Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease.

Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Role of CFTR in diabetes-induced pancreatic ductal fluid and HCO3 - secretion.

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild-type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO3 - secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real-time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme-linked immunosorbent assay. Ductal fluid and HCO3 - secretion, CFTR activity, and the expression of CFTR, Na+ /H+ exchanger-1, anoctamine-1 and aquaporin-1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO3 - secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO3 - secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO3 - secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. KEY POINTS: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditions The most common disease affecting the endocrine part is type-1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiency Compared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO3 - produced by ductal cells is essential for maintaining normal pancreatic functions Ductal fluid and HCO3 - secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role. We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue.

Restoring CFTR function with Orkambi decreases the severity of alcohol-induced acute pancreatitis.

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

Detailed Characteristics of Post-discharge Mortality in Acute Pancreatitis.

BACKGROUND & AIMS: The in-hospital survival of patients suffering from acute pancreatitis (AP) is 95% to 98%. However, there is growing evidence that patients discharged after AP may be at risk of serious morbidity and mortality. Here, we aimed to investigate the risk, causes, and predictors of the most severe consequence of the post-AP period: mortality. METHODS: A total of 2613 well-characterized patients from 25 centers were included and followed by the Hungarian Pancreatic Study Group between 2012 and 2021. A general and a hospital-based population was used as the control group. RESULTS: After an AP episode, patients have an approximately threefold higher incidence rate of mortality than the general population (0.0404 vs 0.0130 person-years). First-year mortality after discharge was almost double than in-hospital mortality (5.5% vs 3.5%), with 3.0% occurring in the first 90-day period. Age, comorbidities, and severity were the most significant independent risk factors for death following AP. Furthermore, multivariate analysis identified creatinine, glucose, and pleural fluid on admission as independent risk factors associated with post-discharge mortality. In the first 90-day period, cardiac failure and AP-related sepsis were among the main causes of death following discharge, and cancer-related cachexia and non-AP-related infection were the key causes in the later phase. CONCLUSION: Almost as many patients in our cohort died in the first 90-day period after discharge as during their hospital stay. Evaluation of cardiovascular status, follow-up of local complications, and cachexia-preventing oncological care should be an essential part of post-AP patient care. Future study protocols in AP must include at least a 90-day follow-up period after discharge.

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

Head-to-head comparison of influenza vaccines in children: a systematic review and meta-analysis.

Although vaccination is considered the most effective weapon against influenza, coverage rates, national vaccination policies, and funding vary largely around the globe. Despite their huge potential for achieving herd immunity, child-focused national vaccination strategies that favor pain-free nasal vaccines are uncommon. CENTRAL, Embase, and MEDLINE were last searched on November 13, 2023. Active-controlled randomized controlled trials comparing the live-attenuated intranasal vaccine with the inactivated intramuscular influenza vaccine in children were included. Event rates of laboratory-confirmed influenza virus infection, all-cause mortality, hospitalization, serious adverse events, adverse events, and financial outcomes were extracted based on the PRISMA 2020 Guideline. PROSPERO: CRD42021285412. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the random-effects model when at least three comparable outcomes were available. We found no significant difference between quadrivalent live-attenuated intranasal and trivalent inactivated intramuscular (OR = 1.48; 95% CI 0.49-4.45) or between trivalent live-attenuated intranasal and inactivated intramuscular vaccines (OR = 0.77, CI = 0.44-1.34) regarding their efficacy. However, the subgroup analysis of large, multi-center trials indicated that the trivalent live attenuated intranasal influenza vaccine was superior to the trivalent inactivated intramuscular influenza vaccine (12,154 people, OR = 0.50, CI = 0.28-0.88). Only 23 "vaccine-related serious adverse events" were recorded among 17 833 individuals, with no significant difference between methods. The widespread initiation of pediatric national flu vaccination programs prioritizing the live-attenuated intranasal influenza vaccine would be beneficial. Multi-continent, high-quality studies that include children younger than two years old and those living in subtropical and tropical regions are needed to further enhance our understanding.

MUC17 is a potential new prognostic biomarker and promotes pancreatic cancer progression in obstructive jaundice.

