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Background In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. Methods Approval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. Results Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. Conclusions This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia. [ABSTRACT FROM AUTHOR]

Background: Gene therapy has the potential to offer people with haemophilia (PwH) a life free from bleeding and the burden posed by current treatment regimens. To date, gene therapy has only been available in clinical trial settings, to PwH without pre-existing or historical factor inhibitors, significant concomitant liver damage or pre-existing neutralising antibodies to the adeno-associated viruses used to deliver the therapy. Thus, most PwH treated at centres not currently involved in gene therapy trials, either as a referral/follow-up centre or as a dosing centre, have been unable to access the therapy. This Exigency sub-study aims to gain a greater understanding of the opinions of PwH in the United Kingdom who have not had access to gene therapy: asking what they understand, what concerns they have, and whether they perceive any barriers preventing their access to gene therapy. Results: Twenty-three PwH were approached; 14 consented, and one withdrew prior to interview. The mean age of the participants was 35.7 years (range 25–74 years). Eleven had haemophilia A and two haemophilia B. Two were treated with standard half-life factor products, five with extended half-life products, five with a FVIII mimetic and one with a clinical trial product. One family member (a participant's partner) was also interviewed. The participants identified four barriers to gene therapy: concerns about the process of gene therapy (Expectations), uncertainty about the results (outcomes), (Access) to treatment, and a lack of understanding about gene therapy (education). Conclusions: This Exigency study subgroup sees gene therapy as a positive treatment development that promises an improved quality of life. For this participant group, four issues impact their decision to undergo gene therapy. If the promise of gene therapy is to be realised, these barriers need to be acknowledged and addressed by healthcare professionals, patient organisations, and gene therapy providers. [ABSTRACT FROM AUTHOR]

Midwives understand the benefits of breastfeeding, both for the infant and mother. However, the biochemical and physiological reasons for the superiority of breast milk are less widely known. This is, in part, because of the extraordinary complexity of breast milk's composition. Its key components include nucleotides, which benefit gut and immune development, human milk oligosaccharides, which promote an optimal gut biome, lipids in the milk fat globule membrane, which promote gut health and brain development, immunoglobulins, which modulate the infant's immune system, and an optimum protein content, which is high in the first 2 weeks after birth but decreases thereafter. A greater awareness and understanding of the mechanisms behind the benefits of breastfeeding could help midwives to have informed discussions with parents and potentially contribute to improving the UK's breastfeeding rates. Growing understanding of breast milk's unique composition may also help infant formula manufacturers drive innovation and improve the formulation of their products. [ABSTRACT FROM AUTHOR]

Supply of immunoglobulin in the UK faces pressures due to increasing demand, cost and variable supply. This paper describes immunoglobulin replacement therapy (IGRT) in primary immunodeficiency (PID) and secondary immunodeficiency (SID) to assist in the ongoing planning of UK immunoglobulin provision. A retrospective analysis of the National Immunoglobulin Database and the UKPID registry was carried out. In total, 3,222 patients are registered as receiving IGRT for immunodeficiencies. Predominately antibody disorders made up the largest diagnostic category (61% of patients). The total cost of IGRT for immunodeficiency for 2015/16 was £40,673,350; an average annual cost of £1,099,254 per centre and £12,124 per PID patient. SCIg accounted for 43.8% and 50.1% of IGRT, with home therapy accounting for 42.7% and 57.5% of place of therapy in the National Immunoglobulin Database and UKPID registry respectively. In 2015/16 use of immunoglobulin in SID increased by 24% over the previous financial year. The overall trends of increasing demand in immunology are mirrored in other specialties, most notably neurology and haematology. These data are the first national overview of IGRT for immunodeficiencies, providing a valuable resource for clinicians and policy makers in the ongoing management of UK immunoglobulin supply. [ABSTRACT FROM AUTHOR]

