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.

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.

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.

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.

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 three main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) 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. ROBINS-I was used to assess the risk of bias. RESULTS: A total of nineteen 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 to 0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57 to 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 to 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 to 0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13 to 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.

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 non-smokers (non-users of any nicotine and tobacco product; NS). METHODS: A systematic search of four electronic databases (PubMed, EMBASE, Web of Science, 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 (PI), bleeding on probing (BOP), modified plaque index (mPI), probing pocket depth > 4mm (PPD>4), gingival index (GI), peri-implant sulcular fluid (PISF) volume, and TNF-α and IL-1ß levels. QUIPS and CINeMA were used to evaluate the risk of bias and certainty of evidence. RESULTS: NS had the smallest MBL. Most nicotine-containing product users had significantly higher MBL (CS, MD:1.34 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. EC 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. CONCLUSION: Most nicotine-containing product users presented worse peri-implant parameters compared to non-smokers, while EC users did not show significant differences to NS in many outcomes. IMPLICATION: 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 non-smokers. 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 multi-armed 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.

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.

Combined Casein Phosphopeptide-Amorphous Calcium Phosphate and Fluoride Is Not Superior to Fluoride Alone in Early Carious Lesions: A Meta-Analysis.

There is a growing need for effective methods in the management of early stage carious lesions. Therefore, the aim of this study was to evaluate the effect of combined casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and fluoride on white spot lesions (WSLs) compared to fluoride-only interventions. This meta-analysis was performed according to PRISMA guidelines and registered in PROSPERO (CRD42021286245). The Medline, Embase, and Cochrane Central databases were searched until October 17, 2022. Eligible studies were randomized controlled trials. Outcome variables included laser fluorescence (LF), quantitative light-induced fluorescence (QLF), and lesion area scores. The random-effects model was used for analysis, and results were given as standardized mean difference (SMD) and mean difference (MD) with a 95% confidence interval. Risk of bias was assessed using the RoB 2 tool, and the level of evidence with GRADE. Our systematic search yielded 973 records after duplicate removal, 21 studies were included for qualitative synthesis, and 15 studies were eligible for quantitative analysis. No significant difference was found between CPP-ACP and fluoride versus fluoride alone in LF at 1, 3, and 6 months of use: SMD -0.30 (-0.64; 0.04); SMD -0.47 (-1.02; 0.07); SMD -0.49 (-1.13; 0.15), respectively. For QLF, the analysis did not demonstrate significant differences between these two kinds of treatment at 1 and 6 months of use: MD 0.21 (-0.30;0.71); MD 0.60 (-1.70;2.90), but at 3 months, higher QLF values were found in the fluoride-only group compared to the CPP-ACP and fluoride combination was shown regarding the WSLs: MD 0.58 (0.25;0.91). On the contrary, data showed a small but statistically significant decrease in the lesion area in favor of the CPP-ACP plus fluoride versus fluoride alone at 6 months MD -0.38 (-0.72; -0.04). None of these observed changes indicated substantial clinical relevance. The combination of CPP-ACP and fluoride did not overcome the effect of fluoride given alone. Our data suggest that fluoride itself is effective in improving WSLs. However, the certainty of evidence was very low. These results indicate that further studies and future development of more effective products than CPP-ACP are needed in addition to fluoride to achieve robust amelioration of WSLs.