Our working group has previously shown that bile acids (BAs) accelerate carcinogenic processes in pancreatic cancer (PC) in which mucin 4 (MUC4) expression has a central role. However, the role of other mucins in PC are less clear, especially in bile-induced cancer progression. The study aim was to investigate expression of MUC17 in BAs- or human serum-treated pancreatic ductal adenocarcinoma (PDAC) cell lines and use different assays with RNA silencing/overexpression to study the role of MUC17 in cancer progression. Protein expression of MUC17 was evaluated in 55 human pancreatic samples by immunohistochemistry, and Kaplan-Meier survival analysis was used to compare survival curves. Expression of MUC17 increased in PDAC patients, especially in obstructive jaundice (OJ) and the elevated MUC17 expression associated with poorer overall survival (10.66±1.99 vs. 15.05±2.03 months; Log rank: 0.0497). Treatment of Capan-1 and AsPC-1 cells with BAs or with human serum obtained from PDAC + OJ patients enhanced the expression of MUC17, as well as the proliferative potential of the cells, whereas knockdown of MUC17 alone or in combination with MUC4 decreased BAs-induced carcinogenic processes. Our results demonstrated that MUC17 has a central role in bile-induced PC progression, and in addition to MUC4, this isoform also can be used as a novel prognostic biomarker.

One third of cases of new-onset diabetic ketosis in adults are associated with ketosis-prone type 2 diabetes-A systematic review and meta-analysis.

AIMS: Ketosis-prone type 2 diabetes was defined by the World Health Organization in 2019. According to the literature, the diagnosis is based on the presence of ketosis, islet autoantibody negativity and preserved insulin secretion. Our meta-analysis assessed the prevalence and clinical characteristics of ketosis-prone type 2 diabetes among patients hospitalised with diabetic ketoacidosis (DKA) or ketosis. METHODS: The systematic search was performed in five main databases as of 15 October 2021 without restrictions. We calculated the pooled prevalence of ketosis-prone type 2 diabetes (exposed group) within the diabetic population under examination, patients with ketoacidosis or ketosis, to identify the clinical characteristics, and we compared it to type 1 diabetes (the comparator group). The random effects model provided pooled estimates as prevalence, odds ratio and mean difference (MD) with 95% confidence intervals. RESULTS: Eleven articles were eligible for meta-analysis, thus incorporating 2010 patients of various ethnic backgrounds. Among patients presenting with DKA or ketosis at the onset of diabetes, 35% (95% CI: 24%-49%) had ketosis-prone type 2 diabetes. These patients were older (MD = 11.55 years; 95% CI: 5.5-17.6) and had a significantly higher body mass index (BMI) (MD = 5.48 kg/m2 ; 95% CI: 3.25-7.72) than those with type 1 diabetes. CONCLUSIONS: Ketosis-prone type 2 diabetes accounts for one third of DKA or ketosis at the onset of diabetes in adults. These patients are characterised by islet autoantibody negativity and preserved insulin secretion. They are older and have a higher BMI compared with type 1 diabetes. C-peptide and diabetes-related autoantibody measurement is essential to identify this subgroup among patients with ketosis at the onset of diabetes.

Fluid resuscitation with balanced electrolyte solutions results in faster resolution of diabetic ketoacidosis than with 0.9% saline in adults - A systematic review and meta-analysis.

Fluid resuscitation during diabetic ketoacidosis (DKA) is most frequently performed with 0.9% saline despite its high chloride and sodium concentration. Balanced Electrolyte Solutions (BES) may prove a more physiological alternative, but convincing evidence is missing. We aimed to compare the efficacy of 0.9% saline to BES in DKA management. MEDLINE, Cochrane Library, and Embase databases were searched for relevant studies using predefined keywords (from inception to 27 November 2021). Relevant studies were those in which 0.9% saline (Saline-group) was compared to BES (BES-group) in adults admitted with DKA. Two reviewers independently extracted data and assessed the risk of bias. The primary outcome was time to DKA resolution (defined by each study individually), while the main secondary outcomes were changes in laboratory values, duration of insulin infusion, and mortality. We included seven randomized controlled trials and three observational studies with 1006 participants. The primary outcome was reported for 316 patients, and we found that BES resolves DKA faster than 0.9% saline with a mean difference (MD) of -5.36 [95% CI: -10.46, -0.26] hours. Post-resuscitation chloride (MD: -4.26 [-6.97, -1.54] mmoL/L) and sodium (MD: -1.38 [-2.14, -0.62] mmoL/L) levels were significantly lower. In contrast, levels of post-resuscitation bicarbonate (MD: 1.82 [0.75, 2.89] mmoL/L) were significantly elevated in the BES-group compared to the Saline-group. There was no statistically significant difference between the groups regarding the duration of parenteral insulin administration (MD: 0.16 [-3.03, 3.35] hours) or mortality (OR: -0.67 [0.12, 3.68]). Studies showed some concern or a high risk of bias, and the level of evidence for most outcomes was low. This meta-analysis indicates that the use of BES resolves DKA faster than 0.9% saline. Therefore, DKA guidelines should consider BES instead of 0.9% saline as the first choice during fluid resuscitation.

