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Background Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. Methods A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements. Results The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long‐term prognosis and life expectancy are favorable. Conclusions and Inferences A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD., Key summary Current knowledge Functional dyspepsia is one of the most common conditions encountered in clinical practice.There is a lack of guidance for clinicians in guiding diagnosis and treatment of this prevalent condition.No treatments are currently approved for the treatment of functional dyspepsia in Europe. What is new here A Delphi panel consisting of 41 experts from 22 European countries established the level of consensus on 87 statements regarding functional dyspepsia.The statements reaching consensus serve to guide clinicians in recognizing, diagnosing and treating FD in clinical practice.Endoscopy is mandatory for establishing a firm diagnosis of functional dyspepsia D, but in primary care patients without alarm symptoms or risk factors can be managed without endoscopy. Helicobacter pylori status should be determined in every patient with dyspeptic symptoms and H. Pylori positive patients should receive eradication therapy.Proton pump inhibitor‐therapy is considered an effective therapy for FD, but no other treatment approach reached consensus support.

In the below-referenced article,1 the name of one of the authors in the ESNM Gastroparesis Consensus Group was misspelled. D. Kestzhelyi's name should have been listed as D. Keszthelyi. Additionally, Jolien Schol and Lucas Wauters should be listed as co-first authors. We apologize for these errors.

Introduction/Objective: Irritable bowel syndrome (IBS) is a bowel disorder characterized by pain accompanying defecation or altered bowel habits, divided into diarrhea-predominant, constipation-predominant, and alternating subtypes, whose pathogenesis is considered to include disordered bowel motility. The hormone ghrelin is a growth hormone secretagogue which furthermore affects gastrointestinal motility. We study the association between its genetic polymorphisms and the risk for IBS. Methods: IBS patients meeting the Rome III criteria and controls similar in age and gender were recruited. Whole blood samples were used for genotyping via polymerase chain reaction and restriction fragment length polymorphism for the polymorphisms rs34911341, rs696217, and rs2075356. Results: Participants included 142 patients and 209 controls. The rs696217 GG genotype frequency was higher in patients (78.87%) compared to controls (55.5%). The rs696217 GT genotype was significantly less frequent among patients than in controls (OR 0.31, 95% CI 0.19-0.52), as was the T allele (OR 0.43, 95% CI 0.28-0.66). No significant differences in genotype distribution were found for the rs34911341 and rs2075356 polymorphisms between patients and controls. The genotype frequencies did not significantly differ between IBS subtype groups for any of the polymorphisms studied. Conclusions: The GG and GT genotypes of the rs696217 polymorphism, as well as the G-allele, demonstrate significant association with IBS susceptibility, while the T allele appears to bear a protective effect. Ghrelin's polymorphisms are plausibly involved in IBS pathogenesis, but do not correlate with any distinct IBS subtype. © 2021 S. Karger AG. All rights reserved.

Background: Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. Methods: A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements. Results: The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long-term prognosis and life expectancy are favorable. Conclusions and Inferences: A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD. © 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.

Background: Gastroparesis is a condition characterized by epigastric symptoms and delayed gastric emptying (GE) rate in the absence of any mechanical obstruction. The condition is challenging in clinical practice by the lack of guidance concerning diagnosis and management of gastroparesis. Methods: A Delphi consensus was undertaken by 40 experts from 19 European countries who conducted a literature summary and voting process on 89 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation criteria. Consensus (defined as ≥80% agreement) was reached for 25 statements. Results: The European consensus defined gastroparesis as the presence of symptoms associated with delayed GE in the absence of mechanical obstruction. Nausea and vomiting were identified as cardinal symptoms, with often coexisting postprandial distress syndrome symptoms of dyspepsia. The true epidemiology of gastroparesis is not known in detail, but diabetes, gastric surgery, certain neurological and connective tissue diseases, and the use of certain drugs recognized as risk factors. While the panel agreed that severely impaired gastric motor function is present in these patients, there was no consensus on underlying pathophysiology. The panel agreed that an upper endoscopy and a GE test are required for diagnosis. Only dietary therapy, dopamine-2 antagonists and 5-HT4 receptor agonists were considered appropriate therapies, in addition to nutritional support in case of severe weight loss. No consensus was reached on the use of proton pump inhibitors, other classes of antiemetics or prokinetics, neuromodulators, complimentary, psychological, or more invasive therapies. Finally, there was consensus that gastroparesis adversely impacts on quality of life and healthcare costs and that the long-term prognosis of gastroparesis depends on the cause. Conclusions and Inferences: A multinational group of European experts summarized the current state of consensus on definition, symptom characteristics, pathophysiology, diagnosis, and management of gastroparesis. © 2021 John Wiley & Sons Ltd

