Dynamic microbial and metabolic changes during Apulian Caciocavallo cheesemaking and ripening produced according to a standardized protocol.

The microbiota of a cheese play a critical role in influencing its sensory and physicochemical properties. In this study, traditional Apulian Caciocavallo cheeses coming from 4 different dairies in the same area and produced following standardized procedures were examined, as well as the different bulk milks and natural whey starter (NWS) cultures used. Moreover, considering the cheese wheels as the blocks of Caciocavallo cheeses as whole, these were characterized at different layers (i.e., core, under-rind, and rind) of the block using a multi-omics approach. In addition to physical-chemical characterization, culturomics, quantitative PCR, metagenomics, and metabolomics analysis were carried out after salting and throughout the ripening time (2 mo) to investigate major shifts in the succession of the microbiota and flavor development. Culture-dependent and 16S rRNA metataxonomics results clearly clustered samples based on microbiota biodiversity related to the production dairy plant as a result of the use of different NWS or the intrinsic conditions of each production site. At the beginning of the ripening, cheeses were dominated by Lactobacillus, and in 2 dairies (Art and SdC), Streptococcus genera were associated with the NWS. The analysis allowed us to show that although the diversity of identified genera did not change significantly between the rind, under-rind, and core fractions of the same samples, there was an evolution in the relative abundance and absolute quantification, modifying and differentiating profiles during ripening. The real-time PCR, also known as quantitative or qPCR, mainly differentiated the temporal adaptation of those species originating from bulk milks and those provided by NWS. The primary starters detected in NWS and cheeses contributed to the high relative concentration of 1-butanol, 2-butanol, 2-heptanol, 2-butanone, acetoin, delta-dodecalactone, hexanoic acid ethyl ester, octanoic acid ethyl ester, and volatile free fatty acids during ripening, whereas cheeses displaying low abundances of Streptococcus and Lactococcus (dairy Del) had a lower total concentration of acetoin compared with Art and SdC. However, the subdominant strains and nonstarter lactic acid bacteria present in cheeses are responsible for the production of secondary metabolites belonging to the chemical classes of ketones, alcohols, and organic acids, reaffirming the importance and relevance of autochthonous strains of each dairy plant although only considering a delimited production area.

Safety and efficacy of venous thromboembolism prophylaxis in patients with cirrhosis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Patients with cirrhosis are considered in a haemostatic balance, though weaker than in normal subjects. In these patients, however, the use of pharmacological prophylaxis for venous thromboembolism (VTE) remains controversial. Therefore, in this study, we aimed to assess the safety and efficacy of VTE prophylaxis in patients with cirrhosis. METHODS: We conducted a systematic review of studies reporting the occurrence of bleeding and VTE events in patients with cirrhosis, and controls, undergoing VTE prophylaxis. Meta-regression analysis was conducted to further explore the determinants of heterogeneity in the study of the occurrence of either bleeding or VTE events. RESULTS: In a total of 10 studies, including 5712 patients, of which 2330 undergoing VTE prophylaxis, bleeding (n = 5513) and VTE events occurred in 8.2% and 2.8% patients respectively. A total of 2963 and 3162 patients were included from low-risk of bias studies in bleeding and VTE analysis respectively: while administration of VTE prophylaxis did not seem to reduce VTE (OR = 1.07, CI 0.39-2.96, p = .89), importantly prophylaxis was not associated with increased bleeding risk (OR = 0.56, CI 0.20-1.59, p = .27). Meta-regression analysis showed that no parameter significantly influenced the heterogeneity of data regarding bleeding or VTE events. CONCLUSIONS: In patients with cirrhosis, current evidence is insufficient to advise for or against the use of VTE prophylaxis, mainly due to lack of quality and homogeneity of available data. However, its use does not appear to be associated with a significant bleeding risk. Adequately designed studies are required to provide a measure of its overall utility.

Association between esophageal motor disorders and pulmonary involvement in patients affected by systemic sclerosis: a retrospective study.

