The classification of obesity based on metabolic status redefines the readmission of non-Hodgkin's lymphoma-an observational study.

BACKGROUND: The relationship between obesity and non-Hodgkin's lymphoma (NHL) was controversial, which may be due to the crudeness definition of obesity based on body mass index (BMI). As obesity and metabolic abnormalities often coexist, we aimed to explore whether the classification of obesity based on metabolic status can help to evaluate the real impact of obesity on the readmission of NHL. METHODS: In this retrospective cohort study, utilizing the 2018 Nationwide Readmissions Database, we identified NHL-related index hospitalizations and followed them for non-elective readmission. The patients with NHL were classified as metabolically healthy non-obese (MHNO) and obese (MHO) and metabolically unhealthy non-obese (MUNO) and obese (MUO). Readmission rates for each phenotype were calculated at 30-day intervals. Multiple COX regression was used to analyze the association of metabolic-defined obesity with 30-day, 90-day, and 180-day readmission rates in patients with NHL. RESULTS: There were 22,086 index hospitalizations with NHL included. In the multivariate COX regression, MUNO was associated with increased 30-day (HR = 1.113, 95% CI 1.036-1.195), 90-day (HR = 1.148, 95% CI 1.087-1.213), and 180-day readmission rates (HR = 1.132, 95% CI 1.077-1.189), and MUO was associated with increased 30-day (HR=1.219, 95% CI: 1.081-1.374), 90-day (HR = 1.228, 95% CI 1.118-1.348), and 180-day readmission rates (HR = 1.223, 95% CI 1.124-1.33), while MHO had no associations with readmission rates. CONCLUSIONS: The presence of metabolic abnormalities with or without obesity increased the risk of non-selective readmission in patients with NHL. However, obesity alone had no associations with the risk of non-selective readmission, suggesting that interventions for metabolic abnormalities may be more important in reducing readmissions of NHL patients.

The short- and long-term readmission of four major categories of digestive system cancers: does obesity or metabolic disorder matter?

Purpose: Patients with digestive system cancers (DSCs) are at a high risk for hospitalizations; however, the risk factors for readmission remain unknown. Here, we established a retrospective cohort study to assess the association between metabolic obesity phenotypes and readmission risks of DSC. Experimental design: A total of 142,753 and 74,566 patients at index hospitalization were ultimately selected from the Nationwide Readmissions Database (NRD) 2018 to establish the 30-day and 180-day readmission cohorts, respectively. The study population was classified into four groups: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). Multivariate Cox regression analysis was used to estimate the effect of metabolic obesity phenotypes on DSC readmission. Results: The MUNO phenotype had 1.147-fold (95% CI: 1.066, 1.235; p < 0.001) increased 180-day readmission risks in patients with neoplasm of the upper digestive tract. The MUNO phenotype had 1.073-fold (95% CI: 1.027, 1.121; p = 0.002) increased 30-day readmission risks and 1.067-fold (95% CI: 1.021, 1.115; p = 0.004) increased 180-day readmission risks in patients with neoplasm of the lower digestive tract. The MUNO and MUO phenotypes were independent risk factors of readmission in patients with liver or pancreatic neoplasm. Metabolic obesity status was independently associated with a high risk of severe and unplanned hospitalization within 30 days or 180 days. Conclusion: Both obesity and metabolic abnormalities are associated with a high risk for the poor prognosis of DSC patients. The effect of metabolic categories on the short- or long-term readmission of liver or pancreas cancers may be stronger than that of obesity.

Association of obesity and different metabolic status with prognosis in patients with bladder cancer: a retrospective cohort study.

