in-hospital mortality than non-LMWH users. The survival benefit was particularly significant among more severely ill patients.

Statin Use and In-hospital Mortality in Patients with COVID-19 and Coronary Heart Disease.

The worsening progress of coronavirus disease 2019 (COVID-19) is attributed to the proinflammatory state, leading to increased mortality. Statin works with its anti-inflammatory effects and may attenuate the worsening of COVID-19. COVID-19 patients were retrospectively enrolled from two academic hospitals in Wuhan, China, from 01/26/2020 to 03/26/2020. Adjusted in-hospital mortality was compared between the statin and the non-statin group by CHD status using multivariable Cox regression model after propensity score matching. Our study included 3133 COVID-19 patients (median age: 62y, female: 49.8%), and 404 (12.9%) received statin. Compared with the non-statin group, the statin group was older, more likely to have comorbidities but with a lower level of inflammatory markers. The Statin group also had a lower adjusted mortality risk (6.44% vs. 10.88%; adjusted hazard ratio [HR] 0.47; 95% CI, 0.29-0.77). Subgroup analysis of CHD patients showed a similar result. Propensity score matching showed an overall 87% (HR, 0.13; 95% CI, 0.05-0.36) lower risk of in-hospital mortality for statin users than nonusers. Such survival benefit of statin was obvious both among CHD and non-CHD patients (HR = 0.30 [0.09-0.98]; HR = 0.23 [0.1-0.49], respectively). Statin use was associated with reduced in-hospital mortality in COVID-19. The benefit of statin was both prominent among CHD and non-CHD patients. These findings may further reemphasize the continuation of statins in patients with CHD during the COVID-19 era.

Molecular Heterogeneity in Localized Diffuse Large B-Cell Lymphoma.

The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network-International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-ß signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase >3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.

Evaluation Framework for Successful Artificial Intelligence-Enabled Clinical Decision Support Systems: Mixed Methods Study.

BACKGROUND: Clinical decision support systems are designed to utilize medical data, knowledge, and analysis engines and to generate patient-specific assessments or recommendations to health professionals in order to assist decision making. Artificial intelligence-enabled clinical decision support systems aid the decision-making process through an intelligent component. Well-defined evaluation methods are essential to ensure the seamless integration and contribution of these systems to clinical practice. OBJECTIVE: The purpose of this study was to develop and validate a measurement instrument and test the interrelationships of evaluation variables for an artificial intelligence-enabled clinical decision support system evaluation framework. METHODS: An artificial intelligence-enabled clinical decision support system evaluation framework consisting of 6 variables was developed. A Delphi process was conducted to develop the measurement instrument items. Cognitive interviews and pretesting were performed to refine the questions. Web-based survey response data were analyzed to remove irrelevant questions from the measurement instrument, to test dimensional structure, and to assess reliability and validity. The interrelationships of relevant variables were tested and verified using path analysis, and a 28-item measurement instrument was developed. Measurement instrument survey responses were collected from 156 respondents. RESULTS: The Cronbach α of the measurement instrument was 0.963, and its content validity was 0.943. Values of average variance extracted ranged from 0.582 to 0.756, and values of the heterotrait-monotrait ratio ranged from 0.376 to 0.896. The final model had a good fit (χ262=36.984; P=.08; comparative fit index 0.991; goodness-of-fit index 0.957; root mean square error of approximation 0.052; standardized root mean square residual 0.028). Variables in the final model accounted for 89% of the variance in the user acceptance dimension. CONCLUSIONS: User acceptance is the central dimension of artificial intelligence-enabled clinical decision support system success. Acceptance was directly influenced by perceived ease of use, information quality, service quality, and perceived benefit. Acceptance was also indirectly influenced by system quality and information quality through perceived ease of use. User acceptance and perceived benefit were interrelated.