Systemic sclerosis (SSc) is a rare autoimmune disease of the connective tissue that can affect multiple organs. The esophagus is the most affected gastrointestinal tract, while interstitial lung disease (ILD) is a main feature associated with SSc. The aim of the present study was to evaluate the association and prognostic implication between motor esophageal disorders and pulmonary involvement in SSc patients. We retrospectively assessed patients with SSc who underwent both the HRM with the new Chicago Classification 4.0 and pulmonary evaluation comprehensive of function tests and high-resolution computer tomography (HrCT) with the use of Warrick score. A total score ≥ 7 was considered predictive of ILD, while a score ≥ 10 in a HrCT acquired prospectively from baseline evaluation was considered to establish significant interstitial involvement. Forty-two patients were included. We found a score ≥ 7 in 11 patients with aperistalsis, in 6 subjects with IEM and in 6 patients with a normal manometry. Otherwise, a score < 7 was observed in 3 patients with aperistalsis, and in 2 and 14 patients with IEM and with a normal contractility, respectively. Higher scores were observed in subjects with absent contractility or ineffective esophageal motility than subjects with normal motility, indeed DCI and HrCT score were inversely correlated in linear and logarithmic regression analysis. Prospectively, lower baseline LESP and greater HrCT scores at follow-up evaluation were significantly correlated. This study shows an association between motor esophageal disorder and pulmonary involvement in SSc patients: more severe is the esophageal involvement, more critical is the pulmonary disease.

The establishment of the gut microbiota in 1-year-aged infants: from birth to family food.

PURPOSE: With the aim of characterizing the gastrointestinal (GI) microbiota and contextually determine how different prenatal, perinatal, and postnatal factors affected its composition in early childhood, infants were enrolled in a longitudinal-prospective study named "A.MA.MI." (Alimentazione MAmma e bambino nei primi MIlle giorni; NCT04122612, October 2019). METHODS: Forty-five fecal samples were collected at 12 months of infants' age, identified as the 3rd follow-up (T3). The evaluated variables were pre-gestational weight and weight gain during pregnancy, delivery mode, feeding, timing of weaning, and presence/absence of older siblings. Fecal alpha and beta-diversities were analyzed. Noteworthy, to determine the impact of the influencing factors, multivariate analyses were conducted. RESULTS: At T3, all prenatal and perinatal variables did not result to be significant whereas, among the postnatal variables, type of milk-feeding and weaning showed the greatest contribution in shaping the microbiota. Although aged 1 year, infants exclusively breastfed until 6 months were mainly colonized by Lactobacillaceae and Enterobacteriaceae. Differently, Bacteroidaceae characterized the microbiota of infants that were never breastfed in an exclusive way. Moreover, although an early introduction of solid foods determined higher values of Faith's PD, high abundances of Ruminococcaceae and Faecalibacterium mainly associated with infants weaned after the 4th month of age. CONCLUSION: The microbial colonization during the first year of life is likely affected by a simultaneous effect of multiple variables playing a significant role at different times. Therefore, these data contribute to add evidence concerning the complex multifactorial interaction between GI microbiota and various stimuli affecting infants during the early stages of life.

Sensory inflow manipulation induces learning-like phenomena in motor behavior.

PURPOSE: Perceptual and goal-directed behaviors may be improved by repetitive sensory stimulations without practice-based training. Focal muscle vibration (f-MV) modulating the spatiotemporal properties of proprioceptive inflow is well-suited to investigate the effectiveness of sensory stimulation in influencing motor outcomes. Thus, in this study, we verified whether optimized f-MV stimulation patterns might affect motor control of upper limb movements. METHODS: To answer this question, we vibrated the slightly tonically contracted anterior deltoid (AD), posterior deltoid (PD), and pectoralis major muscles in different combinations in forty healthy subjects at a frequency of 100 Hz for 10 min in single or repetitive administrations. We evaluated the vibration effect immediately after f-MV application on upper limb targeted movements tasks, and one week later. We assessed target accuracy, movement mean and peak speed, and normalized Jerk using a 3D optoelectronic motion capture system. Besides, we evaluated AD and PD activity during the tasks using wireless electromyography. RESULTS: We found that f-MV may induce increases (p < 0.05) in movement accuracy, mean speed and smoothness, and changes (p < 0.05) in the electromyographic activity. The main effects of f-MV occurred overtime after repetitive vibration of the AD and PD muscles. CONCLUSION: Thus, in healthy subjects, optimized f-MV stimulation patterns might over time affect the motor control of the upper limb movement. This finding implies that f-MV may improve the individual's ability to produce expected motor outcomes and suggests that it may be used to boost motor skills and learning during training and to support functional recovery in rehabilitation.

Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region.

Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.