Background and objectives: Patients with bladder cancer (BC) are at high risk for recurrence rates and readmission costs. However, the evidence about obesity and metabolic abnormalities on the BC prognosis was inconsistent. Our primary aim was to determine the impact of obesity and different metabolic status on the readmission risk in patients with BC. Design and methods: We identified 16,649 patients with BC using the 2018 Nationwide Readmissions Database who were hospitalized from January to June 2018 and followed for 180 days. The primary outcome was 180-day readmission. The multivariate Cox regression analysis and ordered logistic regression were performed to analyze data. Results: Obesity and metabolic abnormalities were associated with an increased readmission risk in patients with BC [obesity: adjusted hazard ratio (aHR) = 1.08, 95% confidence interval (CI): 1.01-1.16; hyperglycemia: aHR = 1.11, 95% CI: 1.05-1.17; hypertension: aHR = 1.09, 95% CI: 1.03-1.15]. Compared with non-obese and no metabolic abnormalities, the risk of readmission was significantly increased in patients with metabolic abnormalities, irrespective of obesity (non-obese and metabolic abnormalities: aHR = 1.07, 95% CI: 1.02-1.13; obese and metabolic abnormalities: aHR = 1.20, 95% CI: 1.10-1.31), but not in obese and no metabolic abnormalities. These associations were consistent in patients aged 60 years or older and the surgery group. Moreover, hyperglycemia, hypertension, and a graded increment of metabolic risk were associated with an increased readmission risk. We also found increased length of stay for readmission in patients with obesity and metabolic abnormalities (aOR = 1.17, 95% CI: 1.00-1.36). Conclusion: Obesity with metabolic abnormalities and metabolic abnormalities alone were associated with higher readmission risks in patients with BC. It is suggested that prevention should focus not only on obesity but also on metabolic abnormalities to decrease the risk of readmission.

Obesity Metabolic Phenotypes and Unplanned Readmission Risk in Diabetic Kidney Disease: An Observational Study from the Nationwide Readmission Database.

BACKGROUND AND AIM: Obesity is a potentially modifiable factor for reducing readmissions, with heterogeneity that varies according to the metabolic status. Our objective was to examine the independent or mutual relationship between obesity and metabolic abnormalities and diabetic kidney disease (DKD)-related hospitalizations. METHODS: 493,570 subjects with DKD were enrolled in the 2018 Nationwide Readmission Database (NRD, United States). The at-risk population was reclassified into refined obesity subtypes based on the body mass index (BMI) classification of metabolic abnormalities (hypertension and/or dyslipidemia) to investigate the 180 d readmission risk and hospitalization costs related to DKD. RESULTS: The overall readmission rate was 34.1%. Patients with metabolic abnormalities, regardless of obesity, had a significantly higher risk of readmission compared to non-obese counterparts (adjusted HR, 1.11 [95% CI, 1.07-1.14]; 1.12 [95% CI, 1.08-1.15]). Hypertension appeared to be the only metabolic factor associated with readmission among individuals with DKD. Obesity without metabolic abnormalities was independently associated with readmission (adjusted HR,1.08 [1.01,1.14]), especially among males and those >65 years (adjusted HR,1.10 [1.01-1.21]; 1.20 [1.10-1.31]). Women or those ≤65 years with metabolic abnormalities (all p <0.050) had elevated readmission rates, regardless of obesity; however, no such trend was observed in obese subjects without metabolic abnormalities (adjusted HR, 1.06 [0.98,1.16]). Additionally, obesity and metabolic abnormalities were associated with elevated hospitalization costs (all p <0.0001). CONCLUSIONS: Increased BMI and hypertension are positively associated with readmissions and related costs among patients with DKD, which should be considered in future studies.

Remnant cholesterol, stronger than triglycerides, is associated with incident non-alcoholic fatty liver disease.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals. Methods: All subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status. Results: In multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p<0.001), high-density lipoprotein cholesterol (HDL-C) (HR, 95% CI: 0.571,0.487-0.670; p<0.001), and remnant-C (HR, 95% CI: 1.143,1.052-1.242; p=0.002), but not total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), were associated with incident NAFLD. Atherogenic dyslipidemia (triglycerides>1.69 mmol/L, HDL-C<1.03 mmol/L in men or<1.29 mmol/L in women) was also associated with NAFLD (HR, 95% CI: 1.343,1.177-1.533; p<0.001). Remnant-C levels were higher in females than in males and increased with increasing BMI and in participants with diabetes and CVD compared with those without diabetes or CVD. After adjusting for other factors in the Cox regression models, we found that serum levels of TG and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes in women group, non-cardiovascular disease status, non-diabetes status and middle BMI categories (24 to 28 kg/m2). Discussion: In the middle aged and elderly subset of the Chinese population, especially those who were women, non-CVD status, non-diabetes status and middle BMI status (24 to 28 kg/m2), levels of triglycerides and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes independent of other risk factors.

