An internal pilot study of a novel rectal mucocellular sampling device to allow next-generation sequencing for colorectal disease (2022)

Type of publication:
Journal article

Author(s):
Humphrey H.N.; Diodato A.; Isner J.-C.; Walker E.; *Lacy-Colson J.; Nedjai B.; Daniels I.R.; McDermott F.D.; Walker E.T.; Battersby N.J.; Sisodia H.; Rottenburg H.; Cunningham C.; Bird S.; Jones G.A.R.; Wise D.; Spencer S.J.;

Citation:
Techniques in Coloproctology. (no pagination), 2022. Date of Publication: 2022 [epub ahead of print]

Abstract:
Background: The ORI-EGI-02 study was designed to test the hypothesis that rectal mucus collected using a novel rectal sampling device (OriColTM), contains sufficient human deoxyribonucleic acid (DNA) of the required quality for Next Generation Sequencing (NGS), for colorectal disease genetic signature discovery. <br/>Method(s): Using National Institute for Health and Care Research methodology, an internal pilot study was performed in January 2020-May 2021, at four sites in the United Kingdom, to assess the process of recruitment, consent, specimen acquisition and viability for analysis. Following an OriCol<sup>TM</sup> test, the sample was stabilized with a buffer solution to preserve the material, which was posted to the laboratory. Samples were processed using QIAamp<sup></sup> DNA Blood Midi kit to extract DNA and Quant-iT<sup>TM</sup> PicoGreen<sup></sup> dsDNA Reagent to quantify the retrieved DNA. DNA integrity was measured by Agilent TapeStation system. 25 ng of human amplifiable DNA was prepared for Next Generation Sequencing (NGS), which was performed on an Illumina NextSeq550 sequencer using the 300-cycle high output kit v2.5. <br/>Result(s): This study assessed the first 300 patients enrolled to the ORI-EGI-02 Study (n = 800). 290/300 (96.67%) were eligible to undergo OriCol<sup>TM</sup> sampling procedure and 285/290 (98.27%) had a successful OriCol<sup>TM</sup> sample taken. After transportation, extraction and quantification of DNA, 96.20% (279/290) of the samples had NGS successfully performed for bioinformatic analysis. <br/>Conclusion(s): Our internal pilot study demonstrated that the OriCol<sup>TM</sup> sampling device can capture rectal mucus from unprepared bowel in subjects who could undergo a digital rectal examination. The technique could be applied irrespective of age, frailty, or co-morbidity. Completion of the study to 800 patients and analysis of NGS data for colorectal cancer mutations will now proceed.

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Intussusception of the Appendix in a Young Adult with Cystic Fibrosis: An Important Differential Diagnosis of Abdominal Pain in Cystic Fibrosis Patients? (2022)

Type of publication:
Conference abstract

Author(s):
*Venkatasami M.; *Cobby E.

Citation:
British Journal of Surgery. Conference: ASiT Surgical Conference 2022. Aberdeen United Kingdom. 109(Supplement 6) (pp vi57), 2022. Date of Publication: September 2022.

Abstract:
Background: Cystic fibrosis (CF) is commonly associated with gastrointestinal manifestations from infancy to adulthood. Intussusception in the paediatric CF population is widely reported, whereas in the adult, distal intestinal obstruction syndrome (DIOS) is common affecting 20%, of which, intussusception is rare and appendiceal intussusception is rarer, affecting 1%. Case-Description: A 20-year-old male with CF presented with 3 days of right iliac fossa pain and diarrhoea. On admission, he was hypotensive and afebrile. Clinical examination revealed tenderness of the right flank with a palpable mass in the right iliac fossa. Serum investigations showed mildly raised inflammatory markers. Contrast CT of the abdomen-pelvis confirmed intussusception of the appendix into the ascending colon. Histological analysis of the appendix further demonstrated intussusception, with intraluminal mucinous material. Fascinatingly, no transmural inflammation was present. The patient underwent a laparotomy-open appendicectomy. Interestingly, intraoperative findings showed the intussusception resolved, no longer requiring surgical reduction. Patient postoperative recovery was complicated by pneumonia for which he was transferred for specialist CF respiratory care and thereafter, discharged. Discussion(s): Literature review highlighted a paucity of data, with 10 reported cases of appendiceal intussusception in adult CF patients. Interestingly, we report the intussusception had reduced by the time of operation. This is in-keeping with previous case reports of transient intussusception which spontaneously resolved. Conclusion(s): From this rare case presentation, we have learnt it is imperative to carry a high index of suspicion for gastrointestinal manifestations in CF patients where acute appendicitis is seen less often and differential diagnoses like DIOS and intussusception should be considered.

