Senior Recital: Andrew Lastrapes, jazz guitar

This recital is presented in partial fulfillment of requirements for the degrees Bachelor of Music in Performance. Mr. Lastrapes studies jazz guitar with Trey Wright.https://digitalcommons.kennesaw.edu/musicprograms/1469/thumbnail.jp

DOP28 Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort

Background Proteomic biomarkers have been linked to anti-TNF treatment failure, but previous studies have been insufficiently powered to stratify associations by drug level. The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a prospective UK-wide study investigating treatment failure in 1610 anti-TNF naïve patients. We aimed to identify proteomic markers of treatment failure. Methods We sampled patients with primary non-response (PNR) (n = 223) and remission (n = 219) who had a baseline CRP ≥4 mg/l and/or calprotectin >100 µg/g. PNR was defined at week 14 as ongoing steroids, or both of HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/l. Non-remission at week 54 was defined as HBI >4 and CRP >3 mg/l and no steroids. Targeted serum proteomic analysis of 180 proteins using Olink Inflammation and Immune Response panels were performed. Mann–Whitney U tests were used to identify baseline proteins that predicted PNR and non-remission. Sub-group analyses stratified by drug level were undertaken. Pharmacokinetic (PK) failure was defined as PNR with low drug level (infliximab level <2 mg/l, adalimumab level <6 mg/l) and pharmacodynamic (PD) failure as PNR despite adequate drug level. Significant proteins were entered into multivariable logistic regression models and Bayesian information criterion (BIC) with backward stepwise selection were used to build predictive models of treatment failure. We applied 10-fold cross-validation to test the models. P-values of < 0.05 were considered significant. Results Elevated fibroblast growth factor 21 (FGF21) (OR 1.3, CI 1.1–1.4, p = 3.4 × 10–5) and interleukin-10 receptor subunit α (IL10RA) (OR 1.6, CI 1.2–2.1, p = 6.3 × 10–4) predicted PNR (Figure 1). At week 14, FGF21 (OR 1.5, CI 1.3–1.9, p = 1.8 × 10–6) and IL10RA (OR 1.8, CI 1.3–2.3, p = 5.8 × 10–5) levels were also associated with PNR. graphic Sub-group analyses showed baseline FGF21 (OR 1.4, CI 1.2–1.7, p = 2.0 × 10–4) predicted PK failure and that IL10-RA (OR 1.6, CI 1.1–2.2, p = 6.7 × 10–3) predicted PD failure (Figure 2). graphic In separate models, non-remission at week 54 was predicted by baseline (FGF21; OR 1.3, CI 1.1–1.4, p = 1.4 × 10–4, IL10-RA; OR 1.5, CI 1.1–2.0, p = 3.6 × 10–3) and week 14 (FGF21; OR 1.4, CI 1.2–1.7, p = 3.6 × 10–4, IL10-RA; OR 1.7, CI 1.3–2.4, p = 1.7 × 10–4) FGF21 and IL10-RA levels. Model validation of baseline FGF21 and IL10-RA showed an area under the curve of 0.61 (CI 0.57–0.64) for PNR and 0.60 (CI 0.56–0.64) for non-remission at week 54. Conclusion Our study identified FGF-21 and IL10-RA as proteins of interest associated with PK and PD treatment failure, respectively. Functional studies to determine the molecular mechanism driving dysregulation of these proteins are required.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

DOP69 Tofacitinib in ulcerative colitis: Early ‘real-world’ experience from four UK tertiary centres