Association of obesity under different metabolic status with adverse outcomes in patients with chronic myeloid leukemia: A retrospective cohort study.

BACKGROUND: Little is known about the association between abnormal metabolic obesity states and the outcomes of chronic myeloid leukemia (CML), especially in patients with obesity with different metabolic status. Here, we used the Nationwide Readmissions Database to assess the effects of metabolically defined obesity on adverse outcomes of CML. METHODS: Of the 35 460 557 (weighted) patients, we included 7931 adults with discharge diagnoses of CML from January 1, 2018 to June 30, 2018. The study population was observed until December 31, 2018 and divided into four groups based on body mass index and metabolic status. The primary outcome was the adverse outcomes of CML, including nonremission (NR)/relapse and severe mortality risk. Multivariate logistic regression analysis was performed to analyze data. RESULTS: Metabolically unhealthy normal weight and metabolically unhealthy obesity were all risk factors for adverse outcomes of CML compared with metabolically healthy normal weight (all p < 0.01), and a significant difference was not found in the metabolically healthy obese. Female patients with metabolically unhealthy normal weight and metabolically unhealthy obesity had 1.23-fold and 1.40-fold increased NR/relapse risk, while male patients did not have this risk. Moreover, patients with a higher number of metabolic risk factors or with dyslipidemia were at higher risk of adverse outcomes, regardless of obesity status. CONCLUSIONS: Metabolic abnormalities were associated with adverse outcomes in patients with CML, irrespective of obesity status. Future treatment of patients with CML should consider the effects of obesity on their adverse outcomes under different metabolic status, especially in female patients.

The systemic immune-inflammation index was non-linear associated with all-cause mortality in individuals with nonalcoholic fatty liver disease.

OBJECTIVE: Systemic immune-inflammation index (SII), a novel inflammatory indicator based on platelets, neutrophils and lymphocytes, has been shown to be associated with prognostic value in several solid tumors. However, its prognostic value in nonalcoholic fatty liver disease (NAFLD) has not been reported yet. Therefore, the present study aimed to investigate the prognostic value of SII in individuals with NAFLD. METHODS: Data was collected from the 2005 to 2014 National Health and Nutrition Examination Survey (NHANES, https://www.cdc.gov/nchs/nhanes/index.htm), and vital status was derived from the National Death Index (NDI) up to 31 December 2015. NAFLD was diagnosed based on Hepatic Steatosis Index (HSI). Multivariate Cox regression and Kaplan-Meier survival curves were performed to measure the hazard ratios (HRs) and 95% confidence interval (CI). Our study investigated the relationship between SII and all-cause mortality by using two-part linear regression models with penalized splines, as well as Cox models with penalized splines. RESULTS: A total of 10,787 NAFLD participants (44.14% men) aged ≥20 years old were enrolled. There were 776 deaths from all causes after a mean follow-up period of 5.6 years. According to the full adjusted Cox regression analysis, the low log2-SII group (quartile 1) and the highest log2-SII group (quartile 4) were significantly associated with increased mortality from all causes (aHR =1.86; 95% CI: 1.47-2.37; p < 0.0001). After controlling for confounders, an increase in log2-SII was associated with an increased all-cause mortality risk of 41% for every unit raised (aHR = 1.41; 95% CI: 1.26-1.57; p < 0.0001). After adjusting for multiple potential confounders, the association between log2-SII and all-cause mortality was nonlinear, and the threshold value was 8.8. There was no association between an increase of one unit in log2-SII and all-cause mortality below the threshold (aHR = 0.90, 95% CI: 0.71-1.15, p = 0.419). However, a higher log2-SII was associated with a higher risk of death from any cause when it exceeded the threshold (aHR = 1. 73, 95% CI: 1.49-2.02, p < 0.001).Based on a study of US NAFLD patients, it was found that the baseline log2-SII is associated with all-cause mortality. Elevated SII is associated with poor survival among NAFLD patients.KEY MESSAGESUsing a large nationally representative survey of individuals among US adults, the study demonstrated that log2-SII was J-shaped and associated with all-cause death among individuals with NAFLD.Spline analyses demonstrated that the association between log2-SII and all-cause mortality was non-linear after adjusting for multiple potential confounders, and the threshold value was 8.8.Higher log2-SII associated with poor survival in NAFLD.