Contrast-enhanced endoscopic ultrasound likely does not improve diagnostic adequacy during endoscopic ultrasound guided tissue acquisition: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Solid pancreatic masses are sampled through tissue acquisition by endoscopic ultrasound (EUS). Inadequate samples may significantly delay diagnosis, increasing costs and carrying risks to the patients. AIM: assess the diagnostic adequacy of tissue acquisition using contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) compared to conventional EUS. METHODS: Five databases (PubMed, Embase, CENTRAL, Scopus and Web of Science) were searched in November 2023. Studies comparing diagnostic adequacy, accuracy and safety using CEH-EUS versus conventional EUS for tissue acquisition of solid pancreatic masses were included. Risk of bias was assessed using the Risk of Bias tool for randomized controlled trials (RoB2) and the Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized studies, level of evidence using the GRADE approach, Odds Ratios (RR) with 95 % Confidence Intervals (CI) calculated and pooled using a random-effects model. I2 quantified heterogeneity. RESULTS: The search identified 3858 records; nine studies (1160 patients) were included. OR for achieving an adequate sample was 1.467 (CI: 0.850-2.533), for randomized trials 0.902 (CI: 0.541-1.505), for non-randomized 2.396 (CI: 0.916-6.264), with significant subgroup difference. OR for diagnostic accuracy was 1.326 (CI: 0.890-1977), for randomized trials 0.997 (CI: 0.593-1.977) and for non-randomized studies 1.928 (CI: 1.096-3.393), significant subgroup difference (p = 0.0467). No differences were observed for technical failures or adverse events. Heterogeneity was low, risk of bias "low" to "some concerns" for most outcomes, mostly moderate for non-randomized studies. CONCLUSION: Non-randomized studies indicated differences in favor of contrast-enhanced EUS, randomized studies showed no difference in diagnostic adequacy, accuracy or sensitivity when using CEH-EUS.

Cesarean delivery is associated with lower neonatal mortality among breech pregnancies: a systematic review and meta-analysis of preterm deliveries ≤32 weeks of gestation.

OBJECTIVE: To investigate the association between actual and planned modes of delivery, neonatal mortality, and short-term outcomes among preterm pregnancies ≤32 weeks of gestation. DATA SOURCES: A systematic literature search was conducted in 3 main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to November 16, 2022. The protocol was registered in advance in the International Prospective Register of Systematic Reviews (CRD42022377870). STUDY ELIGIBILITY CRITERIA: Eligible studies examined pregnancies ≤32nd gestational week. All infants received active care, and the outcomes were reported separately by different modes of delivery. Singleton and twin pregnancies at vertex and breech presentations were included. Studies that included pregnancies complicated with preeclampsia and abruptio placentae were excluded. Primary outcomes were neonatal mortality and intraventricular hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random effects model-based odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. Risk Of Bias In Non-randomized Studies - of Interventions-I was used to assess the risk of bias. RESULTS: A total of 19 observational studies were included involving a total of 16,042 preterm infants in this systematic review and meta-analysis. Actual cesarean delivery improves survival (odds ratio, 0.62; 95% confidence interval, 0.42-0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57-0.85) compared to vaginal delivery. Planned cesarean delivery does not improve the survival of very and extremely preterm infants compared to vaginal delivery (odds ratio, 0.87; 95% confidence interval, 0.53-1.44). Subset analysis found significantly lower odds of death for singleton breech preterm deliveries born by both planned (odds ratio, 0.56; 95% confidence interval, 0.32-0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13-0.88) cesarean delivery. CONCLUSION: Cesarean delivery should be the mode of delivery for preterm ≤32 weeks of gestation breech births due to the higher mortality in preterm infants born via vaginal delivery.

Very young and advanced maternal age strongly elevates the occurrence of nonchromosomal congenital anomalies: a systematic review and meta-analysis of population-based studies.

