A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.

FIT negative clinic as a safety net for low-risk patients with colorectal cancer: impact on endoscopy and radiology utilisation-a retrospective cohort study.

Background: Faecal immunochemical testing (FIT) is recommended by the National Institute for Health and Care Excellence to triage symptomatic primary care patients who have unexplained symptoms but do not meet the criteria for a suspected lower gastrointestinal cancer pathway. During the COVID-19 pandemic, FIT was used to triage patients referred with urgent 2-week wait (2ww) cancer referrals instead of a direct-to-test strategy. FIT-negative patients were assessed and safety netted in a FIT negative clinic. Methods: We reviewed case notes for 622 patients referred on a 2ww pathway and seen in a FIT negative clinic between June 2020 and April 2021 in a tertiary care hospital. We collected information on demographics, indication for referral, dates for referral, clinic visit, investigations and long-term outcomes. Results: The average age of the patients was 71.5 years with 54% female, and a median follow-up of 2.5 years. Indications for referrals included: anaemia (11%), iron deficiency (24%), weight loss (9%), bleeding per rectum (5%) and change in bowel habits (61%). Of the cases, 28% (95% CI 24% to 31%) had endoscopic (15%, 95% CI 12% to 18%) and/or radiological (20%, 95% CI 17% to 23%) investigations requested after clinic review, and among those investigated, malignancy rate was 1.7%, with rectosigmoid neuroendocrine tumour, oesophageal cancer and lung adenocarcinoma. Conclusion: A FIT negative clinic provides a safety net for patients with unexplained symptoms but low risk of colorectal cancer. These real-world data demonstrate significantly reduced demand on endoscopy and radiology services for FIT-negative patients referred via the 2ww pathway.

Why Studying Urgency Is Urgent.

Bowel urgency, the sudden and immediate need to have a bowel movement, is one of the most widely reported and debilitating symptoms of ulcerative colitis. Urgency has a profound impact on patient well-being, often resulting in patient disengagement from education, employment, and social activities. Although its prevalence correlates with disease activity, it is present in states of both disease flare and remission. Postulated pathophysiologic mechanisms are complex, but urgency is likely a consequence of both acute inflammation and structural sequelae of chronic inflammation. Bowel urgency is not widely incorporated into clinical assessment indices or clinical trial endpoints, despite being a pivotal symptom influencing patient health-related quality of life. Addressing urgency can be challenging owing to the associated embarrassment for patients in volunteering this symptom, and its management can be nuanced in the context of a paucity of specific evidence to target it, independently of disease activity. Explicitly inquiring about urgency and integrating it into a multidisciplinary team combining gastroenterologists, psychological support, and continence services is essential to achieving shared satisfaction from treatment. This article outlines the prevalence of urgency and its impact on the quality of life of patients, describes postulated driving mechanisms, and makes recommendations for its inclusion in clinical care and research.

Update on the management of multiple sclerosis during the COVID-19 pandemic and post pandemic: An international consensus statement.

In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world. Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online. The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues.

Estimated and projected burden of multiple sclerosis attributable to smoking and childhood and adolescent high body-mass index: a comparative risk assessment.

BACKGROUND: Smoking and childhood and adolescent high body-mass index (BMI) are leading lifestyle-related risk factors of global premature morbidity and mortality, and have been associated with an increased risk of developing multiple sclerosis (MS). This study aims to estimate and project the proportion of MS incidence that could be prevented with elimination of these risk factors. METHODS: Prevalence estimates of high BMI during childhood/adolescence and smoking in early adulthood, and relative risks of MS, were obtained from published literature. A time-lag of 10 years was assumed between smoking in early adulthood and MS incidence, and a time-lag of 20 years was assumed between childhood/adolescent high BMI and MS incidence. The MS population attributable fractions (PAFs) of smoking and high BMI were estimated as individual and combined risk factors, by age, country and sex in 2015, 2025 and 2035 where feasible. RESULTS: The combined estimated PAFs for smoking and high BMI in 2015 were 14, 11, 12 and 12% for the UK, USA, Russia and Australia in a conservative estimate, and 21, 20, 19 and 16% in an independent estimate, respectively. Estimates for smoking are declining over time, whereas estimates for high early life BMI are rising. The PAF for high early life BMI is highest in the USA and is estimated to increase to 14% by 2035. CONCLUSIONS: Assuming causality, there is the potential to substantially reduce MS incidence with the elimination of lifestyle-related modifiable risk factors, which are the target of global public health prevention strategies.