Association between metabolic obesity phenotypes and multiple myeloma hospitalization burden: A national retrospective study.

Background & purpose: Obesity and metabolic disorders were associated with increased risk of MM, a disease characterized by high risk of relapsing and require frequent hospitalizations. In this study, we conducted a retrospective cohort study to explore the association of metabolic obesity phenotypes with the readmission risk of MM. Patients & methods: We analyzed 34,852 patients diagnosed with MM from the Nationwide Readmissions Database (NRD), a nationally representative database from US. Hospitalization diagnosis of patients were obtained using ICD-10 diagnosis codes. According to obesity and metabolic status, the population was divided into four phenotypes: metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). The patients with different phenotypes were observed for hospital readmission at days 30-day, 60-day, 90-day and 180-day. Multivariate cox regression model was used to estimate the relationship between obesity metabolic phenotypes and readmissions risk. Results: There were 5,400 (15.5%), 7,255 (22.4%), 8,025 (27.0%) and 7,839 (35.6%) unplanned readmissions within 30-day, 60-day, 90-day and 180-day follow-up, respectively. For 90-day and 180-day follow-up, compared with patients with the MHNO phenotype, those with metabolic unhealthy phenotypes MUNO (90-day: P = 0.004; 180-day: P = < 0.001) and MUO (90-day: P = 0.049; 180-day: P = 0.004) showed higher risk of readmission, while patients with only obesity phenotypes MHO (90-day: P = 0.170; 180-day: P = 0.090) experienced no higher risk. However, similar associations were not observed for 30-day and 60-day. Further analysis in 90-day follow-up revealed that, readmission risk elevated with the increase of the combined factor numbers, with aHR of 1.068 (CI: 1.002-1.137, P = 0.043, with one metabolic risk factor), 1.109 (CI: 1.038-1.184, P = 0.002, with two metabolic risk factors) and 1.125 (95% CI: 1.04-1.216, P = 0.003, with three metabolic risk factors), respectively. Conclusion: Metabolic disorders, rather than obesity, were independently associated with higher readmission risk in patients with MM, whereas the risk elevated with the increase of the number of combined metabolic factors. However, the effect of metabolic disorders on MM readmission seems to be time-dependent. For MM patient combined with metabolic disorders, more attention should be paid to advance directives to reduce readmission rate and hospitalization burden.

The effects of obesity and metabolic abnormalities on severe COVID-19-related outcomes after vaccination: A population-based study.

Breakthrough SARS-CoV-2 infections of vaccinated individuals are being reported globally, resulting in an increased risk of hospitalization and death among such patients. Therefore, it is crucial to identify the modifiable risk factors that may affect the protective efficacy of vaccine use against the development of severe COVID-19 and thus to initiate early medical interventions. Here, in population-based studies using the UK Biobank database and the 2021 National Health Interview Survey (NHIS), we analyzed 20,362 participants aged 50 years or older and 2,588 aged 18 years or older from both databases who tested positive for SARS-COV-2, of whom 33.1% and 67.7% received one or more doses of vaccine, respectively. In the UK Biobank, participants are followed from the vaccination date until October 18, 2021. We found that obesity and metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, and hypertension) were modifiable factors for severe COVID-19 in vaccinated patients (all p < 0.05). When metabolic abnormalities were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal individuals (all p < 0.05). Moreover, pharmacological interventions targeting such abnormalities (namely, antihypertensive [adjusted hazard ratio (aHR) 0.64, 95% CI 0.48-0.86; p = 0.003], glucose-lowering [aHR 0.55, 95% CI 0.36-0.83; p = 0.004], and lipid-lowering treatments [aHR 0.50, 95% CI 0.37-0.68; p < 0.001]) were significantly associated with a reduced risk for this outcome. These results show that more proactive health management of patients with obesity and metabolic abnormalities is critical to reduce the incidence of severe COVID-19 after vaccination.

A Universal Formation Mechanism of Hollow Multi-Shelled Structures Dominated by Concentration Waves.