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Response to Tofacitinib in British Asians with ulcerative colitis: a real-world tertiary centre experience (2022)

Type of publication:Conference abstract

Author(s):Forsyth K.; *Bhandal H.; Macfarlane M.; Gray C.; Hannah G.; Parkes G.

Citation:Gut. Conference: Annual Meeting of the British Society of Gastroenterology, BSG 2022. Birmingham United Kingdom. 71(Supplement 1) (pp A47), 2022. Date of Publication: June 2022

Abstract:Introduction We have previously shown UK South Asians (SA) with IBD are prescribed TNF antagonists earlier in disease course in comparison with white British (WB) patients, but are more likely to stop due to treatment failure (Gadhok 2020). However, it is currently unknown whether there is a similar variation in response to Tofacitinib, a non-selective JAK inhibitor. We aim to determine whether persistence to tofacitinib varies with ethnicity and evaluate real world efficacy in an inner-city tertiary referral centre. Methods Patients prescribed Tofacitinib since 2019 were identified from electronic prescribing records. The following data was collected: ethnicity (as per UK standard coding), disease history including Montreal classification of disease extent, prior advanced therapies, persistence on therapy, indication for cessation, side effects, and endoscopic and biochemical markers of disease activity. Results 30 adults with UC were prescribed tofacitinib, with a median duration of follow up of 833 days (n=31). 11 patients were female, and ethnicity was as follows: SA:11: Black:1:WB:12:Other/unstated:7. The median failure free survival was 447 days, with no significant variation associated with number of prior advanced therapies (1 prior biologic, 303.5 days (n=12) vs >1 prior biologic, 715 days (n=19) p=0.28). Comparison between characteristics and response to treatment of South Asian and White British patients, presented in table 1: There was no difference between median failure free survival of SA and WB patients (304 days vs 447 days, p=0.28). There was a trend towards lower primary non-response in SA patients, with fewer stopping treatment by 12 weeks, although this was not statistically significant (9.09% vs 33.33% p=0.17). No difference in disease duration at first prescription of tofacitinib between SA and WB patients was found (78.75 months vs 86.80 months p=0.78). 2 patients stopped treatment due to side effects, with 1 patient (SA) stopping due to MACE. Conclusion In contrast to our previous work on TNF antagonists, British SA patients prescribed tofacitinib for UC had failure free survival comparable with WB patients, with a trend towards fewer primary non responders. Although limited by sample size, these findings are reassuring given that SA patients are underrepresented in trials of novel therapies in IBD and warrants a larger study.

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Treatment with bile acid sequestrants improves quality-of-life in specific patients with bile acid diarrhoea (2022)

Type of publication:Conference abstract

Author(s):Kumar A.; Galbraith N.; Al-Hassi H.; Jain M.; *Butterworth J.; Steed H.; McLaughlin J.; Brookes M.

Citation:Gut. Conference: Annual Meeting of the British Society of Gastroenterology, BSG 2022. Birmingham United Kingdom. 71(Supplement 1) (pp A156), 2022. Date of Publication: June 2022

Abstract:Background Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea and up to 30% of patients can be misdiagnosed as irritable bowel syndrome. Type 1 BAD is secondary to ileal resection or inflammation; type 2 is idiopathic; and type 3 is secondary to other intestinal conditions such as cholecystectomy. BAD can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multicentre prospective study exploring QoL outcomes in patients with BAD before and after treatment with colesevelam. Methods Patients with or without BAD (defined by a 23- seleno-25-homotaurocholic acid (SeHCAT) retention < 19%) were recruited into four groups: 1) SeHCAT normal control group (CG), 2) idiopathic (BAD), BAD secondary to 3) postcholecystectomy (PC) and 4) post-terminal ileal resection for Crohn's disease (CD). Patients in groups 2-4 were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL evaluated by EQ-5D-3L, SF-36, IBDQ-32 (where relevant). Clinical response was defined as patients who had improved bowel frequency by >50% or <3 bowel movements per day. Results 47 patients (BAD=24, PC=12, CD=11) completed QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. The CD cohort had improved IBDQ-32 mean scores after treatment (134.6 vs 158.4, p=0.007). The BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, whilst the PC cohort showed a general decline in mean scores after treatment. The CG cohort generally had higher baseline scores than the other three groups. 55% of patients clinically responded to treatment (41.7% BAD, 58.3% PC, 81.8% CD). Correlations between those deemed as responders with improvements on the IBDQ-32, SF-36 and EQ-5D-3L dimensions were not statistically significant. Conclusion Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists.