Dynamic evaluation of the prognostic value of 18F-FDG PET/CT in extranodal NK/T-cell lymphoma, nasal type.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Comparison of Nasopharyngeal MR, 18 F-FDG PET/CT, and 18 F-FDG PET/MR for Local Detection of Natural Killer/T-Cell Lymphoma, Nasal Type.

OBJECTIVES: The present study aims to compare the diagnostic efficacy of MR, 18F-FDG PET/CT, and 18F-FDG PET/MR for the local detection of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). PATIENTS AND METHODS: Thirty-six patients with histologically proven early-stage ENKTL were enrolled from a phase 2 study (Cohort A). Eight nasopharyngeal anatomical regions from each patient were imaged using 18F-FDG PET/CT and MR. A further nine patients were prospectively enrolled from a multicenter, phase 3 study; these patients underwent 18F-FDG PET/CT and PET/MR after a single 18F-FDG injection (Cohort B). Region-based sensitivity and specificity were calculated. The standardized uptake values (SUV) obtained from PET/CT and PET/MR were compared, and the relationship between the SUV and apparent diffusion coefficients (ADC) of PET/MR were analyzed. RESULTS: In Cohort A, of the 288 anatomic regions, 86 demonstrated lymphoma involvement. All lesions were detected by 18F-FDG PET/CT, while only 70 were detected by MR. 18F-FDG PET/CT exhibited a higher sensitivity than MR (100% vs. 81.4%, χ2 = 17.641, P < 0.001) for local detection of malignancies. The specificity of 18F-FDG PET/CT and MR were 98.5 and 97.5%, respectively (χ2 = 0.510, P = 0.475). The accuracy of 18F-FDG PET/CT was 99.0% and the accuracy of MR was 92.7% (χ2 = 14.087, P < 0.001). In Cohort B, 72 anatomical regions were analyzed. PET/CT and PET/MR have a sensitivity of 100% and a specificity of 92.5%. The two methods were consistent (κ = 0.833, P < 0.001). There was a significant correlation between PET/MR SUVmax and PET/CT SUVmax (r = 0.711, P < 0.001), and SUVmean (r = 0.685, P < 0.001). No correlation was observed between the SUV and the ADC. CONCLUSION: In early-stage ENKTL, nasopharyngeal MR showed a lower sensitivity and a similar specificity when compared with 18F-FDG PET/CT. PET/MR showed similar performance compared with PET/CT.

Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of lymphoma, and multiple extranodal involvement (ENI) indicates adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in DLBCL. METHODS: The clinical features of 1960 patients with newly diagnosed DLBCL were analyzed, and DNA and RNA sequencing was performed on 670 and 349 patients, respectively. Oncogenic mutations and tumor microenvironment alterations were compared according to ENI and evaluated in zebrafish patient-derived tumor xenograft models. RESULTS: Multiple ENI was significantly associated with poor performance status, advanced stage, elevated serum lactate dehydrogenase, low response rate, and inferior prognosis. Lymphoma invasion of the bones, spleen, bone marrow, liver, and central nervous system were independent unfavorable prognostic factors. MYD88 was frequently mutated in patients with multiple ENI, co-occurred with mutations in CD79B, PIM1, TBL1XR1, BTG1, MPEG1, and PRDM1, and correlated with invasion of the bones, kidney/adrenal glands, breasts, testes, skin, and uterus/ovaries. For tumor microenvironment alterations, patients with multiple ENI showed higher regulatory T-cell (Treg)-recruiting activity, but lower extracellular matrix-encoding gene expression, than those without ENI and with single ENI. Elevated Treg-recruiting activity was related to mutations in B2M, SGK1, FOXO1, HIST1H1E, and ARID1A, and correlated with invasion of the bone marrow and thyroid. Additionally, mutations in MYD88, PIM1, TBL1XR1, SGK1, FOXO1, HIST1H1E, and ARID1A were associated with decreased major histocompatibility complex class I expression. Zebrafish models further revealed relationships between MYD88 mutations and invasion of the kidneys and gonads, as well as B2M mutations and invasion of the bone marrow. Increased CXCR4 expression is linked to bone marrow invasion in an organotropic way. CONCLUSIONS: Our findings thus contribute to an improved understanding of the biological behavior of multiple ENI and provide a clinical rationale for targeting ENI in DLBCL.

