What is the role of out of programme clinical fellowships in the era of Shape of Training? A single-centre cohort study.

BACKGROUND: The updated Shape of Training curriculum has shortened the duration of specialty training. We present the potential role of out of programme clinical fellowships. METHOD: An electronic online survey was sent to all current fellows to understand their experiences, training opportunities and motivations.Data were collected on fellows' endoscopic experiences and publications using PubMed for all previous doctors who have completed the Sheffield Fellowship Programme. RESULTS: Since 2004, 39 doctors have completed the Sheffield Fellowship.Endoscopic experience: current fellows completed a median average of 350 (IQR 150-500) gastroscopies and 150 (IQR 106-251) colonoscopies per year. Fellows with special interests completed either 428 hepato-pancreato-biliary procedures or 70 endoscopic mucosal resections per year.Medline publications: Median average 9 publications(IQR 4-17). They have also received multiple national or international awards and 91% achieved a doctoral degree.The seven current fellows in the new Shape of Training era (57% male, 29% Caucasian, aged 31-40 years) report high levels of enjoyment due to their research projects, supervisory teams and social aspects. The most cited reasons for undertaking the fellowship were to develop a subspecialty interest, take time off the on-call rota and develop endoscopic skills. The most reported drawback was a reduced income.All current fellows feel that the fellowship has enhanced their clinical confidence and prepared them to become consultants. CONCLUSION: Out of programme clinical fellowships offer the opportunity to develop the required training competencies, subspecialty expertise and research skills in a supportive environment.

Sensory Symptoms without Structural Pathology in Patients with Gluten Sensitivity.

We report on a group of patients with gluten sensitivity with and without coeliac disease presenting with unexplained sensory symptoms in the absence of structural pathology. METHODS: The patients were selected from the gluten neurology clinic based at the Royal Hallamshire Hospital, Sheffield, UK, on the basis of sensory symptoms but normal neuroaxis imaging and peripheral nerve evaluation. RESULTS: A total of 30 patients were identified with a mean age at presentation of 47 years. The prevalence of enteropathy was 78%. The sensory disturbance was characterised by tingling at 50%, numbness at 27%, pain at 20%, burning at 13% and "buzzing" feeling at 7%. The distribution of the sensory symptoms included hands and feet in 27% of the patients, torso in 27%, legs only in 23%, face in 17% and arms only in 10%. For five patients, the sensory disturbance was migratory and affected different parts of the body at any given time. After the introduction of a gluten-free diet, 77% of patients noted significant improvement in their sensory symptoms. In one-third of the patients, there was a complete resolution of the sensory symptoms. CONCLUSION: Unexplained sensory symptoms can be seen in patients with gluten sensitivity and respond to strict adherence to a gluten-free diet.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Road map to small bowel endoscopy quality indicators.

PURPOSE OF REVIEW: Quality indicators for upper and lower gastrointestinal endoscopy are well established and linked to patient outcomes. However, there is a perceived gap in the development and implementation of quality indicators for small bowel endoscopy. In this review, we aimed to discuss the development of quality indicators in small bowel endoscopy and their implementation in clinical practice. RECENT FINDINGS: The proposed quality indicators for small bowel endoscopy focus on process measures, which mainly evaluate the procedural aspects, rather than the outcomes or the overall patient experience. These quality indicators have rarely been studied in clinical practice, leading to a limited understanding of their applicability and impact on patient outcomes and experience. SUMMARY: Real-world studies evaluating the quality indicators of small bowel endoscopy are warranted to establish an evidence-based framework for their practical application and effectiveness. Linking these indicators to relevant patient outcomes is crucial for their broader acceptance and implementation.

