Introduction

Risankizumab (RZB) is an interleukin [IL]-23 p19 inhibitor approved for the treatment of Crohn’s disease (CD). In the SEQUENCE head-to-head trial in patients with moderately to severely active CD, RZB was more effective in achieving endoscopic outcomes over ustekinumab (UST; IL-12/IL-23 p40 inhibitor),¹ with higher rates of endoscopic remission, regardless of CD location, observed in post hoc analyses.^2-3 Here, we evaluate the changes from baseline in Simple Endoscopic Score for Crohn’s Disease (SES-CD) total score and SES‑CD components at weeks 24 and 48.

Aims & Methods

SEQUENCE was an open-label, multicenter, randomized, efficacy assessment–blinded study in adults with moderately to severely active CD who had experienced inadequate response to ≥ 1 anti-tumor necrosis factor (TNF) therapy. Patients in the primary efficacy analysis set were randomized 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, followed by a subcutaneous [SC] 360 mg maintenance dose every 8 weeks starting at week 12) or UST (single weight-based IV induction dose, followed by a SC 90 mg maintenance dose every 8 weeks starting at week 8) up to week 48. A mandatory corticosteroid taper started at week 2. In this post hoc analysis, the mean changes from baseline in total SES-CD score and individual SES-CD components (affected surface, ulcerated surface, size of ulcers, and presence of narrowing) at weeks 24 and 48 were evaluated. Data include patients with nonmissing values at both baseline and the corresponding visit; all P values are nominal.

Results

Of 520 enrolled patients (RZB, 255; UST, 265), evaluable endoscopy data were available at week 24 for 461 patients (RZB, 238; UST, 223) and at week 48 for 379 patients (RZB, 210; UST, 169). Baseline SES-CD scores were generally similar between treatment groups (Table). At week 24, treatment with RZB resulted in greater improvement in total SES‑CD from baseline compared with UST (−6.6 vs −3.9; nominal P < .0001), and similarly, improvements at week 48 were greater with RZB vs UST (−7.3 vs −4.8; nominal P = .0006). Further, numerically greater improvements were observed with RZB vs UST across all individual SES-CD components at weeks 24 and 48, with notable differences between RZB and UST seen in the individual SES-CD components of affected surface, ulcerated surface, and size of ulcers (nominal P < .01).

Table. Total SES-CD and Individual SES-CD Components Over Time
Parameter, mean (SD)	Baselinea		Change From Baseline at Week 24a		Change From Baseline at Week 48b
	RZB (n = 238)	UST (n = 223)	RZB (n = 238)	UST (n = 223)	RZB (n = 210)	UST (n = 169)
Total SES-CD	13.4 (7.1)	13.8 (7.2)	−6.6 (7.4)***	−3.9 (6.4)	−7.3 (7.4)***	−4.8 (6.8)
SES-CD components
Affected surface	4.7 (2.9)	5.0 (3.3)	−2.5 (2.9)***	−1.5 (3.0)	−2.6 (3.0)**	−1.8 (3.1)
Ulcerated surface	3.6 (2.4)	3.7 (2.3)	−1.9 (2.4)***	−1.2 (2.0)	−2.1 (2.4)**	−1.4 (2.2)
Size of ulcers	4.3 (2.5)	4.4 (2.5)	−2.2 (2.7)***	−1.4 (2.2)	−2.5 (2.7)***	−1.7 (2.1)
Presence of narrowing	0.8 (1.3)	0.7 (1.2)	−0.1 (1.3)	0.1 (1.1)	−0.1 (1.2)	0.1 (1.1)
RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease; UST, ustekinumab. **Nominal P < .01; ***nominal P < .001 vs UST based on Student’s t test. aValues only include patients with nonmissing values at both baseline and week 24. bValues only include patients with nonmissing values at both baseline and week 48. Patients discontinuing the study before week 24 or 48 were not included in the analysis for that respective timepoint.

