Glycoengineering of Antibodies for Modulating Functions.

Antibodies are immunoglobulins that play essential roles in immune systems. All antibodies are glycoproteins that carry at least one or more conserved N-linked oligosaccharides (N-glycans) at the Fc domain. Many studies have demonstrated that both the presence and fine structures of the attached glycans can exert a profound impact on the biological functions and therapeutic efficacy of antibodies. However, antibodies usually exist as mixtures of heterogeneous glycoforms that are difficult to separate in pure glycoforms. Recent progress in glycoengineering has provided useful methods that enable production of glycan-defined and site-selectively modified antibodies for functional studies and for improved therapeutic efficacy. This review highlights major approaches in glycoengineering of antibodies with a focus on recent advances in three areas: glycoengineering through glycan biosynthetic pathway manipulation, glycoengineering through in vitro chemoenzymatic glycan remodeling, and glycoengineering of antibodies for site-specific antibody-drug conjugation.

Outdoor Light at Night, Air Pollution, and Risk of Cerebrovascular Disease: A Cohort Study in China.

BACKGROUND: We sought to explore the associations of outdoor light at night (LAN) and air pollution with the risk of cerebrovascular disease (CeVD). METHODS: We included a total of 28 302 participants enrolled in Ningbo, China from 2015 to 2018. Outdoor LAN and air pollution were assessed by Satellite-derived images and land-use regression models. CeVD cases were confirmed by medical records and death certificates and further subdivided into ischemic and hemorrhagic stroke. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. RESULTS: A total of 1278 CeVD cases (including 777 ischemic and 133 hemorrhagic stroke cases) were identified during 127 877 person-years of follow-up. In the single-exposure models, the hazard ratios for CeVD were 1.17 (95% CI, 1.06-1.29) for outdoor LAN, 1.25 (1.12-1.39) for particulate matter with an aerodynamic diameter ≤2.5 µm, 1.14 (1.06-1.22) for particulate matter with aerodynamic diameter ≤10 µm, and 1.21 (1.06-1.38) for NO2 in every interquartile range increase. The results were similar for ischemic stroke, whereas no association was observed for hemorrhagic stroke. In the multiple-exposure models, the associations of outdoor LAN and PM with CeVD persisted but not for ischemic stroke. Furthermore, no interaction was observed between outdoor LAN and air pollution. CONCLUSIONS: Levels of exposure to outdoor LAN and air pollution were positively associated with the risk of CeVD. Furthermore, the detrimental effects of outdoor LAN and air pollution might be mutually independent.

Age at diagnosis modifies associations of type 2 diabetes with cancer incidence and mortality: a retrospective matched-cohort study.

AIMS/HYPOTHESIS: The age-specific associations between type 2 diabetes and cancer risk are not fully understood. The aim of this study was to assess how age at diagnosis modifies the associations between type 2 diabetes and cancer risk. METHODS: We used data from the Yinzhou Health Information System, and included 42,279 individuals who were newly diagnosed with type 2 diabetes between 2010 and 2014, as well as 166,010 age- and sex-matched control individuals without diabetes who were selected randomly from the electronic health records of the entire population. Patients were divided into four age groups according to age at diagnosis: <50, 50-59, 60-69 and ≥70 years. Stratified Cox proportional hazards regression models, with age as the time scale, were used to estimate the HRs and 95% CIs for the associations of type 2 diabetes with the risks of overall and site-specific cancers. Population-attributable fractions were also calculated for outcomes associated with type 2 diabetes. RESULTS: During median follow-up periods of 9.20 and 9.32 years, we identified 15,729 incident cancer cases and 5383 cancer deaths, respectively. Patients diagnosed with type 2 diabetes before 50 years of age had the highest relative risks of cancer incidence and mortality, with HRs (95% CI) of 1.35 (1.20, 1.52) for overall cancer incidence, 1.39 (1.11, 1.73) for gastrointestinal cancer incidence, 2.02 (1.50, 2.71) for overall cancer mortality, and 2.82 (1.91, 4.18) for gastrointestinal cancer mortality. Risk estimates decreased gradually with each decade increase in diagnostic age. The population-attributable fractions for overall cancer and gastrointestinal cancer mortality also decreased with increasing age. CONCLUSIONS/INTERPRETATION: The associations of type 2 diabetes with cancer incidence and mortality varied by age at diagnosis, with a higher relative risk among patients who were diagnosed at a younger age.