Somatic complex I disruptive mitochondrial DNA mutations are modifiers of tumorigenesis that correlate with low genomic instability in pituitary adenomas.

Mitochondrial DNA (mtDNA) mutations leading to the disruption of respiratory complex I (CI) have been shown to exhibit anti-tumorigenic effects, at variance with those impairing only the function but not the assembly of the complex, which appear to contribute positively to cancer development. Owing to the challenges in the analysis of the multi-copy mitochondrial genome, it is yet to be determined whether tumour-associated mtDNA lesions occur as somatic modifying factors or as germ-line predisposing elements. Here we investigated the whole mitochondrial genome sequence of 20 pituitary adenomas with oncocytic phenotype and identified pathogenic and/or novel mtDNA mutations in 60% of the cases. Using highly sensitive techniques, namely fluorescent PCR and allele-specific locked nucleic acid quantitative PCR, we identified the most likely somatic nature of these mutations in our sample set, since none of the mutations was detected in the corresponding blood tissue of the patients analysed. Furthermore, we have subjected a series of 48 pituitary adenomas to a high-resolution array comparative genomic hybridization analysis, which revealed that CI disruptive mutations, and the oncocytic phenotype, significantly correlate with low number of chromosomal aberrations in the nuclear genome. We conclude that CI disruptive mutations in pituitary adenomas are somatic modifiers of tumorigenesis most likely contributing not only to the development of oncocytic change, but also to a less aggressive tumour phenotype, as indicated by a stable karyotype.

Extraction and annotation of human mitochondrial genomes from 1000 Genomes Whole Exome Sequencing data.

BACKGROUND: Whole Exome Sequencing (WES) is one of the most used and cost-effective next generation technologies that allows sequencing of all nuclear exons. Off-target regions may be captured if they present high sequence similarity with baits. Bioinformatics tools have been optimized to retrieve a large amount of WES off-target mitochondrial DNA (mtDNA), by exploiting the aspecificity of probes, partially overlapping to Nuclear mitochondrial Sequences (NumtS). The 1000 Genomes project represents one of the widest resources to extract mtDNA sequences from WES data, considering the large effort the scientific community is undertaking to reconstruct human population history using mtDNA as marker, and the involvement of mtDNA in pathology. RESULTS: A previously published pipeline aimed at assembling mitochondrial genomes from off-target WES reads and further improved to detect insertions and deletions (indels) and heteroplasmy in a dataset of 1242 samples from the 1000 Genomes project, enabled to obtain a nearly complete mitochondrial genome from 943 samples (76% analyzed exomes). The robustness of our computational strategy was highlighted by the reduction of reads amount recognized as mitochondrial in the original annotation produced by the Consortium, due to NumtS filtering. CONCLUSIONS: To the best of our knowledge, this is likely the most extended population-scale mitochondrial genotyping in humans enriched with the estimation of heteroplasmies.

HmtDB, a genomic resource for mitochondrion-based human variability studies.

HmtDB (http://www.hmtdb.uniba.it:8080/hmdb) is a open resource created to support population genetics and mitochondrial disease studies. The database hosts human mitochondrial genome sequences annotated with population and variability data, the latter being estimated through the application of the SiteVar software based on site-specific nucleotide and amino acid variability calculations. The annotations are manually curated thus adding value to the quality of the information provided to the end-user. Classifier tools implemented in HmtDB allow the prediction of the haplogroup for any human mitochondrial genome currently stored in HmtDB or externally submitted de novo by an end-user. Haplogroup definition is based on the Phylotree system. End-users accessing HmtDB are hence allowed to (i) browse the database through the use of a multi-criterion 'query' system; (ii) analyze their own human mitochondrial sequences via the 'classify' tool (for complete genomes) or by downloading the 'fragment-classifier' tool (for partial sequences); (iii) download multi-alignments with reference genomes as well as variability data.

How to do bedside mediastinal decompression in tension pneumomediastinum.

Tension pneumomediastinum is uncommon but it is a rapidly progress condition that can lead to cardiogenic shock. Mediastinal decompression is an emergency procedure and the knowledge of this technique is a life-saving treatment.

Assessment of Italian Population Awareness on One-Health, Zoonoses and the Mpox Vaccine: A Nationwide Cross-Sectional Study.