Risk Factors for the Occurrence and Progression of Posttraumatic Elbow Stiffness: A Case-Control Study of 688 Cases.

Background: Elbow stiffness is a severe complication after trauma. Surgical or conservative treatments may be ineffective for restoring functional elbow motion. We aim to evaluate intrinsic and extrinsic factors for the occurrence and severity of elbow stiffness. Methods: This retrospective case-control study included mild/moderate stiffness, severe stiffness, and non-stiffness groups between January 2011 and December 2017 at a single orthopedic center. Multivariable logistic regression analysis and subgroup analysis were used to evaluate age, gender, body mass index, muscle strength, fracture type and site, injury mechanism, immobilization time, elbow dysfunction time, multiple surgeries, nerve symptoms, physical therapy, smoking and alcohol abuse, and dominant hand of stiff elbow as potential risk factors for the occurrence and severity of elbow stiffness. Results: There were 461 patients in the stiffness group and 227 patients in the non-stiffness group. The odds ratios (ORs) of the age, muscle strength, and injury mechanism were 0.960, 0.333, and 0.216 for the occurrence of elbow stiffness. In subgroup evaluation, increased cast immobilization time might be a risk factor for patients receiving conservative therapies (OR = 2.02; p = 0.014). In the evaluation on factors for progression of elbow stiffness, "multiple surgeries" might be a risk factor in surgical treatment by subgroup analysis (OR = 1.943; p = 0.026). Nevertheless, alcohol abuse might increase severity of elbow stiffness in conservatively treated patients (OR = 3.082; p = 0.025). Conclusion: Increased cast immobilization time in the conservative therapy might be a risk factor for stiffness occurrence. Multiple surgeries might be risk factors for stiffness progression. Alcohol abuse potentially increased stiffness severity after conservative treatment.

Excessive daytime sleepiness, metabolic syndrome, and obstructive sleep apnea: two independent large cross-sectional studies and one interventional study.

BACKGROUND: Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) were considered to contribute to MetS. This study was performed to assess the association between MetS and EDS in two independent large-scale populations, and in subjects who underwent upper-airway surgery. METHODS: A total of 6312 patients without self-reported depression and 3578 suspected OSA patients were consecutively recruited, during health screening examinations and from our sleep center, respectively. A total of 57 subjects with OSA who underwent upper-airway surgery were also included. Demographic, anthropometric, biochemical, and polysomnographic data were obtained. RESULTS: In the health screening examination group, 233 (9.23%) women and 350 (10.93%) men had complaints of EDS. A total of 229 (7.04%) women and 1182 (36.88%) men met the criteria for MetS. In the OSA group, 147 (21.18%) women and 1058 (36.69%) men reported EDS. In addition, 93 (13.4%) women and 1368 (47.43%) men reported MetS. In the health screening examination group, EDS did not contribute significantly to MetS (OR = 1.125, 95% CI: 0.907-1.395; p = 0.283). In the OSA group, EDS significantly contributed to MetS (OR = 1.249, 95% CI: 1.063-1.468; p = 0.007); however, the results were not significant after adjusting for sleep variables (OR = 1.071, 95% CI: 0.905-1.268; p = 0.423). Upper-airway surgery did not affect cardio-metabolic variables in OSA patients with or without EDS. CONCLUSIONS: EDS was not associated with MetS in two independent large-scale cohorts. In addition, upper-airway surgery did not affect components of MetS in OSA patients with and without EDS.

Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial.

BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

Prognostic nomogram incorporating inflammatory cytokines for overall survival in patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND: This study aimed to investigate the association of pre-treatment inflammatory status with survival time and to develop a prognostic nomogram incorporating inflammatory cytokines in non-Hodgkin's lymphoma. METHODS: A total of 228 patients with diffuse large B-cell lymphoma (DLBCL) received R-CHOP-based regimens from a prospective randomized study (NCT01852435) were included as a training cohort. Other cohorts of 886 lymphoma patients were served as validation cohorts. Lymphocyte-monocyte ratio (LMR), serum levels of soluble interleukin s(IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α), were assessed before treatment. Least absolute shrinkage and selection operator (LASSO) regression were used to select variables for nomogram of overall survival (OS). The predictive accuracy of the nomogram was determined by concordance index (C-index). FINDINGS: The nomogram included lactate dehydrogenase (LDH), sIL-2R, TNF-α and decreased LMR. The C-index of the nomogram for OS prediction were range from 0.61 to 0.86 for training cohort of DLBCL and validation cohorts of DLBCL, PTCL, NKTCL and ASCT, which were superior to the predictive power of International Prognostic Index (IPI, 0.67 to 0.84) or NCCN-IPI (0.59 to 0.78), but not in those of indolent lymphoma like FL and MALT. INTERPRETATIONS: The nomogram incorporating inflammatory cytokines provides a useful tool for risk stratification in aggressive non-Hodgkin's lymphomas. FUND: National Natural Science Foundation of China, the Shanghai Commission of Science and Technology, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of SHDC, and Chang Jiang Scholars Program.

The association between obstructive sleep apnea syndrome and metabolic syndrome: a confirmatory factor analysis.

BACKGROUND: Growing evidence suggests an independent relationship between obstructive sleep apnea syndrome (OSAS) and metabolic syndrome (MS). Patients with OSAS always show clustering of metabolic components. However, the understanding of interplay between OSAS and metabolic components is still lacking. METHODS: Participants were consecutively enrolled from our sleep center during the period 2009-2013. Anthropometric variables, metabolic indicators, and sleep parameters were collected from all participants. The factor structure for MS in OSAS and non-OSAS was examined by confirmatory factor analysis. RESULTS: The OSAS and non-OSAS demonstrated clustering of metabolic components. MS in patients with OSAS was strongly associated with insulin resistance (standardized factor loading = 0.93, p < 0.001), obesity (loading = 0.92, p < 0.001), and the lipid profile (loading = 0.72, p < 0.001). Furthermore, insulin resistance was correlated with obesity and lipid profile (r = 0.86, p < 0.001; r = 0.68, p < 0.001, respectively). Obesity and lipid profile were also highly correlated in OSAS (r = 0.66, p < 0.001). In non-OSAS, MS was strongly associated with insulin resistance, obesity, and lipid profile (loading = 0.95, p < 0.001; loading = 0.74, p < 0.001; loading = 0.68, p < 0.001, respectively). Insulin resistance was most strongly associated with fasting insulin (loading = 0.65, p < 0.001). Lipid profile was most strongly associated with TG (loading = 0.88, p < 0.001). Obesity was most strongly associated with BMI (loading = 0.80, p < 0.001). CONCLUSIONS: OSAS is more prone to show clustering of metabolic components compared with non-OSAS. In particular, insulin resistance, obesity, and the lipid profile were independently and strongly correlated with MS in OSAS.

Development and validation of a simple-to-use clinical nomogram for predicting obstructive sleep apnea.

BACKGROUND: The high cost and low availability of polysomnography (PSG) limits the timely diagnosis of OSA. Herein, we developed and validated a simple-to-use nomogram for predicting OSA. METHODS: We collected and analyzed the cross-sectional data of 4162 participants with suspected OSA, seen at our sleep center between 2007 and 2016. Demographic, biochemical and anthropometric data, as well as sleep parameters were obtained. A least absolute shrinkage and selection operator (LASSO) regression model was used to reduce data dimensionality, select factors, and construct the nomogram. The performance of the nomogram was assessed using calibration and discrimination. Internal validation was also performed. RESULTS: The LASSO regression analysis identified age, sex, body mass index, neck circumference, waist circumference, glucose, insulin, and apolipoprotein B as significant predictive factors of OSA. Our nomogram model showed good discrimination and calibration in terms of predicting OSA, and had a C-index value of 0.839 according to the internal validation. Discrimination and calibration in the validation group was also good (C-index = 0.820). The nomogram identified individuals at risk for OSA with an area under the curve (AUC) of 0.84 [95% confidence interval (CI), 0.83-0.86]. CONCLUSIONS: Our simple-to-use nomogram is not intended to replace standard PSG, but will help physicians better make decisions on PSG arrangement for the patients referred to sleep center.