Objective The LRG, HMGB1, MMP3 and ANXA1 proteins have been implicated in different inflammatory pathways in ulcerative colitis (UC), but their role as specific biomarkers of both endoscopic and histological activity has yet to be elucidated. In the present study, we aimed to evaluate the LRG1, HMGB1, MMP3 and ANXA1 as potential serum biomarkers for UC endoscopic and histological activity. Methods This cross-sectional study included UC patients under 5-ASA, and healthy controls (HC) undergoing colonoscopy. Blood and biopsy samples were obtained and endoscopic Mayo sub-score (Ms) was recorded for the UC patients. Intramucosal calprotectin as a marker of histologic activity was evaluated in all biopsy samples and serum LRG1, HMGB1, MMP3 and ANXA1 levels were measured in the blood samples. Results The HCs ANXA1 level was lower compared to that of the UC group [P = 0.00, area under the curve (AUC) = 0.881] and so was the HCs MMP3 level compared to that of patients (P = 0.00, AUC = 0.835). The HCs ANXA1 levels were also lower compared to these of the independent Ms groups, even to the Ms = 0 (P = 0.00, AUC = 0.913). UC endoscopic activity was associated with MMP3 levels (r = 0.54, P = 0.000) but not with ANXA1, LRG1 and HMGB1 levels Conclusion Serum ANXA1 is a potential diagnostic biomarker of UC and serum MMP3 is a potential biomarker of UC endoscopic and histological activity. © 2020 Lippincott Williams and Wilkins. All rights reserved.

Dumping syndrome is a common but underdiagnosed complication of gastric and oesophageal surgery. We initiated a Delphi consensus process with international multidisciplinary experts. We defined the scope, proposed statements and searched electronic databases to survey the literature. Eighteen experts participated in the literature summary and voting process evaluating 62 statements. We evaluated the quality of evidence using grading of recommendations assessment, development and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 33 of 62 statements, including the definition and symptom profile of dumping syndrome and its effect on quality of life. The panel agreed on the pathophysiological relevance of rapid passage of nutrients to the small bowel, on the role of decreased gastric volume capacity and release of glucagon-like peptide 1. Symptom recognition is crucial, and the modified oral glucose tolerance test, but not gastric emptying testing, is useful for diagnosis. An increase in haematocrit >3% or in pulse rate >10 bpm 30 min after the start of the glucose intake are diagnostic of early dumping syndrome, and a nadir hypoglycaemia level

Aim: To evaluate the uptake of screening colonoscopy among physicians as compared to the general population. Methods: Asymptomatic physicians, aged 45-67 years, at average risk for colorectal cancer (CRC), working in the participating National Health System hospitals were asked to complete a questionnaire regarding the uptake of screening colonoscopy. The results were compared to those in a background healthy population, aged 50-75 years, inhabitants of a Greek county, who were offered a free access to a screening colonoscopy program for CRC. High-risk adenomas were those ≥10 mm in diameter or any adenoma, regardless of size, with villous histology or high-grade dysplasia. Results: Overall, 267 of 782 physicians and 402 of 6,534 nonphysicians underwent a screening colonoscopy (uptake rates 34.2 and 6.2% respectively, p = 0.00001). Screening colonoscopy has yielded 4 adenocarcinomas (1.6%), 14 high-risk adenomas (5.5%), and 61 low-risk adenomas (25.7%) in the physicians' group. Corresponding figures in the nonphysician arm were 4 (1), 26 (6.5), and 107 (26.6%), respectively. The main reason among physicians for nonadherence was indifference/negligence (n = 213). Conclusion: The proportion of physicians undergoing screening colonoscopy for CRC is significantly higher compared to the general population; however, it does remain suboptimal. © 2019 S. Karger AG, Basel.

BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as candidate biomarkers of cancer, having regulatory functions in both oncogenic and tumor-suppressive pathways. Concerning pancreatic cancer (PC), deregulation of lncRNAs involved in tumor initiation, invasion, and metastasis seem to play a key role. However, data is scarce about regulatory mechanism of lncRNA expression. OBJECTIVE: The aim of our study was to investigate the contribution of two lncRNAs polymorphisms (rs1561927 and rs4759313 of PVT1 and HOTAIR, respectively) in PC susceptibility. METHODS: A case-control study was conducted analysing rs1561927 and rs4759313 polymorphisms using DNA collected in a population-based case-control study of pancreatic cancer (111 pancreatic ductal adenocarcinoma cases (PDAC), 56 pancreatic neuroendocrine tumor (PNET), and 125 healthy controls). RESULTS: Regarding the PVT1 rs1561927 polymorphism the G allele was significantly overrepresented in both PDAC and PNET patients compared to the controls, while the presence of the HOTAIR rs4759314 G allele was found to be overrepresented in the PNET patients only compared to the controls. The PVT1 rs1561927 AG/GG genotypes were associated with poor overall survival in PDAC patients. CONCLUSIONS: Our results suggested that polymorphisms of these two lncRNA polymorphisms implicated in pancreatic carcinogenesis. Further large-scale and functional studies are needed to confirm our results. © 2019-IOS Press and the authors. All rights reserved.

Main Recommendations ESGE recommends offering stone extraction to all patients with common bile duct stones, symptomatic or not, who are fit enough to tolerate the intervention. Strong recommendation, low quality evidence. ESGE recommends liver function tests and abdominal ultrasonography as the initial diagnostic steps for suspected common bile duct stones. Combining these tests defines the probability of having common bile duct stones. Strong recommendation, moderate quality evidence. ESGE recommends endoscopic ultrasonography or magnetic resonance cholangiopancreatography to diagnose common bile duct stones in patients with persistent clinical suspicion but insufficient evidence of stones on abdominal ultrasonography. Strong recommendation, moderate quality evidence. ESGE recommends the following timing for biliary drainage, preferably endoscopic, in patients with acute cholangitis, classified according to the 2018 revision of the Tokyo Guidelines: - severe, as soon as possible and within 12 hours for patients with septic shock - moderate, within 48-72 hours - mild, elective. Strong recommendation, low quality evidence. ESGE recommends endoscopic placement of a temporary biliary plastic stent in patients with irretrievable biliary stones that warrant biliary drainage. Strong recommendation, moderate quality of evidence. ESGE recommends limited sphincterotomy combined with endoscopic papillary large-balloon dilation as the first-line approach to remove difficult common bile duct stones. Strong recommendation, high quality evidence. ESGE recommends the use of cholangioscopy-assisted intraluminal lithotripsy (electrohydraulic or laser) as an effective and safe treatment of difficult bile duct stones. Strong recommendation, moderate quality evidence. ESGE recommends performing a laparoscopic cholecystectomy within 2 weeks from ERCP for patients treated for choledocholithiasis to reduce the conversion rate and the risk of recurrent biliary events. Strong recommendation, moderate quality evidence. © Georg Thieme Verlag KG Stuttgart - New York.