BACKGROUND: Nonchromosomal congenital anomalies (NCAs) are the most common cause of infant mortality and morbidity. The role of maternal age is well known, although the specifics are not thoroughly elucidated in the literature. OBJECTIVE: To evaluate the role of maternal age in the incidence of NCAs and to pinpoint age groups at higher risk to refine screening protocols. STUDY DESIGN: A systematic review and meta-analysis were conducted following the PRISMA 2020 guidelines and Cochrane Handbook. Searches were performed on October 19, 2021, across MEDLINE (via PubMed), Cochrane Library (CENTRAL), and Embase. Population-based studies assessing the impact of maternal age on the incidence of NCAs in pregnant women were included, without restrictions on age range, country, or comorbidities. A random-effects model was used for pooling effect sizes, considering the heterogeneity across studies. RESULTS: From 15,547 studies, 72 were synthesized. Maternal age >35 showed an increased NCA risk (risk ratio [RR]: 1.31, confidence interval [CI]: 1.07 -1.61), rising notably after>40 (RR: 1.44, CI: 1.25 -1.66). The latter changes to 1.25 (CI: 1.08 -1.46) if the co-occurrence of chromosomal aberrations is excluded. Specific anomalies like cleft lip/palate (>40, RR: 1.57, CI: 1.11 -2.20) and circulatory system defects (>40, RR: 1.94, CI: 1.28 -2.93) were significantly associated with advanced maternal age. Conversely, gastroschisis was linked to mothers <20 (RR: 3.08, CI: 2.74 -3.47). CONCLUSION: The study confirms that both very young and advanced maternal ages significantly increase the risk of NCAs. There is a pressing need for age-specific prenatal screening protocols to better detect these anomalies, especially considering the current trend of delayed childbearing. Further research is required to fully understand the impact of maternal age on the prevalence of rarer NCAs.

Umbilical cord management in newborn resuscitation: a systematic review and meta-analysis.

BACKGROUND: Evidence supporting the benefits of delayed cord clamping is increasing; however, there is no clear recommendation on cord management during newborn resuscitation. This study aimed to investigate the effects of resuscitation initiated with an intact umbilical cord, hypothesizing it is a safe stabilization procedure that improves neonatal outcomes. METHODS: Systematic search was conducted in MEDLINE, Embase, CENTRAL, and Web of Science from inception to March 1, 2024. Eligible articles compared neonatal outcomes in newborns receiving initial stabilization steps before and after cord clamping. RESULTS: Twelve studies met our inclusion criteria, with six RCTs included in the quantitative analysis. No statistically significant differences were found in delivery room parameters, in-hospital mortality, or neonatal outcomes between the examined groups. However, intact cord resuscitation group showed higher SpO2 at 5 min after birth compared to cord clamping prior to resuscitation group (MD 6.67%, 95% CI [-1.16%, 14.50%]). There were no significant differences in early complications of prematurity (NEC ≥ stage 2: RR 2.05, 95% CI [0.34, 12.30], IVH: RR 1.25, 95% CI [0.77, 2.00]). CONCLUSION: Intact cord management during resuscitation appears to be a safe intervention; its effect on early complications of prematurity remains unclear. Further high-quality RCTs with larger patient numbers are urgently needed. IMPACT: Initiating resuscitation with an intact umbilical cord appears to be a safe intervention for newborns. No statistically significant differences were found in delivery room parameters, in-hospital mortality, and neonatal outcomes between the examined groups. The utilization of specialized resuscitation trolleys appears to be promising to reduce the risk of intraventricular hemorrhage in preterm infants. Further high-quality RCTs with larger sample sizes are urgently needed to refine recommendations.

