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Dyslipolysis of adipocytes plays a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, the degree of adipocyte lipolysis related to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. Herein, the visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in cerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue–specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/obAP models. This study indicated that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mouse AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis aggravated AP. Genetic blockage of ATGL specifically in adipocytes alleviated the damage to AP. The application of atglistatin effectively protected against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Hypertriglyceridemia (HTG) is the third most common cause of acute pancreatitis (AP), and the incidence of HTG-induced AP (HTG-AP) is rising worldwide as a result of changes in lifestyle and dietary habits. In China, HTG accounts for 10% to 20% of the causes of AP, even becoming the second leading cause of AP. The presentation and diagnosis of HTG-AP is similar to that of AP from other causes, however, the complication rates and severe AP are significantly higher in patients with HTG-AP than in patients with other etiologies. Regarding the management of HTG-AP, the initial management is similar to that of AP from other causes and mainly includes fluid resuscitation, pain control, and nutritional support. In addition to supportive care, it is necessary to take appropriate measures to decrease serum TG levels, in order to alleviate the progression of AP and prevent recurrence. This review aims to summarize existing clinical and basic research evidence of HTG-AP and seeks to highlight the epidemiology, definition, pathogenesis, clinical course, diagnosis, management, prevention of recurrence, and specific clinical scenarios, such as HTG-AP during pregnancy, HTG-AP with diabetic ketoacidosis.

Background and aims: The optimal energy delivery for mechanically ventilated patients is controversial, particularly during the first week of ICU admission. This study aimed to investigate the association between different caloric adequacy and 28-day mortality in a cohort of critically ill adults on mechanical ventilation. Methods: This is a secondary analysis of a multicenter, cluster-randomized controlled trial. Eligible patients were divided into four quartiles (Q1-Q4) according to caloric adequacy calculated by the actual average daily energy delivery during the first seven days of ICU stay divided by energy requirement as a percentage. Cox proportional hazards models were used to examine the impact of different quartiles of caloric adequacy on 28-day mortality in the whole cohort and subgroups with different nutritional risk status at enrollment. Results: A total of 1587 patients were included in this study, with an overall 28-day mortality of 15.8%. The average caloric adequacy was 26.3 ± 11.9% (Q1), 52.5 ± 5.5% (Q2), 71.7 ± 6.4% (Q3), 107.0 ± 22.2% (Q4), respectively (p< 0.001 among quartiles). Compared with Q1, Q3 was associated with lower mortality in the unadjusted model (hazard ratio [HR] = 0.536; 95% confidence interval [CI], 0.375–0.767; P= 0.001) and adjusted model (adjusted HR = 0.508; 95% CI, 0.339–0.761; P= 0.001). This association remained valid in the subgroup of high nutritional risk patients (unadjusted HR = 0.387; 95% CI, 0.238–0.627; P< 0.001 and adjusted HR = 0.369; 95% CI, 0.216–0.630; P< 0.001, respectively), but not in those with low risk. Conclusions: Energy delivery near the 70% energy requirements in the first week of ICU stay was associated with reduced 28-day mortality among mechanically ventilated critically ill patients, especially in patients with high nutrition risk at admission.

Infected pancreatic necrosis (IPN) is a significant complication of acute necrotizing pancreatitis (ANP). Early identification of patients at high risk of IPN would enable appropriate treatment, but there is a lack of valid tools. This study aimed to assess the performance of the Pancreatitis Activity Scoring System (PASS) and its modifications (by removing or reducing the weight of opioid usage) in predicting IPN in a cohort of predicted severe ANP patients. Data was prospectively collected in the TRACE trial (2017–2020) involving 16 sites across China. The predictive performance of PASS, modified PASS (mPASS), and conventional indices were assessed by the area under the receiver operating characteristic curve (AUC), Hosmer‐Lemeshow Ĉ‐test, Brier score, and Fagan's nomogram. Multivariate logistic regression analysis (MLRA) was used to define the relationship between the best‐performing PASS/mPASS model and IPN. A total of 508 subjects were enrolled (median age, 43 years; 62.8% males) in the original trial, and 122 developed IPN (24%) within 90 days after randomization. Compared with non‐IPN patients, the scores of PASS and its modified models were significantly higher in the IPN patients (all p< 0.001). Among the PASS and its modifications, mPASS‐4 had the largest AUC, the lowest Brier score, and good calibration. The mPASS‐4 model demonstrated an AUC of 0.752 in predicting IPN (the optimal cut‐off for the mPASS‐4 was 292.5) and outperformed the conventional indices. The MLRA results showed that mPASS‐4 >292.5 was an independent risk factor of IPN (OR: 3.6, 95% CI: 2.1–6.3). The PASS and its modifications during the first week of ANP onset predict the development of IPN, with mPASS‐4 performing best. The mPASS‐4 model simplifies the original PASS, increasing the likelihood of clinical implementation.