In recent decades, the rise of zoonotic diseases has emerged as a significant human health concern, highlighting the interconnectedness of human and animal health within the framework of the "One Health" (OH) concept. This study, conducted in Italy in 2023, sought to gauge the general population's awareness of OH and zoonotic diseases while identifying influencing factors. Additionally, it aimed to assess awareness of an Mpox virus vaccine, particularly pertinent due to the 2022 outbreak across Europe. The online cross-sectional study encompassed 1058 participants, revealing that 54.26% were unfamiliar with OH and zoonoses. Median knowledge scores were 12 points (IQR = 9-15) for zoonoses and 8 points (IQR = 6-11) for OH. Notably, factors such as age, economic situation, healthcare employment, educational level, and health literacy significantly influenced knowledge scores. Merely 26.8% of participants were aware of the existence of an Mpox vaccine, with healthcare workers, individuals engaged in animal-related work, and non-heterosexual men demonstrating higher awareness. The findings underscored a limited public understanding of zoonotic diseases and One Health, with variations observed across specific demographic groups. Given the potential impact on public health, urgent educational initiatives are warranted. Moreover, the study highlighted a low awareness of the Mpox vaccine, emphasizing the necessity for targeted awareness campaigns directed at both professionals and the general public.

Food Intolerances, Food Allergies and IBS: Lights and Shadows.

This narrative review delves into the intricate relationship between irritable bowel syndrome (IBS) and food intolerances. IBS, a chronic functional gastrointestinal disorder, is characterized by symptoms like abdominal pain and altered bowel habits. The prevalence of IBS has increased globally, especially among young adults. Food and dietary habits play a crucial role in IBS management. About 85-90% of IBS patients report symptom exacerbation linked to specific food consumption, highlighting the strong connection between food intolerances and IBS. Food intolerances often exhibit a dose-dependent pattern, posing a challenge in identifying trigger foods. This issue is further complicated by the complex nature of gastrointestinal physiology and varying food compositions. This review discusses various dietary patterns and their impact on IBS, including the low-FODMAP diet, gluten-free diet, and Mediterranean diet. It highlights the importance of a personalized approach in dietary management, considering individual symptom variability and dietary history. In conclusion, this review emphasizes the need for accurate diagnosis and holistic management of IBS, considering the complex interplay between dietary factors and gastrointestinal pathophysiology. It underlines the importance of patient education and adherence to treatment plans, acknowledging the challenges posed by the variability in dietary triggers and the psychological impact of dietary restrictions.

Patient journey in gastroesophageal reflux disease: real-world perspectives from Italian gastroenterologists, primary care physicians, and ENT specialists.

Background: Gastroesophageal reflux disease (GERD) is a challenging condition that involves different physicians, such as general practitioners (GPs), gastroenterologists, and ears, nose and throat (ENT) specialists. A common approach consists of proton-pump inhibitors (PPIs) administration. Adjunctive pharmacological treatment may have a role in the management of non-responders to PPIs. Objectives: We aimed to survey GPs and different medical specialists to investigate the medical approaches to patients reporting GERD symptoms. In addition, we examined the use of adjunctive pharmacological treatments in patients with GERD symptoms who do not respond to PPIs. Design: Retrospective observational study. Methods: A survey was conducted among a large sample of gastroenterologists, GPs, and ENT specialists. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life were explored with the GERD Impact Scale and with Reflux Symptom Index (RSI). All therapies administered usually for GERD were investigated. Results: A total of 6211 patients were analyzed in this survey. Patients with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p < 0.0001). The GSI was higher in patients followed by gastroenterologists (9 points) and GPs (9 points) than ENT specialists (8 points), but the RSI was higher in the ENT group (14.3 ± 6.93) than in GPs and gastroenterologist groups (10.36 ± 6.36 and 10.81 ± 7.30, p < 0.0001). Chest pain had the highest negative impact on quality of life (p < 0.0001). Of the 3025 patients who used PPIs, non-responders showed a lower GSI when treated with a combination of adjunctive pharmacological treatments and bioadhesive compounds, than with single-component drugs. Conclusion: Patients with GERD referred to a gastroenterologist had more severe disease and poorer quality of life. The combination of adjunctive pharmacological treatments and bioadhesive compounds seems to be effective in the management of PPI refractory patients.