Elevated plasma and vitreous levels of leucine-rich-α2-glycoprotein are associated with diabetic retinopathy progression.

PURPOSE: To investigate the association of plasma and vitreous leucine-rich-α2-glycoprotein (LRG1) with diabetic retinopathy (DR) progression. METHODS: A total of 86 outpatients and 33 inpatients were recruited. Outpatients with type 2 diabetes mellitus (T2DM) were classified as T2DM without DR (n = 22), nonproliferative DR (NPDR) (n = 20) and proliferative DR (PDR) (n = 22) based on international clinical DR severity scales. A total of 86 plasma and 33 vitreous samples were collected and subjected to enzyme-linked immunosorbent assay. The diagnostic value of plasma LRG1 was tested using receiver operating characteristic (ROC) curves. RESULTS: Plasma LRG1 in PDR patients (9025 ± 1870 pg/ml) was significantly increased as compared with controls (5975 ± 2022 pg/ml), T2DM without DR (6550 ± 2359 pg/ml) and NPDR patients (6550 ± 2359 pg/ml) (p < 0.0001). Vitreous LRG1 in PDR patients was elevated by approximately 4.3-fold than that in controls (562.1 ± 273.5 ng/ml versus 130.0 ± 102.8 ng/ml, p = 0.000). The area under the ROC curve value for plasma LRG1 was 0.786 (p < 0.0001). The maximal Youden index was 0.4372 and the optimal cut-off value of LRG1 was 7357.043 pg/ml with 81.82% sensitivity and 61.90% specificity. CONCLUSION: Plasma and vitreous LRG1 levels were elevated in patients with PDR. Leucine-rich-α2-glycoprotein (LRG1) might be a potential risk-warning marker for PDR.

Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study.

PURPOSE: Age-related macular degeneration (AMD) can cause irreversible vision loss leading to blindness. We aim to evaluate the efficacy and safety of intravitreal injections of 0.5 mg conbercept, a new anti-vascular endothelial growth factor (anti-VEGF) drug, for treatment of AMD on a schedule more manageable for patients. DESIGN: A prospective, double-masked, multicenter, sham-controlled, phase III randomized trial. METHODS: Patients: Patients with choroidal neovascularization (CNV) secondary to AMD were enrolled and randomized to the conbercept group or the sham control group. INTERVENTION: The conbercept group received intravitreal injections of conbercept (0.5 mg) once monthly for the first 3 months, then once quarterly until month 12 (3 + Q3M). The sham group received first 3 monthly sham injections and then 3 monthly injections of conbercept (0.5 mg) followed by quarterly administrations until month 12. MAIN OUTCOME MEASURES: The primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA) at month 3. RESULTS: A total of 114 patients (91.9%) from 9 sites in China completed the 12-month study. At the 3-month primary endpoint, the mean changes in BCVA from baseline were +9.20 letters in the conbercept group and +2.02 letters in the sham group, respectively (P < .001). At 12 months, the mean changes from baseline in BCVA letter score were +9.98 letters in the conbercept group and +8.81 letters in the sham group (P = .64). The most common ocular adverse events were associated with intravitreal injections, such as conjunctival hemorrhage, and increased intraocular pressure. CONCLUSIONS: A conbercept dosing regimen of 3 initial monthly administrations followed by quarterly treatments is effective for treatment of AMD. In previous reports, other anti-VEGF agents were unable to maintain similar clinical benefits with the same regimen.