Apixaban-Induced Esophagitis Dissecans Superficialis-Case Report and Literature Review.

Novel direct oral anticoagulants (DOACs) are prescribed worldwide in the treatment of non-valvular atrial fibrillation. Adverse reactions have been reported following the use of DOACs. One notable trend in the literature is the growing number of reported cases of esophagitis dissecans superficialis (EDS) generated by DOAC use. We hereby report the case of a 73-year-old woman who presented to the hospital with asthenia, dysphagia, and melena two days prior to admission. The patient had taken apixaban due to non-valvular paroxysmal atrial fibrillation for a few weeks. The biological panel showed moderate anemia with a hemoglobin level of 7.7 g/dL Apixaban-induced EDS was diagnosed by the characteristic endoscopic findings. The patient received treatment with a proton pump inhibitor (pantoprazole) in a double dose. Also, an iron treatment was recommended for a period of six months. The follow-up endoscopy at one month confirmed the healing of the esophageal lesions. The case was discussed with the cardiologist. The first anticoagulant treatment proposed after discharge was a vitamin K antagonist (acenocumarol) but the patient refused this medication and thus it was decided to initiate rivaroxaban. Although DOACs have demonstrated their efficacy in the prevention and treatment of stroke and thromboembolism among the aging demographic, cases of DOAC-induced EDS will continue to pose numerous challenges for physicians worldwide.

Systematic review and meta-analysis: proton pump inhibitors slightly decrease the severity of chronic cough.

The Montreal consensus recognizes chronic cough as an extra-esophageal manifestation of gastroesophageal reflux disease. We performed a meta-analysis to assess the effects of acid-suppressive medications in adults with non-specific chronic cough. The protocol was registered on PROSPERO (CRD42022368769). Placebo-controlled randomized trials evaluating the impact of acid-suppressive medications on persistent cough were included. The systematic search was performed on the 1st of November 2022 in three databases. A random-effects model was used for the calculations. The effect size was the standardized mean difference (SMD) with 95% confidence interval (CI). A total number of 11 double-blinded placebo-controlled randomized trials were included in the meta-analysis. Data showed that compared to placebo, PPIs decreased the severity of cough (SMD 0.33; CI 0.05; 0.61). Therapeutic response was not different in patients with non-specific chronic cough only, compared to those with laryngopharyngeal reflux. Prolonged treatment durations did not result in greater symptomatic improvement, with SMD 0.33 (CI - 0.22; 0.88), 0.31 (CI - 1.74; 2.35), 0.32 (CI - 0.29; 0.93) and 0.34 (CI - 0.16; 0.85), following 4, 6, 8 and 12 weeks of treatment, respectively. The pooled analysis of the improvement in quality of life with PPIs found an SMD of 0.39 (CI - 0.51; 1.29). PPIs mildly decrease the severity of non-specific chronic cough, irrespective of treatment duration.

Early-Onset Colorectal Cancer-A Retrospective Study from a Tertiary Referral Hospital in Romania.

Early-onset colorectal cancer emerges as a distinctive clinical and biological entity and is generally defined as the onset of colon or rectal neoplasia before the age of 50. Several reports describe an increasing incidence worldwide of colorectal cancers occurring in individuals younger than 50 years, along with particular histologic and molecular features. Although heredity may be an explanation in some cases with young-onset colorectal cancer, other driving factors remain partially unknown. The present study explores demographic, clinical, and pathological features within a group of patients diagnosed with colorectal cancer before the age of 50. It is a retrospective survey based on data collected between 2017 and 2023 within three surgical departments from a tertiary Romanian hospital. The clinical and pathological features we identified (later-stage disease, distal colon tumor localization, mucinous histology) are mainly superimposed with the existing data in the literature regarding this pathology. In order to lower the burden that colorectal neoplasia diagnosed in the young implies, a change of paradigm should be made in terms of establishing effective and targeted screening programs but also in the direction of enhancing complex clinical, pathological, and molecular diagnosis.

Aggressive Male Breast Cancer-Clinical and Therapeutic Aspects Correlated with the Histopathological Examination: A Case Report and Literature Review.