Acute pancreatitis (AP) is an inflammatory disease, and NLRP3 inflammasome activation is involved in the pathogenesis of AP. Previous research showed that inhibition of NLRP3 inflammasome may exert protective effects on animal models of AP and reduces disease severity. The aim of this systematic review and meta-analysis is to evaluate the effects of drug treatment of NLRP3 inflammasome on the outcomes of experimental AP. PubMed, Embase, Medline, and Web of Science databases were searched for relevant articles without language restrictions. The main outcomes for this study included local pancreatic injury, the incidence of systemic inflammatory responses, and the incidence of organ failure. Twenty-eight animal studies including 556 animals with AP were included in the meta-analysis. Compared with controls, inhibition of NLRP3 inflammasome significantly reduced the pancreatic histopathological scores, serum amylase, and lipase levels. In addition, inhibition of NLRP3 inflammasome reduced the levels of circulating inflammatory cytokines, as well as mitigating severity of AP-associated acute lung injury and acute intestinal injury. To conclude, inhibition of NLRP3 inflammasome has protective effects on AP by mitigating organ injury and systemic inflammation in animal studies, indicating that NLRP3 inflammasome holds promise as a target for specific AP therapy.

ABSTRACTAcute pancreatitis (AP) is one of the most widespread clinical emergencies. Macrophages are the most common immune cells in AP pancreatic tissue and are closely associated with pancreatic necrosis and recovery. The level of heparin-binding protein (HBP) is closely linked to inflammation. In this study, we assessed the effect of HBP on AP tissue necrosis severity and whether HBP is associated with M1 macrophages in pancreatic necrosis. We observed the dynamic changes of HBP levels in the pancreas during acute inflammation in the caerulein-induced AP mice model. We used hematoxylin–eosin staining to evaluate pancreatic edema and necrosis, and to detect infiltration of macrophages by immunohistochemistry. Moreover, expressions of the maker and cytokines of macrophages, including inducible nitric oxide synthase (iNOS), and arginase 1 (Arg-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNA, were detected by real-time polymerase-chain reaction (RT-PCR). High levels of HBP in the pancreas were detected at 48 h, and heparin inhibited HBP expression in AP pancreatic tissue. Inhibiting HBP expression by injecting heparin before AP can alleviate pancreatic necrosis and inhibit F4/80 labeled M1 macrophage infiltration and IL-6, TNF-α, and iNOS mRNA expression. Clodronate liposome (CLDL) intraperitoneally treated mice showed no change in pancreatic HBP levels, but pancreatic macrophage-specific antigen F4/80 and TNF-α, IL-1β, and IL-6 mRNA levels decreased after CLDL treatment. HBP is critical for pancreatic necrosis response in acute pancreatitis by increasing the infiltration of M1 macrophages and promoting the secretion of inflammatory factors, such as TNF-α, IL-6, IL-1β, which can be reduced by heparin.

Rechargeable aqueous zinc-ion batteries (ZIBs) have been proven to be an alternative energy storage system because of their high safety, low cost, and eco-friendliness. However, the poor stability of metallic Zn anodes suffering from uncontrolled dendrite formation and electrochemical corrosion has brought troublesome hindrances for their practical application. In this work, we report a dual porous Zn-3D@600 anode prepared by coating a Zn@C protective layer on a 3D zinc skeleton. The Zn-3D@600 anode exhibits a highly stable and low polarization voltage during the Zn plating/stripping process and possesses a smooth and dendrite-free interface after long-term cycling. Moreover, the assembled Zn-3D@600 cell shows excellent cycle stability and superlative rate performance, delivering a discharge capacity of 198.8 mAh g–1after 1000 cycles at 1 A g–1. Such excellent electrochemical performance can be credited to the Zn@C protective layer regulating uniform Zn nucleation and the 3D zinc skeleton accommodating Zn deposition at a high current density.