Prospective population-based studies investigating associations between reactive symptoms following SARS-CoV-2 vaccination and serologic responses to vaccination are lacking. We therefore conducted a study in 9003 adults from the UK general population receiving SARS-CoV-2 vaccines as part of the national vaccination programme. Titres of combined IgG/IgA/IgM responses to SARS-CoV-2 spike (S) glycoprotein were determined in eluates of dried blood spots collected from all participants before and after vaccination. 4262 (47.3%) participants experienced systemic reactive symptoms after a first vaccine dose. Factors associating with lower risk of such symptoms included older age (aOR per additional 10 years of age 0.85, 95% CI: 0.81–0.90), male vs. female sex (0.59, 0.53–0.65) and receipt of an mRNA vaccine vs. ChAdOx1 nCoV-19 (0.29, 0.26–0.32 for BNT162b2; 0.06, 0.01–0.26 for mRNA-1273). Higher risk of such symptoms was associated with SARS-CoV-2 seropositivity and COVID-19 symptoms prior to vaccination (2.23, 1.78–2.81), but not with SARS-CoV-2 seropositivity in the absence of COVID-19 symptoms (0.94, 0.81–1.09). Presence vs. absence of self-reported anxiety or depression at enrolment associated with higher risk of such symptoms (1.24, 1.12–1.39). Post-vaccination anti-S titres were higher among participants who experienced reactive symptoms after vaccination vs. those who did not (P < 0.001). We conclude that factors influencing risk of systemic symptoms after SARS-CoV-2 vaccination include demographic characteristics, pre-vaccination SARS-CoV-2 serostatus and vaccine type. Participants experiencing reactive symptoms following SARS-CoV-2 vaccination had higher post-vaccination titres of IgG/A/M anti-S antibodies. Improved public understanding of the frequency of reactogenic symptoms and their positive association with vaccine immunogenicity could potentially increase vaccine uptake. [ABSTRACT FROM AUTHOR]

Objectives Juvenile-onset systemic lupus erythematosus (jSLE) affects 15–20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. Methods Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. Results Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. Conclusion Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity. [ABSTRACT FROM AUTHOR]

Background Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes pre-plasma B cells. It is used in paediatric rheumatology for conditions including juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), vasculitides and refractory juvenile idiopathic arthritis (JIA). We aim to describe the cohort of patients treated with rituximab in the Scottish Paediatric and Adolescent Rheumatology Network (SPARN) in a 5-year period, and assess the need for a network guideline. Methods A review of paper and electronic case records. Patients seen within the SPARN network who received Rituximab between 2014 and 2018 were included. Results Vasculitis Rituximab was given to 16 patients in 5 different SPARN centres between 2014 and 2018. Male: Female ratio was 1:4.3. Mean age at first dose of rituximab was 12.75 years. Mean disease duration pre rituximab was 1 year. 8 (50%) patients had jSLE, 7 multisystem and 1 isolated lupus nephritis. 3 had ANCA-positive vasculitis and 5 had other conditions. (1 had RF+ve JIA; 1 severe panuveitis; 1 had an unspecified autoinflammatory condition; 1 had COPA syndrome with severe interstitial lung disease and 1 had autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Documentation of pre-rituximab checks was poor. Baseline bloods were done in all 16 patients. 11 patients had lymphocyte subsets and 13 immunoglobulins documented. Disease-specific antibodies were measured in all patients in whom applicable (11). 11 had a chest x-ray prior to rituximab. In 9 cases a pre-rituximab pregnancy test was indicated: none were documented. In only 3 patients was a pre-rituximab history of recent infections documented. In 8 patients a discussion regarding treatment risks and benefits was documented. Post-infusion lymphocyte subset monitoring was variable but documented in 15. 1 patient was never B cell deplete. 9 never fully reconstituted. RTX dose information was available for 14. All received doses of 750mg/m2 with 6 having the dose capped at 1g. Dose frequency information was available for all. The majority (9) received 2 doses. Of the rest, 1 patient received a single dose. 3 received 3 doses, 2 had 4 and 1 had 5. All patients in whom information was available, received pre-medication with paracetamol, chlorphenamine and methylprednisolone (n = 14). 4 patients had side effects noted (rash/itch in 1, anaphylaxis in 1, facial flushing in 1 and post-infusion infection in 1). Clinical response was clearly documented in 8 patients, 7 of whom showed clinical improvement (2 had systemic jSLE, 2 had ANCA +ve vasculitis, 1 had isolated lupus nephritis, 1 had COPA syndrome and 1 had RF+ JIA). Conclusion Rituximab is used for a range of conditions and in a number of centres within SPARN. This review highlights variation in and poor documentation of pre-rituximab discussions and investigations, prescribing, monitoring and response. A SPARN rituximab protocol is being developed to address this. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in individuals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37–63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was >1 year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection. The impact of prior infection on the immune response to COVID-19 vaccination has not been fully characterised. Here, the authors use data from ~100,000 adults in the UK and find that a single vaccine dose in those with prior infection produces a comparable or stronger response to two doses in those without infection. [ABSTRACT FROM AUTHOR]

