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Background While rotavirus causes severe diarrheal disease in children aged Methods In the Vaccine Impact on Diarrhea in Africa study (2015–2018), we analyzed stool from children aged 0–59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5. The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality. Results Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia. Conclusions In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged

Background Despite antibiotic prescription being recommended for dysentery and suspected cholera only, diarrhea still triggers unwarranted antibiotic prescription. We evaluated antibiotic-prescribing practices and their predictors among children aged 2–59 months in the Vaccine Impact on Diarrhea in Africa (VIDA) Study performed in The Gambia, Mali, and Kenya. Methods VIDA was a prospective case-control study (May 2015–July 2018) among children presenting for care with moderate-to-severe diarrhea (MSD). We defined inappropriate antibiotic use as prescription or use of antibiotics when not indicated by World Health Organization (WHO) guidelines. We used logistic regression to assess factors associated with antibiotic prescription for MSD cases who had no indication for an antibiotic, at each site. Results VIDA enrolled 4840 cases. Among 1757 (36.3%) who had no apparent indication for antibiotic treatment, 1358 (77.3%) were prescribed antibiotics. In The Gambia, children who presented with a cough (adjusted odds ratio [aOR]: 2.05; 95% confidence interval [95% CI]: 1.21–3.48) were more likely to be prescribed an antibiotic. In Mali, those who presented with dry mouth (aOR: 3.16; 95% CI: 1.02–9.73) were more likely to be prescribed antibiotics. In Kenya, those who presented with a cough (aOR: 2.18; 95% CI: 1.01–4.70), decreased skin turgor (aOR: 2.06; 95% CI: 1.02–4.16), and were very thirsty (aOR: 4.15; 95% CI: 1.78–9.68) were more likely to be prescribed antibiotics. Conclusions Antibiotic prescription was associated with signs and symptoms inconsistent with WHO guidelines, suggesting the need for antibiotic stewardship and clinician awareness of diarrhea case-management recommendations in these settings.

Background Statistical modeling suggests that decreasing diarrhea-associated mortality rates in recent decades are largely attributed to improved case management, rotavirus vaccine, and economic development. Methods We examined data collected in 2 multisite population-based diarrhea case-control studies, both conducted in The Gambia, Kenya, and Mali: the Global Enteric Multicenter Study (GEMS; 2008–2011) and Vaccine Impact on Diarrhea in Africa (VIDA; 2015–2018). Population-level diarrhea mortality and risk factor prevalence, estimated using these study data, were used to calculate the attribution of risk factors and interventions for diarrhea mortality using a counterfactual framework. We performed a decomposition of the effects of the changes in exposure to each risk factor between GEMS and VIDA on diarrhea mortality for each site. Results Diarrhea mortality among children under 5 in our African sites decreased by 65.3% (95% confidence interval [CI]: –80.0%, −45.0%) from GEMS to VIDA. Kenya and Mali had large relative declines in diarrhea mortality between the 2 periods with 85.9% (95% CI: −95.1%, −71.5%) and 78.0% (95% CI: −96.0%, 36.3%) reductions, respectively. Among the risk factors considered, the largest declines in diarrhea mortality between the 2 study periods were attributed to reduction in childhood wasting (27.2%; 95% CI: −39.3%, −16.8%) and an increased rotavirus vaccine coverage (23.1%; 95% CI: −28.4%, −19.4%), zinc for diarrhea treatment (12.1%; 95% CI: −16.0%, −8.9%), and oral rehydration salts (ORS) for diarrhea treatment (10.2%). Conclusions The VIDA study sites demonstrated exceptional reduction in diarrhea mortality over the last decade. Site-specific differences highlight an opportunity for implementation science in collaboration with policymakers to improve the equitable coverage of these interventions globally.

Background Studies conducted before rotavirus vaccine introduction found that moderate-to-severe diarrhea (MSD) in children aged Methods The Global Enteric Multicenter Study (GEMS) and the Vaccine Impact on Diarrhea in Africa (VIDA) study, two comparable matched case-control studies, were conducted during 2007–2011 and 2015–2018, respectively. We analyzed data from 3 African sites where rotavirus vaccine was introduced after GEMS and before starting VIDA. Children with acute MSD ( Results We analyzed data from 8808 children from GEMS and 10 579 from VIDA. Among those who were not stunted at enrollment in GEMS, 8.6% with MSD and 6.4% without MSD became stunted during the follow-up period. In VIDA, 8.0% with MSD and 5.5% children without MSD developed stunting. An episode of MSD was associated with higher odds of being stunted at follow-up compared with children without MSD in both studies (adjusted odds ratio [aOR], 1.31; 95% confidence interval [CI]: 1.04–1.64 in GEMS and aOR, 1.30; 95% CI: 1.04–1.61 in VIDA). However, the magnitude of association was not significantly different between GEMS and VIDA (P = .965). Conclusions The association of MSD with subsequent stunting among children aged

Background Stunting affects >20% of children Methods In this prospective, matched, case-control study among children Results The proportion of stunting at enrollment was similar when 4603 children with MSD and 5976 children without MSD were compared (21.8% vs 21.3%; P = .504). Among children not stunted at enrollment, those with MSD had 30% higher odds of being stunted at follow-up than children without MSD after controlling for age, sex, study site, and socioeconomic status (adjusted OR: 1.30; 95% CI: 1.05–1.62: P = .018). Conclusions Children