Background Tofacitinib is a partially selective Janus kinase inhibitor that was approved for the treatment of refractory moderate to severe ulcerative colitis (UC) in 2018. We report the real-world clinical effectiveness and adverse effects of tofacitinib in UC. Methods We conducted a retrospective observational cohort study of tofacitinib-treated patients with UC between October 2018 to October 2019 from 4 UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI) or Partial Mayo Score (PMS) depending on the study site. Response and remission were defined at week 8 and 26 as a reduction in SCCAI or PMS of ≥3, and SCCAI <3 or PMS <2, respectively. Corticosteroid-free remission was defined as remission with no corticosteroid use at the time of assessment irrespective of baseline corticosteroid status. Results We included 140 patients (65% M; median age 37y [range 16–81]) with a median disease duration of 5.5y (IQR 2.2–11.8). Forty-six per cent (65/140) were receiving corticosteroids at baseline and 83% (116/140) had previously received at least one biologic (62 anti-TNF, 4 vedolizumab, 50 both). Median (IQR) serum CRP and faecal calprotectin levels at baseline were 4 mg/l (1.6–15) and 540 µg/g (316–1175). Response and remission rates were 73% (81/111) and 56% (62/111) respectively at week 8 (median ΔSCCAI of −3 [IQR -6 to -1], median ΔPMS −4 [−6 to −1]) and 48% (39/82) and 39% (32/82) respectively at week 26 (median ΔSCCAI −3 [IQR −7 to –1], median ΔPMS −4 [−6 to –1]). Steroid-free remission was seen in 47% (52/111) and 37% (30/82) patients at week 8 and 26. Patients with response or remission had a significantly lower CRP (p = 0.02) but not calprotectin (p = 0.38) levels at baseline. Response and remission rates were no different stratified by prior biologic use (p = 0.56). Treatment was discontinued after a median of 3 months (IQR 2–4) in 43 patients: 32 with primary non-response, 9 loss of response and in 1 each because of an adverse drug reaction (headache) and patient choice. 7/17 patients had a clinical response to dose re-escalation following a loss of response on dose reduction. The median time to dose de-escalation was 67 (IQR 25–240) days. Seven patients were hospitalised and 5 underwent colectomy. Six serious infections were noted including 2 herpes zoster infections but there were no venous thromboembolic events. Median total cholesterol, low-density lipoprotein and high-density lipoprotein increased from 4.4 mmol/l (IQR 3.7–5.2), 2.47 (1.9–2.9) and 1.5 (1.1–1.9) to 4.8 mmol/l (4.1–6.0), 2.8 (2.13.5) and 1.7 (1.4–1.9) respectively after 8 weeks of tofacitinib. graphic Conclusion Clinical effectiveness and side-effect profile of tofacitinib in UC in this multi-centre real-world cohort were similar to that reported in the pivotal OCTAVE clinical trials.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

OP21 Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: The prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service

Background Anti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of a drug. We sought to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in a sample of healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab. Methods Serum was obtained from a random sample of 498 anti-TNF-naïve healthy adults recruited to the Exeter Ten Thousand study and tested for total anti-drug antibodies to infliximab and adalimumab. Using recommendations for confirmatory anti-drug antibody validation, we used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile to define assay thresholds. We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs. non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests). Results The 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/ml and 5.9 AU/ml, respectively. Using the manufacturer’s recommended threshold of 10 AU/ml for both total anti-TNF antibody assays, in healthy individuals, the prevalence of positive antibodies to infliximab and adalimumab was 1% (5/498) and 0.2% (1/498), respectively. Using the manufacturer’s threshold, at the time of last testing, of 7447 and 4054 patients treated with infliximab and adalimumab; 20.9% (n = 1,554) and 8.0% (n = 326) had clearing antibodies and 26.5% (n = 1973) and 12.1% (n = 490) had non-clearing antibodies, respectively (Figure 1). Using our newly defined threshold in the same cohorts; 21.1% (n = 1573) and 8.4% (n = 339) had clearing antibodies and 28.0% (n = 2083) and 20.0% (n = 812) had non-clearing antibodies, to infliximab and adalimumab, respectively. Amongst patients with at least two tests, most developed persistent antibodies (Figure 2). Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies. graphic graphic Conclusion We report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

Anti-TNF Biologicals Enhance the Anti-Inflammatory Properties of IgG N-Glycome in Crohn's Disease

Crohn’s disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients’ quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD,yet many patients do not adequately respond to such therapy. Previous studies have demonstrated apro-inflammatory pattern in the composition of CD patients’ immunoglobulin G (IgG) N-glycomecompared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumabon N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential ofIgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. Wediscovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation,digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapyresponse, all of which suggested a diminished inflammatory environment in CD patients treated withanti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain informationregarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycomecomposition at baseline

Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays

Background: When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. Aim: To validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays. Methods: We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. Results: The 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and -adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P < 0.0001) treated patients were reclassified as antibody-positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5-11.0 mg/L) were lower than those below the new threshold (<5AU/mL) (median 9.9, IQR 7.1-13.0 mg/L; P < 0.0001), but higher than at the manufacturer's threshold (10-29 AU/mL) (median 5.9 mg/L, IQR 3.5-8.7; P < 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti-adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non-response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non-remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti-drug antibody concentrations in the group below the new threshold (0-5 AU/mL); this was not seen for anti-infliximab antibodies. Conclusion: Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low-concentration anti-drug antibodies were associated with lower drug levels and treatment failure.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

Trust in genomic data sharing among members of the general public in the UK, USA, Canada and Australia