Adequate follow-up in celiac disease is important to improve dietary compliance and treat disease-related symptoms and possible complications. However, data on the follow-up of celiac children is scarce. We aimed to assess current pediatric celiac follow-up practices across Europe. Pediatricians and pediatric gastroenterologists from 35 countries in Europe, Israel, Turkey, and Russia completed an anonymous survey which comprised a 52-item questionnaire developed by the ESPGHAN Special Interest Group on Celiac Disease. A total of 911 physicians, the majority of whom exclusively worked in pediatric care (83%) and academic institutions (60%), completed the questionnaire. Mean age and mean experience with celiac care were 48.7 years (± 10.6) and 15.7 years (± 9.9), respectively. The vast majority (≥ 92%) always assessed anthropometry, dietary adherence, and tissue-transglutaminase IgA-antibodies at every visit, with the first visit being between 3 and 6 months after diagnosis. Other parameters (% always tested) were as follows: complete blood count (60%), iron status (48%), liver enzymes (42%), thyroid function (38%), and vitamin D (26%). Quality of life was never assessed by 35% of the responding physicians. Transition to adult care was mostly completed via a written transition report (37%) or no formal transition at all (27%). Conclusions: Follow-up of celiac children and adolescents in Europe may be improved, especially regarding a more rational use of (laboratory) tests, dietary and QoL assessment, and transition to adult care. Evidence-based advice from international scientific societies is needed. What is Known: • Follow-up in celiac disease is important to treat disease-related symptoms, improve dietary compliance, and prevent possible complications. • There is a lack of consensus about the appropriate follow-up. What is New: • Almost all European physicians assess anthropometry, tissue-transglutaminase IgA-antibodies, and dietary adherence at every visit, but there are large variations in other follow-up aspects. • Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance, and quality of life together with transition programs to adult care. [ABSTRACT FROM AUTHOR]

Objectives: A major COVID‐19 vaccine strategy is to induce antibodies that prevent interaction between the Spike protein's receptor‐binding domain (RBD) and angiotensin‐converting enzyme 2 (ACE2). These vaccines will also induce T‐cell responses. However, concerns were raised that aberrant vaccine‐induced immune responses may exacerbate disease. We aimed to identify minimal epitopes on the RBD that would induce antibody responses that block the interaction of the RBD and ACE2 as a strategy leading to an effective vaccine with reduced risk of inducing immunopathology. Methods: We procured a series of overlapping 20‐amino acid peptides spanning the RBD and asked which were recognised by plasma from COVID‐19 convalescent patients. Identified epitopes were conjugated to diphtheria‐toxoid and used to vaccinate mice. Immune sera were tested for binding to the RBD and for their ability to block the interaction of the RBD and ACE2. Results: Seven putative vaccine epitopes were identified. Memory B‐cells (MBCs) specific for one of the epitopes were identified in the blood of convalescent patients. When used to vaccinate mice, six induced antibodies that bound recRBD and three induced antibodies that could partially block the interaction of the RBD and ACE2. However, when the sera were combined in pairs, we observed significantly enhanced inhibition of binding of RBD to ACE2. Two of the peptides were located in the main regions of the RBD known to contact ACE2. Of significant importance to vaccine development, two of the peptides were in regions that are invariant in the UK and South African strains. Conclusion: COVID‐19 convalescent patients have SARS‐CoV‐2‐specific antibodies and MBCs, the specificities of which can be defined with short peptides. Epitope‐specific antibodies synergistically block RBD–ACE2 interaction. [ABSTRACT FROM AUTHOR]

Background and Aims: A variety of auto‐antibody assays are available as part of the clinical care of patients with liver disease. We sought to better understand the clinical utility of immune serological testing in patients with primary biliary cholangitis (PBC). Methods: We retrospectively analysed data from 2846 patients investigated for liver disease at a UK liver centre between 2001 and 2017. A total of 499 patients with PBC were identified. Immune serology results were examined for their diagnostic utility and prognostic significance to predict transplant‐free survival. Results: Antimitochondrial antibodies (AMAs) were specific (94.5%) and sensitive (85.6%) for PBC; antinuclear antibodies (ANAs) against glycoprotein 210 (gp210) and sp100 were specific (>98%) but not sensitive (<25%). The disease‐specific ANAs were detectable in 29.6% of AMA‐negative patients. Anti‐gp210 auto‐antibodies were significantly associated with elevated serum aminotransferase activity, bilirubin and liver stiffness at presentation (P <.010). Anti‐gp210 auto‐antibodies predicted non‐response to ursodeoxycholic acid (UDCA) by GLOBE criteria (39.3% vs 16.7%, P =.005). Moreover, anti‐gp210 was independently associated with death or liver transplantation (HR 3.22, 95% CI 1.49‐6.96; P =.003), after accounting for other significant baseline determinants of outcome. Serologic finding of anti‐gp210 antibodies conferred an independent risk of death or transplantation (HR 4.13, 95% CI 1.85‐9.22; P =.001) after accounting for treatment response. Conclusion: In our single‐centre cohort of patients with PBC, the presence of anti‐gp210 was associated with an adverse presenting phenotype, predicted treatment non‐response and independently predicted reduced transplant‐free survival. [ABSTRACT FROM AUTHOR]