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom.

BACKGROUND: Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. METHODS: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. RESULTS: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. CONCLUSIONS: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

Effect of different financial competing interest statements on readers' perceptions of clinical educational articles: a randomised controlled trial.

OBJECTIVES: To investigate how different competing interest (COI) statements affect clinical readers' perceptions of education articles. DESIGN: Randomised controlled trial. SETTING AND PARTICIPANTS: Random sample of UK doctors. INTERVENTIONS: We created four permutations of each of two clinical reviews (on gout or dyspepsia), which varied only in terms of the COI statement. Volunteers were blinded and randomised to receive one review and asked to complete a questionnaire after reading it. Blinded factorial analyses of variance and analyses of covariance were carried out to assess the influence of each review and type of COI on outcomes. PRIMARY AND SECONDARY OUTCOMES: Confidence in the article's conclusions (primary outcome), its importance, their level of interest in the article and their likelihood to change practice after reading it. RESULTS: Of 10 889 doctors invited to participate, 1065 (10%) volunteered. Of these, 749 (70%) completed the survey. Analysis of covariance (adjusting for age, sex, job type, years since qualification) showed no significant difference between the groups in participants' confidence in the article (gout: p=0.32, dyspepsia: p=0.78) or their rating of its importance (gout: p=0.09, dyspepsia: p=0.79). For the gout review, participants rated articles with advisory board and consultancies COI as significantly less interesting than those with no COI (p=0.028 with Bonferroni correction). Among participants indicating that they treat the condition and that the article's recommendations differed from their own practice, there was no significant difference in likelihood to change practice between groups (gout: p=0.59, n=59; dyspepsia: p=0.56, n=80). CONCLUSIONS: Doctors' confidence in educational articles was not influenced by the COI statements. Further work is required to determine if doctors do not perceive these COIs as important in educational articles or if they do not pay attention to these statements. More meaningful COI disclosure practices may be needed, which highlight context-specific potential sources of bias to readers. TRIAL REGISTRATION NUMBER: NCT02548312; Results.

Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study.

OBJECTIVE: To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD). METHODS: Linked English national Hospital Episode Statistics and mortality data (1999-2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis. RESULTS: A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29-1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42-1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84-5.11 in age group 25-44 years). CONCLUSIONS: We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.

Associations between clinically diagnosed testicular hypofunction and systemic lupus erythematosus: a record linkage study.

Systemic lupus erythematosus (SLE) has a high female predominance with a 9:1 female-to-male sex ratio, but males have poorer clinical outcomes than females. Gonadal hormones may mediate gender differences in SLE, but their role in SLE remains largely uncharacterised. We aimed to investigate a potential association between testicular hypofunction (TH), as a proxy for low testosterone levels, and SLE in males. A retrospective cohort study was conducted by analysing linked English national Hospital Episode Statistics (HES) and mortality data from 1999 to 2011. We calculated rates for SLE following TH, and TH following SLE, stratified and standardised by age, calendar year of first recorded admission, region of residence, and quintile of patients' Index of Deprivation score. The adjusted rate ratio (RR) of SLE following TH was 7.7 (95% confidence interval (95% CI) 2.5-18.1, p < 0.0001). The adjusted RR for TH following SLE was 6.5 (95% CI 2.1-15.1, p < 0.0001). The positive association between TH and SLE supports a hypothesis that low testosterone levels may influence the development of male SLE. Of clinical importance, it suggests that males with SLE are at increased risk of co-morbid TH (regardless of which precedes which) and this may warrant consideration in the management of patients.

Psychiatric disorders in children with demyelinating diseases of the central nervous system.

