Type of publication:
Journal article

Author(s):
Grossi U; *Lacy-Colson J; Brown SR; Cross S; Eldridge S; Jordan M; Mason J; Norton C; Scott SM; Stevens N; Taheri S; Knowles CH

Citation:
Techniques in Coloproctology, 2022 May 19 [epub ahead of print]

Abstract:
Background: The effectiveness of laparoscopic ventral mesh rectopexy (LVMR) in patients with defecatory disorders secondary to internal rectal prolapse is poorly evidenced. A UK-based multicenter randomized controlled trial was designed to determine the clinical efficacy of LVMR compared to controls at medium-term follow-up. Methods: The randomized controlled trial was conducted from March 1, 2015 TO January 31, 2019. A stepped-wedge RCT design permitted observer-masked data comparisons between patients awaiting LVMR (controls) with those who had undergone surgery. Adult participants with radiologically confirmed IRP refractory to conservative treatment were randomized to three arms with different delays before surgery. Efficacy outcome data were collected at equally stepped time points (12, 24, 36, 48, 60, and 72 weeks). Clinical efficacy of LVMR compared to controls was defined as ≥ 1.0-point reduction in Patient Assessment of Constipation-Quality of Life and/or Symptoms (PAC-QOL and/or PAC-SYM) scores at 24 weeks. Secondary outcome measures included 14-day diary data, the Generalized Anxiety Disorder scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), St Marks incontinence score, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), the chronic constipation Behavioral Response to Illness Questionnaire (CC-BRQ), and the Brief Illness Perception Questionnaire (BIPQ).Results: Of a calculated sample size of 114, only 28 patients (100% female) were randomized from 6 institutions (due mainly to national pause on mesh-related surgery). Nine were assigned to the T0 arm, 10 to T12, and 9 to T24. There were no substantial differences in baseline characteristics between the three arms. Compared to baseline, significant reduction (improvement) in PAC-QOL and PAC-SYM scores were observed at 24 weeks post-surgery (- 1.09 [95% CI – 1.76, – 0.41], p = 0.0019, and – 0.92 [- 1.52, – 0.32], p = 0.0029, respectively) in the 19 patients available for analysis (9 were excluded for dropout [n = 2] or missing primary outcome [n = 7]). There was a clinically significant long-term reduction in PAC-QOL scores (- 1.38 [- 2.94, 0.19], p = 0.0840 at 72 weeks). Statistically significant improvements in PAC-SYM scores persisted to 72 weeks (- 1.51 [- 2.87, – 0.16], p = 0.0289). Compared to baseline, no differences were found in secondary outcomes, except for significant improvements at 24 and 48 weeks on CC-BRQ avoidance behavior (- 14.3 [95% CI – 23.3, – 5.4], and – 0.92 [- 1.52, – 0.32], respectively), CC-BRQ safety behavior (- 13.7 [95% CI – 20.5, – 7.0], and – 13.0 [- 19.8, – 6.1], respectively), and BIPQ negative perceptions (- 16.3 [95% CI – 23.5, – 9.0], and – 10.5 [- 17.9, – 3.2], respectively).Conclusions: With the caveat of under-powering due to poor recruitment, the study presents the first randomized trial evidence of short-term benefit of LVMR for internal rectal prolapse. Trial Registration: ISRCTN Registry (ISRCTN11747152)