Conclusion

In this head-to-head study, RZB was more effective than UST in improving endoscopic disease activity per SES-CD scores in patients with CD who had experienced inadequate response to anti-TNF therapy. Differences were observed both at weeks 24 and 48 and were driven by SES-CD components of the size of ulcers, ulcerated surface, and affected surface.

References

1. Peyrin-Biroulet L, et al. United European Gastroenterol J. 2023;11:919−922. Abstract LB01.
2. Peyrin-Biroulet L, et al. J Crohns Colitis. 2024;18:i90−i91. Abstract DOP10.
3. Peyrin-Biroulet L, et al. J Crohns Colitis. 2024;18:i104−i105. Abstract DOP18.

Disclosure

PMI has received speaking fees, research grants, and/or advisory fees from AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Dr Falk, Ferring, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Samsung Bioepis, Sandoz, Sapphire, Shire, Takeda, Tillotts, Topivert, VH2, Vifor, and Warner Chilcott.
J-FC has been a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Arena, Celgene, Celltrion, Enterome, Ferring, Genentech, Gilead, J&J, Lilly, Medimmune, Merck, Nextbiotix, Novartis, Otsuka, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, and Theradiag. He is a speaker for AbbVie, Celgene, Ferring, and Takeda; holds stock options for Intestinal Biotech Development, and GENFIT; and has received research grants from AbbVie, J&J, and Takeda.
GD’H has been an advisor for AbbVie, Ablynx, Active Biotech AB, Agomab, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AM, Applied Molecular Therapeutics, Arena, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celltrion, DSM, Echo, Engene, Exeliom, Dr Falk, Ferring, Galapagos, Genentech/Roche, Gilead, GSK, Gossamerbio, Immunic, J&J, Kintai, Lilly, Lument, Lycera, Medtronic, MSD, Mitsubishi Tanabe, Novo Nordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus laboratories/Nestlé, Protagonist, RedHill, Samsung Bioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, and Vifor.
MF has received research grants from AbbVie, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, AgomAb, Boehringer Ingelheim, Celgene, Celltrion, Janssen-Cilag, Lilly, MRM Health, MSD, Pfizer, Takeda, and ThermoFisher; and speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion, and Viatris.
FC has received consulting fees from AbbVie, Biogen, BMS, Celgene, Ferring, Galapagos, Gilead, Janssen, Lilly, Lionhealth, MSD, Mundipharma, Pfizer, Roche, and Takeda; lecture fees from AbbVie, Allergy Therapeutics, Biogen, Ferring, Janssen, Pfizer, and Takeda; and unrestricted research grants from AbbVie, Giuliani, MSD, Sofar, and Takeda.
BS has received consulting fees from AbbVie, Abivax, Arena, Boehringer Ingelheim, BMS, Celgene, Dr Falk, Endpoint Health, Galapagos, Gilead, Janssen, Lilly, Pfizer, Prometheus, and Takeda, and speaker’s fees from AbbVie, BMS, CED Service, Dr Falk, Ferring, Galapagos, Janssen, Lilly, Novartis, Pfizer, and Takeda.
SvH, BK, TA, and AG are full-time employees of AbbVie and may own AbbVie stock or stock options.
LP-B has received personal fees from AbbVie, Abivax, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic, Novartis, OM, ONO, OSE Immunotherapeutics, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, VectivBio, Ventyx, Viatris, Vifor, and Ysopia.

Introduction

The most common among surgical antireflux methods for the treatment of hiatal hernias (HH) are Nissen, Toupet, or Dor surgery. Among the disadvantages of these interventions, the greatest importance is the destruction of the physiological cardia, which is accompanied by the recurrence of HH, dysphagia, gas-bloat syndrome and heartburn recovery. Despite the advances in HH surgery, the performance of antireflux operations remains debatable.