Summary: Antibody incompatibility is a barrier to living kidney transplantation; antibody incompatible transplantation (AIT) is an accepted treatment modality, albeit higher risk. This study aims to determine changes to clinical decision making and access to AIT in the UK. An electronic survey was sent to all UK renal transplant centres (n = 24), in 2014, and again in 2018. Questions focused on entry & duration in the UKLKSS for HLA and ABO‐incompatible pairs, Can and provision of direct AIT transplantation within those centres. Between 2014 & 2018, the duration recommended for patients in the UKLKSS increased. In 2014, 34.8% of centres reported leaving HLA‐i pairs in the UKLKSS indefinitely, or reviewing on a case by case basis, by 2018 this increased to 61%. Centres offering direct HLA‐i transplantation reduced from 58% to 37%. For low titre (1:8) ABO‐i recipients, 66% of centres recommended at least 9 months (3 matching runs) in the UKLKSS scheme in 2018, compared to 47% in 2014, 50% fewer units consider direct ABO‐i transplantation for unsuccessful pairs with high ABO titres (>1:512). Over time, clinicians appear to be facilitating more conservative management of AIT patients, potentially limiting access to living donor transplantation. [ABSTRACT FROM AUTHOR]

Anti‐HLA‐antibody characteristics aid to risk‐stratify patients and improve long‐term renal graft outcomes. Complement activation by donor‐specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross‐match‐positive). We explored the role of C3d‐positive DSAs in sub‐stratification of cross‐match‐positive cases and relate to the graft outcomes. We investigated 139 cross‐match‐positive living‐donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post‐transplant. C3d‐positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post‐transplant. Median follow‐up of patients was 48 months (IQR 20.47–77.57). In the multivariable analysis, pretreatment C3d‐positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37–7.86). The relative risk of death‐censored five‐year graft failure was 2.83 (95% CI 1.56–5.13). Patients with both pretreatment and Day 14 C3d‐positive DSAs had the worst five‐year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d‐negative DSA patients with the relative risk of death‐censored five‐year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub‐stratify the risk of poor graft outcome in cross‐match‐positive living‐donor renal transplantation. [ABSTRACT FROM AUTHOR]

Summary: Blood group O or B recipients wait longer for a kidney transplant. We studied the distribution of anti‐ABO blood group antibody titres in patients awaiting a kidney transplant, and modelled the effect of altering the UK National Kidney Allocation Scheme to allow for patients with 'LOW' titres (≤1:8, ≤3 dilutions) to receive a deceased donor ABOi (ddABOi) transplant. In a prospective study of 239 adult patients on the waiting list for a transplant in 2 UK centres, ABO‐antibody titres (anti‐A and anti‐B) were measured. Based on the proportions of 'LOW' anti‐A or anti‐B antibodies, four simulations were performed to model the current allocation rules compared with variations allowing ddABOi allocation under various conditions of blood group, HLA matching, and waiting time. The simulations permitting ddABOi resulted in more blood group B recipients being transplanted, with median waiting time reduced for this group of recipients, and more equitable waiting times across blood groups. Additionally, permitting ddABOi resulted in greater numbers of 000MM allocations overall in compatible transplants under modelled conditions. Changing allocation in the UK to permit ddABOi in patients with 'LOW' titres would not change the total number of transplants, but redistributes allocation more equitably amongst blood groups, altering waiting times accordingly. [ABSTRACT FROM AUTHOR]

Background: There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). Methods: Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case–control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. Results: VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. Conclusions: This case–control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context. [ABSTRACT FROM AUTHOR]

Data obtained recently in the United Kingdom following a nationwide infant immunization program against serogroup B Neisseria meningitidis (MenB) reported >80% 4CMenB vaccine-mediated protection. Factor H-binding protein (fHbp) is a meningococcal virulence factor and a component of two new MenB vaccines. Here, we investigated the structural bases underlying the fHbp-dependent protective antibody response in humans, which might inform future antigen design efforts. We present the co-crystal structure of a human antibody Fab targeting fHbp. The vaccine-elicited Fab 1A12 is cross-reactive and targets an epitope highly conserved across the repertoire of three naturally occurring fHbp variants. The free Fab structure highlights conformational rearrangements occurring upon antigen binding. Importantly, 1A12 is bactericidal against MenB strains expressing fHbp from all three variants. Our results reveal important immunological features potentially contributing to the broad protection conferred by fHbp vaccination. Our studies fuel the rationale of presenting conserved protein epitopes when developing broadly protective vaccines. [ABSTRACT FROM AUTHOR]