Ranking the dietary interventions by their effectiveness in the management of polycystic ovary syndrome: a systematic review and network meta-analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common condition in women, characterised by reproductive and metabolic dysfunction. While dietary approaches have been evaluated as a first-line treatment for patients with PCOS, there is limited evidence to support preference for a specific dietary composition. This systematic review and network meta-analysis was performed with the objective of comparing different dietary interventions in terms of positive impact. Metformin, the currently preferred treatment, was also compared. METHODS: The latest systematic search was performed on the 20th of March, 2023. Eligible randomised controlled trials (RCTs) included patients with PCOS and compared the dietary approach with another intervention or a standard diet. Outcomes were expressed via anthropometric measurements and hormonal, glycemic, and lipid levels. The Bayesian method was used to perform a network meta-analysis and to calculate the surface under the cumulative ranking curve (SUCRA) values in order to rank the dietary interventions. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: 19 RCTs were identified, comprising data from 727 patients who were variously treated with 10 types of dietary interventions and metformin. The Dietary Approaches to Stop Hypertension (DASH) diet was the most effective in reducing Homeostatic Model Assessment of Insulin Resistance (SUCRA 92.33%), fasting blood glucose (SUCRA 85.92%), fasting insulin level (SUCRA 79.73%) and triglyceride level (SUCRA 82.07%). For body mass index (BMI), the most effective intervention was the low-calorie diet (SUCRA 84.59%). For weight loss, the low-calorie diet with metformin (SUCRA 74.38%) was the most effective intervention. Metformin produced the greatest reductions in low-density lipoprotein cholesterol (SUCRA 78.08%) and total testosterone levels (SUCRA 71.28%). The low-carb diet was the most effective intervention for reducing cholesterol levels (SUCRA 69.68%), while the normal diet (SUCRA 65.69%) ranked first for increasing high-density lipoprotein cholesterol levels. CONCLUSION: Dietary interventions vary in their effects on metabolic parameters in women with PCOS. Based on our results, the DASH diet is the most effective dietary intervention for treating PCOS. Registration PROSPERO ID CRD42021282984.

Hyaluronate acid plus platelet-rich plasma is superior to steroids for pain relief less than 6 months using injection therapy of partial rotator cuff tears: A systematic review and network meta-analysis.

PURPOSE: We conducted our network meta-analysis to compare the efficacy of the steroid injections to other injectable therapies in partial-thickness rotator cuff tears (PTRCTs). METHODS: A systematic literature search was performed until October 25, 2021 in three databases (CENTRAL, Embase, MEDLINE). Eligible studies compared the efficacy of steroid, hyaluronic acid (HA), platelet-rich plasma (PRP), the combination of HA and PRP (HA+PRP), and adipose-derived regenerative cells (ADRC) in RC tears. The primary outcomes were the Visual Analogue Scale (VAS), Constant Murley Score (CMS), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. Using paired and network meta-analysis, we calculated pooled mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: We included a total of seven articles in the quantitative synthesis. In shorter periods, the HA+PRP combination was superior to the other substances we investigated (HA+PRP: VAS (0-4 weeks): MD: -0.99 [CI = -1.62, -0.36]; CMS (0-3 months): 20.56 [CI = 16.18, 24.94]. This combination was followed by the use of HA or PRP alone, depending on the duration of follow-up and the outcome being studied. In our study, short-term results suggest that saline is superior to steroids for partial tears, but this trend is reversed at six-month follow-up. CONCLUSION: Our results suggest the combination of HA and PRP to be a more effective therapeutic option for partial RC ruptures for short terms, but there is no significant difference after 6 months. LEVEL OF EVIDENCE: II, Included of Level of Evidence studies I-II.

No evidence for the superiority of 3 T MRI over 1.5 T MRI for diagnosing wrist ligamentous lesions: a systematic review and meta-analysis.