Background Diarrheal disease is heterogeneous, including watery diarrhea (WD) and dysentery, some cases of which become persistent diarrhea (PD). Changes in risk over time necessitate updated knowledge of these syndromes in sub-Saharan Africa. Methods The Vaccine Impact on Diarrhea in Africa (VIDA) study was an age-stratified, case-control study of moderate-to-severe diarrhea among children Results Among 4606 children with moderate-to-severe diarrhea, 3895 (84.6%) had WD and 711 (15.4%) had dysentery. PD was more frequent among infants (11.3%) than in children 12–23 months (9.9%) or 24–59 months (7.3%), P = .001 and higher in Kenya (15.5%) than in The Gambia (9.3%) or Mali (4.3%), P < .001; the frequencies were similar among children with WD (9.7%) and those with dysentery (9.4%). Compared to children not treated with antibiotics, those who received antibiotics had a lower frequency of PD overall (7.4% vs 10.1%, P = .01), and particularly among those with WD (6.3% vs 10.0%; P = .01) but not among children with dysentery (8.5% vs 11.0%; P = .27). For those with watery PD, Cryptosporidium and norovirus had the highest AFs among infants (0.16 and 0.12, respectively), while Shigella had the highest AF (0.25) in older children. The odds of PD decreased significantly over time in Mali and Kenya while increasing significantly in The Gambia. Conclusions The burden of PD endures in sub-Saharan Africa, with nearly 10% of episodes of WD and dysentery becoming persistent.

Background Reducing diarrhea-related morbidity and mortality is a global priority, particularly in low-resource settings. We assessed adherence to diarrhea case management indicators in the Global Enteric Multisite Study (GEMS) and Vaccine Impact of Diarrhea in Africa (VIDA) study. Methods GEMS (2007–2010) and VIDA (2015–2018) were age-stratified case-control studies of moderate-to-severe diarrhea (MSD) in children aged Results For home-based management of children with MSD and no signs of dehydration, 16.6% in GEMS and 15.6% in VIDA were adherent to guidelines. Adherence to guidelines in the facility was likewise low during GEMS (some dehydration, 18.5%; severe dehydration, 5.5%). The adherence to facility-based rehydration and zinc guidelines improved during VIDA to 37.9% of those with some dehydration and 8.0% of children with severe dehydration. Conclusions At research sites in The Gambia, Kenya, and Mali, suboptimal adherence to diarrhea case management guidelines for children aged

Background To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin–producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya. Methods Between May 2015 and July 2018, children aged 0–59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection. Results Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged Conclusions No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease.

Background Non-typhoidal Salmonella (NTS) is a common cause of gastroenteritis in young children, with limited data on NTS serovars and antimicrobial resistance in Africa. Methods We determined the prevalence of Salmonella spp. and frequency of antimicrobial resistance among serovars identified in stools of 0–59 month-old children with moderate-to-severe diarrhea (MSD) and controls enrolled in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in The Gambia, Mali, and Kenya in 2015–2018, and compared with data from the Global Enteric Multicenter Study (GEMS; 2007–2010) and the GEMS-1A study (2011). Salmonella spp. was detected by quantitative real-time PCR (qPCR) and culture-based methods. Identification of serovars was determined by microbiological methods. Results By qPCR, the prevalence of Salmonella spp. among MSD cases was 4.0%, 1.6%, and 1.9% and among controls was 4.6%, 2.4%, and 1.6% in The Gambia, Mali, and Kenya, respectively, during VIDA. We observed year-to-year variation in serovar distribution and variation between sites. In Kenya, Salmonella enterica serovar Typhimurium decreased (78.1% to 23.1%; P < .001) among cases and controls from 2007 to 2018, whereas serogroup O:8 increased (8.7% to 38.5%; P = .04). In The Gambia, serogroup O:7 decreased from 2007 to 2018 (36.3% to 0%; P = .001) but S. enterica serovar Enteritidis increased during VIDA (2015 to 2018; 5.9% to 50%; P = .002). Only 4 Salmonella spp. were isolated in Mali during all 3 studies. Multidrug resistance was 33.9% in Kenya and 0.8% in The Gambia across all 3 studies. Ceftriaxone resistance was only observed in Kenya (2.3%); NTS isolates were susceptible to ciprofloxacin at all sites. Conclusions Understanding variability in serovar distribution will be important for the future deployment of vaccines against salmonellosis in Africa.

Background We evaluated the burden of Shigella spp from children aged 0–59 months with medically attended moderate-to-severe diarrhea and matched controls at sites in Mali, The Gambia, and Kenya participating in the Vaccine Impact on Diarrhea in Africa (VIDA) study from 2015 to 2018. Methods Shigella spp were identified using coprocultures and serotyping in addition to quantitative polymerase chain reaction (qPCR). Episode-specific attributable fractions (AFe) for Shigella were calculated using Shigella DNA quantity; cases with AFe ≥0.5 were considered to have shigellosis. Results The prevalence of Shigella was determined to be 359 of 4840 (7.4%) cases and 83 of 6213 (1.3%) controls by culture, and 1641 of 4836 (33.9%) cases and 1084 of 4846 (22.4%) controls by qPCR (cycle threshold Conclusions A high prevalence of shigellosis continues in sub-Saharan Africa. Strains are highly resistant to commonly used antibiotics while remaining susceptible to ciprofloxacin, ceftriaxone, and azithromycin.