Breast cancer is often seen as a disease that occurs in women, but it can also appear in men in a very small percentage, below 1%. Men have a minimal amount of breast tissue compared to women, which has the potential to become malignant in a similar way to women, although much less frequently. A patient presented with advanced local invasion due to the low amount of breast tissue, with the tumor quickly invading the adjacent structures. Histopathological and immunohistochemical examinations have an extremely important role in the pathology of breast cancer. Given that male breast cancer is rare and there are not enough surgeons specializing in breast surgery in our country, there is a lack of experience in the management and early diagnosis of this type of cancer, which will be highlighted in this article.

Evaluation of Disease Activity in Inflammatory Bowel Disease: Diagnostic Tools in the Assessment of Histological Healing.

Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. In long-standing ulcerative colitis disease activity, histological persistent inflammation has been linked to an increased risk of relapse, and long-term corticosteroid use, even when endoscopic remission is reached. In Crohn's disease, the discontinuous nature of lesions and transmural inflammation have limited the standardized histological assessment. The current evidence from research proposes that besides clinical and endoscopic healing, the achievement of histological healing constitutes an endpoint to assess disease activity and remission in IBD patients concerning better long-term disease outcomes. Histological alterations may persist even in the absence of endoscopic lesions. For these reasons, new advanced techniques promise to revolutionize the field of IBD by improving the endoscopic and histologic assessment, disease characterization, and ultimately patient care, with an established role in daily practice for objective assessment of lesions. This review outlines the importance of including microscopic evaluation in IBD, highlighting the clinical benefits of a deep state of disease remission using validated diagnostic methods and scoring systems for daily clinical practice.

The Potential Use of Artificial Intelligence in Irritable Bowel Syndrome Management.

Irritable bowel syndrome (IBS) has a global prevalence of around 4.1% and is associated with a low quality of life and increased healthcare costs. Current guidelines recommend that IBS is diagnosed using the symptom-based Rome IV criteria. Despite this, when patients seek medical attention, they are usually over-investigated. This issue might be resolved by novel technologies in medicine, such as the use of Artificial Intelligence (AI). In this context, this paper aims to review AI applications in IBS. AI in colonoscopy proved to be useful in organic lesion detection and diagnosis and in objectively assessing the quality of the procedure. Only a recently published study talked about the potential of AI-colonoscopy in IBS. AI was also used to study biofilm characteristics in the large bowel and establish a potential relationship with IBS. Moreover, an AI algorithm was developed in order to correlate specific bowel sounds with IBS. In addition to that, AI-based smartphone applications have been developed to facilitate the monitoring of IBS symptoms. From a therapeutic standpoint, an AI system was created to recommend specific diets based on an individual's microbiota. In conclusion, future IBS diagnosis and treatment may benefit from AI.

Clinicopathological Analysis of Complicated Colorectal Cancer: A Five-Year Retrospective Study from a Single Surgery Unit.

Patients with primary colorectal cancer can present with obstructions, tumor bleeding, or perforations, which represent acute complications. This paper aimed to analyze and compare the clinical and pathological profiles of two patient groups: one with colorectal cancer and a related complication and another without any specific complication. We performed a five-year retrospective study on colorectal cancer patients admitted to a surgery unit and comparatively explored the main clinical and pathological features of the tumors belonging to the two groups. A total of 250 patients with colorectal cancer were included in the analysis. Of these, 117 (46.8%) had presented a type of complication. The comparative analysis that examined several clinical and pathological parameters showed a statistically significant difference for unfavorable prognosis factors in the group with complications. This was evident for features such as vascular and perineural invasion, lymph node involvement, pathological primary tumor stage, and TNM stage. Colorectal cancers with a related complication belonged to a group of tumors with a more aggressive histopathologic profile and more advanced stages. Furthermore, the comparable incidence of cases in the two groups of patients warrants further efforts to be made in terms of early detection and prognosis prediction of colorectal cancer.

Gastro-Esophageal Reflux Disease and Paroxysmal Atrial Fibrillation Ablation.