Application of the AngioJet Ultra Thrombectomy Device for the Percutaneous Mechanical Treatment (PMT) of Iliac Limb Occlusion after Endovascular Aneurysm Repair (EVAR).

BACKGROUND: To investigate the safety and efficacy of applying the AngioJet Ultra thrombectomy device in treating endograft occlusions in the iliac arteries following endovascular aneurysm repair (EVAR). METHODS: This study utilized a retrospective analysis of 452 patients with infrarenal abdominal aortic aneurysm (AAA). Twelve of the patients experienced iliac limb occlusion during their follow-up period, and the AngioJet Ultra thrombectomy device was used in tandem with iliac angioplasty to treat these patients. The safety of the device was assessed through the amount of blood drawn, the duration of the procedure, and the occurrence of post-operative complications, while its efficacy was assessed through aortic computed tomography angiography (CTA) imaging and post-operative symptomatology results. RESULTS: All 12 patients were male, and they had a mean age of 62.8 ± 11.8 years. Iliac limb occlusion occurred on the left side of 4 patients and on the right side of 8 patients. The AngioJet Ultra thrombectomy device was used together with iliac angioplasty during surgery, with a success rate of 100%. A bifurcated endograft was successfully implanted in 9 patients following AngioJet Ultra thrombectomy and balloon dilation angioplasty, while a unibody endograft was successfully implanted in 3 patients following AngioJet Ultra thrombectomy and balloon dilation angioplasty. The mean surgery duration was 2.4 hrs, and the patients were hospitalized for an average of 4.5 days. After surgery, the patients' intermittent claudication/buttock claudication gradually vanished. Two patients experienced hemoglobinuria, with one of them developing mild renal dysfunction. Currently, the twelve patients have been followed up for an average of 12 months, and none have experienced any lower extremity ischemia. CONCLUSIONS: The use of the AngioJet Ultra thrombectomy device as a supplementary treatment for iliac limb occlusion following abdominal EVAR is safe, effective, and minimally invasive.

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models.

The transplantation of organs across species offers the potential to solve the shortage of human organs. While activation of human platelets by human von Willebrand factor (vWF) requires vWF activation by shear stress, contact between human platelets and porcine vWF (pvWF) leads to spontaneous platelet adhesion and activation. This non-physiologic interaction may contribute to the thrombocytopenia and coagulation pathway dysregulation often associated with xenotransplantation of pig organs in nonhuman primates. Pigs genetically modified to decrease antibody and complement-dependent rejection (GTKO.hCD46) were engineered to express humanized pvWF (h*pvWF) by replacing a pvWF gene region that encodes the glycoprotein Ib-binding site with human cDNA orthologs. This modification corrected for non-physiologic human platelet aggregation on exposure to pig plasma, while preserving in vitro platelet activation by collagen. Organs from pigs with h*pvWF demonstrated reduced platelet sequestration during lung (p ≤ .01) and liver (p ≤ .038 within 4 h) perfusion ex vivo with human blood and after pig-to-baboon lung transplantation (p ≤ .007). Residual platelet sequestration and activation were not prevented by the blockade of canonical platelet adhesion pathways. The h*pvWF modification prevents physiologically inappropriate activation of human or baboon platelets by porcine vWF, addressing one cause of the thrombocytopenia and platelet activation observed with xenotransplantation.

Effect of COVID-19 on hospital visits in Ningbo, China: an interrupted time-series analysis.