Background:Gestational diabetes mellitus (GDM) is a major macrosomia risk factor. Variations in the catechol-O-methyltransferase (COMT; rs4680) genotypes are associated with heightened susceptibility to environmental exposures and nutritional conditions. However, macrosomia risks associated with COMT genetics, epigenetics, and the interaction between genetic and epigenetics among children with and without exposure to GDM are unknown.Methods:Data from women/children pairs (n= 1087) who participated in the Tianjin Gestational Diabetes Birth Cohort were used to examine the odds of being born with macrosomia associated with COMT-genotypes, 55 CpG sites located on the COMT gene, and genetic and epigenetic interactions. Odds of macrosomia associated with COMT genetic, epigenetic, genetic and epigenetic interactions, and moderations with GDM were tested using adjusted logistic regression models.Results:Overall, 16.1% (n= 175) of children were born with macrosomia. Models showed that children with at least one copy of the minor allele (A) had higher odds of macrosomia (odds ratio, 1.82; 95% confidence interval 1.25–2.64) compared with children with the GG-genotype. After false discovery rate corrections, none of the 55 CpG sites located on the COMT gene was associated with odds of macrosomia. The genetic and epigenetic associations were not modified by exposure to GDM.Conclusion:Findings suggest carriers of the COMT GG-genotype had lower odds of macrosomia, and this association was not modified by epigenetics or exposure to GDM.

Given the previously reported harmful effects of abdominal fat burden on kidney function, we aim to investigate the relationship between major adverse kidney events within 30 days (MAKE30) and abdominal obesity in acute necrotizing pancreatitis (ANP) patients and explore the underlying risk factors.

ABSTRACTBackground: We investigated the association between prenatal GDM exposure and offspring DNA methylation (DNAm) age at 3–10 years of age in the Tianjin GDM Observational Study.Methods: This study included 578 GDM and 578 non-GDM mother-child pairs. Children underwent an exam with anthropometric measurements and blood draw for DNAm analysis (Illumina 850 K array) at a median age of 5.9 years (range 3.1–10.2). DNAm age was calculated using two epigenetic clock algorithms (Horvath and Hannum). The residual resulting from regressing DNAm age on chronological age was used as a metric for age acceleration.Results: Chronological age was positively correlated with Horvath DNAm age (r = 0.53, p < 0.0001) and Hannum DNAm age (r = 0.38, p < 0.0001). Offspring age acceleration was higher in the GDM group than non-GDM group after adjustment for potential confounders (Horvath: 4.96 months higher, adjusted for sex, pre-pregnancy BMI, cell-type proportions, and technical bias, p = 0.0002; Hannum: 11.2 months higher, adjusted for cell-type proportions and technical bias, p < 0.0001). Increased offspring DNAm age acceleration was associated with increased offspring weight-for-age Z-score, BMI-for-age-Z-score, waist circumference, body fat percentage, subscapular skinfold, suprailiac skinfold, upper-arm circumference, and blood pressure; findings were stronger in the GDM group.Conclusions: We found that offspring of women with GDM exhibit accelerated epigenetic age compared to control participants, independent of other maternal factors. Epigenetic age in offspring was associated with cardiometabolic risk factors, suggesting that GDM and GDM-associated factors may have long-term effects on offspring epigenetic age and contribute to health outcomes.

To analyze the interactions between maternal gestational diabetes mellitus (GDM) and genetically determined maternal body mass index (BMI) during pregnancy on offspring childhood obesity.

Previous studies have linked short sleep duration, poor sleep quality, and late sleep timing with lower health-related quality of life (HRQoL) in children. However, almost all studies relied solely on self-reported sleep information, and most studies were conducted in high-income countries. To address these gaps, we studied both device-measured and self-reported sleep characteristics in relation to HRQoL in a sample of children from 12 countries that vary widely in terms of economic and human development.

This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM).

Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitroand pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.