Type of publication:
Journal article

Author(s):
Asselta R.; Paraboschi E.M.; Cardamone G.; Duga S.; Gerussi A.; Ciaccio A.; Cristoferi L.; D'Amato D.; Malinverno F.; Mancuso C.; Massironi S.; Milani C.; O'Donnell S.E.; Ronca V.; Barisani D.; Carbone M.; Invernizzi P.; Cordell H.J.; Mells G.F.; Sandford R.N.; Jones D.E.; Nakamura M.; Ueno K.; Tokunaga K.; Hitomi Y.; Kawashima M.; Nishida N.; Kawai Y.; Kohn S.-S.; Nagasaki M.; Gervais O.; Tanaka A.; Takikawa H.; Tang R.; Xiong M.; Li Z.; Shi Y.; Liu X.; Hirschfield G.; Siminovitch K.A.; Gershwin M.E.; Seldin M.F.; Walker E.; Xie G.; Mason A.; Myers R.; Peltekian K.; Ghent C.; Atkinson E.; Juran B.; Lazaridis K.; Lu Y.; Gu X.; Jing K.; Amos C.; Affronti A.; Brunetto M.; Coco B.; Spinzi G.; Elia G.; Ferrari C.; Lleo A.; Muratori L.; Muratori P.; Portincasa P.; Colli A.; Bruno S.; Colloredo G.; Azzaroli F.; Andreone P.; Bragazzi M.; Alvaro D.; Cardinale V.; Cazzagon N.; Rigamonti C.; Floreani A.; Rosina F.; Lampertico P.; Donato F.; Fagiuoli S.; Almasio P.L.; Giannini E.; Cursaro C.; Colombo M.; Valenti L.; Miele L.; Andriulli A.; Niro G.A.; Grattagliano I.; Morini L.; Casella G.; Vinci M.; Battezzati P.M.; Crosignani A.; Zuin M.; Mattalia A.; Calvaruso V.; Colombo S.; Benedetti A.; Marzioni M.; Galli A.; Marra F.; Tarocchi M.; Picciotto A.; Morisco F.; Fabris L.; Croce L.S.; Tiribelli C.; Toniutto P.; Strazzabosco M.; Ch'ng C.L.; Thomas C.; Rahman M.; Yapp T.; Sturgess R.; Harrison M.; Healey C.; Galaska R.; Czajkowski M.; Kendall J.; Whiteman J.; Gunasekera A.; Lawlor C.; Gray C.; Gyawali P.; Premchand P.; Kapur K.; Elliott K.; Marley R.; Foster G.; Watson A.; Dias A.; Subhani J.; Harvey R.; McCorry R.; Ramanaden D.; Gasem J.; Mulvaney-Jones C.; Hobson L.; Evans R.; Mathialahan T.; Shorrock C.; Van Duyvenvoorde G.; Lipscomb G.; Loftus A.; Southern P.; Seward K.; Tibble J.; Gorard D.; Penn R.; Palegwala A.; Maiden J.; Damant R.; Jones S.; Dawwas M.; Alexander G.; Dolwani S.; Cloudsdale R.; Prince M.; Foxton M.; Silvestre V.; Elphick D.; Glenn S.; Mitchison H.; Dungca E.; Gooding I.; Wheatley N.; Karmo M.; Doyle H.; Saksena S.; Kent M.; Mendall M.; Patel M.; Hamilton C.; Braim D.; Ede R.; Austin A.; Paton A.; Sayer J.; Lancaster N.; Hankey L.; Hovell C.; Fisher N.; Carter M.; Desousa P.; Koss K.; Piotrowicz A.; Muscariu F.; Musselwhite J.; Grimley C.; Neal D.; Lim G.; Tan L.; Levi S.; Ala A.; Broad A.; Saeed A.; Wood G.; Flahive K.; Brown J.; Nambela E.; Townshend P.; Ford C.; Holder S.; Wilkinson M.; Gordon H.; Palmer C.; Ramage J.; Ridpath J.; Featherstone J.; Ngatchu T.; Grover B.; Nasseri M.; Shaukat S.; Shidrawi R.; Sadeghian J.; Abouda G.; Ali F.; Rolls S.-A.; Rees I.; Salam I.; Narain M.; Brown A.; Crossey M.; Taylor-Robinson S.; Williams S.; Stansfield G.; MacNicol C.; Grellier L.; Wilkins J.; Banim P.; Das D.; Chilton A.; Raymode P.; Heneghan M.; Lee H.-J.; Curtis H.; Gess M.; Drake I.; Durant E.; Aldersley M.; Davies M.; Jones R.; Bishop R.; McNair A.; Srirajaskanthan R.; Pitcher M.; Tripoli S.; Sen S.; Bird G.; Casey R.; Barnardo A.; Kitchen P.; Cowley C.; Yoong K.; Miller R.; Chirag O.; Sivaramakrishnan N.; MacFaul G.; Jones D.; Shah A.; Wright F.; Evans C.; Saha S.; Pollock K.; Bramley P.; Mukhopadhya A.; Fraser A.; Williams D.; Mills P.; Shallcross C.; Campbell S.; Bathgate A.; Shepherd A.; Dillon J.; Rushbrook S.; Przemioslo R.; Macdonald C.; Metcalf J.; Shmueli U.; Davis A.; Naqvi A.; Lee T.; Ryder S.D.; Collier J.; Klass H.; Kent L.; Ninkovic M.; Cramp M.; Sharer N.; Aspinall R.; Goggin P.; Ghosh D.; Douds A.; Hoeroldt B.; Booth J.; Williams E.; Gunter E.; Dewhurst H.; Hussaini H.; Stableforth W.; Ayres R.; Thorburn D.; Marshall E.; Burroughs A.; Mann S.; Lombard M.; Richardson P.; Patanwala I.; Maltby J.; Brookes M.; Mathew R.; Vyas S.; Singhal