Hollow multi-shelled structures (HoMS), a new family of hierarchical nano/micro-structured materials, have evoked intensive studies to discover their unique temporal-spatial ordering features. The theoretical understanding of the general synthetic methods of HoMS, i.e. the sequential templating approach (STA), makes it possible to understand, predict, and control the shell formation process. Herein, a mathematical model is established based on the experiment results, which reveal the appearance of concentration waves in the STA. The numerical simulation results not only correspond well to the experimental observations but also explain the regulation methods. Whereby, the underlying physical essence of STA is elucidated, suggesting that HoMS is the concrete representation of the concentration waves. Thereafter the formation of HoMS is not limited to the solid-gas reactions through high-temperature calcination, but could be extended to solution systems under low-temperature conditions.

Changes in Clinical Manifestations Due to AFLD Retyping Based on the New MAFLD Criteria: An Observational Study Based on the National Inpatient Sample Database.

(1) Background: As the introduction of "positive" diagnostic criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) does not exclude alcohol consumption, some patients originally diagnosed with alcoholic fatty liver disease (AFLD) may be diagnosed with dual- etiology fatty liver disease (AFLD&MAFLD), which requires us to urgently explore the impact of the changes in this classification of AFLD on clinical manifestations. (2) Methods: Utilizing data from the Nationwide Inpatient Sample database 2016-2018, a total of 9269 participants with AFLD were selected. With the definition of MAFLD, these patients were further categorized into two groups: single AFLD and AFLD&MAFLD. The primary outcome was the risk of comorbidities and organ failures. The secondary outcomes were the length of stay, total charges, and in-hospital all-cause mortality. (3) Results: The patients with AFLD&MAFLD were older, were predominantly male, and had more comorbidities and organ failures compared to the patients with AFLD. These comorbidities included coronary atherosclerosis, myocardial infarction, cerebrovascular disease, arrhythmia, asthma, chronic obstructive pulmonary disease, and chronic kidney disease (all p values < 0.05). The patients with AFLD&MAFLD were more likely to develop acute and chronic heart and/or kidney failures than those with single AFLD (all p < 0.05). The length of stay and total charges of the patients in the AFLD&MAFLD group were greater than the single AFLD group (p = 0.029 and p < 0.001, respectively). No significant difference in all-cause mortality was observed. (4) Conclusions: The patients with AFLD&MAFLD have more comorbidities and organ failures, longer hospital stays, and higher hospitalization costs than the patients with single AFLD. Hence, patients with dual-etiology fatty liver disease deserve more attention from clinical staff during treatment.

Association between Regional Body Muscle Mass and Non-Alcoholic Fatty Liver Disease: An Observational Study Using Data from the REACTION Study.

Background and aims: Regional muscle distribution is associated with abdominal obesity and metabolic syndrome. However, the relationship between muscle distribution and nonalcoholic fatty liver disease (NAFLD) remains unclear. This study was to determine the relationship between regional muscle distribution and the risk and severity of NAFLD. Methods: This cross-sectional study ultimately included 3161 participants. NAFLD diagnosed by ultrasonography was classified into three groups (non, mild, and moderate/severe). We estimated the regional body muscle mass (lower limbs, upper limbs, extremities, and trunk) through multifrequency bioelectrical impedance analysis (BIA). The relative muscle mass was defined as the muscle mass adjusted for the body mass index (BMI). Results: NAFLD participants accounted for 29.9% (945) of the study's population. Individuals with a higher lower limb, extremity, and trunk muscle mass had a lower risk of NAFLD (p < 0.001). Patients with moderate/severe NAFLD had a lower muscle mass of the lower limbs and trunk than patients with mild NAFLD (p < 0.001), while the muscle mass of the upper limbs and extremities did not differ significantly between the two groups. Moreover, similar results were found for both sexes and among different age groups. Conclusions: A higher muscle mass of the lower limbs, extremities, and trunk was negatively associated with the risk of NAFLD. A lower muscle mass of the limbs and trunk was inversely associated with the severity of NAFLD. This study provides a new theoretical basis for the development of individualized exercise prescriptions for the prevention of NAFLD in non-NAFLD patients.

Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis.