OBJECTIVE: Unprecedented rigorous public health measures were implemented during the coronavirus disease 2019 (COVID-19) epidemic, but it is still unclear how the intervention influenced hospital visits for different types of diseases. We aimed to evaluate the impact of the intervention on hospital visits in Yinzhou District, Ningbo, Zhejiang province, China. METHODS: We conducted an interrupted time-series analysis from 1 January 2017 to 6 September 2020 based on the Yinzhou Health Information System in Ningbo, Zhejiang province. The beginning of the intervention was on 23 January 2020, and thus, there were 160 weeks before the intervention and 32 weeks after the implementation of the intervention. Level changes between expected and observed hospital visits in the post-intervention period were estimated using quasi-Poisson regression models. RESULTS: Compared with the expected level, there was an estimated decrease of -22.60% (95% confidence interval (CI): -27.53%, -17.36%) in the observed total hospital visits following the intervention. Observed hospital visits for diseases of the respiratory system were found to be decreased dramatically (-62.25%; 95% CI: -65.62%, -58.60%). However, observed hospital visits for certain diseases were estimated to be increased, including diseases of the nervous system (+11.17%; 95% CI: +3.21%, +19.74%); diseases of pregnancy, childbirth and the puerperium (+27.01%; 95% CI: +17.89%, +36.85%); certain conditions originating in the perinatal period (+45.05%; 95% CI: +30.24%, +61.56%); and congenital malformation deformations and chromosomal abnormalities (+35.50%; 95% CI: +21.24%, +51.45%). CONCLUSIONS: Our findings provided scientific evidence that cause-specific hospital visits evolve differently following the intervention during the COVID-19 epidemic.

Modulating IgG effector function by Fc glycan engineering.

IgG antibodies contain a conserved N-glycosylation site on the Fc domain to which a complex, biantennary glycan is attached. The fine structures of this glycan modulate antibody effector functions by affecting the binding affinity of the Fc to diverse Fc receptor family members. For example, core fucosylation significantly decreases antibody-dependent cellular cytotoxicity (ADCC), whereas terminal α2,6-sialylation plays a critical role in the anti-inflammatory activity of human i.v. immunoglobulin therapy. The effect of specific combinations of sugars in the glycan on ADCC remains to be further addressed, however. Therefore, we synthesized structurally well-defined homogeneous glycoforms of antibodies with different combinations of fucosylation and sialylation and performed side-by-side in vitro FcγR-binding analyses, cell-based ADCC assays, and in vivo IgG-mediated cellular depletion studies. We found that core fucosylation exerted a significant adverse effect on FcγRIIIA binding, in vitro ADCC, and in vivo IgG-mediated cellular depletion, regardless of sialylation status. In contrast, the effect of sialylation on ADCC was dependent on the status of core fucosylation. Sialylation in the context of core fucosylation significantly decreased ADCC in a cell-based assay and suppressed antibody-mediated cell killing in vivo. In contrast, in the absence of fucosylation, sialylation did not adversely impact ADCC.

Generation and Comparative Kinetic Analysis of New Glycosynthase Mutants from Streptococcus pyogenes Endoglycosidases for Antibody Glycoengineering.

Chemoenzymatic glycan remodeling by endoglycosidase-catalyzed deglycosylation and reglycosylation is emerging as an attractive approach for producing homogeneous glycoforms of antibodies, and the success of this approach depends on the discovery of efficient endoglycosidases and their glycosynthase mutants. We report in this paper a systematic site-directed mutagenesis of an endoglycosidase from Streptococcus pyogenes (Endo-S) at the critical Asp-233 (D233) site and evaluation of the hydrolysis and transglycosylation activities of the resulting mutants. We found that in addition to the previously identified D233A and D233Q mutants of Endo-S, most of the Asp-233 mutants discovered here were also glycosynthases that demonstrated glycosylation activity using glycan oxazoline as the donor substrate with diminished hydrolytic activity. The glycosynthase activity of the resultant mutants varied significantly depending on the nature of the amino acid substituents. Among them, the D233M mutant was identified as the most efficient glycosynthase variant with the highest transglycosylation/hydrolysis ratio, which is similar to the recently reported D184M mutant of Endo-S2, another S. pyogenes endoglycosidase. Kinetic studies of the D233M and D233A mutants of Endo-S, as well as glycosynthase mutants D184M and D184A of Endo-S2, indicated that the enhanced catalytic efficacy of the Asp-to-Met mutants of both enzymes was mainly due to an increased turnover number (increased kcat) for the glycan oxazoline substrate and the significantly enhanced substrate affinity (as judged by the reduced KM value) for the antibody acceptor.