Background Diarrheal diseases remain a health threat to children in low- and middle-income countries. The Vaccine Impact on Diarrhea in Africa (VIDA) study was a 36-month, prospective, matched case-control study designed to estimate the etiology, incidence, and adverse clinical consequences of moderate-to-severe diarrhea (MSD) in children aged 0–59 months. VIDA was conducted following rotavirus vaccine introduction at 3 censused sites in sub-Saharan Africa that participated in the Global Enteric Multicenter Study (GEMS) ∼10 years earlier. We describe the study design and statistical methods of VIDA and where they differ from GEMS. Methods We aimed to enroll 8–9 MSD cases every 2 weeks from sentinel health centers in 3 age strata (0–11, 12–23, 24–59 months) and 1 to 3 controls matched by age, sex, date of case enrollment, and village. Clinical, epidemiological, and anthropometric data were collected at enrollment and ∼60 days later. A stool specimen collected at enrollment was analyzed by both conventional methods and quantitative PCR for enteric pathogens. For the matched case-control study, we estimated the population-based, pathogen-specific attributable fraction (AF) and attributable incidence adjusted for age, site, and other pathogens, and identified episodes attributable to a specific pathogen for additional analyses. A prospective cohort study nested within the original matched case-control study allowed assessment of (1) the association between potential risk factors and outcomes other than MSD status and (2) the impact of MSD on linear growth. Conclusions GEMS and VIDA together comprise the largest and most comprehensive assessment of MSD conducted to date in sub-Saharan Africa populations at highest risk for morbidity and mortality from diarrhea. The statistical methods used in VIDA have endeavored to maximize the use of available data to produce more robust estimates of the pathogen-specific disease burden that might be prevented by effective interventions.

Background The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study. Methods In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged Results Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold Conclusions Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children.

Fast fashion has become a subject of interest to politicians as they grapple with the development of a sustainability strategy. To date the agenda has largely been informed by an examination of production methodologies and techniques documenting the rapid turnover of trends, the speed and efficiency of the production process and the lack of socially cohesive labour practices this consistently engenders. Whilst governments seek to raise awareness and begin to generate initiatives to tackle the environmental fall out of fast fashion, this paper turns its attention to the temporal patterns of consumer behaviour and why such a high percentage of what we buy is readily discarded soon after point of purchase. All stages in this linear model of consumption, it is argued, are shaped by a very specific relationship to time that ultimately informs our buying habits. Utilising the work of the philosopher A.N. Whitehead and adopting a more psychosocial approach to fashion consumption, this paper recognises that even when purposefully seeking to consume sustainably, a greater need to align our use of time with a results-driven mind set locates the acquisition of something new as a highly achievable goal. As a consequence, rather than positioning the rationale for fashion purchases in the context of conspicuous consumption and emulation, here it functions to mitigate a lack of temporal control in other areas of our lives. In response, it is proposed that any successful attempts at tackling the problems associated with fast fashion must also seek to understand the temporal dynamics of consumption. For whilst governments’ attention is turned to ways to reduce the environmental impact associated with the production of clothing, increasing consumer demand derived from ‘neophilia’ (Booker, 1970) will negate and indeed overturn any successes achieved. The conclusion will therefore suggest that promotional culture has a duty to explore ways in which it might engender greater emotional attachments to what we own. Future research into brand messaging, exploring the consequences of placing emphasis on quality over quantity and a subsequent potential deepening of a sense of brand loyalty, is also recommended as a way forward.

Background The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. Methods The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. Results Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below −1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0–11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12–23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). Conclusions Linear growth faltering among children aged 0–23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

Sensory differences and anxiety disorders are highly prevalent in autistic individuals with and without ADHD. Studies have shown that sensory differences and anxiety are associated and that intolerance of uncertainty (IU) plays an important role within this relationship. However, those studies predominantly assessed sensory reactivity using questionnaires (i.e., observational reports), which can be subjective, and do not differentiate between perceptual, affective, and behavioural levels of sensory processing. Psychophysical approaches can offer useful additional insight, by providing objective measures of sensory differences at the perceptual level. In the current study, we used psychophysical vibrotactile tasks to assess how alterations in sensory perception contribute to observationally assessed sensory reactivity, IU, and anxiety. 38 autistic children (aged 8-12 years; 27 with co-occurring ADHD) were included in the analyses. Consistent with previous findings, parent-report measures of sensory reactivity, anxiety, and child-reported IU, were intercorrelated. Mediation analyses showed that IU fully mediated an association between sensory reactivity and anxiety, and that anxiety partially mediated an association between sensory reactivity and IU. Of the measured vibrotactile thresholds, only simultaneous frequency discrimination (SFD) thresholds significantly correlated with parent-reported sensory reactivity. Interestingly, we found that sensory reactivity fully mediated an association between SFD threshold and anxiety, and between SFD threshold and IU. Taken together, these findings suggest a mechanistic pathway whereby low-level perceptual alterations contribute to sensory differences at the affective level, leading in turn to increased IU and anxiety. This stepwise association can inform therapeutic interventions for IU and anxiety in autistic individuals with or without ADHD.