Abstract: Trust may be important in shaping public attitudes to genetics and intentions to participate in genomics research and big data initiatives. As such, we examined trust in data sharing among the general public. A cross-sectional online survey collected responses from representative publics in the USA, Canada, UK and Australia (n = 8967). Participants were most likely to trust their medical doctor and less likely to trust other entities named. Company researchers were least likely to be trusted. Low, Variable and High Trust classes were defined using latent class analysis. Members of the High Trust class were more likely to be under 50 years, male, with children, hold religious beliefs, have personal experience of genetics and be from the USA. They were most likely to be willing to donate their genomic and health data for clinical and research uses. The Low Trust class were less reassured than other respondents by laws preventing exploitation of donated information. Variation in trust, its relation to areas of concern about the use of genomic data and potential of legislation are considered. These findings have relevance for efforts to expand genomic medicine and data sharing beyond those with personal experience of genetics or research participants

Root-cause analyses of missed opportunities for the diagnosis of colorectal cancer in patients with inflammatory bowel disease

Background: Colonoscopic surveillance in patients with inflammatory bowel disease (IBD) leads to earlier detection of colorectal cancer (CRC) and reduces CRC-associated mortality. However, it is limited by poor adherence in practice. Aim: To identify missed opportunities to detect IBD-associated CRC at our hospital METHODS: We undertook root-cause analyses to identify patients with missed opportunities to diagnose IBD-associated CRC. We matched patients with IBD-associated CRC to patients with CRC in the general population to identify differences in staging at diagnosis and clinical outcomes. Results: Compared with the general population, patients with IBD were at increased risk of developing CRC (odds ratio 2.7 [95% CI 1.6-3.9], P < 0.001). The mean incidence of IBD-associated CRC between 1998 and 2019 was 165.4 (IQR 130.4-199.4) per 100 000 patients and has not changed over the last 20 years. Seventy-eight patients had IBD-associated CRC. Forty-two (54%) patients were eligible for CRC surveillance: 12% (5/42) and 10% (4/42) patients were diagnosed with CRC at an appropriately timed or overdue surveillance colonoscopy, respectively. Interval cancers occurred in 14% (6/42) of patients; 64% (27/42) of patients had a missed opportunity for colonoscopic surveillance where root-cause analyses demonstrated that 10/27 (37%) patients known to secondary care had not been offered surveillance. Four (15%) patients had a delayed diagnosis of CRC due to failure to account for previous colonoscopic findings. Seventeen (63%) patients were managed by primary care including seven patients discharged from secondary care without a surveillance plan. Matched case-control analysis did not show significant differences in cancer staging or 10-year survival outcomes. Conclusion: The incidence of IBD-associated CRC has remained static. Two-thirds of patients eligible for colonoscopic surveillance had missed opportunities to diagnose CRC. Surveillance programmes without comprehensive and fully integrated recall systems across primary and secondary care are set to fail.published version, accepted version (12 month embargo), submitted versionThis article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site

Root-cause analyses of missed opportunities for the diagnosis of colorectal cancer in patients with inflammatory bowel disease

Background: Colonoscopic surveillance in patients with inflammatory bowel disease (IBD) leads to earlier detection of colorectal cancer (CRC) and reduces CRC-associated mortality. However, it is limited by poor adherence in practice. Aim: To identify missed opportunities to detect IBD-associated CRC at our hospital METHODS: We undertook root-cause analyses to identify patients with missed opportunities to diagnose IBD-associated CRC. We matched patients with IBD-associated CRC to patients with CRC in the general population to identify differences in staging at diagnosis and clinical outcomes. Results: Compared with the general population, patients with IBD were at increased risk of developing CRC (odds ratio 2.7 [95% CI 1.6-3.9], P < 0.001). The mean incidence of IBD-associated CRC between 1998 and 2019 was 165.4 (IQR 130.4-199.4) per 100 000 patients and has not changed over the last 20 years. Seventy-eight patients had IBD-associated CRC. Forty-two (54%) patients were eligible for CRC surveillance: 12% (5/42) and 10% (4/42) patients were diagnosed with CRC at an appropriately timed or overdue surveillance colonoscopy, respectively. Interval cancers occurred in 14% (6/42) of patients; 64% (27/42) of patients had a missed opportunity for colonoscopic surveillance where root-cause analyses demonstrated that 10/27 (37%) patients known to secondary care had not been offered surveillance. Four (15%) patients had a delayed diagnosis of CRC due to failure to account for previous colonoscopic findings. Seventeen (63%) patients were managed by primary care including seven patients discharged from secondary care without a surveillance plan. Matched case-control analysis did not show significant differences in cancer staging or 10-year survival outcomes. Conclusion: The incidence of IBD-associated CRC has remained static. Two-thirds of patients eligible for colonoscopic surveillance had missed opportunities to diagnose CRC. Surveillance programmes without comprehensive and fully integrated recall systems across primary and secondary care are set to fail.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations. INTERPRETATION: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised. FUNDING: Pfizer