One-pot enzymatic glycan remodeling of a therapeutic monoclonal antibody by endoglycosidase S (Endo-S) from Streptococcus pyogenes.

A facile, one-pot enzymatic glycan remodeling of antibody rituximab to produce homogeneous high-mannose and hybrid type antibody glycoforms is described. This method was based on the unique substrate specificity of the endoglycosidase S (Endo-S) from Streptococcus pyogenes. While Endo-S efficiently hydrolyzes the bi-antennary complex type IgG Fc N-glycans, we found that Endo-S did not hydrolyze the "ground state" high-mannose or hybrid glycoforms, and only slowly hydrolyzed the highly activated high-mannose or hybrid N-glycan oxazolines. Moreover, we found that wild-type Endo-S could efficiently use high-mannose or hybrid glycan oxazolines for transglycosylation without product hydrolysis. The combination of the remarkable difference in substrate specificity of Endo-S allows the deglycosylation of heterogeneous rituximab and the transglycosylation with glycan oxazoline to take place in one-pot without the need of isolating the deglycosylated intermediate or changing the enzyme to afford the high-mannose type, hybrid type, and some selectively modified truncated form of antibody glycoforms.

Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeling.

Glycosylation can exert a profound impact on the structures and biological functions of antibodies. Glycosylation remodeling using the endoglycosidase-catalyzed deglycosylation and transglycosylation approach is emerging as a promising platform to produce homogeneous glycoforms of antibodies, but the broad application of this method will require the availability of highly efficient glycosynthase mutants. We describe in this paper a systematic site-directed mutagenesis of an endoglycosidase from Streptococcus pyogenes of serotype M49 (Endo-S2) and the evaluation of the resulting mutants for their hydrolysis and transglycosylation activities. We found that mutations at the Asp-184 residue gave mutants that demonstrated significantly different properties, some possessed potent transglycosylation activity with diminished hydrolysis activity but others did not, which would be otherwise difficult to predict without the comparative study. In contrast to the previously reported Endo-S mutants that are limited to action on complex type N-glycans, the Endo-S2 glycosynthases described here, including D184M and D184Q, were found to have remarkably relaxed substrate specificity and were capable of transferring three major types (complex, high-mannose, and hybrid type) of N-glycans for antibody glycosylation remodeling. In addition, the Endo-S2 glycosynthase mutants were found to be much more active in general than the Endo-S mutants for transglycosylation. The usefulness of these Endo-S2 glycosynthase mutants was exemplified by an efficient glycosylation remodeling of two therapeutic monoclonal antibodies, rituximab and trastuzumab (Herceptin).

Synthesis of N-acetyl-d-quinovosamine in Rhizobium etli CE3 is completed after its 4-keto-precursor is linked to a carrier lipid.

Bacterial O-antigens are synthesized on lipid carriers before being transferred to lipopolysaccharide core structures. Rhizobium etli CE3 lipopolysaccharide is a model for understanding O-antigen biological function. CE3 O-antigen structure and genetics are known. However, proposed enzymology for CE3 O-antigen synthesis has been examined very little in vitro, and even the sugar added to begin the synthesis is uncertain. A model based on mutagenesis studies predicts that 2-acetamido-2,6-dideoxy-d-glucose (QuiNAc) is the first O-antigen sugar and that genes wreV, wreQ and wreU direct QuiNAc synthesis and O-antigen initiation. Previously, synthesis of UDP-QuiNAc was shown to occur in vitro with a WreV orthologue (4,6-hexose dehydratase) and WreQ (4-reductase), but the WreQ catalysis in this conventional deoxyhexose-synthesis pathway was very slow. This seeming deficiency was explained in the present study after WreU transferase activity was examined in vitro. Results fit the prediction that WreU transfers sugar-1-phosphate to bactoprenyl phosphate (BpP) to initiate O-antigen synthesis. Interestingly, WreU demonstrated much higher activity using the product of the WreV catalysis [UDP-4-keto-6-deoxy-GlcNAc (UDP-KdgNAc)] as the sugar-phosphate donor than using UDP-QuiNAc. Furthermore, the WreQ catalysis with WreU-generated BpPP-KdgNAc as the substrate was orders of magnitude faster than with UDP-KdgNAc. The inferred product BpPP-QuiNAc reacted as an acceptor substrate in an in vitro assay for addition of the second O-antigen sugar, mannose. These results imply a novel pathway for 6-deoxyhexose synthesis that may be commonly utilized by bacteria when QuiNAc is the first sugar of a polysaccharide or oligosaccharide repeat unit: UDP-GlcNAc → UDP-KdgNAc → BpPP-KdgNAc → BpPP-QuiNAc.