Accuracy of the No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Current international guidelines recommend duodenal biopsies to confirm the diagnosis of celiac disease in adult patients. However, growing evidence suggests that immunoglobulin A (IgA) anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict celiac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of celiac disease in adults. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected celiac disease. We used a bivariate random effects model to calculate the summary estimates of sensitivity, specificity, and positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value of the no-biopsy approach across different pretest probabilities of celiac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS: A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven celiac disease in the included studies was 62% (95% confidence interval [CI], 40%-83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24%-40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42%-60%), and the summary specificity was 100% (95% CI, 98%-100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The positive predictive value of the no-biopsy approach to identify patients with celiac disease was 65%, 88%, 95%, and 99% if celiac disease prevalence was 1%, 4%, 10%, and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only 1 study had a low risk of bias across all domains. CONCLUSION: The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pretest probability of celiac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy.

Systematic review: Clinical phenotypes, histopathological features and prognosis of enteropathy due to angiotensin II receptor blockers.

BACKGROUND: Although enteropathy due to angiotensin II receptor blockers (ARBs) has been known for over 10 years, clinicians' awareness of this condition is still low. AIMS: To systematically review the literature about clinical phenotypes, distribution of mucosal changes throughout the gastrointestinal tract and prognosis of enteropathy due to ARBs. METHODS: According to PRISMA guidelines, we searched PubMed and Embase for relevant articles up to November 6, 2023. We included full-text papers, letters, case reports and case series describing enteropathy due to ARBs. Patients were classified into subgroups based on endoscopic and histological findings of different regions of the gastrointestinal tract. The protocol was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/TK67C). RESULTS: We included 94 articles reporting 183 cases (101 female, mean age at diagnosis 69 ± 10 years). The clinical picture at diagnosis was characterised by severe diarrhoea (97%) and weight loss (84%, median -13 kg), leading to hospital admission in 167 (95%) patients. Olmesartan (90%) was most frequently implicated. Villous atrophy (VA) was reported in 164/183 (89%) patients. One hundred and nine had only VA, 12 had pan-gastrointestinal involvement, 23 had VA and gastric involvement and 19 had VA and colon involvement (predominantly microscopic colitis). Outcomes were reported for 178/183 (97%) patients, who all recovered clinically on ARBs withdrawal. Histological recovery occurred in all 96 patients with VA at baseline who underwent follow-up duodenal biopsy. CONCLUSIONS: Enteropathy due to ARBs is characterised by severe malabsorption often requiring hospital admission and can involve the entire gastrointestinal tract. Clinician awareness can lead to prompt diagnosis and excellent prognosis.

Device-assisted enteroscopy performance measures in the United Kingdom: DEEP-UK quality improvement project.

BACKGROUND: Device-assisted enteroscopy (DAE) has become a well-established diagnostic and therapeutic tool for the management of small-bowel pathology. We aimed to evaluate the performance measures for DAE across the UK against the quality benchmarks proposed by the European Society of Gastrointestinal Endoscopy (ESGE). METHODS: We retrospectively collected data on patient demographics and DAE performance measures from electronic endoscopy records of consecutive patients who underwent DAE for diagnostic and therapeutic purposes across 12 enteroscopy centers in the UK between January 2017 and December 2022. RESULTS: A total of 2005 DAE procedures were performed in 1663 patients (median age 60 years; 53% men). Almost all procedures (98.1%) were performed for appropriate indications. Double-balloon enteroscopy was used for most procedures (82.0%), followed by single-balloon enteroscopy (17.2%) and spiral enteroscopy (0.7%). The estimated depth of insertion was documented in 73.4% of procedures. The overall diagnostic yield was 70.0%. Therapeutic interventions were performed in 42.6% of procedures, with a success rate of 96.6%. Overall, 78.0% of detected lesions were marked with a tattoo. Patient comfort was significantly better with the use of deep sedation compared with conscious sedation (99.7% vs. 68.5%; P<0.001). Major adverse events occurred in only 0.6% of procedures. CONCLUSIONS: Performance measures for DAE in the UK meet the ESGE quality benchmarks, with high diagnostic and therapeutic yields, and a low incidence of major adverse events. However, there is room for improvement in optimizing sedation practices, standardizing the depth of insertion documentation, and adopting marking techniques to aid in the follow-up of detected lesions.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Guidelines for best practices in monitoring established coeliac disease in adult patients.

Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies.

A Cohort Study of the Diversity in Animated Films From 1937 to 2021: In a World Less Enchanted Can We Be More Encanto?

Background Exposure to gender stereotypes in the media can develop and reinforce these attitudes in children. Individuals who are overweight, have health conditions, or are from a minority ethnic group (IMEG) are both underrepresented and poorly portrayed in the media. Role models can raise the aspirations of young children both professionally and in taking ownership of their health. We aimed to assess how the portrayal and diversity of characters in Disney, Pixar, and Dreamworks animated films have changed over time. Method A cohort study of all main characters in Disney, Pixar, and Dreamworks feature-length, theatrical, animated films from 1937 to 2021 was conducted. The portrayal of characters (R-score divided into negative, neutral, and positive -1, 0, and 1, respectively) was scored. The proportion of individuals with certain protected characteristics (sex, increased body mass index, physical or mental health conditions, being from an IMEG or part of the lesbian, gay, bisexual, transexual, and queer community) was also recorded. Results In total, 116 films and 1,275 characters were included. From the 1930s to 2020s, the proportion of women in films increased (16.7% to 47.3%, p=0.008) and their representation was more positive (mean R-score = -0.10 (SD:0.692) versus 0.49 (SD:0.837), p<0.001, respectively). The portrayal of overweight individuals has improved to a neutral position (mean R-score: -0.67 to 0.0). Both physical and mental illnesses are better portrayed (mean R-score: -0.18 to 0.34, p=0.004 and 0.5 to 1.0, p= 0.019, respectively). IMEGs introduced in 1953 now play more than just negative roles (mean R-score = -1 to 0.76, p=0.008). There is only one explicitly stated homosexual character. The most diverse film is Encanto. Conclusion This is the first study to comprehensively assess the diversity of animated film characters. We have identified an improvement in diversity and the way diverse individuals are portrayed which we hope continues.

Narrow-band imaging for optical diagnosis of duodenal villous atrophy in patients with suspected coeliac disease: A systematic review and meta-analysis.

BACKGROUND: Narrow-band imaging (NBI) is a readily accessible imaging technique that enhances mucosal visualisation, allowing for a more accurate assessment of duodenal villi. However, its role in the diagnosis of coeliac disease (CD) in clinical practice remains limited. METHODS: We systematically searched several databases in June 2023 for studies evaluating the diagnostic accuracy of NBI for detecting duodenal villous atrophy (VA) in patients with suspected CD. We calculated the summary sensitivity, specificity, and likelihood ratios using a bivariate random-effects model. The study followed PRISMA guidelines and was registered at PROSPERO (CRD42023428266). RESULTS: A total of 6 studies with 540 participants were included in the meta-analysis. The summary sensitivity of NBI to detect VA was 93% (95% CI, 81% - 98%), and the summary specificity was 95% (95% CI, 92% - 98%). The area under the summary receiver operating characteristic curve was 0.98 (95% CI, 96 - 99). The positive and negative predictive values of NBI were 94% (95% CI, 92% - 97%) and 92% (95% CI, 90% - 94%), respectively. CONCLUSION: NBI is an accurate non-invasive tool for identifying and excluding duodenal VA in patients with suspected CD. Further studies using a validated classification are needed to determine the optimal role of NBI in the diagnostic algorithm for CD.

Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study.

BACKGROUND: Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease. METHODS: In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data. FINDINGS: We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet. INTERPRETATION: Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA. FUNDING: None.

Long-term follow-up in patients with coeliac disease in the pandemic-era: a view from Sheffield the NHS England national centre for adult coeliac disease.