Aims Non-valvular atrial fibrillation (AF) greatly increases the risk of ischaemic stroke. For people with contraindications to oral anticoagulation, left atrial appendage occlusion (LAAO) provides a non-pharmacological management alternative. The aim of this study was to measure the procedural safety and longer-term effectiveness of LAAO for AF in a UK setting. Methods and results This was a prospective, single-armed registry of patients with AF for whom anticoagulation was unsuitable. Registry data were collected between October 2014 and April 2018 and linked to routine data sources for follow-up. Data from 583 LAAO procedures were entered into the registry, of which 537 (from 525 patients) were eligible for inclusion (median CHA2DS2-VASc score 4). A closure device was successfully implanted in 93.4% of cases, with a procedural success rate (device implanted without major complication) of 88.9%. Five patients (1.0%) died in hospital. During follow-up [median 729 (Q1:Q3, 523:913) days] 45 patients experienced neurological events; 33 of which were ischaemic. The ischaemic neurological event rate was 3.3 (1.6–5.0)% at 1 year (n = 387) and 7.0 (4.3–9.6)% at 2 years (n = 196). There were significant improvements in overall patient health (via Visual Analogue Scale) measured at 6 weeks and 6 months, but no significant improvements observed in patient utility over time. Conclusion The findings of our study suggest that LAAO is not without procedural risk, but that this risk may be justified in high-risk patients with AF who cannot take an anticoagulant. Moreover, the data do not provide support for more widespread use of LAAO as the complication rate was relatively high and would be difficult to justify in many patients with AF who tolerate anticoagulation.

Background The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. Methods Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. Results Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. Conclusions Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa., In agreement with prior studies, we show that nontyphoidal Salmonella is prevalent in stool of children

Summary Background Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far. Methods In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24–60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed. Findings Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62–76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6–23). Overall survival was 92·3% (95% CI 90·5–93·9) at 1 year and 79·2% (76·0–82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported. Interpretation In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. ’The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease. Funding NHS England Commissioning through Evaluation scheme.

Background. Individuals on the autism spectrum have been longed described to process sensory information differently than neurotypical individuals. While much effort has been leveraged towards characterising and investigating the neurobiology underlying the sensory differences of autism, there has been a notable lack of consistency in the terms being used to describe the nature of those differences. Main body. We argue that inconsistent and interchangeable terminology-use when describing the sensory differences of autism has become problematic beyond mere pedantry and inconvenience. We begin by highlighting current popular terms used to describe sensory differences (e.g., “sensitivity”, “reactivity” and “responsivity”) that are often observed in autism and discuss why poor nomenclature may hamper efforts towards understanding the aetiology of sensory differences in autism. We then provide a solution to interchangeable terminology-use by proposing a hierarchical taxonomy for describing and referring to various sensory domains, with specific attention to those that are different of autism. Conclusion. Inconsistency in terminology-use when describing the sensory features of autism has stifled discussion and scientific understanding of the sensory differences of autism. An agreed-upon hierarchical taxonomy will help resolve lack of clarity when discussing the sensory differences of autism and place future research targets at appropriate levels of analysis.

The COVID-19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS-CoV-2 lifecycle and COVID-19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID-19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as 'pivotal clinical trials' (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data.

Aims PFO closure is a percutaneous intervention, which aims to reduce risk of recurrent stroke by preventing paradoxical embolism. The objective of this study was to measure procedural safety and longer-term effectiveness of PFO closure in a UK setting. Methods and results Prospective registry data from patients with cryptogenic stroke eligible for PFO closure were collected for up to 2 years and linked to routine data sources for additional follow-up. Outcomes of interest included procedural success rate, health related quality of life, and longer-term death and neurological event rates. A total of 973 PFO closure procedures in 971 patients were included in analysis. Successful device implantation was achieved in 99.4 [95% CI 98.6 to 99.8]% of procedures, with one in-hospital death. During median follow-up of 758 (Q1:Q3 527:968) days, 33 patients experienced a subsequent neurological event, 76% of which were ischaemic in origin. Neurological event rate was 2.7 [95%CI 1.6 to 3.9]% at 1-year (n = 751) and 4.1 [95% CI 2.6 to 5.5]% at 2-years (n = 463) using Kaplan-Meier analysis. Improvements in patient quality of life (utility and visual analogue scale) were observed at 6-weeks and 6-months follow-up. Conclusion Our observational study demonstrates that PFO closure for prevention of recurrent stroke is a relatively safe procedure but in routine clinical practice is associated with a slightly higher risk of recurrent neurological events than in randomised trials. We hypothesize that our study enrolled unselected patients with higher baseline risk, who were excluded from randomised trials, but who may benefit from a similar relative reduction in risk from the intervention.