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The use of a faecal bile acid test for diagnosing patients with bile acid diarrhoea (2022)

Type of publication:Conference abstract

Author(s):Kumar A.; Al-Hassi H.; Jain M.; Ford C.; Gama R.; Steed H.; *Butterworth J.; McLaughlin J.; Galbraith N.; Brookes M.; Hughes L.;

Citation:Gut. Conference: Annual Meeting of the British Society of Gastroenterology, BSG 2022. Birmingham United Kingdom. 71(Supplement 1) (pp A157), 2022. Date of Publication: June 2022.

Abstract:Introduction BAD is a common cause of chronic diarrhoea, affecting 1% of the general population. Type 1 is secondary to ileal resection or inflammation; type 2 is idiopathic; and type 3 is a result of other intestinal conditions such as cholecystectomy. Although the UK gold standard diagnostic test for BAD is the 75selenium-homotaurocholic acid (SeHCAT) scan, this is not widely available. This study examines the validity of measuring faecal bile acids (FBA) in a single stool sample as a diagnostic tool for bile acid diarrhoea (BAD) by direct comparison to the SeHCAT. Methods Patients with chronic diarrhoea investigated for BAD with a SeHCAT scan were prospectively recruited to the study. Patients provided random stool samples to measure FBA, using an enzyme-linked immunosorbent assay. Patients were characterised into four groups: SeHCAT negative control group (CG), post-cholecystectomy (PC), idiopathic BAD and post-terminal ileal resection Crohn's disease (CD). SeHCAT retention of <5%, 5-10%, 10-15% and >15% were considered to be severe BAD, moderate, mild and normal, respectively. Results 108 patients had a stool with a comparative SeHCAT result. FBA concentrations (umol/g) and interquartile ranges in patients in CG (2.6; 1.6-4.1), PC (4.0; 2.4-6.6) and BAD (3.6; 1.9-7.2) were similar, but all were significantly lower (p<0.001) compared to patients with CD (12.5; 10.2-16.1). FBA concentrations in patients with SeHCAT retention of <5% (8.6; 4.3-15.4) were significantly higher (p<0.005) than those with a SeHCAT retention >15% (2.6; 1.5-4.2). Using <=15% SeHCAT retention as diagnostic for BAD, the sensitivity and specificity with FBA cut-off of 1.6umol/g were 89% and 26% respectively. Conclusion This pilot study demonstrated that a single random stool sample may have potential use in diagnosing severe BAD or BAD in CD patients. Larger studies are needed to confirm the potential efficacy of a single, random FBA test to accurately diagnose BAD in the absence of SeHCAT testing.

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Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: Results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study (2022)

Type of publication:Journal article

Author(s):Chanchlani N.; Lin S.; Auth M.K.; Lee C.L.; Robbins H.; Looi S.; Murugesan S.V.; Riley T.; Preston C.; Stephenson S.; Cardozo W.; Sonwalkar S.A.; Allah-Ditta M.; Mansfield L.; Durai D.; Baker M.; London I.; London E.; Gupta S.; Di Mambro A.; Murphy A.; Gaynor E.; Jones K.D.J.; Claridge A.; Sebastian S.; Ramachandran S.; Selinger C.P.; Borg-Bartolo S.P.; Knight P.; Sprakes M.B.; Burton J.; Kane P.; Lupton S.; Fletcher A.; Gaya D.R.; Colbert R.; Seenan J.P.; MacDonald J.; Lynch L.; McLachlan I.; Shields S.; Hansen R.; Gervais L.; Jere M.; Akhtar M.; Black K.; Henderson P.; Russell R.K.; Lees C.W.; Derikx L.A.A.P.; Lockett M.; Betteridge F.; De Silva A.; Hussenbux A.; Beckly J.; Bendall O.; Hart J.W.; Thomas A.; Hamilton B.; Gordon C.; Chee D.; McDonald T.J.; Nice R.; Parkinson M.; Gardner-Thorpe H.; *Butterworth J.R.; *Javed A.; *Al-Shakhshir S.; *Yadagiri R.; *Maher S.; Pollok R.C.G.; Ng T.; Appiahene P.; Donovan F.; Lok J.; Chandy R.; Jagdish R.; Baig D.; Mahmood Z.; Marsh L.; Moss A.; Abdulgader A.; Kitchin A.; Walker G.J.; George B.; Lim Y.-H.; Gulliver J.; Bloom S.; Theaker H.; Carlson S.; Cummings J.R.F.; Livingstone R.; Beale A.; Carter J.O.; Bell A.; Coulter A.; Snook J.; Stone H.; Kennedy N.A.; Goodhand J.R.; Ahmad T.

