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Anti-tumour necrosis factor (TNF) agents are associated with increased infection risk among elderly IBD patients, but little is known about non anti-TNF biologics in this cohort. We examined the safety and effectiveness of ustekinumab in elderly Crohn's patients.This retrospective multi-centre cohort study included Crohn's patients ≥60-years old who commenced ustekinumab. We recorded Harvey-Bradshaw index (HBI), concomitant steroid therapy, treatment persistence and new infections or malignancies. Primary outcome was serious infections requiring hospitalisation.Seventy patients were included, with median age of 68 years. 43 (61.4%) had prior anti-TNF exposure, and 15 (21.4%) vedolizumab. Median treatment duration was 12 months, totalling 84 patient-years. Nine serious infections were reported, incidence 106.7/1000 patient-years. Systemic steroids were associated with increased risk of serious infections [odds ratio (OR) 7.83, 95% confidence interval (CI): 1.44-44.32, P = 0.02]. There were 27 "non-serious" infections; 321.4/1000 patient-years. Charlson co-morbidity index (OR 1.49, 95% CI: 1.05-2.12, P = 0.03) and steroid exposure (OR 44.10, 95% CI: 1.75-1112.10, P = 0.02) increased non-serious infection risk (Pamp;lt; 0.05). Mean HBI improved from 8.13 to 4.64 at 6 months and 4.10 at last follow up (Pamp;lt; 0.0001). 12-month treatment persistence was 55.7% (N = 39); 34 (48.6%) were steroid-free.Ustekinumab was safe and effective in a cohort of elderly Crohn's disease patients. Infections were mostly mild, not resulting in therapy discontinuation. Serious infection risk was comparable to previously reported rates with anti-TNF agents. Steroid exposure was associated with an increased serious infection risk.

The solar chromosphere hosts a wide variety of transients, including dynamic fibrils (DFs) that are characterised as elongated, jet-like features seen in active regions, often through Hα diagnostics. So far, these features have been difficult to identify in coronal images, primarily due to their small size and the lower spatial resolution of the current extreme-ultraviolet (EUV) imagers. Here we present the first unambiguous signatures of DFs in coronal EUV data using high-resolution images from the Extreme Ultraviolet Imager (EUI) on board Solar Orbiter. Using the data acquired with the 174 Å High Resolution Imager (HRIEUV) of EUI, we find many bright dot-like features (with a size of 0.3-0.5 Mm) that move up and down (often repeatedly) in the core of an active region. In a space-time map, these features produce parabolic tracks akin to the chromospheric observations of DFs. Properties such as their speeds (14 km s-1), lifetime (332 s), deceleration (82 m s-2), and lengths (1293 km) are also reminiscent of the chromospheric DFs. The EUI data strongly suggest that these EUV bright dots are basically the hot tips (of the cooler chromospheric DFs) that could not be identified unambiguously before because of a lack of spatial resolution., Astronomy & Astrophysics, 670, ISSN:0004-6361, ISSN:1432-0746

Contains fulltext : 291657.pdf (Publisher’s version ) (Open Access) BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p

Purpose Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by inflammatory colitis and is associated with systemic inflammation. Herein, we aimed to investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation. Methods We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients' colons and conducted compositional and functional pathway prediction analyses. Results The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha-diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilization were enriched in patients with colitis and correlated positively with fecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by fecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance is associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into "high" and "low" systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta-diversity analyses. Conclusion The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

Yndiamides offer opportunities for the synthesis of vicinally nitrogen-disubstituted aromatics and azacycles. Here we report the Rh-catalyzed cyclotrimerization of alkynyl yndiamides with alkynes, the regiochemical outcome of which is controlled by the electronic properties of the alkyne partner, enabling the formation of 7-aminoindolines with excellent selectivity (up to >20:1 r.r.). We also report a complementary synthesis of bicyclic 1,2-dianiline derivatives by cyclotrimerization of yndiamides with terminal diynes, where slow addition of the diyne overcomes self-dimerization.

One of the impacts of the pandemic has been a rapid increase in the development and offering of online courses focused on cognitive systems engineering. This presents opportunities to: ● Identify and share alternative instructional design strategies and more specific instructional tactics tailored to the online environment and learn from each others’ experiences. ● Discuss how lessons learned from the design and offering of online courses can not only inform future offerings of online courses but also generalize to in-person courses. ● Identify the opportunities created by online instruction to reach a broader audience, not only geographically but also in terms of reaching practitioners whose specializations are outside of human factors. The panelists have expertise and experience in all of these areas. Their perspectives are briefly described below.

Yndiamides (bis-N-substituted alkynes) are valuable precursors to azacycles. Here we report a cycloisomerization/1,2-sulfonyl migration of alkynyl-yndiamides to form tetrahydropyrrolopyrroles, unprecedented heterocyclic scaffolds that are relevant to medicinal chemistry. This functional group tolerant transformation can be achieved using Au(I) catalysis that proceeds at ambient temperature, and a thermally promoted process. The utility of the products is demonstrated by a range of reactions to functionalize the fused pyrrole core.