Objective In 2018, the UK National Institute for Health and Care Excellence (NICE), in partnership with Public Health England, NHS England, NHS Improvement and others, developed an evidence standards framework (ESF) for digital health and care technologies (DHTs). The ESF was designed to provide a standardised approach to guide developers and commissioners on the levels of evidence needed for the clinical and economic evaluation of DHTs by health and care systems. Methods The framework was developed using an agile and iterative methodology that included a literature review of existing initiatives and comparison of these against the requirements set by NHS England; iterative consultation with stakeholders through an expert working group and workshops; and questionnaire-based stakeholder input on a publicly available draft document. Results The evidence standards framework has been well-received and to date the ESF has been viewed online over 55,000 times and downloaded over 19,000 times. Conclusions In April 2021 we published an update to the ESF. Here, we summarise the process through which the ESF was developed, reflect on its global impact to date, and describe NICE’s ongoing work to maintain and improve the framework in the context for a fast moving, innovative field.

Background: Selective dorsal rhizotomy (SDR) is an irreversible surgical procedure involving the division of selected sensory nerve roots, followed by intensive physiotherapy. The aim is to improve function and quality of life in children with cerebral palsy and a Gross Motor Function Classification System (GMFCS) level of II or III (walks with or without assistive devices, respectively). We assessed gross motor function before and after SDR and postoperative quality of life in a study commissioned by NHS England. Methods: We did a prospective observational study in five hospitals in England who were commissioned to perform SDR on children aged 3–9 years with spastic diplegic cerebral palsy. The primary outcome was score changes in the 66-item Gross Motor Function Measure (GMFM-66) and seven domains of the Cerebral Palsy Quality of Life Questionnaire ([CP-QoL] social wellbeing and acceptance, feelings about functioning, participation and physical health, emotional wellbeing and self-esteem, access to services, family health, and pain and impact of disability) from before to 24 months after SDR. Findings: From Sept 4, 2014, to March 21, 2016, 137 children underwent SDR. The mean age was 6·0 years (SD 1·8). The mean GMFM-66 score increased after SDR with an annual change of 3·2 units (95% CI 2·9 to 3·5, n=137). Of the seven CP-QoL domains, five showed significant improvements over time: feelings about functioning mean annual change 3·0 units (95% CI 2·0 to 4·0, n=133), participation and physical health 3·9 units (2·5 to 5·3, n=133), emotional wellbeing and self-esteem 1·3 units (0·2 to 2·3, n=133), family health 2·0 units (0·7 to 3·3, n=132), and pain and impact of disability −2·5 units (−3·9 to −1·2, n=133). 17 adverse events were reported in 15 children, of which none were severe and 15 (88%) resolved. Interpretation: SDR improved function and quality of life in the 24 months after surgery in children with cerebral palsy classified as GMFCS levels II and III. On the basis of these findings, an interim national policy decision was made that SDR would be funded for eligible children in England from 2018. Funding: National Institute for Health and Care Excellence, National Institute for Health Research Biomedical Research Centre, NHS England.

A total of 1080 individual patient samples (158 positive serology samples from confirmed, predominantly mildly symptomatic COVID-19 patients and 922 serology negative including 496 collected pre-COVID) from four states in Australia were analysed on four commercial SARS-CoV-2 serological assays targeting antibodies to different antigens (Roche Elecsys and Abbott Architect: nucleocapsid; Diasorin Liaison and Euroimmun: spike). A subset was compared to immunofluorescent antibody (IFA) and micro-neutralisation. Sensitivity and specificity of the Roche (n = 1033), Abbott (n = 806), Diasorin (n = 1034) and Euroimmun (n = 175) were 93.7 %/99.5 %, 90.2 %/99.4 %, 88.6 %/98.6 % and 91.3 %/98.8 %, respectively. ROC analysis with specificity held at 99 % increased the sensitivity for the Roche and Abbott assays from 93.7% to 98.7% (cut-off 0.21) and 90.2 % to 94.0 % (cut-off 0.91), respectively. Overall seropositivity of samples increased from a maximum of 23 % for samples 0-7 days-post-onset of symptoms (dpos), to 61 % from samples 8-14dpos and 93 % from those >14dpos. IFA and microneutralisation values correlated best with assays targeting antibodies to spike protein with values >80 AU/mL on the Diasorin assay associated with neutralising antibody. Detectable antibody was present in 22/23 (96 %), 20/23 (87 %), 15/23 (65 %) and 9/22 (41 %) patients with samples >180dpos on the Roche, Diasorin, Abbott and microneutralisation assays respectively. Given the low prevalence in this community, two-step algorithms on initial positive results saw an increase in the positive predictive value (PPV) of positive samples (39 %-65 % to ≥98 %) for all combinations. Similarly accuracy increased from a range of 98.5 %-99.4 % to ≥99.8 % assuming a 1 % seroprevalence. Negative predictive value (NPV) was high (≥99.8 %) regardless of which assay was used initially.

