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.

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.

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.

Applying Lyon consensus criteria in the work-up of patients with extra-oesophageal symptoms - A multicentre retrospective study.

BACKGROUND: The diagnosis of gastro-oesophageal reflux disease (GERD) based on otolaryngologist's assessment of laryngoscopic findings remains contentious in terms of sensitivity and specificity. AIMS: To evaluate GERD prevalence, applying Lyon 2.0 Consensus criteria, in patients with extra-oesophageal symptoms undergoing laryngoscopic examination and impedance-pH monitoring. METHODS: In this retrospective assessment, we included 470 patients with extra-oesophageal symptoms, either isolated or combined with typical symptoms, who had been referred to six tertiary Italian Gastroenterology Units between January and December 2020. Of these, 274 underwent 24-h impedance-pH monitoring and laryngoscopy off PPI therapy. GERD diagnosis followed Lyon Consensus 2.0 criteria, incorporating mean nocturnal baseline impedance when pH-impedance monitoring was inconclusive. RESULTS: Laryngoscopic examination revealed pathological findings (predominantly posterior laryngitis) in 71.2% (195/274). GERD was diagnosed in 29.2% (80/274) via impedance-pH monitoring. The prevalence of GERD in patients with positive or negative laryngoscopy was similar (32.3% vs. 21.5%, p = 0.075). No significant difference in proximal reflux occurrences was noted between positive and negative laryngoscopy groups (33.3% vs. 24.1%, p = 0.133). Laryngoscopy demonstrated sensitivity and specificity of 78.8% and 32.0%, respectively, with a positive predictive value (PPV) of 32.3% and negative predictive value (NPV) of 28.4%. In contrast, a threshold of four concurrent laryngoscopic signs, identified in only eight patients, demonstrated a PPV of 93.8% and a NPV of 73.6% (sensitivity 25.4%, specificity 99.2%). CONCLUSION: This study underscores the limited diagnostic accuracy of laryngoscopy, emphasising the necessity of impedance-pH monitoring for confirming GERD diagnoses using Lyon 2.0 criteria in patients with suspected extra-oesophageal symptoms.

Association between Ustekinumab Trough Levels, Serum IL-22, and Oncostatin M Levels and Clinical and Biochemical Outcomes in Patients with Crohn's Disease.

Background: Ustekinumab (UST) has demonstrated effectiveness in treating patients with Crohn's disease. Monitoring treatment response can improve disease management and reduce healthcare costs. We investigated whether UST trough levels (TLs), serum IL22, and Oncostatin M (OSM) levels could be early indicators of non-response by analysing their correlation with clinical and biochemical outcomes in CD. Methods: Patients with CD initiating UST treatment from October 2018 to September 2020 were enrolled at six Italian centres for inflammatory bowel disease (IBD). Clinical and biochemical data were collected at four time points: baseline, second subcutaneous (SC) dose, fourth SC dose, and 52 weeks. TLs were measured during maintenance, at the second SC dose, and at the fourth SC dose. IL-22 and OSM serum levels were assessed at baseline and the second SC dose. We analysed whether TLs, IL22 levels, and OSM serum levels were associated with clinical response, clinical remission, biochemical remission, and endoscopic remission using the appropriate statistical tests. Results: Out of eighty-four initially enrolled patients, five were lost to follow-up, and eleven discontinued the drug before 52 weeks. At the 52-week time point, 47% achieved biochemical remission based on faecal calprotectin levels, and 61.8% achieved clinical remission. TLs at the second SC dose significantly correlated with biochemical remission at the same time point (p = 0.011). However, TLs did not correlate with clinical remission. Baseline OSM levels did not correlate with biochemical or clinical remission or response. IL22 levels notably decreased during UST therapy (p = 0.000), but its values did not correlate with biochemical or clinical remission. Conclusions: UST is an effective therapy for patients with CD. TLs measured at the second SC dose significantly correlated with biochemical remission, emphasising their potential role in treatment monitoring. Levels of OSM and IL-22, despite a significant decrease in the latter during therapy, did not exhibit correlations with clinical or biochemical outcomes in our study. Further studies are needed to confirm these findings.

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. METHODS: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. RESULTS: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p < .0001; Child-Turcotte-Pugh score: 7 vs. 5, p < .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p < .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). CONCLUSIONS: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival.

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.

Ustekinumab safety and effectiveness in patients with ulcerative colitis: results from a large real-life study.