Anti-tumour necrosis factor (anti-TNF) agents are associated with increased infection risk among elderly inflammatory bowel disease (IBD) patients, and thus, alternative biologics may be preferable. However, little comparative data exist on the safety and efficacy of vedolizumab and ustekinumab in elderly IBD patients.To compare the safety and effectiveness of ustekinumab and vedolizumab in elderly Crohn's disease patients.Patients ≥ 60 years old who commenced ustekinumab or vedolizumab for Crohn's disease (CD) were included. Primary outcome was serious infections, defined as requiring hospitalisation. Efficacy was assessed by treatment persistence and clinical response rates. We appropriately adjusted for confounders using propensity score-matched analysis weighted by the inverse predicted probability of treatment weighing and performed a logistic regression analysis to assess factors associated with serious infections and treatment persistence.Eighty-three patients commencing ustekinumab and 42 commencing vedolizumab therapy were included. In a propensity adjusted cohort, the rate of serious infection and treatment persistence were comparable between ustekinumab and vedolizumab. There was a significant reduction in HBI at 6 and 12 months compared to baseline in both groups. Male gender was positively associated with serious infection risk at 12 months, and penetrating disease behaviour was positively associated with 12-month treatment persistence. Baseline HBI score was negatively associated with 12-month treatment persistence. Cox regression analysis showed no overall difference in treatment discontinuation-free and serious infection-free survival by 12 months.We observed comparable safety and effectiveness for ustekinumab and vedolizumab in treating elderly CD patients.

ObjectiveAntitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.DesignThird dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.ResultsGeometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), pCompared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.ConclusionsFollowing a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.Trial registration numberISRCTN45176516.

Key points The first #FGDebates of 2021 tackled ‘Controversies in liver transplantation’ in a double-header inspired by the recent liver transplantation guidelines.1 2 The debates stimulated much discussion with nearly 900 tweets from over 100 participants across the two debates. This fantastic interaction generated a cumulative 3.7 million impressions worldwide with both debates ranking in the top 5 #FGDebates of all time for total impressions made. In this article, we aim to discuss the key discussion points from each of the #FGDebates. Liver transplantation for patients with alcohol use disorders (AUDs) has historically been viewed as a controversial area for both the general public and healthcare profession. This was largely due to the perceived ‘self-inflicted’ component and the risk of recidivism post-transplant.3 However, the majority of our attendees felt that it was the correct time to assess our patient with an AUD (figure 1) and alcohol-related liver disease remains the most common aetiology at registration for liver transplantation in the UK with good long-term outcomes.4 A common misconception is that patients require a period of 6 months abstinence prior to referral for assessment. While a period of 3 months abstinence may demonstrate the potential for recompensation, there is no absolute rule for abstinence duration prior to assessment in the UK other than patients must be abstinent.1 However, these patients should be assessed for their individual risk of return to drinking and should …

Yndiamides, underexplored cousins of ynamides, offer rich synthetic potential as doubly nitrogenated two carbon building blocks. Here we report a gold-catalyzed oxidative functionalization of yndiamides to access unnatural amino acid derivatives, using a wide range of nucleophiles as a source of the amino acid side chain. The transformation proceeds under mild conditions, is highly functional group tolerant, and displays excellent regioselectivity through subtle steric differentiation of the yndiamide nitrogen atom substituents.

The COVID-19 pandemic disrupted healthcare services across the world with only essential care being continued.1 2 For paediatric and adult patients with inflammatory bowel disease (IBD), this resulted in significant changes to accessing health services. In some services, IBD advice lines were stopped, specialist nurses and medical staff were redeployed to support acute admissions, outpatient clinics were deferred, and home care services were under threat.3 4 In addition, there was a reluctance from patients to come to hospital or contact their services due to concerns over their personal safety.5 6 The Crohn's and Colitis United Kingdom (CCUK) ‘life in lockdown’ patient survey reported that patients felt their IBD teams kept them well informed of coronavirus and their condition. Importantly, one in five patients reported that they also received inaccurate information on other aspects such as shielding.7 The pandemic has also highlighted the disparities in accessing healthcare8 and addressing these alongside organisational transformation will support personalised care, which is one of the main recommendations of the Inflammatory Bowel Disease United Kingdom (IBD UK) standards.9 Healthcare services have restarted routine clinical practices responding swiftly to regional and national lockdowns in the second wave.10 Additionally, local data have allowed clinical teams to refine service delivery supporting those most vulnerable to poorer outcomes if they develop COVID-19.11 12 The British Society of Gastroenterology (BSG) has commissioned independent reviews on the redesign of outpatient services focusing on telemedicine and restarting endoscopy safely.13–20 The COVID-19 pandemic effect on clinical research and trial activity are being addressed separately by the BSG IBD research committee.1 21 We are currently in our second wave of the pandemic and a third national lockdown with increasing pressure to maintain specialist services as well as directly supporting care for patients with COVID-19. …