Prevalence of autoimmune pancreatitis in pancreatic resection for suspected malignancy: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Autoimmune pancreatitis (AIP) is a diagnosis-challenging disease that often mimics pancreatic malignancy. Pancreatic resection is considered to be a curative treatment for pancreatic ductal adenocarcinoma (PDAC). This meta-analysis aims to study the incidence of AIP in patients who have undergone pancreatic resection for clinical manifestation of cancer. METHODS: A comprehensive search was conducted in three databases, PubMed, Embase and the Cochrane Library, using the terms 'autoimmune pancreatitis' and 'pancreatic resection' and supplemented by manual checks of reference lists in all retrieved articles. RESULTS: Ten articles were included in the final analysis. 8917 pancreatic resections were performed because of a clinical suspicion of pancreatic cancer. AIP accounted for 140 cases (1.6%). Type 1 AIP comprised the majority of cases, representing 94% (132 cases), while type 2 AIP made up the remaining 6% (eight cases) after further classification. AIP accounted for almost 26% of all cases of benign diseases involving unnecessary surgery and was overrepresented in males in 70% of cases compared to 30% in females. The mean age for AIP patients was 59 years. Serum CA 19 - 9 levels were elevated in 23 out of 47 (49%) AIP patients, where higher levels were detected more frequently in patients with type 1 AIP (51%, 22 out of 43) than in those with type 2 AIP (25%, 1 out of 4). The sensitivity of IgG4 levels in type 1 AIP was low (43%, 21/49 patients). CONCLUSION: Even with modern diagnostic methods, distinguishing between AIP and PDAC can still be challenging, thus potentially resulting in unnecessary surgical procedures in some cases. Serum CA 19 - 9 levels are not useful in distinguishing between AIP and PDAC. Work must thus be done to improve diagnostic methods and avoid unnecessary complicated surgery.

The Effect of Nicotine-Containing Products on Peri-Implant Tissues: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Smokers have a higher chance of developing peri-implant diseases and are therefore considered an at-risk population. Our aim was to compare peri-implant characteristics in users of electronic cigarettes (EC), waterpipes (WP), cigarettes (CS), smokeless tobacco (ST), and nonsmokers (nonusers of any nicotine and tobacco product; NS). AIMS AND METHODS: A systematic search of four electronic databases (PubMed, EMBASE, Web of Science, and CENTRAL) was performed until April 2023, restricted to English language. Thirty-nine observational studies were included in the qualitative synthesis, of which 32 studies were included in a Bayesian network meta-analysis. Using a predesigned form, two researchers independently collected data about marginal bone loss (MBL), probing pocket depth (PPD), plaque index, bleeding on probing, modified plaque index, probing pocket depth > 4 mm (PPD > 4), gingival index, peri-implant sulcular fluid volume, and TNF-α and IL-1ß levels. QUIPS and CINeMA were used to evaluate the risk of bias and certainty of evidence. RESULTS: Nonsmokers had the smallest MBL. Most nicotine-containing product users had significantly higher MBL (CS, mean difference [MD]: 1.34 credible interval [CrI]: 0.85, 1.79; WP, MD: 1.58 CrI: 0.84, 2.35; ST, MD: 2.53, CrI: 1.20, 3.87) than NS. Electronic cigarettes did not show significant difference compared to NS (MD: 0.52 CrI: -0.33, 1.36). In secondary outcomes, NS were ranked in first place. Subset analysis based on smoking habit, implant duration, and maintenance control revealed no differences in ranking probability. CONCLUSIONS: Most nicotine-containing product users presented worse peri-implant parameters compared to NS, while EC users did not show significant differences to NS in many outcomes. IMPLICATIONS: Alternative nicotine-containing products are gaining popularity and are often considered less harmful by the general public compared to traditional cigarettes. This is the first network meta-analysis comparing users of four nicotine-containing products and NS. This study shows that CS, WP, and ST have a detrimental effect on the overall health of peri-implant tissues. EC users also presented inferior parameters compared to NS; however, the difference was not significant in many outcomes. It is essential to educate patients who are using nicotine-containing products, and to provide proper maintenance and appropriate cessation support. Well-designed multiarmed studies are needed for direct comparison of different products, including heated tobacco products. Greater transparency of confounding factors is needed regarding smoking habit and oral hygiene.

Robot-assisted laparoscopy does not have demonstrable advantages over conventional laparoscopy in endometriosis surgery: a systematic review and meta-analysis.

BACKGROUND: Endometriosis is a chronic condition affecting 6-10% of women of reproductive age, with endometriosis-related pain and infertility being the leading symptoms. Currently, the gold standard treatment approach to surgery is conventional laparoscopy (CL); however, the increasing availability of robot-assisted surgery is projected as a competitor of CL. This study aimed to compare the perioperative outcomes of robot-assisted laparoscopy (RAL) and CL in endometriosis surgery. OBJECTIVES: We aimed to compare the effectiveness and safety of these two procedures. METHODS: A systematic search was conducted in three medical databases. Studies investigating different perioperative outcomes of endometriosis-related surgeries were included. Results are presented as odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI). RESULTS: Our search yielded 2,014 records, of which 13 were eligible for data extraction. No significant differences were detected between the CL and RAL groups in terms of intraoperative complications (OR = 1.07, CI 0.43-2.63), postoperative complications (OR = 1.3, CI 0.73-2.32), number of conversions to open surgery (OR = 1.34, CI 0.76-2.37), length of hospital stays (MD = 0.12, CI 0.33-0.57), blood loss (MD = 16.73, CI 4.18-37.63) or number of rehospitalizations (OR = 0.95, CI 0.13-6.75). In terms of operative times (MD = 28.09 min, CI 11.59-44.59) and operating room times (MD = 51.39 min, CI 15.07-87.72;), the RAL technique remained inferior. CONCLUSION: RAL does not have statistically demonstrable advantages over CL in terms of perioperative outcomes for endometriosis-related surgery.