S.; Gleeson D.; Misra S.; *Butterworth J.; George K.; Harding T.; Douglass A.; Tregonning J.; Panter S.; Sanghi P.; Shearman J.; Bray G.; Butcher G.; Forton D.; Mclindon J.; Cowan M.; Whatley G.; Mandal A.; Gupta H.; Jain S.; Pereira S.; Prasad G.; Watts G.; Wright M.; Neuberger J.; Gordon F.; Unitt E.; Grant A.; Delahooke T.; Higham A.; Brind A.; Cox M.; Ramakrishnan S.; King A.; Collins C.; Whalley S.; Li A.; Fraser J.; Bell A.; Hughes M.; Wong V.S.; Singhal A.; Gee I.; Ang Y.; Ransford R.; Gotto J.; Millson C.; Bowles J.; Hails J.; Wooldridge H.; Abrahams R.; Gibbins A.; Hogben K.; McKay A.; Foale C.; Brighton J.; Williams B.; Hynes A.; Duggan C.; Wilhelmsen E.; Ncube N.; Houghton K.; Ducker S.; Bird B.; Baxter G.; Keggans J.; Grieve E.; Young K.; Ocker K.; Hines F.; Martin K.; Innes C.; Valliani T.; Fairlamb H.; Thornthwaite S.; Eastick A.; Tanqueray E.; Morrison J.; Holbrook B.; Browning J.; Walker K.; Congreave S.; Verheyden J.; Slininger S.; Stafford L.; O'Donnell D.; Ainsworth M.; Lord S.; March L.; Dickson C.; Simpson D.; Longhurst B.; Hayes M.; Shpuza E.; White N.; Besley S.; Pearson S.; Wright A.; Jones L.; Fouracres A.; Farrington L.; Graves L.; Marriott S.; Leoni M.; Tyrer D.; Dalikemmery L.; Lambourne V.; Green M.; Sirdefield D.; Amor K.; Orpe J.; Colley J.; Shinder B.; Jones J.; Mills M.; Carnahan M.; Taylor N.; Boulton K.; Brown C.; Clifford G.; Archer E.; Hamilton M.; Curtis J.; Shewan T.; Walsh S.; Warner K.; Netherton K.; Mupudzi M.; Gunson B.; Gitahi J.; Gocher D.; Batham S.; Pateman H.; Desmennu S.; Conder J.; Clement D.; Gallagher S.; Chan P.; Currie L.; O'Donohoe L.; Oblak M.; Morgan L.; Quinn M.; Amey I.; Baird Y.; Cotterill D.; Cumlat L.; Winter L.; Greer S.; Spurdle K.; Allison J.; Dyer S.; Sweeting H.; Kordula J.; Aiba Y.; Nakamura H.; Abiru S.; Nagaoka S.; Komori A.; Yatsuhashi H.; Ishibashi H.; Ito M.; Migita K.; Ohira H.; Katsushima S.; Naganuma A.; Sugi K.; Komatsu T.; Mannami T.; Matsushita K.; Yoshizawa K.; Makita F.; Nikami T.; Nishimura H.; Kouno H.; Ota H.; Komura T.; Nakamura Y.; Shimada M.; Hirashima N.; Komeda T.; Ario K.; Nakamuta M.; Yamashita T.; Furuta K.; Kikuchi M.; Naeshiro N.; Takahashi H.; Mano Y.; Tsunematsu S.; Yabuuchi I.; Shimada Y.; Yamauchi K.; Sugimoto R.; Sakai H.; Mita E.; Koda M.; Tsuruta S.; Kamitsukasa H.; Sato T.; Masaki N.; Kobata T.; Fukushima N.; Higuchi N.; Ohara Y.; Muro T.; Takesaki E.; Takaki H.; Yamamoto T.; Kato M.; Nagaoki Y.; Hayashi S.; Ishida J.; Watanabe Y.; Kobayashi M.; Koga M.; Saoshiro T.; Yagura M.; Hirata K.; Zeniya M.; Abe M.; Onji M.; Kaneko S.; Honda M.; Arai K.; Arinaga-Hino T.; Hashimoto E.; Taniai M.; Umemura T.; Joshita S.; Nakao K.; Ichikawa T.; Shibata H.; Yamagiwa S.; Seike M.; Honda K.; Sakisaka S.; Takeyama Y.; Harada M.; Senju M.; Yokosuka O.; Kanda T.; Ueno Y.; Kikuchi K.; Ebinuma H.; Himoto T.; Yasunami M.; Murata K.; Mizokami M.; Shimoda S.; Miyake Y.; Takaki A.; Yamamoto K.; Hirano K.; Ichida T.; Ido A.; Tsubouchi H.; Chayama K.; Harada K.; Nakanuma Y.; Maehara Y.; Taketomi A.; Shirabe K.; Soejima Y.; Mori A.; Yagi S.; Uemoto S.; Tanaka T.; Yamashiki N.; Tamura S.; Sugawara Y.; Kokudo N.

Citation:
Gastroenterology; Jun 2021; vol. 160 (no. 7); p. 2483

Abstract:
Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Method(s): We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Result(s): Single-marker association analyses found approximately 100 loci displaying P < 5 x 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 x 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 x 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 x 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusion(s): This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

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