A Ti(Oi-Pr)4 promoted 5 or 6-endo-trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di- & tri-substituted pyrrolidines and piperidines while forming a new C-C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C-C and a C-N bond in a single step. Notably, either 2,3-trans or 2,3-cis substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Inflammatory bowel disease (IBD) is increasing in prevalence around the world.1 It can be divided into Crohn’s disease (CD), an inflammatory condition of the entire gastrointestinal tract, or ulcerative colitis, which predominantly affects the large bowel. Advances in therapy, such as anti-integrins, anti IL12/23 and particularly anti-tumour necrosis alpha biologics, have contributed to a decrease in surgical intervention.2 Unfortunately, there is a cohort of patients with a severe phenotype, who are refractory to available therapy and ultimately develop intestinal failure (IF). Risk factors which have been identified for this phenotype include a younger age at diagnosis or at first surgery, ileocolonic and perianal disease, family history, smoking and initial need for corticosteroids.3 4 In fact, a recent study has shown surgical complications (abdominal sepsis) as being the most common cause of IF in patients with CD.4 This may explain why, in combination with the development of targeted biological therapies, a study from a national IF unit found a decrease in the number of patients with IF due to CD directly and an increase in those whose aetiology was from surgical complications.5 A 40-year study from a Danish IF unit showed the number of home parenteral nutrition (HPN) patients due to IBD increased by around 30 patients a decade but reduced as percentage of total cases.6 The accepted definition of IF is “the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth”.7 IF still remains rare, with a prevalence of patients on parenteral nutrition (PN) of between 5 and 20 patients per million7 and around one-third of these patients have CD.3 IF has been defined into three types (table 1).7–9 Many …

Tofacitinib is an oral, Janus kinase (JAK) molecule, which selectively inhibits Janus-associated tyrosine kinases JAK1 and JAK3. It has already shown efficacy in the treatment of rheumatoid arthritis and the prevention of organ allograft rejection in kidney transplantation. Two separate phase III placebo-controlled trials, assessing 8-week efficacy of tofacitinib induction for ulcerative colitis (UC), demonstrated superiority when compared with placebo. Tofacitinib also demonstrated robust efficacy versus placebo in the 52-week maintenance component of the same study. Tofacitinib has been recommended by the National Institute for Health and Care Excellence as an effective treatment option for adult patients with moderate to severe UC when conventional therapy or a biological agent cannot be tolerated or the disease has responded inadequately or lost response to treatment. We review the guidelines and provide brief commentary on the post hoc analysis related to lipid increases and thromboembolism risk, which have lead to changes in current therapeutic guidance.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government’s advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Ulcerative colitis (UC) is a chronic relapsing and remitting gastrointestinal disorder of uncertain aetiology. The last two decades have seen an expansion in the therapeutic arsenal used to treat UC. This has resulted in improved clinical remission and response rates. Nonetheless, staples in our current medical management originate from trials conducted in the early 20th century. In this review article, we aim to outline the key milestones in the history of the medical management of UC in addition to highlighting promising therapeutic developments for the future.

Background and Aims Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. Methods Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. Results Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94–9.96] vs 5.02 [2.18–18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39–68.10, p Conclusion Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

Background Anti-TNF drugs increase the risk of serious respiratory infections and impair protective immunity following pneumococcal, influenza, and viral hepatitis vaccinations. Therefore, we sought to determine whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses following SARS-CoV-2 infection. Methods CLARITY IBD is a multicentre, prospective observational cohort study. Antibody responses in participants treated with infliximab were compared to a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22nd September and 23rd December 2020. Nucleocapsid anti-SARS-CoV2 antibodies were measured using the Roche Elecsys assay. Clinical data and serum were collected every 8 weeks. Durability was defined as nonreduction in antibody level by at least 50% from baseline. Results At baseline, rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab- than vedolizumab-treated patients (3.4% [161/4685], vs 6.0% [134/2250], p Conclusion Seroprevalence, seroconversion in PCR-confirmed cases, and the magnitude and durability of anti-SARS-CoV2 antibodies were reduced in infliximab- compared with vedolizumab-treated patients. Serological testing and virus surveillance should be considered in patients treated with anti-TNF drugs to detect suboptimal vaccine responses, persistent infection, and viral evolution to inform public health policy.

OFR-8 Figure 1ConclusionsInfliximab is associated with attenuated immunogenicity to a single-dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by inflammatory colitis and is associated with systemic inflammation. Herein, we aimed to investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation.We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients' colons and conducted compositional and functional pathway prediction analyses.The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha-diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilization were enriched in patients with colitis and correlated positively with fecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by fecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance is associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into "high" and "low" systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta-diversity analyses.The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

Purpose Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. Methods We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. Results MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p