INTRODUCTION: The profile of psychiatric disorders associated with multiple sclerosis (MS) may differ in children. We aimed to assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa. PATIENTS AND METHODS: We analyzed linked English Hospital Episode Statistics, and mortality data, 1999-2011. Cohorts were constructed of children admitted with MS and other central nervous system (CNS) demyelinating diseases. We searched for any subsequent episode of care with psychiatric disorders in these cohorts and compared to a reference cohort. RESULTS: Children with CNS demyelinating diseases had an increased rate of psychotic disorders (rate ratio (RR) = 5.77 (95% confidence interval (CI) = 2.48-11.41)); anxiety, stress-related, and somatoform disorders (RR = 2.38 (1.39-3.81)); intellectual disability (RR = 6.56 (3.66-10.84)); and other behavioral disorders (RR = 8.99 (5.13-14.62)). In analysis of the pediatric MS cohort as the exposure, there were elevated rates of psychotic disorders (RR = 10.76 (2.93-27.63)), mood disorders (RR = 2.57 (1.03-5.31)), and intellectual disability (RR = 6.08 (1.25-17.80)). In reverse analyses, there were elevated rates of a recorded hospital episode with CNS demyelinating disease after a previous recorded episode with anxiety, stress-related, and somatoform disorders; attention-deficit hyperactivity disorder (ADHD); autism; intellectual disability; and other behavioral disorders. CONCLUSION: This analysis of a national diagnostic database provides strong evidence for an association between pediatric CNS demyelinating diseases and psychiatric disorders, and highlights a need for early involvement of mental health professionals.

Dietary factors and pediatric multiple sclerosis: A case-control study.

BACKGROUND: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. OBJECTIVE: To determine the association between dietary factors and MS in children. METHODS: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. RESULTS: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). CONCLUSION: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

Maternal and perinatal characteristics of infants who, later in life, developed multiple sclerosis: Record-linkage study.

BACKGROUND: Pre-natal and early life factors may have a role in multiple sclerosis (MS) pathogenesis in some people. However, the reporting of any influence of maternal and perinatal factors on MS risk has been limited. We aimed to study maternal and perinatal characteristics of babies who went on to develop MS. METHODS: Data were analysed from the historical Oxford Record Linkage Study dataset 1970-1989, which incorporated a specialised maternity dataset with record linkage between mother and baby, covering a population of 850,000. Each maternal admission record, and records of her baby, were linked to any prior or subsequent recorded day-case or inpatient hospital admission episodes 1963-2011. The file of the offspring was searched for a subsequent record of MS, and the maternal and perinatal characteristics of the offspring with a record of MS were compared with those with no record of MS. RESULTS: There was a record of MS for 75 of the offspring, of whom 60 were female. MS was significantly more common in children of mothers who smoked (OR=2.1 (95%CI 1.0-4.7). There was a tendency towards an elevated risk of MS in children of mothers of lower social classes (social class 4+5 OR=1.9 (0.9-3.9)). There were no significant associations between MS in the offspring and mothers' marital status, maternal weight, parity, pre-eclampsia, blood group, or babies' birth weight, birth weight for gestational age, mode of delivery, or presentation at delivery. CONCLUSIONS: This study does not support an important role for most studied maternal and perinatal factors in influencing MS risk. The possible exceptions, speculatively because numbers of subjects with MS were small, were maternal smoking, and pre-term birth. Future work, using datasets that would yield bigger numbers of cases of MS, should explore interactions between perinatal factors that are unlikely to be acting independently.

Viral hepatitis and Parkinson disease: A national record-linkage study.

OBJECTIVE: To study associations between viral hepatitis and Parkinson disease (PD). METHODS: A retrospective cohort study was done by analyzing linked English National Hospital Episode Statistics and mortality data (1999-2011). Cohorts of individuals with hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis, and HIV were constructed, and compared to a reference cohort for subsequent rates of PD. RESULTS: The standardized rate ratio (RR) of PD following hepatitis B was 1.76 (95% confidence interval [CI] 1.28-2.37) (p < 0.001), based on 44 observed compared with 25 expected cases. The RR of PD following hepatitis C was 1.51 (95% CI, 1.18-1.9) (p < 0.001), based on 48.5 expected and 73 observed cases. There was no significant association between autoimmune hepatitis, chronic active hepatitis or HIV, and subsequent PD. When including only those episodes of care for PD that occurred first at least 1 year following each exposure condition, the RR for hepatitis B and hepatitis C were 1.82 (1.29-2.5) and 1.43 (1.09-1.84), respectively. CONCLUSIONS: We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly.