Association between human papillomavirus and preterm delivery: A systematic review and meta-analysis.

INTRODUCTION: The lifetime prevalence of human papillomavirus infection (HPV) is estimated to be around 80% and it is the most common sexually transmitted infection. Despite being well known for its oncologic relevance, it has been associated with adverse pregnancy outcomes, though available evidence is contradicting. Previous meta-analyses involved articles which based HPV infection on Pap smear results, leading to a significant source of bias. Therefore, we aimed to assess the burden of genetically proven HPV infection on adverse pregnancy outcomes. MATERIAL AND METHODS: In our meta-analysis, pregnant women tested for HPV DNA were only considered eligible. We conducted a systematic search in three major databases (PubMed, Embase, and CENTRAL) on September 22, 2023. Cohort, cross-sectional, and case-control studies were eligible for the analysis. The exposed group consisted of HPV-infected patients. We assessed the odds ratios (OR) with a confidence interval (CI) of 95%. In order to reduce the heterogeneity, we performed subgroup analyses based on different strains (high risk HPV, HPV 16/18, study design). The study was prospectively registered on PROSPERO (CRD42022370228). RESULTS: Our study involved 14 articles with 7008 women. A significant association was found between preterm delivery and HPV infection (OR: 1.94, CI: 1.31-2.87). No significant association was found when separately examining high-risk HPV-infected women (OR: 1.94, CI: 0.82-4.59), and HPV 16 or 18-infected women (OR: 2.08, CI: 0.50-8.63) in terms of preterm delivery. No significant association was found between spontaneous abortion and HPV infection (OR: 1.02, CI: 0.16-6.31). CONCLUSIONS: Our analysis indicates an association between HPV infection and preterm delivery. It is imperative that future studies consider confounding variables more comprehensively. Additionally, the global implementation of HPV vaccination programs holds significance not only in oncology but also in obstetrics.

Thiopurines impair the apical plasma membrane expression of CFTR in pancreatic ductal cells via RAC1 inhibition.

BACKGROUND AND AIMS: Thiopurine-induced acute pancreatitis (TIP) is one of the most common adverse events among inflammatory bowel disease patients treated with azathioprine (AZA), representing a significant clinical burden. Previous studies focused on immune-mediated processes, however, the exact pathomechanism of TIP is essentially unclear. METHODS: To model TIP in vivo, we triggered cerulein-induced experimental pancreatitis in mice receiving a daily oral dose of 1.5 mg/kg AZA. Also, freshly isolated mouse pancreatic cells were exposed to AZA ex vivo, and acinar cell viability, ductal and acinar Ca2+ signaling, ductal Cl- and HCO3- secretion, as well as cystic fibrosis transmembrane conductance regulator (CFTR) expression were assessed using microscopy techniques. Ras-related C3 botulinum toxin substrate (RAC1) activity was measured with a G-LISA assay. Super-resolution microscopy was used to determine protein colocalization. RESULTS: We demonstrated that AZA treatment increases tissue damage in the early phase of cerulein-induced pancreatitis in vivo. Also, both per os and ex vivo AZA exposure impaired pancreatic fluid and ductal HCO3- and Cl- secretion, but did not affect acinar cells. Furthermore, ex vivo AZA exposure also inhibited RAC1 activity in ductal cells leading to decreased co-localization of CFTR and the anchor protein ezrin, resulting in impaired plasma membrane localization of CFTR. CONCLUSIONS: AZA impaired the ductal HCO3- and Cl- secretion through the inhibition of RAC1 activity leading to diminished ezrin-CFTR interaction and disturbed apical plasma membrane expression of CFTR. We report a novel direct toxic effect of AZA on pancreatic ductal cells and suggest that the restoration of ductal function might help to prevent TIP in the future.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.