PURPOSES: Our aim was to determine the diagnostic accuracy of native MRI regarding different ligamentous lesions of the wrist and to analyze the influence of technical characteristics, such as field strength, application of fat saturation, 3D sequences, and wrist coils. METHODS: The systematic search was performed using MEDLINE, Embase, and CENTRAL databases. Studies that were published before the 12th of February 2024 were included. All studies comparing the diagnostic accuracy of native wrist MRI to that of wrist arthroscopy for suspected ligamentous lesions were included. Results were analyzed by anatomic localization and technical aspects of the MRI. To assess the quality of included studies, we used the revised QUADAS-2 tool. RESULTS: The systematic search revealed 5,181 articles. Thirty-seven studies, reporting 3893 ligamentous lesions, were eligible for inclusion. The studies displayed heterogeneity in terms of technical conditions, such as field strength, the use of wrist coils, the application of 3D sequences and fat saturation. Research methods also varied. Overall sensitivity and specificity were 0.78 (0.66 - 0.86) and 0.81 (0.70 - 0.89) for 1.5T MRI, while sensitivity was 0.73 (0.68 - 0.78) and specificity was 0.90 (0.59 - 0.98) for 3T MRI. There was no significant difference between the two subgroups (p=0,3807 and p=0,4248). Sensitivity was 0.82 (0.75 - 0.87) for triangular fibrocartilage complex (TFCC) lesions, 0.63 (0.50 - 0.74) for scapholunate ligament (SL) tears, and 0.41 (0.25 - 0.60) for lunotriquetral ligament (LT) lesions. Specificity for TFCC lesions was 0.82 (0.73 - 0.89), for SL tears 0.86 (0.73 - 0.93), and for LT lesions 0.93 (0.81 - 0.98). CONCLUSION: The sensitivity and specificity of MRI is influenced by the anatomic location of the lesion and technical conditions. In terms of diagnostic accuracy, no significant difference was found between 1.5T and 3T MRI. LEVEL OF EVIDENCE: III. Systematic review of Level II. - III.

Predicting residual cholesteatoma with the Potsic staging system still lacks evidence: a systematic review and meta-analysis.

PURPOSE: To investigate the rate of residual disease in the Potsic staging system for congenital cholesteatomas. METHODS: A protocol registration was published on PROSPERO (CRD42022383932), describing residual disease as a primary outcome and hearing improvement as secondary. A systematic search was performed in four databases (PubMed, Embase, Cochrane Library, Web of Science) on December 14, 2022. Articles were included if cholesteatomas were staged according to the Potsic system and follow-up duration was documented. Risk of bias was evaluated using the Quality In Prognosis Studies (QUIPS) tool. In the statistical synthesis a random effects model was used. Between-study heterogeneity was assessed using I2. RESULTS: Thirteen articles were found to be eligible for systematic review and seven were included in the meta-analysis section. All records were retrospective cohort studies with high risk of bias. Regarding the proportions of residual disease, analysis using the χ2 test showed no statistically significant difference between Potsic stages after a follow-up of minimum one year (stage I 0.06 (confidence interval (CI) 0.01-0.33); stage II 0.20 (CI 0.09-0.38); stage III 0.06 (CI 0.00-0.61); stage IV: 0.17 (CI 0.01-0.81)). Postoperative and preoperative hearing outcomes could not be analyzed due to varied reporting. Results on cholesteatoma location and mean age at staging were consistent with those previously published. CONCLUSION: No statistically significant difference was found in the proportions of residual disease between Potsic stages, thus the staging system's applicability for outcome prediction could not be proven based on the available data. Targeted studies are needed for a higher level of evidence.

Persistently High Procalcitonin and C-Reactive Protein Are Good Predictors of Infection in Acute Necrotizing Pancreatitis: A Systematic Review and Meta-Analysis.

Infected necrotizing pancreatitis (INP) is associated with an increased risk of organ failure and mortality. Its early recognition and timely initiation of antibiotic therapy can save patients' lives. We systematically searched three databases on 27 October 2022. In the eligible studies, the presence of infection in necrotizing pancreatitis was confirmed via a reference test, which involved either the identification of gas within the necrotic collection through computed tomography imaging or the examination of collected samples, which yielded positive results in Gram staining or culture. Laboratory biomarkers compared between sterile necrotizing pancreatitis and INP were used as the index test, and our outcome measures included sensitivity, specificity, the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). Within the first 72 hours (h) after admission, the AUC of C-reactive protein (CRP) was 0.69 (confidence interval (CI): 0.62-0.76), for procalcitonin (PCT), it was 0.69 (CI: 0.60-0.78), and for white blood cell count, it was 0.61 (CI: 0.47-0.75). After the first 72 h, the pooled AUC of CRP showed an elevated level of 0.88 (CI: 0.75-1.00), and for PCT, it was 0.86 (CI: 0.60-1.11). The predictive value of CRP and PCT for infection is poor within 72 h after hospital admission but seems good after the first 72 h. Based on these results, infection is likely in case of persistently high CRP and PCT, and antibiotic initiation may be recommended.