In vitro biosynthesis and chemical identification of UDP-N-acetyl-d-quinovosamine (UDP-d-QuiNAc).

N-acetyl-d-quinovosamine (2-acetamido-2,6-dideoxy-d-glucose, QuiNAc) occurs in the polysaccharide structures of many Gram-negative bacteria. In the biosynthesis of QuiNAc-containing polysaccharides, UDP-QuiNAc is the hypothetical donor of the QuiNAc residue. Biosynthesis of UDP-QuiNAc has been proposed to occur by 4,6-dehydration of UDP-N-acetyl-d-glucosamine (UDP-GlcNAc) to UDP-2-acetamido-2,6-dideoxy-d-xylo-4-hexulose followed by reduction of this 4-keto intermediate to UDP-QuiNAc. Several specific dehydratases are known to catalyze the first proposed step. A specific reductase for the last step has not been demonstrated in vitro, but previous mutant analysis suggested that Rhizobium etli gene wreQ might encode this reductase. Therefore, this gene was cloned and expressed in Escherichia coli, and the resulting His6-tagged WreQ protein was purified. It was tested for 4-reductase activity by adding it and NAD(P)H to reaction mixtures in which 4,6-dehydratase WbpM had acted on the precursor substrate UDP-GlcNAc. Thin layer chromatography of the nucleotide sugars in the mixture at various stages of the reaction showed that WbpM converted UDP-GlcNAc completely to what was shown to be its 4-keto-6-deoxy derivative by NMR and that addition of WreQ and NADH led to formation of a third compound. Combined gas chromatography-mass spectrometry analysis of acid hydrolysates of the final reaction mixture showed that a quinovosamine moiety had been synthesized after WreQ addition. The two-step reaction progress also was monitored in real time by NMR. The final UDP-sugar product after WreQ addition was purified and determined to be UDP-d-QuiNAc by one-dimensional and two-dimensional NMR experiments. These results confirmed that WreQ has UDP-2-acetamido-2,6-dideoxy-d-xylo-4-hexulose 4-reductase activity, completing a pathway for UDP-d-QuiNAc synthesis in vitro.

[Value of fractional flow reserve measurement in intracavitary therapy for patients with moderate renal artery stenosis].

OBJECTIVE: To analyze the value of fractional flow reserve (FFR) measurement on endovascular therapy for patients with renal artery stenosis. METHODS: Clinical data of 9 patients underwent endovascular therapy due to moderate renal artery stenosis (50%-69%) in Anzhen hospital from May to September 2013 were retrospectively analyzed. Fractional flow reserve (FFR) were measured in patients with moderate stenosis in renal artery and abnormal glomerular filtration rate (GFR) or different between renal artery angiography and ultrasound before the procedure. Endovascular therapy was not applied for patients with FFR > 0.90, and the patients were subsequently followed up clinically. Endovascular therapy was applied in patients with FFR less than 0.90 or the pressure difference between the two ends of stenosis was more than 20 mmHg (1 mmHg = 0.133 kPa). Blood pressure, ultrasound and contrast-enhanced ultrasonography data were obtained at 1 and 3 months later, respectively. RESULTS: There were 6 patients diagnosed as severe renal artery stenosis (≥ 70%) and the other 3 patients diagnosed as moderate renal artery stenosis by renal artery ultrasound before operation. Two patients with FFR > 0.90 were not undertaken the endovascular therapy. Seven patients with FFR < 0.90 underwent endovascular therapy. After renal artery stenting, renal stenosis was relieved immediately and the transstent blood flow was fluency in these 7 patients. There was significant difference in the FFR before and after operation (0.81 ± 0.09 vs.0.94 ± 0.03, P = 0.008). Among the patients underwent endovascular therapy, blood pressure was normal without medication in 2 patients and well controlled with 1 or 2 combined antihypertensive drugs in the rest 5 patients. CONCLUSION: In patients with moderate renal artery stenosis, fractional flow reserve measurement could be used as a useful index to guide intervention procedure and to evaluate the efficacy of endovascular therapy.

