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BackgroundThere is emerging data on the continued efficacy of infliximab when switched from intravenous (IV) to subcutaneous (SC) route in Inflammatory bowel disease (IBD). The impact of cessation of concomitant immunomodulators (IMMs) following switch on trough levels or development of anti-drug antibodies (ADAs) is not evaluated in real world practice. We aimed to study the impact of cessation of IMMs following switch of infliximab from IV to SC route and determine relationship with HLA- DQA1 *05 status.MethodsConsecutive patients who participated in a planned switch programme were prospectively included. Clinical, biomarker and pharmacokinetic data were collected pre-switch, and at 8 weekly intervals post switch for 6 months. Trough levels and remission status in patients who discontinued or reduced the dose of IMMs were compared with those who remained or continued same dose on IMMs. All patients had HLA-DQA1*05 status determined at initiation of Infliximab and we evaluated the impact of HLA status on development of anti-Infliximab antibodies post switch.ResultsOne hundred and fifteen patients (M: F=1.4:1, Median age 44 years (13-76), UC/CD (48/67) who completed 6 month follow up were included. All patients were in clinical and biomarker remission prior to the switch. 72 patients (62.6%) were on concomitant IMMs and 46 (40.86%) was HLADQA1*05 positive. The mean infliximab trough level prior to switch was 5.54 µg/mL which increased 8 weeks post switch to 12.52 µg/mL (p=0.006). The enhancement of levels persisted at 16 weeks (Mean 16.28) and at week 24 (17.25). 36 patients (32%) were positive for ADAs before switch; in 8 patients (22%) the ADAs disappeared at 8 weeks and in further 4 (total 33%) by 6 months. In total antibody titre reduced or become negative in 17 patients (48.6%), static in 14 patients (40%) but increased in 5 patients (14%) without significant lowering of trough levels. 18 of the 72 patients (25%) had IMMs discontinued, and dose reduced in further 21 patients. The total de-escalation rate was 54% and none of these patients developed ADAs at 6 months irrespective of the HLADQA1*05 status (HR = 0.76, 95% = 0.64 to 1.73, p 0.12). One patient switched back to IV due to personal preference. At 6 months none of the patients discontinued SC infliximab or were switched within or out of class.Abstract O40 Figure 1ConclusionsSwitch from IV to SC infliximab is effective in maintaining and enhancing trough levels with positive impact on reducing ADAs. It is feasible to de-escalate concomitant IMMs in a considerable proportion of patients following switch. Economic analysis of switch should be incorporated in the feasibility of IMMs withdrawal.

BackgroundInformed choice about treatment options in the setting of Acute Severe Ulcerative Colitis (ASUC) is often challenging for the patient due to state of heightened stress in this acute setting and the ongoing uncertainties about treatment outcomes, it is uncertain whether patients reconcile with their choice made in this acute setting. We aimed to evaluate decisional conflict and decisional regret among ASUC patients and examine whether decisional conflict contributed to regret.MethodsPatients included in a prospective observational study of ASUC filled two psychometric instruments Decisional Conflict Scale (DCS) and Decisional Regret Scale (DRS). Patients were followed up for 12 months. Differences in DCS scores between patients who underwent colectomy versus those treated with medical therapy were evaluated. Changes in DRS scores at follow up was analysed and factors resulting in high decisional regret scores were evaluated.ResultsOf the 219 patients admitted with ASUC 87 completed the DRS at 12 months. Of these, 70 had no regrets about their treatment, 11 were neutral, and 6 regretted their decision figure 1.Among patients who underwent colectomy, 12 patients completed the DCS at 90 days, with 8 agreeing that it was the right decision by 12 months.For biologic treatment, 70 patients completed the DCS at 90 days, with 63 agreeing it was the right choice, and 44 patients completed the DCS at 12 months, with 43 agreeing. A subgroup of 36 patients who were unsure about their treatment choice at 90 days showed a more divided response, with 17 agreeing it was the right choice by 12 months, while 11 remained uncertain.Abstract P316 Figure 1ConclusionThis study highlights the psychological challenges faced by ASUC patients in their treatment decisions. Decisional conflict is highly prevalent, particularly among those uncertain about their treatment options. These findings suggest the need for developing tailored decision aid tools to facilitate improved shared decision-making processes in ASUC.