Perinatal characteristics and obstetric complications in mothers with multiple sclerosis: Record-linkage study.

BACKGROUND: Multiple sclerosis (MS) predominantly onsets in women of reproductive age. The possibility of adverse obstetric and perinatal outcomes is a likely source of concern to pregnant women with MS and their clinicians. We aimed to compare the characteristics of the pregnancies of mothers with or without MS. METHODS: The historical Oxford Record Linkage Study specialised maternity dataset (850,000 people, 1970-1989), with record-linkage between mother and baby, was analysed. The dataset was linked to any prior recorded day-case or inpatient hospital admission episodes back to 1963. The file of mothers' records was searched for a record of MS in either the maternity admission or in a previous admission. The pregnancies and babies of mothers with MS were compared with those of mothers without MS. RESULTS: There were 181 pregnancies and babies born to 98 mothers with MS. These were compared with 244,573 pregnancies and babies of 124,830 mothers without MS. There was a significant social class gradient with a higher than expected number of cases of MS in the least deprived social classes. Mothers with MS tended to be lighter than other mothers. There were no significant associations between MS and mothers' marital status, history of smoking during the pregnancy, parity, pre-eclampsia, ABO blood group or rhesus group. There were no significant associations with babies' birth weight, and no significant associations with gestational age, being small for gestational age, Caesarian delivery, or forceps delivery. There were no stillbirths, no neonatal deaths, and no postneonatal deaths in the babies born to mothers with MS. CONCLUSIONS: We hope that our findings will add to the available literature in addressing the understandable anxieties of young women with MS, and reassure them that the characteristics of their pregnancies are generally normal.

Effect of different financial competing interest statements on readers' perceptions of clinical educational articles: study protocol for a randomised controlled trial.

INTRODUCTION: Financial ties with industry are varied and common among academics, doctors and institutions. Clinical educational articles are intended to guide patient care and convey authors' own interpretation of selected data. Author biases in educational articles tend to be less visible to readers compared to those in research papers. Little is known about which types of competing interest statements affect readers' interpretation of the credibility of these articles. This study aims to investigate how different competing interest statements in educational articles affect clinical readers' perceptions of the articles. METHODS AND ANALYSIS: 2040 doctors who are members of the British Medical Association (BMA) and receive a copy of the British Medical Journal (The BMJ) each week will be randomly selected and invited by an email to participate in the study. They will be randomised to receive 1 of 2 Clinical Reviews, each with 1 of 4 possible competing interest statements. Versions of each review will be identical except for permutations of the competing interest statement. Study participants will be asked to read their article and complete an online questionnaire. The questionnaire will ask participants to rate their confidence in the conclusions drawn in the article, the importance of the article, their level of interest in the article and their likeliness to change their practice from the article. Factorial analyses of variance and analyses of covariance will be carried out to assess the impact of the type of competing interest statement and Clinical Review on level of confidence, importance, interest and likeliness to change practice. ETHICS AND DISSEMINATION: The study protocol, questionnaire and letter of invitation to participants have been reviewed by members of The BMJ's Ethics Committee for ethical concerns. The trial results will be disseminated to participants and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02548312; Pre-results.

Gender identity disorders and multiple sclerosis risk: A national record-linkage study.

BACKGROUND: An altered balance of gonadal hormones in males with gender identity disorders (GIDs) may increase multiple sclerosis (MS) risk both inherently and secondary to treatment in undergoing male-to-female conversion. OBJECTIVE: We investigated any association between GIDs and MS through analysis of record-linked hospital statistics. METHOD: Analysis of English Hospital Episode Statistics, 1999-2012. RESULTS: The adjusted rate ratio (RR) of MS following GIDs in males was 6.63 (95% confidence interval (95% CI) = 1.81-17.01, p = 0.0002). The RR of MS following GIDs in females was 1.44 (95% CI = 0.47-3.37, p = 0.58). CONCLUSION: We report a strong association between GIDs and MS in male-to-females, supporting a potential role for low testosterone and/or feminising hormones on MS risk in males.