Aims To compare the cost-effectiveness of stereotactic ablative body radiation therapy (SABR) with radiofrequency ablation and surgery in adult patients with metastatic liver cancer and hepatocellular carcinoma (HCC). Materials and methods Two patient cohorts were assessed: liver oligometastases and HCC. For each patient cohort, a decision analytic model was constructed to assess the cost-effectiveness of interventions over a 5-year horizon. A Markov process was embedded in the decision model to simulate the possible prognosis of cancer. Data on transition probabilities, survival, side-effects, quality of life and costs were obtained from published sources and the SABR Commissioning through Evaluation (CtE) scheme. The primary outcome was the incremental cost-effectiveness ratio with respect to quality-adjusted life-years. The robustness of the results was examined in a sensitivity analysis. Analyses were conducted from a National Health Service and Personal Social Services perspective. Results In the base case analysis, which assumed that all three interventions were associated with the same cancer progression rates and mortality rates, SABR was the most cost-effective intervention for both patient cohorts. This conclusion was sensitive to the cancer progression rate, mortality rate and cost of interventions. Assuming a willingness-to-pay threshold of £20 000 per quality-adjusted life-year, the probability that SABR is cost-effective was 57% and 50% in liver oligometastases and HCC, respectively. Conclusions Our results indicate a potential for SABR to be cost-effective for patients with liver oligometastases and HCC. This finding supports further investigation in clinical trials directly comparing SABR with surgery and radiofrequency ablation.

Background: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0–59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. Methods: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0–59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50–90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. Findings: 223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69–11·68, p

Objectives Selective dorsal rhizotomy (SDR) has gained interest as an intervention to reduce spasticity and pain, and improve quality of life and mobility in children with cerebral palsy mainly affecting the legs (diplegia). We evaluated the cost-effectiveness of SDR in England. Methods Cost-effectiveness was quantified with respect to Gross Motor Function Measure (GMFM-66) and the pain dimension of the Cerebral Palsy Quality of Life questionnaire for Children (CPQOL-Child). Data on outcomes following SDR over two years were drawn from a national evaluation in England which included 137 children, mean age 6.6 years at surgery. The incremental impact of SDR on GMFM-66 was determined through comparison with data from a historic Canadian cohort not undergoing SDR. Another single centre provided data on hospital care over ten years for 15 children undergoing SDR at a mean age of 7.0 years, and a comparable cohort managed without SDR. The incremental impact of SDR on pain was determined using a before and after comparison using data from the national evaluation. Missing data were imputed using multiple imputation. Incremental costs of SDR were determined as the difference in costs over 5 years for the patients undergoing SDR and those managed without SDR. Uncertainty was quantified using bootstrapping and reported as the cost-effectiveness acceptability curve. Results In the base case, the incremental cost-effectiveness ratios (ICERs) for SDR are £1,382 and £903 with respect to a unit improvement in GMFM-66 and the pain dimension of CPQOL-Child, respectively. Inclusion of data to 10 years indicates SDR is cheaper than management without SDR. Incremental costs and ICERs for SDR rose in sensitivity analysis applying an alternative regression model to cost data. Conclusions Data on outcomes from a large observational study of SDR and long-term cost data on children who did and did not receive SDR indicates SDR is cost-effective.

Background Retinitis pigmentosa is an incurable, degenerative retinal condition causing progressive sight loss, significantly affecting patients’ quality of life. The Argus II Retinal Prosthesis is a surgically implanted medical device that delivers electrical stimulation to the retina. It is intended to produce a form of artificial vision for blind people with severe-to-profound retinitis pigmentosa by stimulating the remaining viable retinal cells to induce visual perception. This study has been initiated by National Health Service England’s Commissioning through Evaluation program and funded through the National Institute of Health Research of the United Kingdom. Objective The aim of this study was to assess the effect of the Argus II device on patient’s daily activities and quality of life. Methods This protocol is a prospective, single-arm, open-label, mixed methods study on 10 consecutive participants receiving the Argus II device. The patient representatives played an integral role in the design of this study. Eligibility criteria include ultra-low vision in both eyes as a result of end-stage retinitis pigmentosa and a willingness and capacity to complete the postimplantation rehabilitation program. Participants will be interviewed by independent researchers at baseline and 12 months later by using a semistructured, in-depth approach, alongside validated questionnaires (Impact of Vision Impairment-Very Low Vision, 5-level EuroQoL-5 dimensions scale, EuroQoL-visual analog scale, and Hospital Anxiety and Depression Scale) and a bespoke device-related questionnaire, which includes questions about users’ experiences with the procedure, the device, and rehabilitation. The effect of the device on patients’ functional vision and activities of daily living will be assessed by vision rehabilitation specialists using a set of tests measured on an ordinal scale (eg, ability to locate objects and avoid obstacles). Clinical outcomes include full-field stimulus light threshold, square localization, direction of motion, grating visual acuity, Landolt-C, procedural success, and adverse events. Qualitative and quantitative outcomes will be linked in a single database to enable individual participant measures to be considered in toto, comparing baseline to the final review. Results This study was approved by the local ethics committee on April 24, 2019 (London-Camberwell St. Giles Research Ethics Committee, reference 19/LO/0429). It has also been approved by the Health Research Authority and Health and Care Research Wales. At the time of protocol writing, Argus II was available for use in the United Kingdom; however, the manufacturer recently withdrew the Argus II device from sale in the United Kingdom. Therefore, the study is not going ahead at this time. Conclusions The mixed methods approach provides a rich and in-depth assessment of the effect of the device on participants’ quality of life. Despite the work not going ahead, the publication of this publicly funded protocol is important for researchers planning similar work. International Registered Report Identifier (IRRID) PRR1-10.2196/17436