IntroductionCombination therapy using thiopurines or methotrexate is recommended to reduce the risk of immunogenicity in IBD patients treated with anti TNF agents. The PANTS study reported the association of HLA DQA1*05 carriage with development of anti-drug antibodies to anti TNFs in patients with Crohn`s disease. Since 2020, we have incorporated determination of HLA status in the pre-biologic screening of IBD patients. We aimed to evaluate persistence at 6 and 12 months in patients stratified to receive mono or combo therapy with anti TNFsMethodsA prospective database of all IBD patients starting biologics was interrogated to select patients initiating on anti TNF agents. We excluded patients Crohn`s disease perianal fistula who had specific indication for combo therapy, patients with acute severe UC receiving accelerated induction those who were already on imunomodulators prior to initiation of anti TNF agents. Data was collected on demographics, disease characteristics, HLA DQA1*05 status, drugs levels and antidrug antibody status at week 6, week 14 and at least one time point during a 1 year maintenance period. The primary outcome was drug persistence at 12 months.ResultsOne hundred and fifty six patients were initiated on anti TNFs during the study period. HLA DQA1*05 was positive in 59 (37.8%) of patients. These patients received combination therapy (Infliximab + thiopurines in 42, Infliximab plus methotrexate in 9, adalimumab plus azathioprine 6, Adalimumab plus methotrexate in 2). All patients negative for HLADQA1805 received monotherapy with infliximab (78) or adalimumab (19). Primary non response was identified in 30 patients (overall 19%, Monotherapy 17(17.5%), combo therapy 13 (22% ) and were switched to a non anti TNF agent Further 9% of patients had dose escalation due to suboptimal drug levels and partial response among whom 6 patients were switched to another class. Eleven patients stopped anti TNFs (4 and 7 in mono and combo therapy group respectively) due to intolerance and five patients discontinued immunomodulators in the combo therapy due to adverse effects.Anti-drug antibodies was detected at week 6 in 2 patients in the monotherapy group and 3 patients in combo therapy group (p=NS). There was no difference in rates of antidrug antibody development during maintenance period between the two groups. One hundred and twelve patients remained on anti TNFs across both groups at 12 months follow up. The overall drug persistence rates was similar in the mono and combination therapy group (66.1% vs 72.2%, p=NS).ConclusionsHLA DQA1*05 status incorporated anti TNF treatment strategy may alleviate the need for combination therapy in IBD patients with no impact on development of anti-drug antibodies and drug persistence. A biomarker stratified randomised trial is recommended.

BackgroundCombination therapy with immunomodulators and anti-TNFs were recommended following the results of the SONIC study. It was determined the main benefit for combination therapy was due to reduction in the risk of anti-drug antibodies. The PANTS study indicated that patients at higher risk of antidrug antibodies to anti-TNF agents could be identified with HLADQA1*05 allele carriage. A HLADQA1*05 stratified withdrawal of immunomodulators has not been evaluated before.MethodsWe included IBD patients on combination immunomodulaotrs and anti TNF agents from a prospective database who had HLADQA1 *05 status determined retrospectively after treatment of minimum 12 months. Patients with Crohn`s disease -perianal fistula or those on immunomodulators due to non-IBD indications were excluded. Immunomodulator withdrawal was offered to all patients in clinical and biomarker remission with a negative HLADQA1805 status. Patients were followed up with structured clinical and biomarker assessment. Therapeutic drug monitoring was performed at 3–6 month intervals. The primary outcome was development of anti-drug antibodies.ResultsThree hundred and eighteen patients on anti-TNF agents had HLA-DQA1*status determined. Among these 248 patients were on combination therapy. Withdrawal of immunomodulaotrs was suggested to 146 (59%) of the HLA-DQA1*05 negative patients. None of the patients declined attempt at withdrawal but five patients preferred dose reduction rather than complete cessation and these were not included in analysis. Median follow up among the remaining 141 patients was 13 months (range 3–27 months). Antidrug antibodies developed in 11 patients (7.8%) including in three patients with undetectable drug levels necessitating switch of agent. An additional 16 patients lost clinical response without development of antibodies.ConclusionIn anti TNF treated IBD patients in long-term remission, withdrawal of immunomodulators is feasible in majority of patients not carrying HLA-DQA1*05 with limited risk of development of antidrug antibodies.