Unambiguously, great progress has been achieved in the unraveling of more pathological pathways implicated in the development and progression of ulcerative colitis during the last decades. Novel effective drugs that have augmented the management armamentarium have been developed alongside this growing comprehension of the disease, rendering mucosal healing not only a feasible but the optimal goal of every therapy. Clinical evaluation, colonoscopy and biomarkers are the tools used by practitioners for the diagnosis and assessment of the status of the disease in order to achieve clinical remission and mucosal healing for their patients. Among these tools, colonoscopy is the gold method for the cause but is still an invasive, high-cost procedure with possible adverse events such as perforation. While clinical evaluation entails much subjectivity, biomarkers are objective, easily reproducible, non-invasive, cheap and potent surrogate tools of mucosal inflammation. Unfortunately, the well-established, currently in use serum biomarkers, such as C-reactive protein, erythrocyte sedimentation rate and others, do not display sufficiently acceptable sensitivity and specificity rates for the diagnosis of ulcerative colitis and, most importantly, do not represent precisely the mucosal inflammation status of the disease. Therefore, the discovery of new serum biomarkers has been the cause of several studies attempting to discover an “optimal” serum biomarker during the recent years. After thorough research, collection and examination of current data, this review focuses on and selectively presents promising, potential, novel serum biomarkers of ulcerative colitis as they are indicated by studies on the patient over the last years. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Functional gastrointestinal disorders (FGID) are heterogeneous disorders with a variety of clinical manifestations, primarily defined by signs and symptoms rather than a definite underlying cause. Their pathophysiology remains obscure and, although it is expected to differ according to the specific FGID, disruptions in the brain-gut axis are now thought to be a common denominator in their pathogenesis. The hormone ghrelin is an important component of this axis, exerting a wide repertoire of physiological actions, including regulation of gastrointestinal motility and protection of mucosal tissue. Ghrelin’s gene shows genetic polymorphism, while its protein product undergoes complex regulation and metabolism in the human body. Numerous studies have studied ghrelin’s relation to the emergence of FGIDs, its potential value as an index of disease severity and as a predictive marker for symptom relief during attempted treatment. Despite the mixed results currently available in scientific literature, the plethora of statistically significant findings shows that disruptions in ghrelin genetics and expression are plausibly related to FGID pathogenesis. The aim of this paper is to review current literature studying these associations, in an effort to uncover certain patterns of alterations in both genetics and expression, which could delineate its true contribution to FGID emergence, either as a causative agent or as a pathogenetic intermediate. ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Background/Aims Gastroesophageal reflux disease (GERD) represents a common condition having a substantial impact on the patients quality of life, as well as the health system. According to many studies, the BARX1 and ADAMTS17 genes have been suggested as genetic risk loci for the development of GERD and its complications. The purpose of this study is to investigate the potential association between GERD and BARX1 and ADAMTS17 polymorphisms. Methods The present is a prospective cohort study of 160 GERD patients and 180 healthy control subjects of Greek origin, examined for BARX1 and ADAMTS17 polymorphisms (rs11789015 and rs4965272) and a potential correlation to GERD. Results The rs11789015 AG and GG genotypes were found to be significantly associated with GERD (P = 0.032; OR, 1.65; 95% CI, 1.06-2.57 and P = 0.033; OR, 3.00; 95% CI, 1.15-7.82, respectively), as well as the G allele (P = 0.007; OR, 1.60; 95% CI, 1.14-2.24). Concerning the rs4965272, only the GG genotype was significantly associated with GERD (P = 0.035; OR, 3.42; 95% CI, 1.06-11.05). Conclusions This is a study investigating the potential correlation between BARX1 and ADAMTS17 polymorphisms and the development of GERD, showing a considerable association between both polymorphisms and the disease. This finding suggests that esophageal differentiation or altered regulation on microfibrils in the cell environment could be implicated as possible mechanisms in the pathogenesis of GERD. © 2019 Korean Society of Neurogastroenterology and Motility. All rights reserved.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett's esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett's esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease. © The Author(s) 2018.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with high incidence, and great heterogeneity of symptoms. Numerous factors are correlated with IBS development; however, the pathophysiology is not yet clear. In addition, there is no appropriate diagnostic tool available. The aim of this study was the identification of protein expression alterations in IBS patients compared to healthy individuals. Serum samples from 30 IBS patients (10 with IBS-Diarrhea, 10 IBS-Constipation and 10 IBS-Mixed) and 10 healthy individuals were subjected to proteomic analysis by 2-dimensional gel electrophoresis. Following evaluation of densitometrical data, protein spots exhibiting differential expression among the groups, were further characterized by matrix-assisted laser desorption tandem time-of-flight mass spectrometer and the results were confirmed by Western blot analysis. Eight significantly different expressed proteins were identified. Seven of them were overexpressed in IBS cases and only one was overexpressed in healthy individuals. These proteins were also differently expressed between the three IBS subgroups. IBS-D group overexpressed immunoglobulin light chain Lambda (LAC3) and apolipoprotein E (APOE), IBS-C group overexpressed apolipoprotein H (APOH) and collagen alpha-1 (XIV) chain (COEA1), and IBS-M group and healthy individuals overexpressed retinol-binding protein 4 (RET4). Our results show a different serum protein profile of IBS patients compared to healthy controls. Understanding the role of these eight proteins which are differently expressed in IBS patients, may contribute to a better clarification of IBS pathogenesis and to patient's stratification. Significance: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with high incidence and great heterogeneity of symptoms without any appropriate diagnostic tool available. Eight significantly different expressed proteins were identified. Seven of them were overexpressed in IBS cases and only one was expressed in healthy individuals. These proteins were also differently expressed between the three IBS subgroups. Our results show that there is a different serum proteome signature in IBS compared to healthy individuals, as well as in IBS subgroups that could be used in the future for patient's stratification and as a diagnostic tool. © 2017 Elsevier B.V.