Background: It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. Methods: We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. Results: We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. Conclusions: This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. Systematic review registration: PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.

Identification and Functional Characterization of a Novel Variant in the SEMA3A Gene in a Chinese Family with Kallmann Syndrome.

Background: Kallmann syndrome (KS) is a rare genetic disease characterized by the reproductive system and olfactory dysplasia due to the defective migration of gonadotropin-releasing hormone (GnRH) neurons. However, this disorder is clinically heterogeneous and the genotype-phenotype relationship has not been determined. Objective: The present study aimed to identify the variant causing KS in a Chinese family and evaluate the functional consequences and phenotypes associated with the novel variant. Methods: A Chinese family with KS was screened for pathogenic variants by whole-exome sequencing (WES). Bioinformatic analysis was performed to predict the consequences of the identified variant. The expression of the mutant protein was examined in vitro. Results: A novel heterozygous variant (NM_006080.2 : c.814G > T) in SEMA3A was identified in the patient and his father, which caused the substitution of aspartic acid with tyrosine in codon 272. It was predicted to result in pathogenic significance with a high damaging score and seriously affect protein structure by bioinformatic analysis. In vitro experiments revealed this variant could significantly decrease the expression of SEMA3A. Furthermore, it may cause the disease by failing to induce the phosphorylation of focal adhesion kinase (FAK) in GnRH neurons. Conclusion: Identification and functional characterization of this novel variant in the SEMA3A gene in a Chinese family with Kallmann syndrome extend the genetic variant spectrum of SEMA3A and provide more data about the heterogeneity of KS, which may provide further insights into the diagnosis of KS and help patients get additional data in genetic counseling and timely treatment.

Identification of a novel MAP3K1 variant in a family with 46, XY DSD and partial growth hormone deficiency.

The 46, XY disorder of sex development (DSD) is the main cause of birth defects; however, as it is a group of highly heterogeneous diseases, >50% of cases are not accurately diagnosed. Identification of more cases will improve understanding of the relationship between genotype and phenotype for DSD. The present study conducted a systematic analysis of the clinical characteristics of a proband with 46, XY DSD, applied genetic analysis by whole­exome sequencing to this pedigree and performed bioinformatics analysis of the identified variant. The proband presented with a short penis, lack of testicles and partial growth hormone (GH) deficiency at 1 year old. Histopathological examination revealed there were oviduct, epididymis and fibrous vascular tissue on both sides of the abdomen. The last follow­up at 5 years of age revealed that the patient exhibited restricted growth, a 1.5­cm penis and lack of testicles. Notably, a novel pathogenic mitogen­activated protein kinase kinase kinase 1 (MAP3K1) variant (c.3020A>G) was identified in the proband, resulting in a change in the 1,007th amino acid (glutamine) of the encoded protein. This variant caused the uncharged neutral glutamine to be replaced by a positively charged basic arginine. p.Gln1007 in MAP3K1 was confirmed to be conserved across various species. Pathogenicity analysis using bioinformatics tools suggested that this MAP3K1 variant may cause functional defects. In conclusion, the present study identified a novel MAP3K1 variant that was the cause of 46, XY DSD and partial GH deficiency. The present findings extend the mutation spectrum of MAP3K1 and provide novel characteristics of 46, XY DSD.

Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia.

Background: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the lipoprotein lipase (LPL) gene. To date, more than 200 mutations in the LPL gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis. Objective: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. Methods: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. In vitro studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant LPL plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium. Results: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of LPL (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 ± 9.46% (p<0.01) and 54.60 ± 9.03% (p<0.01), respectively, compared with the control. In vitro studies showed a substantial reduction in the expression or enzyme activity of LPL in the LPL variants. Conclusions: Two novel compound heterozygous variants of LPL induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated LPL mutant activity.

Association between metabolic overweight/obesity phenotypes and readmission risk in patients with lung cancer: A retrospective cohort study.