Gastroesophageal reflux disease management: real-world perspectives from Italian gastroenterologists, primary care physicians and ENT specialists Gastroesophageal reflux disease (GERD) is a prevalent and chronic condition that affects millions of individuals worldwide, causing significant discomfort and impacting their overall quality of life. In the comprehensive management of GERD, a collaborative approach involving different physicians is essential to address the various aspects of this complex condition. Given the wide range of diagnostic and therapeutic possibilities in clinical practice, we aimed to investigate how GERD is managed in clinical practice by general practitioners and different medical specialists, including gastroenterologists and ears, nose, and throat (ENT) specialists. A total of 6,211 observations were carried out from a survey. The severity and impact of GERD on quality-of-life was higher in patients followed by gastroenterologists and general practitioners than ENT specialists. Non-cardiac chest pain had the highest negative impact on quality-of-life. Of the 3,025 patients who used PPIs, non-responders showed an improved quality of life when treated with a combination of adjunctive pharmacological treatments and bio adhesive compounds.

Are Small Molecules Effective in Treating Inflammatory Pouch Disorders Following Ileal Pouch-Anal Anastomosis for Ulcerative Colitis? Here Is Where We Stand.

Ulcerative colitis (UC) management encompasses conventional and advanced treatments, including biological therapy and small molecules. Surgery, particularly in the form of ileal pouch-anal anastomosis (IPAA), is indicated in cases of refractory/severe disease. IPAA can lead to acute complications (e.g., acute pouchitis) as well as late complications, including chronic inflammatory disorders of the pouch. Chronic pouchitis, including the antibiotic-dependent (CADP) and antibiotic-refractory (CARP) forms, represents a significant and current therapeutic challenge due to the substantial need for evidence regarding viable treatment options. Biological therapies have shown promising results, with infliximab, adalimumab, ustekinumab, and vedolizumab demonstrating some efficacy in chronic pouchitis; however, robust randomized clinical trials are only available for vedolizumab. This narrative review focuses on the evidence concerning small molecules in chronic pouchitis, specifically Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P-R) modulators. According to the preliminary studies and reports, Tofacitinib shows a potential effectiveness in CARP. Upadacitinib presents variable outcomes from the case series, necessitating further evaluation. Filgotinib and ozanimod demonstrate anecdotal efficacy. This review underscores the need for high-quality studies and real-world registries to develop robust guidelines for advanced therapies in post-IPAA inflammatory disorders, supported by vigilant clinical monitoring and ongoing education from international IBD specialist societies.

Safety and Efficacy of Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma and Impaired Liver Function: A Systematic Review and Meta-Analysis.

Background: Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized. Objectives: In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis. Methods: We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available. Results: Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients (p = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21-0.90; p = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; p = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; p = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; p = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12-2.86; p = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01-11.1, p < 0.0001). Lastly, OS was longer in patients with ALBI grades 1-2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, p = 0.0008). Conclusions: Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade.

Diagnostic delay in achalasia.

BACKGROUND: Achalasia is a rare disorder characterized by impaired esophageal motility and symptoms like dysphagia, regurgitation, chest pain, and weight loss. A timely diagnosis is crucial to adequately manage this condition. AIMS: This study aimed to assess the diagnostic delay from symptom onset to a definite diagnosis of achalasia, and to identify associated factors. METHODS: This retrospective, single-center study included patients diagnosed with achalasia between January 2013 and September 2023. Demographic data, symptoms, manometric, endoscopic, and radiological findings were collected. We also considered socio-economic deprivation. Early diagnosis was defined as occurring within 12 months of symptom onset, while late diagnosis was defined as occurring more than 12 months. RESULTS: We included 278 patients (142 males, median age 58 years). Dysphagia was the most common symptom (96 %), followed by regurgitation (70.1 %). The median diagnostic delay was 24 months (IQR 12-72, range 0-720), with 213 patients (76.6 %) experiencing late diagnosis. Early diagnosis was more common in patients with weight loss (63.1% vs. 42.0 %, p = 0.003). Lower material deprivation correlated with shorter diagnostic delay (24 months, IQR 10-60 vs. 60 months, IQR 18-300, p = 0.001). CONCLUSIONS: Achalasia diagnosis is often delayed. Weight loss along with socio-economic factors, influence the timeliness of diagnosis. Improving awareness of disease and relevance of initial symptoms may facilitate earlier diagnosis and treatment.

Effect of hiatal hernia and esophagogastric junction morphology on esophageal motility: Evidence from high-resolution manometry studies.