Citation:Alimentary Pharmacology and Therapeutics. (no pagination), 2022. Date of Publication: 2022 [epub ahead of print]

Abstract:Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). <Aim(s): To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to their second, irrespective of drug sequence. <br/>Method(s): We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF drug, defined at any timepoint as an anti-TNF antibody concentration >=9 AU/ml for infliximab and >=6 AU/ml for adalimumab. Result(s): In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. Conclusion(s): Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second anti-TNF, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

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Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab (2022)

Type of publication:Journal article

Author(s):Lin S.; Kennedy N.A.; Saifuddin A.; Sandoval D.M.; Reynolds C.J.; Seoane R.C.; Kottoor S.H.; Pieper F.P.; Lin K.-M.; Butler D.K.; Chanchlani N.; Nice R.; Chee D.; Bewshea C.; Janjua M.; McDonald T.J.; Sebastian S.; Alexander J.L.; Constable L.; Lee J.C.; Murray C.D.; Hart A.L.; Irving P.M.; Jones G.-R.; Lees C.W.; Altmann D.M.; Boyton R.J.; Goodhand J.R.; Powell N.; Kok K.B.; Bokth F.; Cipriano B.; Francia C.; Khalid N.; Khatun H.; Kingston A.; Lee I.; Lehmann A.; Naik K.; Pabriaga E.; Plaatjies N.; Samuels K.; Saich R.; Cousins H.; Thomas R.; Brown M.; White B.; Tilley B.; Muhammed R.; Bi R.; Cotter C.; Grove J.; Hong K.; Howman R.; Clayton S.; Sultan S.; Rooney M.; Cottrill C.; Singh S.; Dawe C.; Hull R.; Silva N.; Manning J.; Finlayson L.; Roebuck A.; Dawson J.; Sonwalkar S.; Chambers N.; Robinson M.; Haigh A.; Matapure L.; Raine T.; Kapizioni C.; Strongili K.; Thompson T.; Ahmed M.; Kontos C.; Bourges C.; Barbutti I.; Gozzard M.E.; Hendy P.; Bull R.; Costa P.; Davey L.; Hannington H.; Nundlall K.; Martins C.; Avanzi L.; Carungcong J.; Barr S.; Appleby R.; Johnson E.; Phillis K.; Gascoyne R.; Crowder A.; Whileman A.; London I.; Grounds J.; Martin E.; Price J.; Cawley K.; Dhar A.; Brown E.; Cowton A.; Warner B.; Stuart C.; Lacey L.; de Silva S.; Allcock C.; Harvey P.; Jones L.; Cooke E.; Brooks J.; Baker P.; Beadle H.; Cruz C.; Potter D.; Collum J.; Masters F.; Kumar A.; Coetzee S.; Peiu M.; Icke B.; Raj M.; Gaynor E.; Chadokufa S.; Huggett B.; Meghari H.; El-Khouly S.; Kiparissi F.; Girshab W.; Claridge A.; Fowler E.; McCafferty L.; Christodoulides K.; Clifford A.; Dawson P.; Honap S.; Lim S.; Luber R.; Mahiouz K.; Meade S.; Reynolds R.; Stanton A.; Tripoli S.; Hare N.; Balachandran S.; North E.; North J.; Browne B.; Jameson E.; Siaw Y.H.; Manzano L.; Segal J.; Al-Bakir I.; Khakoo I.; Thoua N.; Davidson K.; Miah J.; Canclini L.; Hall A.; Hayes M.; Myers S.; Talbot A.; Turnbull J.; Whitehead E.; Stamp K.; Pattinson A.; Mathew V.; Sherris L.; Harvey A.; Hicks L.; Byrne T.-M.; Cabreros L.; Downing-Wood H.; Hunter S.; Prabhudev H.; Balarajah S.; Ibraheim H.; Torkizadeh M.; Lo J.W.; Liu Z.; Sutherland H.; Wilhelmsen E.; Mackintosh K.; Verma A.M.; Sebastian J.; Peerally M.F.; Raymode P.; Guerdette A.-M.; Kent A.; Choong L.M.; Pantaloni B.; Ravdas P.; Vadamalayan B.; Foley S.; Arnold B.; Heeley C.; Lovegrove W.; Sowton D.; Allsop L.; Gregory H.; Smith P.J.; Bretland G.; King S.; Lofthouse M.; Rigby L.; Subramanian S.; Tyrer D.; Martin K.; Probert C.; Kamperidis N.; Adedoyin T.; Baden M.; Chacko F.; Cicchetti M.; Saifuddin M.A.; Yesupatham P.; Gowda R.; Williams M.; Kemp K.; Akhand R.; Gray G.; John A.; John M.; Mohammed T.; Sathe D.; Jones N.; Soren J.; Sprakes M.; Burton J.; Kane P.; Lupton S.; Bartholomew J.; MacFaul G.; Scaletta D.; Siamia L.; Williams F.; Green C.; Ver Z.; Lamb