Aim: To explore patients' follow-up preferences. Background: Optimal follow-up strategies for patients with coeliac disease remain a subject of debate. Research suggests patients' prefer review by dietitians with a doctor available as required. Methods: Patients with coeliac disease under review at our centre, completed a questionnaire assessing their views on what makes follow-up useful based on specific criteria. Bloods tests, symptoms review, dietary assessment, opportunity to ask questions and reassurance. Patients' preferences between follow-up with a hospital doctor, a hospital dietitian, a hospital dietitian with a doctor available, a general practitioner, no follow-up or access when needed were also evaluated. Results: 138 adult patients completed the questionnaire, 80% of patients reported following a strict gluten free diet (mean diagnosis was 7.2 years). Overall, 60% found their follow-up to be 'very useful' valuing their review of blood tests and symptoms (71%) reassurance (60%) and opportunity to ask questions (58%). Follow-up by a dietitian with a doctor available was the most preferred option of review (p<0.001) except when compared to hospital doctor (p=0.75). Novel modalities of follow-up such as telephone and video reviews were regarded as of equal value to face-to-face appointments (65% and 62% respectively). Digital applications were significantly less preferable (38%, p<0.001). Conclusion: Follow-up by a dietitian with a doctor available as needed was the most preferred follow-up method. However, in this study follow-up by a dietitian with doctor available and hospital doctor alone was statistically equivalent. Many patients consider telephone and video follow-up of equal value to face-to-face reviews.

Does a Gluten-Free Diet Improve Quality of Life and Sleep in Patients with Non-Coeliac Gluten/Wheat Sensitivity?

INTRODUCTION: The role of a gluten-free diet (GFD) in Non-Coeliac Gluten/Wheat Sensitivity (NCGWS) is unclear. We present the largest study comparing adherence to a GFD in patients with Coeliac Disease (CD) and NCGWS and assess its impact on quality of life (QoL) and sleep in patients with NCGWS. METHODS: Patients with NCGWS at a tertiary centre completed the Coeliac Disease Adherence Test (CDAT), Coeliac Symptom Index (CSI) and Sleep Condition Indicator (SCI). Higher CDAT scores indicate worse adherence, higher CSI scores indicate poorer QoL, and higher SCI scores indicate better sleep. CDAT scores were correlated with CSI and SCI scores. A second group of patients with CD completed the CDAT questionnaire only. Results were compared with the CDAT responses from the NCGWS group. RESULTS: For the NCGWS cohort (n = 125), the median CDAT score was 17/35, indicating poor adherence. The median CSI score was 44/80, with 40% of scores associated with a poor QoL. The median SCI score was 14/32, and DSM-V criteria for insomnia was met by 42% of patients. There was a positive correlation between CSI and CDAT scores (r = 0.59, p < 0.0001) and a negative correlation between SCI and CDAT scores (r = -0.37, p = 0.0002). In the CD cohort (n = 170), the median CDAT score was 13/35. Patients with NCGWS had poorer adherence compared to CD (CDAT: 17.0 vs. 13.0, respectively, p = 0.0001). CONCLUSION: Patients with NCGWS adhere to a GFD less than those with CD. Poorer adherence to a GFD in patients with NCGWS correlates with a worse QoL and sleep performance.

Updates in the diagnosis and management of coeliac disease.

Coeliac disease is a common autoimmune disorder induced by ingesting gluten, the protein component of wheat, barley, and rye. It is estimated that one-in-hundred people worldwide have coeliac disease, of whom the majority remain undiagnosed. Coeliac disease is characterized by a wide range of gastrointestinal and extraintestinal symptoms but can also present asymptomatically. Diagnosing coeliac disease depends on the concordance of clinical, serological and histopathological data. However, the diagnosis can be challenging and frequently overlooked. Undiagnosed coeliac disease is associated with an increased risk of complications and detrimental effects on quality of life. Early diagnosis and treatment of coeliac disease are necessary to reduce the risk of long-term complications.