Anti-tumor necrosis factor alpha (TNF-α) agents have become an established treatment option for rheumatoid arthritis (RA), but are not without risks. As TNF-α has a role in tumour surveillance, anti-TNF-α blockade could potentially increase the risk of malignancy. Recent meta-analysis by Bongartz et al. (JAMA 295:2275–2285, ) reported an increase in the incidence of malignancy attributed to anti-TNF-α antibodies, and the information has quickly and uncritically reached several secondary sources with huge effects on public perception of risks related to anti-TNF-α therapy. In contrast, the results from the British Society for Rheumatology Biologics Register show that in clinical practice, anti-TNF-α therapy in RA does not appear to increase the risk of malignancy in those patients with low risk of malignancy. We discuss the issues emerging from these published data and suggest caution against giving weight to meta-analysis of short-term drug studies. [ABSTRACT FROM AUTHOR]

The article discusses the public and patient involvement (PPI) in paediatric research. Topics include the importance of PPI, status of PPI in paediatric research in Great Britain, and the PEPtalk 2 randomised pilot study of varicella zoster immunoglobulin (VZIG) injection. Also provided are ten tips to involve young people and families in research.

Purpose: Selenium is an essential trace mineral and a component of selenoproteins that are involved in the production of thyroid hormones and in regulating the immune response. We aimed to explore the effect of low-dose selenium supplementation on thyroid peroxidase antibody (TPO-Ab) concentration and thyroid function in pregnant women from a mild-to-moderate iodine-deficient population. Methods: Samples and data were from a secondary analysis of Selenium in PRegnancy INTervention (SPRINT), a double-blind, randomized, placebo-controlled study that recruited 230 women with singleton pregnancies from a UK antenatal clinic at 12 weeks of gestation. Women were randomized to receive 60 µg/day selenium or placebo until delivery. Serum thyroid peroxidase antibodies (TPO-Ab), thyrotropin (TSH) and free thyroxine (FT4) were measured at 12, 20 and 35 weeks and thyroglobulin antibodies (Tg-Ab) at 12 weeks. Results: 93.5 % of participants completed the study. Se supplementation had no more effect than placebo in decreasing TPO-Ab concentration or the prevalence of TPO-Ab positivity during the course of pregnancy. In women who were either TPO-Ab or Tg-Ab negative at baseline (Thy-Ab), TSH increased and FT4 decreased significantly throughout gestation ( P < 0.001), with no difference between treatment groups. In women who were Thy-Ab at baseline, TSH tended to decrease and was lower than placebo at 35 weeks ( P = 0.050). FT4 fell more on Se than placebo supplementation and was significantly lower at 35 weeks ( P = 0.029). Conclusions: Low-dose selenium supplementation in pregnant women with mild-to-moderate deficiency had no effect on TPO-Ab concentration, but tended to change thyroid function in Thy-Ab women. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to see whether lessons could be learned from the prospectively maintained nationwide database on solitary pancreas transplantation (SPTx) performed in the UK. Methods: Two hundred and forty-five SPTx were utilized from the 2004-2013 period (113 pancreas transplant alone and 132 pancreas after kidney). The statistical analysis included donor, recipient, transplant variables, and the effect of a rejection episode on graft survival. Results: Cold ischemia time (CIT), CIT > 12 h, donor body mass index (BMI) > 30, and non-lymphocyte-depleting induction immunosuppression achieved p-value <0.05 in the unadjusted univariate hazard model analysis. In a multivariate analysis, variables that persisted in demonstrating increased independent risk included CIT > 12 h (hazard ratio [HR] 1.94, p = 0.035) and the use of non-depleting induction immunosuppression (HR 1.95, p = 0.002). Factors such as bladder-drained grafts and donor variables including age, BMI, and donation after cardiac death (DCD) vs. donation after brain-stem death did not attain significance. Rejection reduces the overall graft survival by approximately 1000 d (1841 ± 114 d vs. 915 ± 119 d, p = 0.001). Conclusions: Cold ischemia time <12 h and the use of depleting antibodies as induction immunosuppression have a positive effect on pancreas allograft survival. Other factors such as bladder-drained grafts and donor variables such as age, BMI, and DCD status did not attain significance in a multivariate analysis. [ABSTRACT FROM AUTHOR]