C.A.; Doona M.; Hogg A.; Jeffrey L.; King A.; Speight R.A.; Doyle J.; Owen R.; Mowat C.; Rice D.; MacFarlane S.; MacLeod A.; Mohammed S.; Murray S.; Elliott A.; Morris M.A.; Coke L.; Hindle G.; Kolokouri E.; Wright C.; Lee C.; Ward N.; Dann A.; Lockett M.; Cranfield C.; Jennings L.; Srivastava A.; Ward L.; Jeynes N.; Ranga P.; Rajasekhar P.; Gallagher L.; Patterson L.; Ward J.; Basnett R.; Murphy J.; Parking L.; Lawson E.; Short S.; Devadason D.; Moran G.; Khan N.; Tarr L.; Olivia C.; Limdi J.; Goulden K.; Javed A.; McKenzie L.; Bhandari P.; Baker-Moffatt M.; Dash J.; Le Poidevin A.; Downe H.; Bombeo L.; Blackman H.; Wiles A.; Bloxham H.; Dias J.; Nadar E.; Curgenven H.; Macdonald J.; Finan S.; McMeeken F.; Mahmood M.; Shields S.; Seenan J.P.; DeSilva D.; Malkakorpi S.; Carson R.; Whiteoak S.; Edger-Earley K.; Vamplew L.; Ingram S.; Botfield S.; Hammonds F.; James C.; Ahmad T.; Aspinall G.; Hawkins S.; Marriott S.; Redstone C.; Windak H.; Adam A.-M.; Mabb H.; Murray C.; Diaba C.; Joseph F.; Pakou G.; Gleeson Y.; Berrill J.; Stroud N.; Pothecary C.; Roche L.; Turner K.; Deering L.; Israel L.; Baker E.; Cutler S.; Evans R.M.; Nash M.; Mallison G.; Roynon A.; Gordon J.; Levell E.; Zagalo S.; Fraser W.; Hoad I.; Kirkineziadis N.; Russell R.; Henderson P.; Millar M.; Fagbemi A.; Jennings F.; Mayor I.; Wilson J.; Alexakis C.; Michalak N.; Saunders J.; Burton H.; Cambridge V.; Clark T.; Ekblad C.; Hierons S.; Katebe J.; Saunsbury E.; Perry R.; Brookes M.; Davies K.; Green M.; Plumbe A.; Ormerod C.; Christensen H.; Keen A.; Ogor J.; Anthony A.; Newitt E.; Trim F.; Casey R.; Seymour K.; Fogden E.; Russell K.; Phillips A.; Abdulla M.; *Butterworth J.; *Adams C.; *Buckingham E.; *Childs D.; *Magness A.; *Stickley J.; *Motherwell N.; *Tonks L.; *Gibson H.; *Pajak S.; Thomas C.; Brinkworth E.; Connor L.; Cook A.; Rees T.; Harford R.; Wesley E.; Moss A.; Lucas J.; Lorimer C.; Oleary M.; Dixon M.; Ramadas A.; Tregonning J.; Okeke O.; Jackson W.; Koumoutsos I.; George V.; Kunhunny S.; Laverick S.; Anderson I.; Smith S.; Patel K.; Ali M.; Mhandu H.; Rana A.; Spears K.; Teixeira J.; Pollok R.; Mencias M.; Seaward A.; Sousa J.; Said N.; Soomaroo M.; Raspa V.; Tacouri A.; Reps N.; Martin R.; Selinger C.; Carbonell J.; Onovira F.; Quartey D.; L'Anson A.; Ashworth A.; Bailey J.; Dunn A.; Mahmood Z.; Campbell R.; Marsh L.; Rahman M.; Davies S.; Habibi R.; Jessup-Dunton E.; Joefield T.; Layug R.; Patel V.; Vere J.; Turner V.; Kilroy S.; Walker G.; Atkins S.; Growdon J.; McNeill C.; Cooney R.; Bennett L.; Bowlas L.; Shariff S.; Fraser A.; Punnette D.; Bishop-Hurman C.; Undrell E.; Belfield K.; Din S.; Addleton C.; Appleby M.; Brown J.; Holding K.; Hooper P.; deCaestecker J.; Watchorn O.; Hayward C.; Inniss S.; Pritchard L.; Rudge K.; Carney A.; Andreyev J.; Hayhurst C.; Lockwood C.; Osborne L.; Roper A.; Warner K.; Hindle J.; Watt C.; Szymiczek K.; Mehta S.; Bell J.; Blad W.; Whitley L.; Dhamaraj D.; Baker M.; Sivamurugan E.J.; Evans M.; Cummings F.; Harris C.; Jones A.; Krauze L.; Rahmany S.; Earl M.; Vowles J.; Torokwa A.; Petrova M.; Procter A.; Stanley J.; Silvamoniz C.; Bettey M.; Wahid A.; Morrison Z.; Thomas-Turner R.; Yendle L.; Muller J.; Mitchell M.; Kirkwood J.; Barnes A.; Chaudhary R.; Claridge M.; Ellis C.; Kemp C.; Tobi O.; Milton J.; Johnston E.; Oblak M.; Godden J.; Lees C.; Alexander D.; Covil K.; Derikx L.; Siakavellas S.; Baxter H.; Robertson S.; Smith L.; Poulose B.; Colemam A.; Balint M.; Rhys-Jones G.; Johns K.; Hughes R.; Phipps J.; Taylor A.; MacPhee C.; Brooks S.; Smith K.; Howard L.; Wood D.; Muddu A.; Barman L.; Mallinson J.; Neale T.; Ionita D.; Elliot K.; Turnball A.; Thomas I.; Andrews K.; Sutton J.; Jones C.M.; Roberts J.; Bishop J.