Background: Increased body mass index (BMI) and metabolic abnormalities are controversial prognostic factors of lung cancer. However, the relationship between metabolic overweight/obesity phenotypes and hospital readmission in patients with lung cancer is rarely reported. Methods: We established a retrospective cohort using the United States (US) Nationwide Readmissions Database (NRD). We included adult patients diagnosed with lung cancer from January 1, 2018 to November 30, 2018 and excluded patients combined with other cancers, pregnancy, died during hospitalization, low body weight, and those with missing data. The cohort was observed for hospital readmission until December 31, 2018. We defined and distinguished four metabolic overweight/obesity phenotypes: metabolically healthy with normal weight (MHNW), metabolically unhealthy with normal weight (MUNW), metabolically healthy with overweight or obesity (MHO), and metabolically unhealthy with overweight or obesity (MUO). The relationship between metabolic overweight/obesity phenotypes and 30-day readmission risk was assessed by multivariable Cox regression analysis. Findings: Of the 115,393 patients included from the NRD 2018 (MHNW [58214, 50.4%], MUNW [44980, 39.0%], MHO [5044, 4.4%], and MUO [7155, 6.2%]), patients with the phenotype MUNW (6531, 14.5%), MHO (771, 15.3%), and MUO (1155, 16.1%) had a higher readmission rate compared to those with MHNW (7901, 13.6%). Compared with patients with the MHNW phenotype, those with the MUNW (hazard ratio [HR], 1.10; 95% CI, 1.06-1.14), MHO (HR, 1.15; 95% CI, 1.07-1.24), and MUO (HR, 1.28; 95% CI, 1.20-1.36) phenotypes had a higher risk of readmission, especially in men, those without surgical intervention, or those aged >60 years. In women, similar results with respect to readmission were observed in people aged >60 years (MUNW [HR, 1.07; 95% CI, 1.01-1.13], MHO [HR, 1.19; 95% CI, 1.06-1.35], and MUO [HR, 1.28; 95% CI, 1.16-1.41]). We also found increased costs for 30-day readmission in patients with MHO (OR, 1.18; 95% CI, 1.07-1.29) and MUO (OR, 1.11; 95% CI, 1.02-1.20). Interpretation: Increased BMI and metabolic abnormalities are independently associated with higher readmission risks in patients with lung cancer, whereas increased BMI also increases the readmission costs. Follow-up and intervention method targeting increased BMI and metabolic abnormalities should be considered for patients with lung cancer. Funding: The National Key Research and Development Program of China (2017YFC1309800).

Association between trichlorophenols and neurodegenerative diseases: A cross-sectional study from NHANES 2003-2010.

PURPOSE OF THE RESEARCH: To evaluate the association of the exposure of trichlorophenols (TCPs) on the morbidity and mortality of patients with Parkinson's disease (PD) and Alzheimer's disease (AD) using the data from the National Health and Nutrition Examination Survey (NHANES) 2003-2010. Multivariable logistic regression models and COX regression were used to evaluate the association between TCP exposure and the AD and PD risk. Least Absolute Shrinkage and Selection Operator (LASSO) methods were used to screen latent covariates. PRINCIPAL RESULTS: A total of 6333 participants over the age of 18 years were included in the analysis. After the adjustments for major confounders, participants with higher concentrations of urinary 2,4,6-TCP had higher risk of AD (odds ratios (ORs), 3.19; 95% CI: 1.07, 9.45) than the group below the limit of detection (LOD). Compared to group of below the LOD, higher urinary concentrations of 2,4,5-TCP was associated with higher risk of all-cause mortality in PD patients (log-rank P = 0.022) and all participants (log-rank P < 0.001) without adjustments for confounders. In addition, a higher risk of all-cause mortality in all participants with high urinary concentrations of 2,4,6-TCP (log-rank P = 0.001) was found without adjustments for confounders. With the adjustments for major confounders, participants with higher concentrations of urinary 2,4,5-TCP had a higher risk of death in patients with PD (hazard ratios (HRs), 53.19; 95% CI: 2.82, 1004.13) than in the group below the LOD. MAJOR CONCLUSIONS: Exposure to high concentration of 2,4,6-TCP may increase the risk of AD, and the level of 2,4,5-TCP may be associated with the risk of death in patients with PD. Our findings reveal the potential toxicity of TCPs, highlight the potential impact of TCPs on neurodegenerative diseases, and express concerns regarding the use of organochlorine pesticides.