Aims & Methods

To improve methods of diagnosis and treatment of complications of insufficiency of the physiological cardia in HH.In 2017-2022, 78 patients with HH were diagnosed and treated surgically in the digestive surgery department of the institute.
The type and degree of HH were determined during X-ray examination. An endoscopic examination was performed to determine the condition of the mucous membrane of the esophagus and the degree of violations of the physiological cardia. Endoscopic balloon manometry was used to study pressure in the lower esophageal sphincter (LES) and monitor the effectiveness of antireflux surgery.

Results

Axial HH (I type) was diagnosed during X-ray examination – in 60 (77.0%); paraesophageal (II type) – in 9 (11.5%); mixed (III type) – in 9 (11.5%) patients. Depending on the amount of penetration of organs into the chest cavity, HH of the 1st degree was established – in 42 (53.8%), 2nd degree – in 27 (34.6%) and 3rd degree – in 9 (11.5%) patients.
Changes in the mucous membrane of the esophagus – in 40 (51.3%) patients with type I and III HH: non-erosive reflux esophagitis – in 9 (11.5%), erosive reflux esophagitis – in 16 (20.5%), esophageal ulcer – in 6 (7.7%), peptic stricture of the esophagus on the background of esophagitis – in 3 (3.8%), Barrett's esophagus - in 6 (7.7%) patients.
During endoscopic balloon manometry, the pressure in the LES is reduced: axial HH – (11.39±2.44) mmHg, paraesophageal – (13.54±3.32) mmHg, mixed – (8.06±3, 64) mm Hg (the norm is 14-21 mm Hg). The first stage of treatment for patients with reflux esophagitis was conservative therapy, for peptic stricture of the esophagus – endoscopic balloon hydrodilatation, for Barrett's esophagus – argon plasma ablation. As a second stage, 78 patients underwent standard laparoscopic antireflux operations according to Nissen – in 32 (41.1%), Toupet – in 7 (8.9%), Dor – in 5 (6.4%), and in 34 (43.6%) patients, according to the proposed method, which preserves the connections of the diaphragm, esophagus, and stomach, and performing cardiocrurorrhaphy, fundocruroesophagorraphy, cardiogastroplication with gastrodiaphragmopexy restores the antireflux function of the physiological cardia.In the long term, from 6 months to 4 years, significantly more complications were diagnosed after standard antireflux operations compared to the proposed method - gas bloat-syndrome (X²=4.65, p=0.031) pylorospasm (X²=4.03, p=0.045), dysphagia (X²=4.30, p=0.038) and recurrence of HH – 11 (25.0%) vs 3 (8.8%) cases (p<0.05).

Conclusion

The proposed two-stage method of surgical treatment of patients with HH is highly effective. The application of the proposed method ensures the elimination of pathological changes in the mucous membrane of the esophagus, the restoration of the physiological cardia, the preservation of the anatomical relationships of the diaphragm and the zone of the esophageal-gastric transition. In the postoperative period, the proposed method reduces the frequency of recurrence of HH, occurrence of gas bloat-syndrome, pylorospasm, and dysphagia.

Introduction

Infliximab (IFX) is the first anti-TNF biologic drug approved for treating moderate to severe ulcerative colitis (UC). While IFX is effective in inducing mucosal healing and enhancing quality of life, concerns persist about the long-term safety and cost-effectiveness of extended immunosuppression. Current guidelines lack clarity on when to discontinue treatment after achieving stable deep remission. Moreover, existing literature is limited to studies characterized by small sample sizes and heterogenous criteria for defining remission. Our study aimed to evaluate the rate of remission maintenance in UC patients who discontinued IFX after achieving stable deep remission, to identify predictors of relapse post-discontinuation, and to examine clinical outcomes in those who experienced a relapse

Aims & Methods

In this single-center, retrospective, observational study, we analyzed UC patients at our tertiary IBD Referral Center who discontinued IFX due to sustained deep remission, defined as the combination of partial Mayo subscore ≤ 1 and endoscopic Mayo score = 0, and who had at least 1 year of follow-up post treatment withrdawl. We assessed the relapse rates at intervals of 6 months, 1 year, 2 years, and beyond 2 years post-IFX discontinuation. For those who relapsed, we recorded the therapeutic strategy and its effectiveness, including the necessity for colectomy. Additionally, we performed univariate and multivariate analyses to identify relapse predictors post-treatment suspension.