Citation:Nature Communications. 13(1) (no pagination), 2022. Article Number: 1379. Date of Publication: December 2022 [epub ahead of print]

Abstract:Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 – 27.5] vs 47.6 days [45.5 – 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 – 36.8] vs 58.0 days [55.0 – 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

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The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea (2022)

Type of publication:Journal article

Author(s):Kumar A; Galbraith N; Al-Hassi HO; Jain M; Phipps O; *Butterworth J; Steed H; McLaughlin J; Brookes MJ

Citation:BMC Gastroenterology, 2022 Jul 02; Vol. 22 (1), pp. 325

Abstract:Background: Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam. Methods: Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study. Results: 47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant. Conclusion: Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.

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Stepped-wedge randomized controlled trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation (2022)

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)

Validation of the OAKS prognostic model for acute kidney injury after gastrointestinal surgery (2022)

Type of publication:Journal article

Author(s):STARSurg Collaborative and EuroSurg Collaborative (includes Chohan K.; Dhuna S.; Haq T.; Kirby S.; Lacy-Colson J.; Logan P.; Malik Q.; McCann J.; Mughal Z.; Sadiq S.; Sharif I.; Shingles C.; Simon A.; Chaudhury N.; Rajendran K.; Akbar Z.)

Citation:BJS Open, 2022, 6(1)

Abstract:Background: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Method(s): The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study ('IMAGINE') of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study ('Tayside') in major abdominal surgery (2011-2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Result(s): In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655-0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323-0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specificity range 0.881-0.890 (Tayside 95 per cent c.i. 0.853 to 0.905; IMAGINE 95 per cent c.i. 0.881 to 0.899). Conclusion(s): The OAKS prognostic model can identify patients who are not at high risk of postoperative AKI after gastrointestinal surgery with high specificity.

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