Objectives To study which salivary proteins form the protective bound mucosal pellicle and to determine the role of transglutaminase in pellicle development. Materials and Methods Oral epithelial cells were collected and underwent washes of different strengths, followed by homogenisation. SDS- PAGE, western blotting, IgA ELISAs and amylase activity assays were completed on cell homogenates and compared to saliva samples to confirm which salivary proteins were bound to cell surfaces. Results Salivary mucins, MUC5B and MUC7, were strongly retained on the oral epithelial cell surface. Other bound proteins including cystatin S, carbonic anhydrase VI, secretory component and IgA could be washed off. IgA was present in concentrated levels in the bound mucosal pellicle compared to amounts in saliva. Amylase, one of the most abundant proteins present in saliva, showed minimal levels of binding. Transglutaminase 3 presence was confirmed, but proteins that it catalyses cross-links between, statherin and proline-rich proteins, showed minimal presence. Conclusion Some protective salivary proteins including mucins and IgA become concentrated on oral surfaces in the bound mucosal pellicle, through specific interactions. Concentration of mucins would contribute to lubrication to prevent abrasion damage to soft tissues, whilst increased IgA could create an 'immune reservoir' against mucosal infection. [ABSTRACT FROM AUTHOR]

Seroepidemiology of chlamydia can offer study opportunities and insights into cumulative risk of exposure that may contribute to monitoring the frequency of, and control of, genital chlamydia–the most commonly diagnosed STI in England. We undertook retrospective anonymous population-based cross-sectional surveys using an indirect IgG ELISA for chlamydia Pgp3 antibody. Sera from 4,732 women aged 17–24 years were tested. Samples were taken at 3-yearly intervals between 1993 and 2002, a period during which other data suggest chlamydia transmission may have been increasing, and from each year between 2007 and 2010. Seroprevalence increased in 17–24 year olds over time between 1993 and 2002. Between 2007 and 2010, age-standardised seroprevalence among 17–24 year olds decreased from 20% (95% CI: 17–23) to 15% (95%CI 12–17) (p = 0.0001). The biggest drop was among 20 to 21 year olds, where seroprevalence decreased from 21% in 2007 to 9% in 2010 (p = 0.002). These seroprevalence data reflect some known features of the epidemiology of chlamydia infection, and show that exposure to antibody-inducing chlamydia infection has declined in recent years. This decline was concurrent with increasing rates of screening for asymptomatic chlamydia. Serology should be explored further as a tool for evaluation of chlamydia control, including chlamydia screening programmes. [ABSTRACT FROM AUTHOR]

Objectives. Our aim was to establish whether alcohol protects against RA development and to determine whether this effect is influenced by alcohol dose, duration and serological status through systematically reviewing the literature and undertaking a meta-analysis. Methods. We searched Medline/EMBASE (1946 to July 2012) using the terms rheumatoid arthritis.mp or arthritis, rheumatoid/ and alcohol.mp or ethanol/. Manuscript bibliographies were reviewed. Observational studies were included that were case–control/cohort, examined the relationship between alcohol and RA risk and reported or allowed the calculation of effect size data [odds ratios (ORs)/relative risks (RRs) with 95% CIs] in drinkers vs non-drinkers. A random-effects model was used to estimate pooled ORs/RRs. Dose–risk relationships were evaluated by trend tests. Results. Nine studies (from 893 articles) met our inclusion criteria, comprising six case–control (3564 cases; 8477 controls) and three cohort studies (444 RA cases; 84 421 individuals). A significant protective effect of alcohol on RA risk was observed—summary OR for RA in drinkers vs non-drinkers 0.78 (95% CI 0.63, 0.96). This effect was confined to ACPA-positive RA—summary OR 0.52 (95% CI 0.36, 0.76), with no significant risk reduction seen for ACPA-negative RA—summary OR 0.74 (95% CI 0.53, 1.05). Subgroup analysis by study design identified a significant relationship in case–control but not cohort studies. Conclusion. Alcohol intake is inversely associated with ACPA-positive RA, suggesting a protective effect. As this finding is confined to case–control studies further research is required with prospective cohort studies incorporating ACPA status to confirm this relationship. [ABSTRACT FROM AUTHOR]