Patients undergoing ablation for atrial fibrillation may be at increased risk of developing gastroesophageal reflux disease. We prospectively studied the presence of symptomatic gastroesophageal reflux disease in naïve patients who underwent atrial fibrillation ablation. METHODS: The presence of typical symptoms suggestive of gastroesophageal reflux disease was clinically assessed by the gastroenterologist at baseline and at 3 months after ablation. In addition to that, all patients underwent upper gastrointestinal endoscopy. RESULTS: Seventy-five patients were included in two groups: 46 patients who underwent atrial fibrillation ablation (study group) and 29 patients without ablation (control group). Patients with atrial fibrillation ablation were younger (57.76 ± 7.66 years versus 67.81 ± 8.52 years; p = 0.001), predominantly male (62.2% versus 33.3%; p = 0.030) and with higher body mass index (28.96 ± 3.12 kg/m2 versus 26.81 ± 5.19 kg/m2; p = 0.046). At three months after the ablation, in the study and control groups, there were 88.9% and 57.1% patients in sinus rhythm, respectively, (p = 0.009). Symptomatic gastroesophageal reflux disease was not more frequent in the study group (42.2% versus 61.9%; p = 0.220). There was no difference in terms of sinus rhythm prevalence in patients with versus without symptomatic gastroesophageal reflux disease (89.5% versus 88.5%; p = 0.709). CONCLUSION: In this small prospective study, typical symptoms suggestive of gastroesophageal reflux disease were not more frequent three months following atrial fibrillation ablation.

Pepsin and the Lung-Exploring the Relationship between Micro-Aspiration and Respiratory Manifestations of Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is one of the most commonly encountered disorders in clinical practice nowadays, with an increasing burden on healthcare systems worldwide. GERD-related respiratory symptoms such as unexplained chronic cough, bronchial asthma or chronic obstructive pulmonary disease (COPD) with frequent exacerbations often pose diagnostic and therapeutic challenges and may require a multidisciplinary approach. Moreover, a potential role of GERD as a risk factor has been proposed for chronic rejection in patients who underwent lung transplantation. Pepsin has gained considerable attention from the scientific community in the last few years as a possible surrogate biomarker for GERD. The aim of this narrative review was to provide an overview of the potential utility of pepsin detection as a marker of micro-aspiration in various biological fluids retrieved from patients with suspected GERD-induced respiratory manifestations and in lung transplant patients with allograft dysfunction. Data on the subject remains highly contradictory, and while certain studies support its applicability in investigating atypical GERD manifestations, at the moment, it would be realistic to accept a modest utility at best. A major lack of consensus persists regarding topics such as the optimal timeframe for fluid collection and cut-off values. Further research is warranted in order to address these issues.

The Biotics Family: Current Knowledge and Future Perspectives in Metabolic Diseases.

Globally, metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease pose a major public health threat. Many studies have confirmed the causal relationship between risk factors and the etiopathogenesis of these diseases. Despite this, traditional therapeutic management methods such as physical education and diet have proven insufficient. Recently, researchers have focused on other potential pathways for explaining the pathophysiological variability of metabolic diseases, such as the involvement of the intestinal microbiota. An understanding of the relationship between the microbiome and metabolic diseases is a first step towards developing future therapeutic strategies. Currently, much attention is given to the use of biotics family members such as prebiotics (lactolose, soy oligosaccharides, galactooligosaccharides, xylooligosaccharides or inulin) and probiotics (genera Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus or Enterococcus). They can be used both separately and together as synbiotics. Due to their direct influence on the composition of the intestinal microbiota, they have shown favorable results in the evolution of metabolic diseases. The expansion of the research area in the biotics family has led to the discovery of new members, like postbiotics. In the age of personalized medicine, their use as therapeutic options is of great interest to our study.

The KIDSCREEN-27 Quality of Life Measure for Romanian Children Aged 6: Reliability and Validity of the Romanian Version.

The KIDSCREEN-27 represents a standardized, worldwide instrument, employed to assess the health-related quality of life in children. The purpose of the present study is to validate the KIDSCREEN-27 questionnaire for 6-year-old preparatory school children and verify its reliability, as well as to perform a comparison regarding the quality of children's lives living in two cities in Romania: Arad, a provincial city, versus the second most developed city in the country, Cluj-Napoca. A total of 256 children of 6 years of age, who come from families with both parents, with a medium to high socioeconomic status and a good health status, were included in the analysis, using the KIDSCREEN-27 questionnaire at three assessment time points with a re-test period of two weeks. Results indicated that the KIDSCREEN-27 turned out to be suitable for use in 6-year-old Romanian children. Analysis regarding the psychometric properties showed that the Cronbach's alpha ranged from 0.554 to 0.661 at the end of the study. The Pearson correlation coefficients showed statistically significant differences between the items of each area investigated. In conclusion, there is a growing need to periodically monitor the health status of children to avoid possible problems which may occur.