Results

From 2006 to 2022, 790 UC patients received IFX treatment at our center; 113 suspended IFX due to stable deep remission with at least 1 year of follow-up and were included in this study. Of these, 41.6% maintained remission over a median of 5.17 years. Flare rates were 14.2%, 23.9%, and 35.5% within 6, 12, and 24 months, respectively, with 58.4% experiencing a flare overall. Multivariate analysis showed that longer treatment duration reduced relapse risk (p=0.001), while steroid use during IFX treatment and early IFX initiation post-diagnosis increased relapse risk (p=0.004 and p=0.043, respectively). Most cases of disease relapsee were successfully managed medically either with a course of steroids, restarting IFX, or initiation of a different type of biologic/small molecule, whereas the rate of colectomy was 7.1%.

Conclusion

This study is one of the largest to date with the longest follow-up that evaluates outcomes post-IFX discontinuation in UC patients in deep remission. Our finding suggest that withdrawal of IFX treatment can be considered in carefully selected cases. In patients who relapse after IFX suspension, medical treatment is often effective, while the rate of colectomy is low. Further studies are warranted to better identify ideal candidates for treatment withdrawal.

Introduction

The place that regular Physical Activity (PA) should occupy in managing patients with Inflammatory Bowel Diseases (IBD) is unclear. Unfortunately, there is little data on PA in patients with IBD, although it appears to be reduced compared to the general population. Nevertheless, PA may provide several multidimensional metabolic, anti-inflammatory, and sarcopenia benefits. Therefore, the World Health Organization recommends for each age group and patients with disabilities regular PA adapted to individual ability/tolerance. However, there are no precise guidelines on the best PA and the intensity to recommend for patients with IBD. Therefore, this study aims to assess PA levels and barriers to PA in a southern European Italian IBD population.

Aims & Methods

IBD patients with non-severe disease activity [assessed with partial Mayo score for Ulcerative Colitis (UC) and Harvey-Bradshaw index for Crohn's Disease (CD)] were approached to receive an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire (IPAQ) and to assess disease activity as Patient-Reported Outcomes 2 (PRO-2) and finally to assess habits, beliefs and barriers in conducting regular PA. Clinical, anthropometric and demographic data of patients were also collected. PA was expressed as continuous units of resting metabolic rate (Met) in minutes/week (Met min/wk). Three PA groups were identified: inactive (< 700 Met min/wk), sufficiently active (700-2500 Met min/wk) and Health Enhancing PA (i.e., HEPA active, > 2500 Met min/wk) patients.

Results

Included patients (219) showed overall PA levels of 834.5 Met min/wk, with a large proportion (94, 42.9%) classified as inactive while only a minority (9, 4.1%) as health-enhancing PA (see Table). Patients without dyslipidaemia (p < 0.0001) or on biologics therapy (p=0.022) showed better IPAQ scores in moderate activities. UC PRO-2 correlated negatively with IPAQ intense activities scores (τ= -0.156, p=0.038). PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity (AUC < 0.6). IBD activity did not differ between active and inactive patients (p > 0.05). Active patients expressed the need to discuss PA with their gastroenterologist. Some barriers (e.g., diagnosis of IBD and fear of flare-ups after PA) are significantly more reported by inactive patients.