AbstractObjectiveTo develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).DesignProspective observational cohort study.SettingInternational Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium—ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020.ParticipantsAdults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.Main outcome measureIn-hospital mortality.Results35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).ConclusionsAn easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.Study registrationISRCTN66726260

This study explored whether the Interpersonal Theory of suicide informs our understanding of high rates of suicidality in autistic adults. Autistic and non-autistic adults (n = 695, mean age 41.7 years, 58% female) completed an online survey of self-reported thwarted belonging, perceived burden, autistic traits, suicidal capability, trauma, and lifetime suicidality. Autistic people reported stronger feelings of perceived burden, thwarted belonging and more lifetime trauma than non-autistic people. The hypothesised interaction between burdensomeness and thwarted belonging were observed in the non-autistic group but not in the autistic group. In both groups autistic traits influenced suicidality through burdensomeness/thwarted belonging. Promoting self-worth and social inclusion are important for suicide prevention and future research should explore how these are experienced and expressed by autistic people.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m 2 ). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI ( P  = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies. Epidemiological analyses coupled with immunological phenotyping suggest that humoral immunity induced by COVID-19 vaccines wanes more rapidly in individuals with severe obesity compared to individuals with a BMI within the normal range.

New Zealand’s temperate climate and bountiful flora are well suited to managed honey bees, and its geographic isolation and strict biosecurity laws have made sure that some pests and diseases affecting bees elsewhere are not present. Nevertheless, given the importance of pollination and high-value export honey to the economy, New Zealand began systematically measuring winter colony losses in 2015. The New Zealand Colony Loss Survey is modelled on the COLOSS survey but has been adapted to the New Zealand apicultural context. Some 49% of New Zealand beekeepers completed the winter 2021 survey. Between 2015 and 2021, overall colony loss rates increased monotonically from 8.37% [95% CI: 7.66%, 9.15%] to 13.59% [95% CI: 13.21%, 13.99%]. Whereas beekeepers most commonly attributed losses to queen problems between 2015 and 2020, attributions to varroa have escalated year-on-year to become the largest attributed cause of colony loss. Losses to varroa are perhaps amplified by the 23.4% of respondents who did not monitor mite loads and the 4.4% of beekeepers who did not treat varroa during the 2020/21 season. Indeed, most beekeepers consider their treatment to be effective and note that treating at the wrong time and reinvasion were major drivers of losses to varroa.

The newly purified extracellular polysaccharides (exopolysaccharides) from Parachlorella kessleri (PCEPS) were evaluated on their antitumor and immunomodulatory effects in cell culture and mouse colon carcinoma peritoneal dissemination model. In two-dimensional cell culture, the PCEPS treatment inhibited cell growth of both murine and human colon carcinoma cells in a dose- and time-dependent manner. In contrast, the growth of mouse splenocytes (SPLs) and bone marrow cells (BMCs) were stimulated by the treatment with PCEPS. The treatment with PCEPS also increased specific subpopulations of the cells in BMCs: antigen presenting cells (CD19+ B cells, 33D1+ dendritic cells and CD68+ macrophage) and CD8+ cytotoxic T cells. In three-dimensional spheroid culture, spheroid growth of CT26 cells co-cultured with HL-60 human neutrophilic promyeloblasts and Jurkat cells (human lymphoblasts), but not THP-1 human monocyte/macrophage was significantly attenuated by PCEPS treatment. In a mouse CT26 colon carcinoma peritoneal dissemination model, intraperitoneal injection of PCEPS (10 mg/kg, twice per week) significantly attenuated the growth of CT26 colon carcinoma in syngeneic mice. The present study suggests that PCEPS inhibits colon carcinoma growth via direct cell growth inhibition and a stimulation of the host antitumor immune responses. Taken together, the current study suggests that exopolysaccharides derived from Parachlorella kessleri contain significant bioactive materials that inhibit colon carcinoma growth.

BackgroundCaring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (ie, deletions and duplications of genetic material) can place a considerable burden on parents and their quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared with the frequency of psychiatric problems in age-matched mothers from a large community study.MethodsCase–control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2680 age-matched mothers taking part in the Avon Longitudinal Study of Parents and Children study.ResultsMothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared with the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, we found that the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared with mothers from the community sample (30%, p=0.03).ConclusionOur study highlights the need for healthcare providers to devise treatment plans that not only focus on meeting the child’s needs but also assess and, if needed, address the mental health needs of the parent.