Hereditary Hemorrhagic Telangiectasia and Arterio-Venous Malformations-From Diagnosis to Therapeutic Challenges.

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant vascular disease defined by the presence of mucosal and cutaneous telangiectasia and visceral arterio-venous malformations. The latter are abnormal capillary-free direct communications between the pulmonary and systemic circulations with the following consequences: arterial hypoxemia caused by right-to-left shunts; paradoxical embolism with transient ischemic attack or stroke and brain abscess caused by the absence of the normally filtering capillary bed; and hemoptysis or hemothorax due to the rupture of the thin-walled arterio-venous malformations (particularly during pregnancy). It is frequently underdiagnosed, commonly presenting as complications from shunting through arterio-venous malformations: dyspnea, chronic bleeding, or embolism. Arterio-venous malformations are present not only in the lungs, but can also be found in the liver, central nervous system (mainly in the brain), nasal mucosa, or the gastrointestinal tract. The first choice of therapy is embolization of the afferent arteries of the arterio-venous malformations, a minimally invasive procedure with a high efficacy, a low morbidity, and low mortality. Other therapeutic modalities are surgery (resection) or stereotactic radiosurgery (using radiation). Routine screening for arterio-venous malformations is indicated in patients diagnosed with this condition and can prevent severe complications such as acute hemorrhages, brain abscesses, or strokes. Clinicians should provide a long-term follow-up for patients with arterio-venous malformations, in an effort to detect their growth or reperfusion in case of previously treated malformations. In spite of two experts' consensuses, it still possesses multiple therapeutic challenges for physicians, as several aspects regarding the screening and management of arterio-venous malformations still remain controversial. Multidisciplinary teams are especially useful in complex cases.

Uncommon Association of Mckittrick-Wheelock Syndrome and Clostridioides difficile Infection in Acute Renal Failure.

We present the case of a 71-year-old male who suffered an episode of acute renal failure caused by the uncommon association of two different diseases (Clostridioides difficile infection and McKittrick-Wheelock syndrome). He presented with hypovolemic shock, severe hypokalemia, hyponatremia, metabolic acidosis and acute renal failure; consequences of secretory diarrhea caused by a giant rectal tumor revealed from colonoscopy. The biopsy results revealed tubulo-villous adenoma with low/high grade dysplasia. After correction of electrolyte imbalances and azotemia, the patient underwent surgical resection with full subsequent recovery. In the literature review, including papers published from which January 1945 to April 2021, we found only one case-report of acute renal failure associated with Clostridioides difficile infection and McKittrick-Wheelock syndrome.

Artificial Intelligence in Digestive Endoscopy-Where Are We and Where Are We Going?

Artificial intelligence, a computer-based concept that tries to mimic human thinking, is slowly becoming part of the endoscopy lab. It has developed considerably since the first attempt at developing an automated medical diagnostic tool, today being adopted in almost all medical fields, digestive endoscopy included. The detection rate of preneoplastic lesions (i.e., polyps) during colonoscopy may be increased with artificial intelligence assistance. It has also proven useful in detecting signs of ulcerative colitis activity. In upper digestive endoscopy, deep learning models may prove to be useful in the diagnosis and management of upper digestive tract diseases, such as gastroesophageal reflux disease, Barrett's esophagus, and gastric cancer. As is the case with all new medical devices, there are challenges in the implementation in daily medical practice. The regulatory, economic, organizational culture, and language barriers between humans and machines are a few of them. Even so, many devices have been approved for use by their respective regulators. Future studies are currently striving to develop deep learning models that can replicate a growing amount of human brain activity. In conclusion, artificial intelligence may become an indispensable tool in digestive endoscopy.