Live commensal intestinal bacteria are present in the peripheral blood where they can induce inflammation. Objective To evaluate the intestinal bacteria composition and translocation of bacteria in IBD. Methods Both blood and tissue biopsy samples were collected from adult patients with active/inactive Crohn's disease (CD), active/inactive ulcerative colitis (UC) and healthy individuals. Most of the patients were newly diagnosed and none of them received antibiotics. Using a reverse transcription-quantitative real-time PCR (RT-qPCR) method, we determined the composition of microbiota. NOD2/CARD15 genotyping was also studied. Results Total bacterial DNA concentration was increased in tissue and blood samples of IBD patients compared to healthy controls. Furthermore, the active IBD cases had higher total bacterial DNA concentration levels compared to the inactive cases. Three species characterized dysbiosis in IBD, namely an increase of Bacteroides spp in active and inactive IBD samples, and a decrease in Clostridium leptum group (IV), and Faecalibacterium prausnitzi in both active and inactive IBD patients. No significant association between bacterial translocation and NOD2/CARD15 mutations was found. Conclusions The composition of the microbiota in IBD patients differs from that of healthy controls. The high rate of bacterial DNA in the blood samples indicates translocation in inflammatory bowel disease. © Copyright 2017 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Introduction: Irritable bowel syndrome (IBS) is a gastrointestinal disease that according to Rome IV criteria is subdivided into four subtypes. The pathophysiology of this disease is not well understood due to numerous factors playing multiple roles in disease development, such as diet, stress and hormones. IBS has a variety of symptoms and overlaps with many other gastrointestinal and non-gastrointestinal diseases. Area covered: This review aims to present an overview of implementation of proteomics in experimental studies in the field of IBS. Expert commentary: Proteomics is commonly used for biomarker discovery in and has also been extensively used in IBS research. The necessity of a sensitive and specific biomarker for IBS is apparent, but despite the intensive research performed in this field, an appropriate biomarker is not yet available. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Background/Aim Immigrants have multiple barriers to access to health care systems. We evaluated the adherence to follow-up and treatment recommendations of chronic hepatitis B virus (HBV) Greek and immigrant patients. Methods In total, 1001 consecutive adult patients with chronic HBV infection who visited our clinics for the first time between 2002 and 2011 were included. All patients born outside Greece were considered immigrants. Diagnosis was considered to be complete if patients could be classified into HBeAg-positive chronic hepatitis B (CHB), inactive carriers, HBeAg-negative CHB, or decompensated cirrhosis. Results Of the patients, 56% were Greeks and 44% were immigrants. Greeks visited our clinics at a significantly older mean age (50 vs. 35 years, P