This study, conducted for the UK Blood Transfusion Services ( UKBTS), evaluated the clinical safety of red cells filtered through a CE-marked prion removal filter (P-Capt™). Patients requiring blood transfusion for elective procedures in nine UK hospitals were entered into a non-randomized open trial to assess development of red cell antibodies to standard red cell ( RCC) or prion-filtered red cell concentrates ( PF- RCC) at eight weeks and six months post-transfusion. Patients who received at least 1 unit of PF- RCC were compared with a control cohort given RCC only. About 917 PF- RCC and 1336 RCC units were transfused into 299 and 291 patients respectively. Twenty-six new red cell antibodies were detected post-transfusion in 10 patients in each arm, an overall alloimmunization rate of 4·4%. Neither the treatment arm [odds ratio ( OR) 0·93, 95% confidence interval ( CI) 0·3, 2·5] nor number of units transfused ( OR 0·95, 95% CI 0·8, 1·1) had a significant effect on the proportion of patients who developed new alloantibodies. No pan-reactive antibodies or antibodies specifically against PF- RCC were detected. There was no difference in transfusion reactions between arms, and no novel transfusion-related adverse events clearly attributable to PF- RCC were seen. These data suggest that prion filtration of red cells does not reduce overall transfusion safety. This finding requires confirmation in large populations of transfused patients. [ABSTRACT FROM AUTHOR]

Noroviruses are a common cause of gastroenteritis worldwide, but outbreaks appear to be more common in industrialized countries than in developing countries, possibly reflecting differences in exposure and immunity. In this study, age-stratified sera from India and UK populations were analysed for the presence of norovirus-genogroup II specific IgG by a time resolved immunofluorescence assay and relative levels of antibodies in the two populations were compared. Antibody levels were higher among all age groups in India than in UK and increased with age in India, whereas in the UK, levels of antibody decreased in adulthood. These results indicate different patterns of exposure to noroviruses in the two countries. [ABSTRACT FROM AUTHOR]

Background and Objectives Transfusion-related acute lung injury (TRALI) is associated with the passive transfusion of leucocyte antibodies in blood products. Blood Transfusion Services have adopted a number of different strategies for reducing the incidence of TRALI, but, while these have been successful, TRALI has not been completely eliminated. Many Transfusion Services have introduced leucocyte antibody screening of donors to further reduce TRALI. This report describes the results of donor leucocyte antibody screening within NHS Blood and Transplant and the guidelines that have been developed for Transfusion Services within the United Kingdom (UK) to reduce the incidence of TRALI. Materials and Methods Blood samples from newly recruited female apheresis donors were tested for human leucocyte antigens (HLA) class I and class II antibodies and granulocyte-specific antibodies. Results A total of 1157 female donors were evaluated. Three hundred and fifteen (27·23%) donors had HLA class I or II antibodies and were returned to red cell component donation. Fifty-seven (6·77%) of the remaining 842 donors were found to have granulocyte-specific antibodies of which 11 (1·31%) had HNA-specific antibodies. A total of 818 donors (70·70%) were accepted for platelet apheresis, 336 donors (29·04%) were returned to red cell component donation, and three donors with HNA-3a antibodies (0·26%) were deferred from therapeutic donation. Conclusions Female donors with leucocyte antibodies were identified in a stratified screening programme. Donors with antibodies were either directed to red cell donation or deferred. This process, combined with other measures that have already been introduced, is anticipated to further reduce the incidence of TRALI. [ABSTRACT FROM AUTHOR]

Objectives. The epidemiological manifestations of ANCA-associated vasculitis (AAV) differ geographically. However, there have been no prospective studies comparing the incidence of AAV between Japan and Europe over the same time period using the same case definitions.Methods. The incidence of AAV was determined by a population-based method in Miyazaki prefecture, Japan, and Norfolk, UK, between 2005 and 2009. Patients with AAV were defined and classified according to the European Medicines Agency (EMEA) algorithm.Results. The number of incident cases of AAV in Japan and the UK were 86 and 50, respectively, and the average annual incidence over the 5-year period was 22.6/million (95% CI 19.1, 26.2) and 21.8/million (95% CI 12.6, 30.9) in Japan and the UK, respectively. The average age was higher in patients in Japan than in patients in the UK [mean (median), 69.7 (72) vs 60.5 (61) years]. Microscopic polyangiitis (MPA) was the predominant subtype in Japan (83%), while granulomatosis with polyangiitis (Wegener's) was more frequent in the UK (66%). As for the pattern of ANCA positivity, >80% of Japanese patients were pANCA/MPO positive, whereas two-thirds of UK patients were cANCA/PR3 positive. Renal involvement in MPA was very common in both countries, but was much less common in granulomatosis with polyangiitis in Japan compared with the UK.Conclusion. There was no major difference in AAV incidence between Japan and the UK, but this prospective study found MPA and MPO-ANCA to be more common in Japan and granulomatosis with polyangiitis and PR3-ANCA to be more common in the UK, in line with earlier reports. [ABSTRACT FROM PUBLISHER]