PA variable	Crohn’s disease (N=92)	Ulcerative colitis (N=127)	P-value*
Intense activities (Met min/wk)	0 (0 – 192)	0 (0 – 240)	0.099
Moderate activities (Met min/wk)	208 (0 – 536)	140 (0 – 540)	0.590
Mild activities (Met min/wk)	293.75 (158.12 – 711.6)	350 (120 – 840)	0.940
Sitting time at work (min)	210 (113 – 292.5)	215 (125 – 292)	0.719
Sitting time at home (min)	174 (118.75 – 221.75)	177 (115 – 229)	0.855
Total score (Met min/wk)	828.25 (339.37 – 1343.5)	839 (390 – 1451)	0.678
PA level Inactive Sufficiently active HEPA active	39 (42.4%) 50 (54.3%) 3 (3.3%)	55 (43.3%) 66 (52%) 6 (4.7%)	0.995

HEPA: Health Enhancing Physical Activity. *The P-value was calculated by checking the difference in the distribution of different variables between the two identified groups (i.e., Crohn's disease and ulcerative colitis). Data are expressed for continuous variables as median (interquartile range) and, for categorical and ordinal variables, as numerosity (%).

Conclusion

There was a significant rate of physical inactivity in patients with IBD in this setting. Many IBD southern European patients are inactive and may be exposed to all the complications of not practising regular PA. This does not seem dependent on disease activity but is affected by patients' beliefs about PA's impact on baseline IBD. There is some patient interest in discussing PA with their gastroenterologist that should be used to inform them about the available evidence on PA and the risks of impact on IBD that they fear.

References

- Ananthakrishnan AN., Kaplan GG., Bernstein CN., Burke KE., Lochhead PJ., Sasson AN., et al. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus. Lancet Gastroenterol Hepatol 2022;7(7):666–78.
- Mareschal J., Douissard J., Genton L. Physical activity in inflammatory bowel disease: benefits, challenges and perspectives. Curr Opin Clin Nutr Metab Care 2022;25(3):159–66. Kim B., Chae J., Kim EH., Yang HI., Cheon JH., Kim TI., et al. Physical activity and quality of life of patients with inflammatory bowel disease. Medicine (Baltimore) 2021;100(27):e26290.

Introduction

Vedolizumab (VED) and ustekinumab (UST) are valid options for ulcerative colitis (UC) and Crohn’s disease (CD) patients who fail anti-tumour necrosis factor (TNF) therapy. However, there are conflicting data on which drug should be preferred as second-line.

Aims & Methods

UC and CD patients who received VED or UST after anti-TNF failure or intolerance were included, and treatment groups were compared. The primary outcome of clinical remission (CR) was evaluated at 6 and 12 months of therapy, as were the secondary outcomes of corticosteroid-free CR and biochemical remission (BR). Endoscopic remission (ER) was evaluated at 12 months. Predictors of these outcomes were assessed using Cox regression.

Results

A total of 72 patients were included, 21 with UC (14 UST | 7 VED) and 51 with CD (35 UST | 16 VED). There were no significant differences in the various remission rates between both treatment groups, in UC and CD. In CD, multivariate analysis revealed baseline Harvey-Bradshaw index (HBI) as an independent predictor of failed CR (p<0.001, HR 1.42, IC 95% 1.18-1.71) and corticosteroid-free CR (p<0.001, HR 1.43, IC 95% 1.19-1.72) at 12 months. Anti-TNF discontinuation due to primary or secondary failure (vs. adverse event) was an independent predictor of BR at 12 months (p=0.028, HR 2.33, IC 95% 1.09-4.98). Interestingly, subanalysis of 16 patients who advanced to a third-line therapy with the opposite drug revealed a tendency for lower CR rates with VED (40.0%), when compared to UST (72.73%), albeit not statistically significant (p=0.299).

Conclusion

In this study, clinical, biochemical and endoscopic remission rates in UC and DC were not significantly different between patients treated with VED or UST as second-line therapy. HBI and reason for anti-TNF withdrawal were independent predictors of failed CR and BR, respectively. There may be a tendency for larger differences in CR when comparing VED and UST as third-line agents, with better results for the latter.