[Efficacy of personalized endovascular repair using two stent-grafts for patients with Stanford B aortic dissection].

OBJECTIVE: To observe the feasibility and clinical efficacy of thoracic endovascular aortic repair (TEVAR) for patients with Stanford B aortic dissection using personalized two stent-grafts implantation (TSI). METHODS: This retrospective review included 56 patients who underwent TSI during TEVAR for Stanford B aortic dissection from Jan 2012 to May 2013 in Beijing Anzhen hospital. There were 8 patients in acute phase (within 2 weeks from onset of symptoms), 11 patients in chronic phase (greater than 2 months following initial dissection) and 37 patients in subacute phase (between 2 weeks and 2 months from onset of symptoms). Infrarenal aorta was involved in 34 patients (60.7%) and suprarenal aorta involved in 22 patients (39.3%), the mean aortic lesion length was (226 ± 13)mm. Thoracic and abdominal aortic angiography was performed during operation to measure aortic diameters of proximal and distal landing zone, and the distance between them. The proximal stent-grafts were implanted in distal aorta to the origin of left subclavian artery with oversize rate of 10%-15% according to proximal landing zone according to procedural guideline. Then the distal newly customized large tapered stent-grafts were sequentially deployed according to the diameters of both the distal end of proximal stent and distal landing zone (aortic true lumen), and overlapping length of the two stent-grafts was more than 30 mm. Patients were followed-up at 3 months, 6 months, and yearly thereafter post operation. RESULTS: TSI procedure was successful in all patients and 122 stent-grafts were implanted. The mean length of implanted stent-grafts was (197.6 ± 20.3)mm. The mean diameter taper span was (7.5 ± 1.8)mm with proximal oversize rate of (12.8 ± 3.4)% and distal oversize rate of (11.2 ± 4.1)%. The mean angle between the distal end of stent and aorta was (2.3 ± 1.3)°. The diameter of proximal and distal landing zone, and angle between the distal end of stent and aorta remained unchanged during follow up (mean: (10.0 ± 4.0) months). The total thrombosis rate of the false lumen was 98.2% (55/56), thrombosis rate of stent segment was 82.1% (46/56) . Stent-related complications were observed in 2 patients (3.6%) , including acute spinal cord ischemia due to paraplegia (n = 1) and malposition of distal stent (n = 1). CONCLUSIONS: Encouraging short-term outcomes are obtained from current personalized two stent-grafts implantation strategy for patients with Stanford B aortic dissection. Further prospective clinical studies are warranted to evaluate the long-term efficacy of this procedure.

Stability analysis of pumped storage hydropower plant in abandoned open-pit mine affected by dynamic surface subsidence of combined mining.

The construction of a pumped storage hydropower plant (PSHP) in an abandoned open-pit mine is a potential alternative to green mining and energy storage, which can increase the utilization rate of renewable energy and develop residual resources of abandoned mines. Dynamic surface subsidence affected by combined underground and open-pit mining (CUOPM) seriously affects the construction and operation of the PSHP and is one of the critical scientific issues that needs to be solved immediately. The stability of the PSHP was analyzed and treatment scheme of the goafs was proposed based on on-site measurement, theoretical analysis, and numerical simulation. First, the distribution of goafs in the Haizhou open-pit mining area was investigated and surface subsidence value was obtained using InSAR technology and ground monitoring. Secondly, the surface subsidence mechanism affected by CUOPM is analyzed and indicates the subsidence maximum values and scope of influence are greater than those of single underground mining. A dynamic surface subsidence prediction model for combined mining is established based on the Knothe time function model. Thirdly, based on the CVISC model, the numerical calculation models were established by using FLAC3D, and the characteristics and laws of surface subsidence in different periods of CUOPM were studied. The comparative analysis of the observation results shows that the proposed model and numerical simulation calculation method have excellent applicability and accuracy. Finally, a stability evaluation method of PSHP was established, and the results of the evaluation show that the affected areas are the semi-ground powerhouse (SGPH) and the west side of the lower reservoir. The method of grouting filling was used to treat the goafs, and the results showed that it effectively alleviates the dynamic surface subsidence affected by CUOPM, and provides a safety guarantee for PSHP.