The Relationship Between Obesity and Depression Is Partly Dependent on Metabolic Health Status: A Nationwide Inpatient Sample Database Study.

Objective: Some studies have demonstrated a bidirectional association between obesity and depression, whereas others have not. This discordance might be due to the metabolic health status. We aimed to determine whether the relationship between obesity and depression is dependent on metabolic health status. Methods: In total, 9,022,089 participants were enrolled and classified as one of four obesity phenotypes: metabolically healthy nonobesity (MHNO), metabolically unhealthy nonobesity (MUNO), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). We then divided the population into eight phenotypes based on obesity and the number of metabolic risk factors. Furthermore, the associations of eight phenotypes, based on obesity and specific metabolic risk factors, with depression were assessed. Result: Among all participants, a higher risk of depression was observed for MUNO, MHO and MUO than for MHNO. The risk was highest for MUO (OR = 1.442; 95% CI = 1.432, 1.451). However, the association between MHO and depression was different for men and women (OR = 0.941, men; OR = 1.132, women). The risk of depression increased as the number of metabolic risk factors increased. Dyslipidemia was the strongest metabolic risk factor. These relationships were consistent among patients ≥ 45 years of age. Conclusions: The increased risk of obesity-related depression appears to partly depend on metabolic health status. The results highlight the importance of a favorable metabolic status, and even nonobese populations should be screened for metabolic disorders.

Metabolic obesity phenotypes: a friend or foe of digestive polyps?-An observational study based on National Inpatient Database.

OBJECTIVE: Obesity is associated with an increased risk of digestive polyps, whereas all obesity are not created equally. The role of metabolic states in occurrence risks of polyps among individuals with varying degrees of obesity remains unknown. Our study aimed to evaluate the association between metabolic obesity phenotypes and the occurrence of digestive polyps. RESEARCH DESIGN AND METHODS: Data from 9,278,949 patients between 2016 and 2018 from the National Inpatient Sample (NIS) database, a nationally representative database of all discharges from US health-care hospitals, were analyzed. According to obesity phenotype, the study population was classified into four groups: metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). We calculated the incidence rates of various digestive polyps (stomach/duodenum, colon and rectum polyps) among these participants by searching the hospital records for ICD-10 diagnosis codes indicating each gastric, duodenum, colon or rectal polyps. The multiple stepwise regression analysis and further in-depth subgroup analysis were used to determine the associations between metabolic obesity phenotypes and the occurrence of digestive polyps. RESULTS: In the total or female population, those with the MUNO and MUO phenotypes had significantly higher prevalence of digestive polyps compared with individuals with the MHNO or MHO phenotypes (all p < 0.05) and a significant difference was not found between MUNO and MUO phenotypes (p > 0.05). Obese subjects seem to be more likely to develop stomach and duodenum polyps or colon polyps than non-obese subjects in metabolically healthy people of males (MHO vs. MHNO, p < 0.05), whereas obesity status seems to have little effect on the occurrence of digestive polyps in metabolically healthy people of females (MHO vs. MHNO, p>0.05). After adjusting for the potential confounders, the MHO, MUNO and MUO phenotypes were all risk factors for stomach and duodenum polyps (OR = 1.46, 95% CI: 1.36-1.58, p< 0.01; OR = 1.19, 95% CI: 1.14-1.25, p< 0.01; OR = 1.44, 95% CI: 1.35-1.55, p< 0.01, respectively) or colon polyps (OR = 1.28, 95% CI: 1.21-1.35, p< 0.01; OR = 1.18, 95% CI: 1.14-1.22, p< 0.01; OR = 1.46, 95% CI: 1.38-1.54, p< 0.01, respectively) compared with the MHNO phenotype，especially in menopausal female. Interestingly, we also observed in further in-depth subgroup analysis that metabolic abnormalities may have a greater impact on the occurrence of digestive polyps than obesity (all p < 0.05). CONCLUSIONS: Both metabolic abnormities and obesity were associated with a higher risk of digestive polyps. The effect of metabolism on digestive polyp occurrence may be stronger than that of obesity, highlighting the importance of abnormal metabolic status modification regardless of obesity status. Clinical intervention should not only focus on obesity, but also on metabolic abnormalities to decrease digestive polyp risk.