Inulin, Choline and Silymarin in the Treatment of Irritable Bowel Syndrome with Constipation-Randomized Case-Control Study.

(1) Background: Irritable bowel syndrome (IBS) is a common disease, with multiple pathophysiological mechanisms involved. A single treatment for all the patients with IBS is not possible. Prebiotics may have a beneficial effect on IBS patients with constipation. (2) Methods: A randomized cross-over case-control study was conducted, including patients with IBS and constipation (IBS-C), who were randomized into two groups receiving a specific constipation diet with or without a food supplement containing inulin, choline and silymarin (Stoptoxin®, Fiterman Pharma, Iasi, Romania). Patients were evaluated at baseline, after four and eight weeks, using a questionnaire to assess IBS symptoms. (3) Results: 51 IBS-C patients were included, of which 47 patients finished the trial (33 women, mean age 52.82 years). Adding Stoptoxin® to a diet for constipation brought extra benefits. Abdominal pain severity improved by 68.3% after the diet and Stoptoxin® (p = 0.004) and abdominal bloating severity parameter improved by 34.8% (p = 0.040). The stool number per week and the stool consistency according to the Bristol scale were improved, but without statistical significance between groups (p > 0.05). (4) Conclusions: The combination of inulin, choline and silymarin associated with a specific-constipation diet had obvious clinical beneficial effects on IBS-C patients in terms of bowel movement, abdominal pain and bloating.

Romanian Guidelines for the Diagnosis and Treatment of GERD-induced Respiratory Manifestations.

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) is a common condition present in daily practice with a wide range of clinical phenotypes. In this line, respiratory conditions may be associated with GERD. The Romanian Societies of Gastroenterology and Neurogastroenterology, in association with the Romanian Society of Pneumology, aimed to create a guideline regarding the epidemiology, diagnosis and treatment of respiratory conditions associated with GERD. METHODS: Delphi methodology was used and eleven common working groups of experts were created. The experts reviewed the literature according to GRADE criteria and formulated 34 statements and recommendations. Consensus (>80% agreement) was reached for some of the statements after all participants voted. RESULTS: All the statements and the literature review are presented in the paper, together with their correspondent grade of evidence and the voting results. Based on >80% voting agreement, a number of 22 recommendations were postulated regarding the diagnosis and treatment of GERD-induced respiratory symptoms. The experts considered that GERD may cause bronchial asthma and chronic cough in an important number of patients through micro-aspiration and vagal-mediated tracheobronchial reflex. GERD should be suspected in patients with asthma with suboptimal controlled or after exclusion of other causes, also in nocturnal refractory cough which needs gastroenterological investigations to confirm the diagnosis. Therapeutic test with double dose proton pump inhibitors (PPI) for 3 months is also useful. GERD induced respiratory conditions are difficult to treat; however,proton pump inhibitors and laparoscopic Nissen fundoplication are endorsed for therapy. CONCLUSIONS: This guideline could be useful for the multidisciplinary management of GERD with respiratory symptoms in current practice.

Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome.

Gardner syndrome is a neoplasic disease that associates intestinal polyposis and colorectal adenocarcinoma with osteomas and soft tissue tumors determined by germline mutations in the APC gene. The early diagnosis and identification of high-risk individuals are important because patients have a 100% risk of colon cancer. We present the case of a family with Gardner syndrome. Cephalometric, panoramic X-rays and CBCT of the proband and her brother showed multiple osteomas affecting the skull bones, mandible and paranasal sinuses. The detailed family history showed an autosomal dominant transmission with the presence of the disease in the mother and maternal grandfather of the proband. Both had the typical signs of disease and died in the fourth decade of life. Based on these aspects the clinical diagnosis was Gardner syndrome. By gene sequencing, a novel pathogenic variant c.4609dup (p.Thr1537Asnfs*7) in heterozygous status was identified in the APC gene in both siblings. We reviewed literature data concerning the correlation between the localization of mutations in the APC gene and the extracolonic manifestations of familial adenomatous polyposis as well as their importance in early diagnosis and adequate oncological survey of patients and families based on abnormal genomic variants.

Sleep Impairment and Psychological Distress among Patients with Inflammatory Bowel Disease-beyond the Obvious.

BACKGROUND: A healthy sleep-wake cycle is fundamental for regulating immune function. Sleepiness and fatigue are often manifestations of chronic inflammatory disorders, such as inflammatory bowel disease (IBD), potentially influencing the course of the disease. Our aim was to characterize sleep impairment in patients with IBD and to identify potential associated factors. METHODS: We conducted a single-center prospective case control study including IBD patients and healthy controls. We evaluated clinical and biochemical parameters, sleep impairment through Pittsburgh Sleep Quality Index (PSQI) and anxiety and depression through Hospital Anxiety and Depression Scale (HADS) questionnaires. RESULTS: In total, 110 patients with IBD and 66 healthy controls were included. Patients with IBD had a significantly altered sleep quality compared to the control group (p < 0.001), with sleep impairment also occurring for patients in remission (median PSQI = 7), but without significant differences between ulcerative colitis and Crohn's disease. However, PSQI was correlated with disease activity scores only for ulcerative colitis and not for Crohn's disease. Among patients with increased PSQI, only 30.19% used sleep medication. Sleep impairment was significantly correlated with altered psychological status (p < 0.01) and the presence of extraintestinal manifestations (p = 0.0172). CONCLUSIONS: Sleep impairment is frequent among patients with IBD, is associated with psychological distress and several disease-related parameters and should be routinely evaluated, at least in several IBD patient subgroups, to improve disease management.

How the Internet influences the relationship between outpatients and gastroenterologists: A multicenter study.

BACKGROUND/AIMS: The Internet offers a lot of non-filtered medical information which may interfere with the patient-doctor relationship. The aim of the present study was to assess the influence of the Internet on the classical doctor-patient relationship in gastroenterological outpatient settings. MATERIALS AND METHODS: A multicenter study was conducted, including a representative sample selected from five major regional medical centers throughout Romania. We designed a questionnaire which had two parts. One had to be filled out by adult patients on their first visit to a gastroenterology clinic and the other by physicians, stating the diagnosis and giving a doctor-patient collaboration score. RESULTS: From a total of 485 patients (49.9% females, mean age 50.42 years), 64.9% had Internet access, 75% out of whom searched for their symptoms online. University graduates searched for their symptoms online more often than secondary school graduates (80% vs. 31.1%, p<0.05). Most patients stated that they used the Internet to identify the most appropriate medical specialist for their condition. Internet users were less likely to visit a general practitioner (GP) before coming to a specialist (85.3% vs. 92.2%, odds ratio (OR) 0.491, 95% confidence interval (CI) 0.24-0.98, p<0.05). Patients who had searched for their symptoms online were less likely to follow the treatment prescribed by the GP (53.6% vs. 67.5%, p=0.004), but they received a better collaboration score (OR 1.12, 95% CI 1.05-1.36, p<0.05). CONCLUSION: The Internet exerts a positive influence on specialist doctor-patient relationship, but it might burden the health system with the incorrect tendency to replace the role of the GP.

Terahertz Spectroscopy and Imaging: A Cutting-Edge Method for Diagnosing Digestive Cancers.

The Terahertz's wavelength is located between the microwave and the infrared region of the electromagnetic spectrum. Because it is non-ionizing and non-invasive, Terahertz (THz)-based detection represents a very attractive tool for repeated assessments, patient monitoring, and follow-up. Cancer acts as the second leading cause of death in many regions, and current predictions estimate a continuous increasing trend. Of all types of tumors, digestive cancers represent an important percentage and their incidence is expected to increase more rapidly than other tumor types due to unhealthy lifestyle habits. Because it can precisely differentiate between different types of molecules, depending on water content, the information obtained through THz-based scanning could have several uses in the management of cancer patients and, more importantly, in the early detection of different solid tumors. The purpose of this manuscript is to offer a comprehensive overview of current data available on THz-based detection for digestive cancers. It summarizes the characteristics of THz waves and their interaction with tissues and subsequently presents available THz-based technologies (THz spectroscopy, THz-tomography, and THZ-endoscope) and their potential for future clinical use. The third part of the review is focused on highlighting current in vitro and in vivo research progress in the field, for identifying specific digestive cancers known as oral, esophageal, gastric, colonic, hepatic, and pancreatic tumors.