Association between visit-to-visit lipid variability and risk of ischemic heart disease: a cohort study in China.

AIMS: To explore the associations between visit-to-visit lipid variability and risk of ischemic heart disease (IHD) in a population-based cohort in China. METHODS: We evaluated lipid variability in 30,217 individuals from the Yinzhou Health Information System who had ≥3 recorded lipid measurements during 2010-2014. We used various indicators including standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV) to quantify the variability in triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Overall, a total of 1305 participants with IHD were identified during the follow-up of 194,421 person-years. Subjects in Q4 had a 21% elevated risk of IHD (HR = 1.21, 95% CI: 1.03-1.41) for LDL-C variability (CV) compared with the reference (Q1). The HRs for Q4 vs Q1 were 1.21 (95% CI: 1.04-1.42) for HDL-C variability, and 1.28 (95% CI: 1.10-1.50) for TC variability. However, no association was observed between triglycerides variability and risk of IHD. CONCLUSIONS: Higher variability in LDL-C, HDL-C, and TC levels was associated with an elevated risk of IHD, suggesting that lipid variability could be considered as an independent risk factor of IHD.

Estimation of cancer mortality attributable to excess body weight during 2006-2015 in China.

BACKGROUND: Cancer is one of the most common causes of death. Excess body weight (EBW), a risk factor for cancer, is highly prevalent in China. We aimed to estimate the number and proportion of cancer deaths attributed to EBW and their changes during 2006-2015 in China. METHODS: Population attributable fractions in 2006, 2010, and 2015 were calculated with 1) prevalence of overweight/obesity, exacted from the China Health and Nutrition Survey conducted in 8-9 provinces of China in 1997, 2000, and 2004; 2) relative risks for EBW and site-specific cancers, obtained from previous studies; 3) data on cancer deaths in 2006, 2010, and 2015, originated from the Chinese Cancer Registry Annual Report. RESULTS: In 2015, EBW contributed to 45,918 (3.1% of all) cancer deaths in China, with 24,978 (2.6%) in men and 20,940 (3.8%) in women. By region, the fraction of cancer deaths attributable to EBW ranged from 1.6% (West) to 4.1% (Northeast). Cancers of liver, stomach, and colorectum were the main EBW-attributable cancers. The fractions of cancer deaths attributable to EBW were 2.4% (95%CI: 0.8-4.2%) in 2006, 2.9% (95%CI: 1.0-5.2%) in 2010, and 3.1% (95%CI: 1.0-5.4%) in 2015, respectively, and increased for all gender, region, and cancer site during 2006-2015. CONCLUSIONS: The proportion of cancer deaths attributed to EBW was higher in women and Northeastern China, with an upward trend in the recent decade. A combination of comprehensive and individualized measures is necessary to reduce the prevalence of EBW and related cancer burden in China.

Association of walkability and NO2 with metabolic syndrome: A cohort study in China.