Previous studies found conflicting results about the associations between the exposure to hyperglycemia in uteroand the later risks of childhood overweight and obesity. The aim of the present study is to compare the children’s BMI growth between offspring exposed to maternal gestational diabetes mellitus (GDM) and those not exposed and assess the associations between maternal GDM and their offspring’s overweight and obesity risk. We performed a large observational study in 1156 women and their offspring (578 GDM and 578 non-GDM mother–child pairs, matched by their offspring’s gender and age). Maternal GDM was diagnosed according to the World Health Organization criteria. Childhood height, weight, waist circumference, body fat and skinfold were measured using standardized methods. After adjustment for maternal and children’s characteristics, children born to mothers with GDM during pregnancy had higher mean values of Z scores for BMI-for-age, Z scores for weight-for-age, waist circumferences, body fat, subscapular skinfold and suprailiac skinfold, in comparison with their counterparts born to mothers with normal glucose during pregnancy (all Pvalues <0.05). Moreover, maternal GDM was associated with a higher risk of childhood overweight and obesity with multivariate-adjusted odds ratios of 1.42 (95% confidence interval (CI): 1.02–1.97) and 1.18 (95% CI: 1.11–1.24), respectively, compared with the children of mothers without GDM during pregnancy. This study demonstrates that maternal GDM is an independent risk factor of childhood overweight and obesity and is associated with higher BMI in the offspring.

Gestational weight gain might modify the effect of the circadian rhythm–related MTNR1Brs10830963 variant on postpartum changes in 2-hour OGTT, and vice versa, among women with a history of GDM.

ABSTRACTIntroduction: Severe acute pancreatitis (SAP) is an acute inflammatory disease with prolonged clinical course, which is complicated by the presence of persistent organ failure and severe infection. Infection mainly occurs in the late phase of SAP and it is found to be the main cause of death. Therefore, developing strategies for the prevention of SAP-related infection has been a crucial approach to improve patients’ outcomes. Due to remarkable immune-cells-regulating properties, thymosin α1 has been recognized as a promising immune therapy, especially in several infectious diseases. Recently, thymosin α1 has been given high expectations to exert clinical benefits in the prevention of SAP-related infection.Areas covered: The review of currently available strategies for SAP-related infection prevention and the use of thymosin α1 in SAP patients.Expert opinion: The current available strategies achieve limited success for preventing SAP-related infection. A possible explanation is that the trigger of infection, immunosuppression has not been concurrently resolved. The application of thymosin α1 in a clinical study showed a prophylactic effect against SAP-related infection. However, the use of thymosin α1 in SAP patients is still at an early stage of clinical investigation and requires high-quality and large sample size evidences.

To explore clinical characteristics and long-term quality of life (QOL) in severe acute pancreatitis (SAP) patients with persistent inflammation-immunosuppression and catabolism syndrome (PICS).

Step-up approach consisting of multiple minimally invasive techniques has gradually become the mainstream for managing infected pancreatic necrosis (IPN). In the present study, we aimed to compare the safety and efficacy of a novel four-step approach and the conventional approach in managing IPN. According to the treatment strategy, consecutive patients fulfilling the inclusion criteria were put into two time intervals to conduct a before-and-after comparison: the conventional group (2010–2011) and the novel four-step group (2012–2013). The conventional group was essentially open necrosectomy for any patient who failed percutaneous drainage of infected necrosis. And the novel drainage approach consisted of four different steps including percutaneous drainage, negative pressure irrigation, endoscopic necrosectomy and open necrosectomy in sequence. The primary endpoint was major complications (new-onset organ failure, sepsis or local complications, etc.). Secondary endpoints included mortality during hospitalization, need of emergency surgery, duration of organ failure and sepsis, etc. Of the 229 recruited patients, 92 were treated with the conventional approach and the remaining 137 were managed with the novel four-step approach. New-onset major complications occurred in 72 patients (78.3%) in the two-step group and 75 patients (54.7%) in the four-step group (p< 0.001). For other important endpoints, although there was no statistical difference in mortality between the two groups (p= 0.403), significantly fewer patients in the four-step group required emergency surgery when compared with the conventional group [14.6% (20/137) vs. 45.6% (42/92), p< 0.001]. In addition, stratified analysis revealed that the four-step approach group presented significantly lower incidence of new-onset organ failure and other major complications in patients with the most severe type of AP. Comparing with the conventional approach, the novel four-step approach significantly reduced the rate of new-onset major complications and requirement of emergency operations in treating IPN, especially in those with the most severe type of acute pancreatitis.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPL). However, Gpihbp1knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPLgene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/-mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/-rat pups, without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/-mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/-rat pups, and reduced the susceptibility and severity of both Gpihbp1-/-animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1deficiency.

In this study, we aimed to evaluate the predictive value of Stewart-derived parameters for the development of severe type of acute pancreatitis (AP) and for AP-related mortality.

Context:Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women and a major female-specific risk factor of obesity, impaired glucose tolerance, and diabetes.Objective:We examined whether the genetic variation predisposing to PCOS affected glycemic changes in women with prior gestational diabetes mellitus (GDM) and whether such an effect was modified by changes in body adiposity, especially during and after pregnancy.Design, Setting, and Participants:This is a longitudinal study in Tianjin, China. We genotyped 7 genome-wide association study–identified PCOS single nucleotide polymorphisms and assessed gestational weight gain and changes in glycemic traits and weight at 1 to 5 years postpartum in 1133 women with prior GDM.Main Outcome Measures:The main outcome measure was postpartum glycemic changes.Results:The PCOS genetic risk score significantly interacted with postpartum weight reduction on changes in fasting glucose and 2-h glucose (Pfor interaction = .032 and .007; respectively) after multivariable adjustment. In women with postpartum weight reduction of ≥5 kg/y, the genetic risk score was associated with decreased fasting and 2-h glucose, whereas an opposite genetic effect was found in women who lost less weight. The association between postpartum weight reduction and glycemic improvement was more significant among women with a higher genetic risk score.Conclusions:In a large cohort of Chinese women with a history of GDM, our data for the first time indicate that the genetic predisposition to PCOS may interact with postpartum weight reduction on long-term glycemic changes, emphasizing the importance of postpartum weight management in prevention of diabetes in this subgroup of women.

Objective To observe the metabolic changes in the early phase of acute pancreatitis (AP) patients induced by continuous renal replacement therapy (CRRT), and to investigate the correlation between the metabolic changes and outcomes of the AP patients.Methods We performed a retrospective analysis in the surgical intensive care unit (ICU) of a tertiary teaching hospital. A total of 169 patients diagnosed as AP were divided into 2 groups: CRRT group (n = 71) and non-CRRT group (n = 98), based on whether they received CRRT for more than 24 hours within 7 days from onset of AP. Measured energy expenditure was measured by indirect calorimetry and predicted energy expenditure was determined by specific equations on admission and day 7 (or the closest day to day 7), respectively. Meanwhile, the body composition was measured by multiple-frequency bioelectrical impedance analyzer. Blood test, body weight and vital signs were analyzed daily for both groups.Results In this study, we found a significant improvement in the hypermetabolism and fluid distribution of the CRRT group compared with the non-CRRT group. Complications, hospital and ICU length of stays were reduced in CRRT patients.Conclusions CRRT is an effective treatment for AP patients. Patients with overhydration and hypermetabolism may get improved outcomes from CRRT.

Epidemiological data on the association between body mass index (BMI) and heart failure (HF) risk among diabetic patients are rare.

Previous studies have evaluated the association of body mass index (BMI) with the risk of all-cause and cardiovascular disease mortality among diabetic patients, and results were controversial. No studies have focused on the association between BMI and stroke risk among diabetic patients. We aimed to examine the association of BMI with stroke risk among diabetic patients.

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The aim of this study was to investigate the risk factors for acute kidney injury (AKI) in patients with acute pancreatitis (AP).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic of coronavirus disease 2019 (COVID-19), which presented as not only respiratory symptoms, but various digestive manifestations have also been recognized, including pancreatic injury and acute pancreatitis (AP). The underlying mechanism is still unclear. Hypertriglyceridemia has become one of the leading causes of AP in recent years and hyperlipidemia is highly reported in COVID-19 cases. The current narrative review aimed to explore the associations between AP, COVID-19 and hyperlipidemia. Substantial cases of COVID-19 patients complicated with AP were reported, while the incidence of AP in the COVID-19 population was relatively low. Hyperlipidemia was common in COVID-19 patients with a pooled incidence of 32.98%. Hyperlipidemia could be a mediating factor in the pathogenesis of AP in COVID-19 patients. Further studies are warranted to clarify the relationship among AP, lipid metabolism disorders and COVID-19.

This study aimed to evaluate the incidence and risk factors for acute cholecystitis (AC) in the late phase of severe acute pancreatitis (SAP).