BACKGROUND Retinitis pigmentosa is an incurable, degenerative retinal condition causing progressive sight loss, significantly affecting patients’ quality of life. The Argus II Retinal Prosthesis is a surgically implanted medical device that delivers electrical stimulation to the retina. It is intended to produce a form of artificial vision for blind people with severe-to-profound retinitis pigmentosa by stimulating the remaining viable retinal cells to induce visual perception. This study has been initiated by National Health Service England’s Commissioning through Evaluation program and funded through the National Institute of Health Research of the United Kingdom. OBJECTIVE The aim of this study was to assess the effect of the Argus II device on patient’s daily activities and quality of life. METHODS This protocol is a prospective, single-arm, open-label, mixed methods study on 10 consecutive participants receiving the Argus II device. The patient representatives played an integral role in the design of this study. Eligibility criteria include ultra-low vision in both eyes as a result of end-stage retinitis pigmentosa and a willingness and capacity to complete the postimplantation rehabilitation program. Participants will be interviewed by independent researchers at baseline and 12 months later by using a semistructured, in-depth approach, alongside validated questionnaires (Impact of Vision Impairment-Very Low Vision, 5-level EuroQoL-5 dimensions scale, EuroQoL-visual analog scale, and Hospital Anxiety and Depression Scale) and a bespoke device-related questionnaire, which includes questions about users’ experiences with the procedure, the device, and rehabilitation. The effect of the device on patients’ functional vision and activities of daily living will be assessed by vision rehabilitation specialists using a set of tests measured on an ordinal scale (eg, ability to locate objects and avoid obstacles). Clinical outcomes include full-field stimulus light threshold, square localization, direction of motion, grating visual acuity, Landolt-C, procedural success, and adverse events. Qualitative and quantitative outcomes will be linked in a single database to enable individual participant measures to be considered in toto, comparing baseline to the final review. RESULTS This study was approved by the local ethics committee on April 24, 2019 (London-Camberwell St. Giles Research Ethics Committee, reference 19/LO/0429). It has also been approved by the Health Research Authority and Health and Care Research Wales. At the time of protocol writing, Argus II was available for use in the United Kingdom; however, the manufacturer recently withdrew the Argus II device from sale in the United Kingdom. Therefore, the study is not going ahead at this time. CONCLUSIONS The mixed methods approach provides a rich and in-depth assessment of the effect of the device on participants’ quality of life. Despite the work not going ahead, the publication of this publicly funded protocol is important for researchers planning similar work. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/17436

Aims Percutaneous mitral valve leaflet repair is a treatment option for some people with severe mitral valve regurgitation for whom conventional mitral valve surgery is clinically inappropriate. This study aimed to determine the safety, efficacy, and costs of percutaneous mitral valve leaflet repair, using the MitraClip device in a UK setting. Methods and results This was a prospective, single-armed registry with a follow-up of 2 years that reported a range of procedural, clinical and patient-orientated outcomes. Registry data were linked to routine data sources to allow for more comprehensive follow up concerning mortality and healthcare resource use. The registry received data for 199 mainly elective patients with mixed mitral regurgitation aetiology. A MitraClip device was implanted in 187 patients (94%), with a procedural success rate of 86%, with 8% of patients having a serious in-hospital adverse event (including 5% mortality). Percutaneous mitral valve leaflet repair reduced mitral regurgitation from 100% MR grade ≥ 3+ to 7% at discharge. There were corresponding improvements in New York Heart Association functional class, reducing from 92% (class ≥ 3) at baseline to 18% at 6 weeks. There were significant improvements in generic and disease specific quality of life indicators up to 2 years. The all-cause mortality rate was estimated to be 12.7% (95% CI 7.5 to 17.7%) at 1 year. Percutaneous mitral valve leaflet repair was associated with reduced hospital readmissions and potential cost-savings in post-procedural care. Conclusion This study shows that percutaneous mitral valve leaflet repair using MitraClip is a relatively safe and effective treatment in patients unable to tolerate surgery and has the potential to reduce ongoing healthcare costs in the UK.

This chapter seeks to provide a mapping of contemporary consumer behaviour that speaks to a consumer that is generally more informed and more demanding. The complexity of consumption patterns and behaviours are identified with a consideration as to how these insights impact promotional culture. However, the movement away from consumption based on class lines brings specific challenges in terms of finding the audience. Through documenting market research history, examining how such research is conducted, and by whom, the chapter develops a discussion of the way advertising and marketing is being transformed by the collection and use of digital data, the strengths of which lie in the immediacy of data collection, including real-time data. It recognises, however, that big data can only be employed to full advantage when used holistically with traditional methods of data capture that allow for a more contextual analysis and evaluation. The chapter concludes with a thought piece by Black Swan who make it their business to work with new data modelling to provide brands with the competitive advantage they require.