References

1. García MJ, Rivero M, Fernández-Clotet A, De Francisco R, Sicilia B, Mesonero F, et al. Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn’s Disease (Versus-CD): Data from the ENEIDA Registry. Journal of Crohn’s and Colitis. 2024 Jan 27;18(1):65–74.

2. Onali S, Pugliese D, Caprioli FA, Orlando A, Biancone L, Nardone OM, et al. An Objective Comparison of Vedolizumab and Ustekinumab Effectiveness in Crohn’s Disease Patients’ Failure to TNF-Alpha Inhibitors. Am J Gastroenterol. 2022 Aug;117(8):1279–87.

3. Hyun HK, Zhang HS, Yu J, Kang EA, Park J, Park SJ, et al. Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn’s disease in patients with prior failure of anti-tumour necrosis factor treatment. BMC Gastroenterol. 2022 Dec;22(1):143.

4. Singh, Amandeep MD; Khan, Freeha MD; Lopez, Rocio MS, MPH; Shen, Bo MD, FACG. Ustekinumab versus Vedolizumab for Moderate to Severe Crohn's Disease: 713. American Journal of Gastroenterology 112():p S393-S394, October 2017.

Introduction

Inflammatory Bowel Disease (IBD), encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC), shares chronic and inflammatory characteristics with Non-Alcoholic Fatty Liver Disease (NAFLD). While their precise pathogenesis remains unclear, emerging evidence implicates dysbiosis and metabolic changes. This study aims to investigate the association between IBD and NAFLD, focusing on metabolic syndrome and its nutritional implications

Aims & Methods

Objective: To evaluate the nutritional status and body composition in IBD patients, comparing groups with and without NAFLD, and identifying the associated factors.
Methods: A cross-sectional study was conducted, assessing clinical data, metabolic syndrome presence, nutritional status, and biochemical markers. Patients were categorized into IBD+NAFLD and IBD-only groups based on hepatic ultrasound findings. Statistical analysis included descriptive statistics and logistic regression.

Results

127 patients were included, comprising 58 CD and 69 UC, with a mean age of 45.56 years. Most patients were female and did not engage in physical activity. Patients were mostly in clinical remission and endoscopic activity. 58 patients (45.67%) had hepatic steatosis on ultrasound, forming the IBD+NAFLD group. The IBD+NAFLD group had higher BMI, fat mass, and all circumference values, Table 1, as well as a higher prevalence of hypertension (p=0.0446) and dyslipidemia (p=0.0377). It is noteworthy that, although most of these patients were classified as overweight by BMI, considering anthropometric data, most IBD+NAFLD patients were classified as eutrophic. 86.21% of patients in the IBD+NAFLD group met the criteria for MAFLD. No difference was observed regarding medication in use. Regarding biochemical tests, the IBD+NAFLD group had higher values of hematocrit (p=0.0023), liver enzymes (AST, p=0.0141 and ALT, p<0.0001), fasting glucose (p=0.0107), glycated hemoglobin (p=0.0146), basal insulin (p=0.0003), and triglycerides (p=0.0001), with lower HDL cholesterol (p=0.0101)

Conclusion

The study highlights a significant association between nutritional status and NAFLD in IBD patients. Those categorized as eutrophic had a higher prevalence of hepatic steatosis, potentially linked to dietary factors.

References

Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and
natural history of non‐alcoholic fatty liver disease and non‐alcoholic
steatohepatitis in adults. Alimentary pharmacology & therapeutics.
2011;34(3):274-285./ Silva A.F; Schieferdecker M.H; Amarante M. B. Ingestão alimentar em pacientes
com doença inflamatória intestinal ABCD, arq. bras. cir. dig. 24 (3) • Set 2011/ Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA.
2015;313(22):2263-73