BACKGROUND: High-resolution Manometry (HRM) is the most sensitive and specific test available for clinical assessment of hiatal hernia (HH), a common condition defined as the separation between the Lower Esophageal Sphincter (LES) and crural diaphragm (CD). While the link between HH and Gastroesophageal Reflux Disease (GERD) is established, the potential association of HH with esophageal dysmotility, independently from GERD, is uncertain. This study aimed to analyze if HH, with or without GERD, can associate with esophageal motility disorders. METHODS: Consecutive patients without previous esophageal surgery who underwent HRM between 2018 and 2022 were enrolled. All patients with symptoms suggestive of GERD underwent impedance-pH testing off-therapy. HH was defined as a separation >1 cm between LES and CD, and esophagogastric junction (EGJ) morphology was classified as: Type I, when there was no separation between LES and CD; Type II, in case of minimal separation (>1 and <3 cm); Type III, when ≥3 cm of separation was present. Demographic and clinical characteristics were collected at baseline, including Age, Gender, Alcohol-, Coffee- and Smoke-habits, GERD diagnosis and symptoms' duration. Two cohorts of patients, with and without HH, were retrospectively individuated, and their association with Ineffective Peristalsis, Hypercontractile Esophagus and Outflow Obstruction was analyzed with univariate and multivariate Logistic regressions using the statistical software R. KEY RESULTS: 848 consecutive patients were enrolled, and 295 cases of HH (34.8%), subdivided into 199 (23.5%) Type II- and 96 (11.3%) Type III-EGJ patients, were identified. Ineffective peristalsis was diagnosed in 162 (19.1%) subjects, Hypercontractile esophagus in 32 (3.8%), and Outflow Obstruction in 91 (10.7%), while GERD was present in 375 (44.2%) patients. HH was significantly associated with Ineffective Peristalsis (p < 0.001) and GERD (p < 0.001). Furthermore, HH resulted to be a risk factor for Ineffective peristalsis (OR 2.0, 95% CI 1.4-2.8, p < 0.001) both when the analysis was conducted in all the 848 subjects, independently from GERD, and when it was carried out in patients without GERD (OR 2.3, 95% CI 1.02-5.3, p = 0.04). The risk for Ineffective Peristalsis increased 1.3 times for every centimeter of HH. No statistically significant association was found between HH and Outflow obstruction or Hypercontractile Esophagus. CONCLUSIONS & INFERENCES: An increasing separation between the LES and CD may lead to a gradual and significant elevation in the risk of Ineffective Peristalsis. Interestingly, this association with HH is true in patients with and in those without GERD, suggesting that the anatomical alteration seems to play a major role in motility change.

Expression of epidermal growth factor receptor (EGFR) in systemic sclerosis patients (SSc) and gastro-oesophageal reflux disease (GORD).

INTRODUCTION: Systemic sclerosis (SSc) affects the connective tissue and leads to an abnormal fibrotic process in the skin and internal organs. Epidermal Growth Factor Receptor (EGFR) is able to induce cell proliferation and differentiation, and its expression is increased in SSc patients with pulmonary artery hypertension and in skin biopsies in patients with scleroderma. To date, no data on esophageal expression of EGFR are available in SSc patients. We aimed to evaluate whether the pro-fibrogenic pathways of SSc may affect EGFR expression in the esophagus. METHODS: A retrospective analysis included patients with SSc and control subjects suffering from gastroesophageal reflux symptoms. Endoscopic assessment and histopathologic analyses were performed in all subjects and the presence of microscopic esophagitis was used to distinguish patients with normal esophageal mucosa and subjects with non-erosive reflux disease. EGFR expression was measured in all subjects. RESULTS: A total of 35 patients with SSc were included, while the control group included 67 non-SSc patients. EGFR expression at the Z-line was higher in SSc patients than non-SSc patients in absence of microscopic esophagitis (median 65 %, IQR 56-71 % vs 42 %, IQR 37-54 %, p < 0.001). Microscopic esophagitis was found in 60 % of patients with SSc and 62.7 % of control patients, and EGFR expression was significantly higher in patients presenting microscopic esophagitis both in SSc and non-SSc patients. CONCLUSION: The EGFR hyperexpression may be due to SSc and/or reflux-related damage in patients with microscopic esophagitis. Further studies are warranted to answer open questions and provide a possible role of EGFR in terms of diagnosis, prognosis, and therapy.