Introduction Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process. Methods An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancer patients treated daily with pazopanib. Results We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 ± 0.0013 % at 40 μg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 μg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to α1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 ± 0.0022 %, 0.992 ± 0.44 % and 7.4 ± 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancer patients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia. Conclusions Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity.

Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.

Background In recent years a number of studies have examined the short-term association between coarse particulate matter (PM10–2.5) and mortality and morbidity outcomes. These studies, however, have produced inconsistent conclusions. Objectives We estimated both the national- and regional-level associations between PM10–2.5 and emergency hospitalizations for both cardiovascular and respiratory disease among Medicare enrollees ≥ 65 years of age during the 12-year period 1999 through 2010. Methods Using air pollution data obtained from the U.S. Environmental Protection Agency air quality monitoring network and daily emergency hospitalizations for 110 large urban U.S. counties assembled from the Medicare Cohort Air Pollution Study (MCAPS), we estimated the association between short-term exposure to PM10–2.5 and hospitalizations using a two-stage Bayesian hierarchical model and Poisson log-linear regression models. Results A 10-μg/m3 increase in PM10–2.5 was associated with a significant increase in same-day cardiovascular hospitalizations [0.69%; 95% posterior interval (PI): 0.45, 0.92]. After adjusting for PM2.5, this association remained significant (0.63%; 95% PI: 0.38, 0.88). A 10-μg/m3 increase in PM10–2.5 was not associated with a significant increase in respiratory-related hospitalizations. Conclusions We found statistically significant evidence that daily variation in PM10–2.5 is associated with emergency hospitalizations for cardiovascular diseases among Medicare enrollees ≥ 65 years of age. This association was robust to adjustment for concentrations of PM2.5. Citation Powell H, Krall JR, Wang Y, Bell ML, Peng RD. 2015. Ambient coarse particulate matter and hospital admissions in the Medicare Cohort Air Pollution Study, 1999–2010. Environ Health Perspect 123:1152–1158; http://dx.doi.org/10.1289/ehp.1408720

Introduction: While immunosuppression for solid organ transplant is associated with an increased risk of lymphoproliferative disease (LPD), this has been more difficult to establish in autoimmune disorders, even though patients are often treated with similar agents. One reason is that autoimmune disease may elevate baseline LPD risk. However, associations have been shown with certain rare types of LPD; most strikingly hepatosplenic lymphoma, now known to occur as a consequence of anti-TNF-alpha therapy in young men with inflammatory bowel disease (IBD) (J Ped Gast Nutr. 2007; 44:265-7). We have noticed a rise in the incidence of another rare lymphoma in autoimmune disease patients: primary central nervous system (PCNS) LPD. Six cases have been diagnosed at our institution since 2010, with none before that dating back to onset of electronic records in 1986. All of these patients were taking mycophenolate mofetil (MMF) and/or thiopurines. A similar rise in reported cases has been seen in the literature (Fig 1) with suggestion of but no direct association with drug treatment shown. We systematically investigated this trend. Methods: We searched our pathology database to identify all LPD cases diagnosed over a 28-year period in patients treated for autoimmune disease as well as all similar cases involving the CNS reported in the literature over the past 40 years. Statistical analyses were performed using the Fisher's exact test. Results: We identified 44 cases of LPD arising in patients treated for autoimmune disease, including 6 with PCNS disease (Table 1). Of LPDs in patients on anti-TNF-alpha agents, 4/5 had a T-cell phenotype, and 3 had IBD. By contrast, in patients who developed LPD while taking methotrexate, the majority for rheumatoid arthritis, only 1/18 had a T-cell phenotype. Instead they were categorized as polymorphous, Hodgkin or large B-cell morphologies, which were frequently EBV-positive (67%), but never involved the brain (0/18). The LPDs arising in patients on MMF and/or thiopurines showed a similar morphologic profile but were more likely to involve the CNS. In particular, MMF was significantly associated with PCNS compared to non-CNS disease (p We reviewed all cases of CNS LPD in patients treated for autoimmune disease reported in the literature (34 reports, 40 patients), including 32 with PCNS LPD and 8 with secondary CNS involvement. The vast majority of PCNS cases arose in patients taking MMF and/or thiopurines (29/32), but only MMF was significantly associated with primary compared to secondary CNS involvement (p Conclusions: While the overall risk of LPD in the context of autoimmune disease treatment has been controversial, the interaction between drug type and individual patient characteristics may dramatically increase risk for certain lymphomas. We now demonstrate a significant association between use of MMF and PCNS LPD, which appears to cluster in patients with a history of SLE, MG or IBD. Of interest, all 3 autoimmune patients in the JHH database who developed PCNS LPD following solid organ transplant (not shown) also had SLE. While methotrexate never produced a PCNS LPD in our series, it has been infrequently found in the literature. There is no evidence of an increased baseline risk of PCNS LPD in autoimmune patients; indeed, only one reported case in an untreated patient could be identified in the literature (J Rheum 1978; 5:75-78). In addition, EBV-associated PCNS lymphoma is virtually always seen in the context of immunosuppression. Further investigation into the increased risk of specific types of LPD with immunosuppressive treatment is warranted with significant implications for tailoring treatment options. Table 1. Demographics of JHH and Reported CNS Cases ('*' p Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding.