Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. 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 caerulein-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/ob AP models. This study found 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 mice AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis could aggravate AP. Genetic blockage of ATGL specifically in adipocytes was able to alleviate the damage to AP. The application of atglistatin could effectively protect 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.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout 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 Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, 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 GPIHBP1 deficiency.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

Maternal gestational diabetes and childhood adiposity risk from 6 to 8 years of age.

BACKGROUND/OBJECTIVE: Previous studies found conflicting results on the association between maternal gestational diabetes mellitus (GDM) and childhood overweight/obesity. This study was to assess the association between maternal GDM and offspring's adiposity risk from 6 to 8 years of age. METHODS: The present study longitudinally followed 1156 mother-child pairs (578 GDM and 578 non-GDM) at 5.9 ± 1.2 years postpartum and retained 912 mother-child pairs (486 GDM and 426 non-GDM) at 8.3 ± 1.6 years postpartum. Childhood body mass index (BMI), waist circumference, body fat and skinfold were measured using standardized methods. RESULTS: Compared with the counterparts born to mothers with normal glucose during pregnancy, children born to mothers with GDM during pregnancy had higher mean values of adiposity indicators (waist circumference, body fat, subscapular skinfold and suprailiac skinfold) at 5.9 and 8.3 years of age. There was a positive association of maternal GDM with changes of childhood adiposity indicators from the 5.9-year to 8.3-year visit, and ß values were significantly larger than zero: +0.10 (95% CI: 0.02-0.18) for z score of BMI for age, +1.46 (95% CI: 0.70-2.22) cm for waist circumference, +1.78% (95% CI: 1.16%-2.40%) for body fat, +2.40 (95% CI: 1.78-3.01) mm for triceps skinfold, +1.59 (95% CI: 1.10-2.09) mm for subscapular skinfold, and +2.03 (95% CI: 1.35-2.71) mm for suprailiac skinfold, respectively. Maternal GDM was associated with higher risks of childhood overweight/obesity, central obesity, and high body fat (Odd ratios 1.41-1.57 at 5.9 years of age and 1.73-2.03 at 8.3 years of age) compared with the children of mothers without GDM. CONCLUSIONS: Maternal GDM was a risk factor of childhood overweight/obesity at both 5.9 and 8.3 years of age, which was independent from several important confounders including maternal pre-pregnancy BMI, gestational weight gain, children's birth weight and lifestyle factors. This significant and positive association became stronger with age.

Interactive effects of gestational diabetes and high pre-pregnancy body mass index on adverse growth patterns of offspring.

AIMS: To examine the independent and interactive effects of maternal gestational diabetes mellitus (GDM) and high pre-pregnancy body mass index (BMI) on the risk of offspring adverse growth patterns. MATERIALS AND METHODS: One thousand six hundred and eighty one mother-child pairs were followed for 8 years in Tianjin, China. Group-based trajectory modelling was used to identify offspring growth patterns. Logistic regression was performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of GDM and high pre-pregnancy BMI for offspring adverse growth patterns. Restricted cubic spline was used to identify cut-off points. Additive interactions and multiplicative interactions were used to test interactive effects between GDM and high pre-pregnancy BMI for adverse growth patterns. RESULTS: Four distinct growth patterns were identified in offspring, including normal growth pattern, persistent lean growth pattern, late obesity growth pattern (LOGP), and persistent obesity growth pattern (POGP). Maternal high pre-pregnancy BMI was associated with LOGP and POGP (adjusted OR, 95% CI: 2.38, 1.74-3.25 & 4.92, 2.26-10.73). GDM greatly enhanced the adjusted OR of high pre-pregnancy BMI for LOGP up to 3.48 (95% CI: 2.25-5.38). Additive interactions and multiplicative interactions between both risk factors were significant for LOGP but not for POGP. CONCLUSIONS: Maternal high pre-pregnancy BMI was associated with increased risk of LOGP and POGP, whereas GDM greatly enhanced the risk of high pre-pregnancy BMI for LOGP.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

Early systemic anticoagulation reduces hospital readmission in acute necrotizing pancreatitis patients: A retrospective cohort study.

BACKGROUND: Early systemic anticoagulation (SAC) is a common practice in acute necrotizing pancreatitis (ANP), and its impact on in-hospital clinical outcomes had been assessed. However, whether it affects long-term outcomes is unknown. This study aimed to evaluate the effect of SAC on 90-day readmission and other long-term outcomes in ANP patients. METHODS: During January 2013 and December 2018, ANP patients admitted within 7 days from the onset of abdominal pain were screened. The primary outcome was 90-day readmission after discharge. Cox proportional-hazards regression model and mediation analysis were used to define the relationship between early SAC and 90-day readmission. RESULTS: A total of 241 ANP patients were enrolled, of whom 143 received early SAC during their hospitalization and 98 did not. Patients who received early SAC experienced a lower incidence of splanchnic venous thrombosis (SVT) [risk ratio (RR) = 0.40, 95% CI: 0.26-0.60, P < 0.01] and lower 90-day readmission with an RR of 0.61 (95% CI: 0.41-0.91, P = 0.02) than those who did not. For the quality of life, patients who received early SAC had a significantly higher score in the subscale of vitality (P = 0.03) while the other subscales were all comparable between the two groups. Multivariable Cox regression model showed that early SAC was an independent protective factor for 90-day readmission after adjusting for potential confounders with a hazard ratio of 0.57 (95% CI: 0.34-0.96, P = 0.04). Mediation analysis showed that SVT mediated 37.0% of the early SAC-90-day readmission causality. CONCLUSIONS: The application of early SAC may reduce the risk of 90-day readmission in the survivors of ANP patients, and reduced SVT incidence might be the primary contributor.

Involvement of transverse mesocolon is associated with development of colonic fistula in patients with acute necrotizing pancreatitis.

BACKGROUND: Involvement of transverse mesocolon (TM) during acute necrotizing pancreatitis(ANP) indicates that inflammation has spread from retroperitoneal space to peritoneum. Nevertheless, the impact of TM involvement, as confirmed by contrast-enhanced computed tomography (CECT), on local complications and clinical outcomes was poorly investigated. PURPOSE: This study aimed to explore the association between CECT-diagnosed TM involvement and the development of colonic fistula in a cohort of ANP patients. METHODS: This is a single-center, retrospective cohort study involving ANP patients admitted from January 2020 to December 2020. TM involvement was diagnosed by two experienced radiologists. The study subjects were enrolled consecutively and divided into two groups: TM involvement and non-TM involvement. The primary outcome was colonic fistula during the index admission. Clinical outcomes were compared between the two groups, and the association between the TM involvement and the development of colonic fistula was assessed using multivariable analysis to adjust for baseline unbalances. RESULTS: A total of 180 patients with ANP were enrolled, and 86 (47.8%) patients had TM involvement. The incidence of the colonic fistula is significantly higher in patients with TM involvement (16.3% vs. 5.3%;p = 0.017). Moreover, the length of hospital stay was 24(13,68) days in patients with TM involvement and 15(7,31) days in those not (p = 0.001). Analysis of multivariable logistic regression revealed that TM involvement is an independent risk factor for the development of colonic fistula (odds ratio: 10.253, 95% CI: 2.206-47.650, p = 0.003). CONCLUSION: TM involvement in ANP patients is associated with development of colonic fistula in ANP patients.

Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.

BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

Clinical and Genomic Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Isolates from Acute Pancreatitis with Infection in China.

BACKGROUND: The aim of the study was to provide a clinical treatment reference for acute pancreatitis (AP) with infection, we analyzed the clinical and genomic characteristic of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates from AP with infection in China. METHODS: Our clinical database was retrospectively analyzed with focus on the carbapenem-resistant characteristics among AP with infection in our Intensive Care Unit (ICU). Whole-genome sequencing (WGS) was used to analyze the antibiotic resistance gene, and antimicrobial susceptibility testing (AST) was performed to study the relevant phenotype in vitro. The CRISPR-Cas9 system was used to verify the relevant phenotype. RESULTS: Based on 2,211 AST data of 627 AP patients with infection, CRKP had the highest proportion among carbapenem-resistant Enterobacteriaceae (CRE), at 37.8% for imipenem and 45.3% for meropenem. WGS revealed key ß-lactamase genes, specifically blaCTX-M-15, blaCTX-M-65, blaKPC-2, blaLAP-2, blaNDM-5, blaTEM-181, blaOXA-1, and blaSHV. A total of 31.3% of CRKP were NDM-5-KPC-2-producing strains, and NDM-5-producing CRKP was resistant to imipenem/meropenem combined with avibactam, with an MIC of 512 mg/L. In addition, after knocking out blaKPC-2 and blaNDM-5, NDM-5-producing and KPC-2-producing CRKP had the same resistance level to imipenem/ meropenem. CONCLUSIONS: We first provided key insights into the clinical and genomic characteristic of CRKP in AP with infection and then made it clear that NDM-5 and KPC-2 had the same resistance level to carbapenems.

Identifying optimal ranges of weight gain at the end of the second trimester result from a population-based cohort study.

OBJECTIVE: To identify the optimal weight gain at the end of the second trimester. DESIGN: This was a population-based cohort study from the antenatal care system in Tianjin, China. We calculated gestational weight gain (GWG) based on the weight measured in the first trimester and the end of the second trimester. Restricted cubic spline analysis was performed to model the possible non-linear relationships between GWG and adverse outcomes. The optimal GWG was defined as the value of the lowest risk. Non-inferiority margins and the shape of the spline curves identified the recommended ranges in Chinese-specific BMI categories. SETTING: Tianjin Maternal and Child Health Cohort. PARTICIPANTS: Singleton pregnant women aged 18-45 years. RESULTS: In total, 69 859 pregnant women were included. Adverse outcome (including stillbirth, preterm birth, hypertensive disorders of pregnancy, gestational diabetes mellitus, small and large for gestational age) was significantly associated with GWG at the end of the second trimester. The risk score was non-linearly correlated with GWG in the underweight, normal weight and overweight groups. GWG at the end of the second trimester should not be < 7 kg in underweight group. For most normal-weight women, a GWG of about 8 kg is optimal. Pregnant women who are overweight should not have a GWG of more than 9 kg. We advised women with overweight and obesity to keep positive growth of GWG (> 0 kg) in the first and second trimesters. CONCLUSIONS: According to the comprehensive adverse maternal and infant outcomes, we recommend the optimal GWG at the end of the second trimester. This study may provide a considerable reference for weight management.

Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype-phenotype relationship for variants reported to date.

BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease. METHODS: All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing. RESULTS: Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data. CONCLUSIONS: This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.

The East Asian-specific LPL p.Ala288Thr (c.862G > A) missense variant exerts a mild effect on protein function.

BACKGROUND: Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified LPL missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare LPL missense variant. METHODS: Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in LPL and four other lipid metabolism-related genes (APOC2, APOA5, GPIHBP1 and LMF1) by Sanger sequencing. The functional consequences of the LPL missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays. RESULTS: Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific LPL missense variant, c.862G > A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of LPL wild-type and c.862G > A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~ 20% reduced secretion compared to wild-type). CONCLUSIONS: In this study, we identified the East Asian-specific LPL c.862G > A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this LPL variant may have combined with alcohol consumption to trigger HTG-AP in these patients.

Aromatic Amino Acids and Their Interactions with Gut Microbiota-Related Metabolites for Risk of Gestational Diabetes: A Prospective Nested Case-Control Study in a Chinese Cohort.

INTRODUCTION: The aim of this study was to explore associations of aromatic amino acids (AAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high AAA and gut microbiota-related metabolites had interactive effects on GDM risk. METHODS: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women from 2010 to 2012. According to the International Association of Diabetes and Pregnancy Study Group's criteria, 243 women were diagnosed with GDM. Binary conditional logistic regression was performed to examine associations of AAA with GDM risk. Interactions between AAA and gut microbiota-related metabolites for GDM were examined using additive interaction measures. RESULTS: High phenylalanine and tryptophan were associated with increased GDM risk (OR: 1.72, 95% CI: 1.07-2.78 and 1.66, 1.02-2.71). The presence of high trimethylamine (TMA) markedly increased the OR of high phenylalanine alone up to 7.95 (2.79-22.71), while the presence of low glycoursodeoxycholic acid (GUDCA) markedly increased the OR of high tryptophan alone up to 22.88 (5.28-99.26), both with significant additive interactions. Furthermore, high lysophosphatidylcholines (LPC18:0) mediated both interactive effects. CONCLUSIONS: High phenylalanine may have an additive interaction with high TMA, while high tryptophan may have an additive interaction with low GUDCA toward increased risk of GDM, both being mediated via LPC18:0.

Catheter-directed thrombolysis versus systemic anticoagulation in the treatment of symptomatic splanchnic venous thrombosis secondary to acute pancreatitis: a retrospective cohort study.

BACKGROUND: Catheter-directed thrombolysis (CDT) has been an important therapy and seems effective in patients with splanchnic venous thrombosis (SVT) secondary to some diseases, but this intervention hasn't been formally evaluated in the setting of acute pancreatitis (AP). METHODS: This was a retrospective study enrolled patients between January 2013 and December 2018. AP patients who developed SVT-induced symptoms, including intractable ascites and/or enteral nutrition intolerance, were included. Demographics, SVT associated parameters, clinical features and outcomes, long-term quality of life evaluated by using SF-36 questionnaire were compared between CDT group and systemic anticoagulation (SAC) group. RESULTS: 6 patients underwent CDT and 17 received SAC. Patients in CDT group had a higher recanalization rate (100% versus 35.3%; p = 0.014) and shorter time to symptoms resolution (median 8 days versus. 31.5 days, p = 0.004). Mortality and length of hospital stay were comparable between two groups. The association analysis indicated that CDT use exerted a significantly beneficial effect on recanalization rate (risk ratio, 2.833; 95% CI, 1.489 to 5.393; p = 0.002) and time to symptoms resolution (mean difference, -33.333; 95% CI, -64.612 to -2.055; p = 0.038). No SVT-related symptoms recurrence was recorded in survivors at six-month follow-up. There was no statistical difference in either item of SF-36 questionnaire between two groups. CONCLUSIONS: Compared with SAC, CDT may facilitate vascular recanalization and shorten symptom resolution for symptomatic SVT.

Early prenatal exposure to air pollutants and congenital heart disease: a nested case-control study.

BACKGROUND: Congenital heart disease (CHD) is one of the most common congenital malformations in humans. Inconsistent results emerged in the existed studies on associations between air pollution and congenital heart disease. The purpose of this study was to evaluate the association of gestational exposure to air pollutants with congenital heart disease, and to explore the critical exposure windows for congenital heart disease. METHODS: The nested case-control study collected birth records and the following health data in Tianjin Women and Children's Health Center, China. All of the cases of congenital heart disease from 2013 to 2015 were selected matching five healthy controls for each case. Inverse distance weighting was used to estimate individual exposure based on daily air pollution data. Furthermore, the conditional logistic regression with distributed lag non-linear model was performed to identify the association between gestational exposure to air pollution and congenital heart disease. RESULTS: A total of 8,748 mother-infant pairs were entered into the analysis, of which 1,458 infants suffered from congenital heart disease. For each 10 µg/m3 increase of gestational exposure to PM2.5, the ORs (95% confidence interval, 95%CI) ranged from 1.008 (1.001-1.016) to 1.013 (1.001-1.024) during the 1st-2nd gestation weeks. Similar weak but increased risks of congenital heart disease were associated with O3 exposure during the 1st week and SO2 exposure during 6th-7th weeks in the first trimester, while no significant findings for other air pollutants. CONCLUSIONS: This study highlighted that gestational exposure to PM2.5, O3, and SO2 had lag effects on congenital heart disease. Our results support potential benefits for pregnancy women to the mitigation of air pollution exposure in the early stage, especially when a critical exposure time window of air pollutants may precede heart development.

Relationship between time to hemostasis and outcomes of pulpotomy using iRoot BP Plus in symptomatic young permanent teeth: a prospective study.

The aim was to investigate the relationship between time to hemostasis and pulpotomy outcomes with the use of iRoot BP Plus (Innovative Bioceramics, Vancouver, Canada) for young permanent teeth of patients aged from 7 to 12 with symptomatic irreversible pulpitis and evaluate the outcomes of pulpotomy. The present study was a prospective cohort study. Two hundred and six young permanent teeth with symptomatic irreversible pulpitis underwent pulpotomy with the use of iRoot BP Plus. All patients underwent pulpotomy in accordance with a standardized protocol. Patients were postoperatively re-called after 3, 6, 12 months. Successful cases were defined according to clinical and radiographic evaluations. Main outcome measures included tooth position, cave shape, previous restoration, preoperative symptoms, time to hemostasis and outcomes. On the basis of univariate linear regression model, the relationships between time to hemostasis was evaluated, and p < 0.05 indicated a difference that achieved statistical significance. One hundred and ninety-three teeth can be evaluated after a follow-up for 6 to 36 months. The mean age of subjects was 9.43 ± 1.51 years. The overall clinical and radiographic success rate of pulpotomy reached 71.5% (138/193). After adjusting potential confounders (age, sex, previous restoration), non-linear relationship was detected between time to hemostasis and pulpotomy outcomes whose point was 4 minutes. The relationship between time to hemostasis and pulpotomy outcomes is non-linear. Pulpotomy outcomes was negatively related with time to hemostasis when time to hemostasis is more than 4 minutes.

Predictive value of serum cholinesterase in the mortality of acute pancreatitis: A retrospective cohort study.

BACKGROUND: Severe acute pancreatitis has a high mortality of 20%-40%, but there is a lack of optimal prognostic biomarker for the severity of acute pancreatitis (AP) or mortality. This study is designed to investigate the relationship between serum cholinesterase (ChE) level and poor outcomes of AP. METHODS: A total of 1904 AP patients were screened in the study, and we finally got 692 patients eligible for analysis. Patients were divided into 2 groups based on serum ChE. The primary outcome was mortality, and multivariable logistic regression analysis for mortality was completed. Additionally, we used receiver operating characteristic (ROC) curve analysis to clarify the predictive value of serum ChE for mortality and organ failure. RESULTS: Three hundred and seventy eight patients and 314 patients were included in the ChE-low and ChE-normal group, respectively. Patients in the ChE-low group were older (46.68 ± 12.70 vs. 43.56 ± 12.13 years old, p = .001) and had a lower percentage of man (62.4% vs. 71.0%, p = .017) when compared to the ChE-normal group. Mortality was significantly different in two groups (10.3% vs. 0.0%, p < .001). Moreover, organ failure also differed significantly in two groups (46.6% vs. 8.6%, p < .001). Decreased ChE level was independently associated with mortality in acute pancreatitis (odds ratio: 0.440; 95% confidence interval, 0.231, 0.838, p = .013). The area under the curve of serum ChE was 0.875 and 0.803 for mortality and organ failure, respectively. CONCLUSIONS: Lower level of serum ChE was independently associated with the severity and mortality of AP.

Incidence and risk factors of nasogastric feeding intolerance in moderately-severe to severe acute pancreatitis.

BACKGROUND: The importance of enteral nutrition (EN) in acute pancreatitis (AP) has been emphasised. Nasogastric (NG) feeding has been the preferred route for EN delivery in most AP patients intolerant to oral intake. However, gastric feeding intolerance (GFI) was frequently reported, especially in patients with more severe diseases. This study aimed to investigate the incidence and risk factors for GFI in moderately-severe to severe AP. METHODS: This is a single-centre, retrospective study. All the data were extracted from an electronic database from April 2020 to May 2021. Data were prospectively collected during hospitalisation. Patients diagnosed with moderately-severe to severe AP and admitted within seven days from the onset of abdominal pain were assessed for eligibility. Patients who showed signs of intolerance to gastric feeding and required switching to nasojejunal (NJ) feeding were deemed GFI. Multivariable logistic regression was performed to assess potential risk factors of GFI. RESULTS: A total of 93 patients were analysed, of whom 24 were deemed GFI (25.8%), and the rest tolerated NG feeding well (n = 69). In patients with GFI, the median time of switching to NJ feeding was five days (interquartile range: 4-7 days) after admission. The multivariable analysis showed that respiratory failure (odds ratio = 3.135, 95% CI: 1.111-8.848, P = 0.031) was an independent risk factor for GFI.The mean daily energy delivery in the following three days after switching to NJ feeding was significantly higher than the first three days after initiation of NG feeding in patients with GFI [920.83 (493.33-1326) vs. 465 (252.25-556.67) kcal, P < 0.001]. CONCLUSION: GFI is common in moderately-severe to severe AP patients with an incidence of 25.8%, and the presence of respiratory failure may increase the risk of GFI.