The specifics of inflammation created by infection with Chlamydia trachomatis could be favourable to the genesis of endometriosis. To investigate this hypothesis, we studied the association between Chlamydia trachomatis specific IgG and IgA antibodies in serum and the peritoneal fluid of 51 women undergoing laparoscopic surgery. There was no significant difference between women with and without endometriosis with respect to the incidence of IgG and IgA in serum or the peritoneal fluid. The results of our preliminary study did not show any significant link between past infection with Chlamydia trachomatis and the presence of endometriosis. [ABSTRACT FROM AUTHOR]

A review of published literature was undertaken to investigate the maternal and fetal effects of measles infection in pregnancy and to inform the need for post-exposure prophylaxis. There is no evidence to support an association between measles in pregnancy and congenital defects. However, the need for effective post-exposure protection is supported by studies suggesting a high risk of severe maternal morbidity, fetal loss and prematurity. Measles in late pregnancy can also lead to perinatal infection in the infant, which may be associated with a high mortality and the risk of subacute sclerosing panencephalitis. UK guidance recommends using human normal immunoglobulin for susceptible pregnant women exposed to measles. Although there is no direct evidence that this will reduce the complications of measles in pregnancy, it may attenuate disease and therefore reduce the rate of complications. Measures to identify women likely to be susceptible include assessment of age, vaccination history, and/or antibody testing. [ABSTRACT FROM AUTHOR]

AIMS: Lack of consensus in HLA antibody reporting in proficiency schemes has previously been attributed to a number of differing factors. This study was set up to eliminate the majority of these factors by reducing analysis to a pure data handling exercise. METHODS: Anonymised raw data files for LABScreen Single Antigen class I and II and related patient information were provided to seven participating centres. The centres reported back the HLA antibody specificities according to their single antigen bead reporting policy. Details of the reporting policy of each centre were retrospectively requested by questionnaire. RESULTS: The number of HLA antibody specificities reported by the different centres varied widely. Software analysis called more HLA antibody specificities than any of the centres. None of the centres matched consensus for reported HLA class I specificities on any of the datasets, and no two centres reported the exact same HLA class I antibody profile; consensus was reached by one centre for HLA class II antibody specificities reported from two of the datasets. Retrospective review found data handling practice between centres to vary widely. CONCLUSIONS: Lack of agreement exists between UK centres in regard to HLA antibody specificity analysis. The fact that the required analysis was limited to interrogation of supplied data files makes the observation more concerning. The root cause of this variation is differences in data handling practice between the participating centres. [ABSTRACT FROM AUTHOR]

Serum samples from 97 clinically healthy domestic rabbits were tested for antibodies to Encephalitozoon cuniculi by an indirect ELISA technique. Fifty (52 per cent) of them were seropositive. The samples were taken as part of a routine health screen or before general anaesthesia at 22 veterinary practices in England, Scotland and Wales, and the veterinary surgeons were asked to complete a questionnaire to provide information concerning the animal's husbandry, diet, vaccination, health status and any preventive medicine routines. None of these factors was found to be associated with the serological status of the rabbits. [ABSTRACT FROM AUTHOR]

We previously reported evidence of West Nile virus (WNV) circulation in UK birds, probably introduced by migratory birds from overseas. We now demonstrate WNV-specific seroconversion in sentinel chickens raised on an English farm. Maternal neutralizing antibodies to WNV in hatchlings declined within three weeks. During the following months, healthy chickens developed WNV neutralizing antibodies that were confirmed by immunoblotting and indirect immunofluorescence tests using WNV antigens. The proportion of seropositive chickens was higher for WNV than for Usutu virus or Sindbis virus. Attempts to isolate infectious virus or to detect viral RNA in the sera, failed. [ABSTRACT FROM AUTHOR]

Thirteen British cases of erythema chronicum migrans are reported. An antibody to the Lyme disease spirochaete was found in three of five recent cases, but Lyme disease was not seen. The distribution and life cycle of the tick Ixodes ricinus is described and related to the occurrence of erythema chronicum migrans in Great Britain. [ABSTRACT FROM AUTHOR]

The article offers a discussion on the interaction process between the T and B lymphocytes with antibody formation as a vital part of gaining a full understanding of immune deficiency diseases in Great Britain. In the views of the author, T-B immunology served as a bridge towards the humans system as cellular basis of interaction, a helper and suppressor in cell interaction, and a requirement of understanding genetic identity.

A correction to the article "The potential overlapping populations for treatment with belimumab and rituximab using current NHS England and National Institute for Health and Care Excellence Guidelines in England and Wales" is presented.