BACKGROUND: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist recently approved for treating ulcerative colitis (UC) but with limited real-world data. Therefore, we evaluated the effectiveness and safety of UST in patients with UC in a real-world setting. RESEARCH DESIGN AND METHODS: This is a multicenter, retrospective, observational cohort study. The primary endpoints were the clinical remission rate (partial Mayo score, PMS, ≤1) and the safety of UST. Other endpoints were corticosteroid-free remission (CSFR) rate, clinical response rate (PMS reduction of at least 2 points), and fecal calprotectin (FC) reduction at week 24. RESULTS: We included 256 consecutive patients with UC (M/F 139/117, median age 52). The clinical remission and clinical response rates at eight weeks were 18.7% (44/235) and 53.2% (125/235), respectively, and 27.6% (42/152) and 61.8% (94/152) at 24 weeks, respectively. At 24 weeks, CSFR was 20.3% (31/152), and FC significantly dropped at week 12 (p = 0.0004) and 24 (p = 0.038). At eight weeks, patients naïve or with one previous biologic treatment showed higher remission (p = 0.002) and clinical >response rates (p = 0.018) than patients previously treated with ≥ 2. Adverse events occurred in six patients (2.3%), whereas four patients (1.6%) underwent colectomy. CONCLUSION: This real-world study shows that UST effectively and safely treats patients with UC.

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.

Reduction of Fecal Calprotectin Levels Induced by a Short Course of Escherichia Coli Nissle is Associated with a Lower Likelihood of Disease Flares in Patients with Ulcerative Colitis in Clinical Remission.

BACKGROUND AND AIMS: Fecal calprotectin (FC) is a biomarker of gut inflammation, and Escherichia coli Nissle 1917 (EcN) is a probiotic strain able to reduce gut inflammation and maintain disease remission in patients with inflammatory bowel disease (IBD). The aim is to assess the effects of EcN administration in patients with IBD in clinical remission and altered FC values. METHODS: We prospectively included 82 patients with ulcerative colitis (UC) (n=49) and Crohn's disease (CD) (n=33) in clinical remission and with FC values above 250 mcg/g (T0) who were treated with EcN alone for 2 months. FC values were assessed at the end of EcN treatment (T1) and clinical disease activity at 3 months (T2). RESULTS: At T1 median FC values were significantly lower compared to T0 both in patients with CD (312 mcg/g vs 626 mcg/g, p<0.0001) and UC (100 mcg/g vs 584 mcg/g; p<0.0001). Patients with UC who experienced disease relapse at T2 had lesser reduction in median FC values at T1 (-229 mcg/g, vs -397 mcg/g, p=0.049), while in patients with CD we observed no statistically significant difference (-358 mcg/g, vs -427; p=0.568). In patients with UC, a reduction of at least 532 mcg/g in FC had an accuracy of 69.7% and a positive predictive value of 65.7% in predicting maintenance of remission. CONCLUSIONS: A short course of EcN was associated with a reduction of FC values in patients with IBD in clinical remission and baseline altered FC values, and in patients with UC this decrease was associated with maintenance of clinical remission.

Albumin-bilirubin score in non-malignant liver diseases should be properly validated.

The albumin-bilirubin (ALBI) score to assess the risk of decompensation in patients with initially compensated cirrhosis may improve their prognostic evaluation. This letter critically evaluates the research, which utilizes the ALBI score to forecast decompensation in cirrhosis patients over a three-year period. This score was initially developed to assess liver function in hepatocellular carcinoma, its prognostic utility for non-malignant liver diseases has now been explored, recognizing decompensation as a pivotal event that significantly affects patient's survival. Some concerns regarding the methodology of this research may be raised, particularly the exclusive use of radiological diagnosis, potentially including patients without definite cirrhosis and thus skewing the decompensation risk assessment. The reported predominance of variceal bleeding as a decompensating event conflicts with established literature, that often reports ascites as the initial decompensation manifestation. The letter highlights the absence of details on esophageal varices and their management, which could introduce bias in evaluating the ALBI score's predictive power. Furthermore, the letter points out the small sample size of patients with high-risk ALBI grades, potentially compromising the score's validity in this context. We suggest prospective future research to investigate the dynamic changes in the ALBI score over time to reinforce the validity of the ALBI score as a predictor of decompensation in non-malignant liver disease.

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.

Clopidogrel-Induced Eosinophilic Colitis.

Eosinophilic colitis is a rare condition characterized by histologic findings of high eosinophilic infiltrate in the gut wall, typically presenting with diarrhea and abdominal pain. The etiology of this entity remains unclear because it can be primary or can occur secondarily to infections, drugs, or even in association with immune-mediated diseases. We present the case of a woman referred to our outpatient clinic for chronic diarrhea that had been worsening for months. Colonoscopy with biopsies was performed, and eosinophilic colitis associated with the use of clopidogrel was diagnosed. After clopidogrel discontinuation, a complete remission of the clinical and histological picture was observed.

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.

Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis.

BACKGROUND AND AIMS: Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT. METHODS: We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy. RESULTS: Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p < 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p < 0.001). CONCLUSIONS: Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.