BACKGROUND: Epidemiological studies have reported an association between traffic-related pollution with risk of metabolic syndrome (MetS). However, evidence from prospective studies on the association of walkability and nitrogen dioxide (NO2) with MetS is still scarce. We, therefore, aimed to evaluate the association of long-term exposure to NO2 and walkability with hazards of incident MetS. METHODS: A total of 17,965 participants without MetS diagnosed within one year at baseline were included in our study from a population-based prospective cohort in Yinzhou District, Ningbo, Zhejiang Province, China. Participants were followed up by the regional Health Information System (HIS) until December 15, 2021. MetS was defined based on the criteria of Chinese Diabetes Society (CDS2004). We used walkscore tools, calculating with amenity categories and decay functions, and spatial-temporal land-use regression (LUR) models to estimate walkability and NO2 concentrations. We used Cox proportional hazards regression models to examine the association of walkability and NO2 with hazards of MetS incidence reporting with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Overall, we followed up 77,303 person-years and identified 4040 incident cases of MetS in the entire cohort. Higher walkability was inversely associated with incident MetS (HR = 0.94, 95 % CI: 0.91-0.99), whereas NO2 was positively associated with MetS incidence (HR = 1.07, 95 %CI: 1.00-1.15) per interquartile range increment in two-exposure models. Furthermore, we found a significant multiplicative interaction between walkability and NO2. Stronger associations were observed for NO2 and incident MetS among men, smokers, drinkers and participants who aged < 60 years and had higher levels of income. CONCLUSION: In summary, we found living in areas with lower walkability and higher concentrations of NO2 were associated with increased incidence of MetS. The beneficial effect of higher walkability may be attenuated by exposure to NO2.

Baseline and longitudinal trajectories of body-mass index and all-cause mortality among patients with type 2 diabetes.

AIM: To investigate the associations of baseline body mass index (BMI) and longitudinal BMI trajectories with all-cause mortality among patients with type 2 diabetes mellitus (T2DM). METHODS,: We used data from the diabetes surveillance system of Yinzhou Health Information System with T2DM patients registered from 2010 to 2015. Participants aged ≥ 40 years were included and were followed up until September 30, 2021. The latent class growth mixture model was used to identify different changing patterns in BMI for 5 years from registration. Cox proportional hazards models were used to examine the associations of baseline BMI and 5-year BMI trajectories with all-cause mortality. RESULTS: We observed a nonlinear association between baseline BMI and all-cause mortality (P for nonlinearity < 0.001), with an increased risk of death for low but not high BMI. However, compared with participants with medium-stable BMI for 5 years from baseline, individuals with increasing BMI had higher mortality, with adjusted hazard ratios (95% confidence intervals) 1.21 (1.02;1.43) for early-increasing and 1.47 (1.19;1.80) for late-sharp increasing groups. CONCLUSION: These findings suggest that while obesity itself may not be associated with an increased risk for mortality, weight gain, and in particular rapid weight gain, is a risk factor for mortality among patients with T2DM.

Association of walkability and fine particulate matter with chronic obstructive pulmonary disease: A cohort study in China.

BACKGROUND: Walkability has been considered to be associated with metabolic and cardiovascular diseases, but the relationship between walkability and chronic obstructive pulmonary disease (COPD) remains unclear. Moreover, fine particulate matter (PM2.5), possibly positively correlated to walkability, may lead to an increased risk of COPD. The separate and joint effects of PM2.5 and walkability on risk of COPD were explored in our study. METHODS: We used prospective data of 29,572 participants from the Yinzhou cohort in Ningbo, China. COPD cases were diagnosed based on the Yinzhou Health Information System (YHIS). Walkability was measured using walk score in relation to the built environment based on geographic information systems (GIS). Air pollution levels were assessed by fitting land use regression (LUR) models. Cox proportional hazards models were used to evaluate the relationships of PM2.5 and walkability with COPD. Furthermore, we also examined additive and multiplicative interactions between walkability and PM2.5. RESULTS: Overall, a total of 29,572 participants were included in the final analysis and 722 COPD incident cases were identified during 134,846 person-years of follow-up. Compared with subjects with lower walkability, individuals with higher walkability had a decreased risk of COPD (HR = 0.88, 95 % CI: 0.82-0.95) for every IQR increase. By contrast, exposure to PM2.5 (every IQR increase) was associated with an elevated risk of COPD (HR = 1.21, 95 % CI: 1.06-1.37). No interaction between PM2.5 and walkability was observed. CONCLUSIONS: Living in a highly walkable neighborhood could decrease risk of COPD, whereas high levels of PM2.5 were positively associated with COPD. In addition, the beneficial effects of walkability were not attenuated by exposure to PM2.5.