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BackgroundImaging is recommended for selected children following urinary tract infections (UTIs) to look for actionable structural abnormalities. Non-E. coliis considered high risk in many national guidelines, but evidence is mainly drawn from small cohorts from tertiary centres.ObjectiveTo ascertain imaging yield from infants and children 100 000 cfu per ml) in primary care or an emergency department without admission stratified by bacteria type.Design, setting, patientsData were collected from an administrative database of a UK citywide direct access UTI service between 2000 and 2021. Imaging policy mandated renal tract ultrasound and Technetium-99m dimercaptosuccinic acid scans in all children, plus micturating cystourethrogram in infants Results7730 children (79% girls, 16% aged E. coliUTI yielded abnormal kidney imaging in 8.9% (566/6384).Enterococcusand KPP (Klebsiella,Proteus,Pseudomonas) yielded 5.6% (42/749) and 5.0% (24/483) with relative risks 0.63 (95% CI 0.47 to 0.86) and 0.56 (0.38 to 0.83)), respectively. No difference was found when stratified by age banding or imaging modality.ConclusionIn this largest published group of infants and children diagnosed in primary and emergency care not requiring admission, non-E. coliUTI was not associated with a higher yield from renal tract imaging.

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection.A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement.Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8–16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52–99%) for TCRαβ-HaploSCT, 80% (41–98%) for MFD, 87% (36–98%) for MUD, and 89% (43–98%) for CB (p = 0.89). Cumulative incidence of grade II–IV acute graft-versus-host disease was 11% (2–79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7–100%) after MUD, and 11% (2–79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0–100%) versus unconditioned transplant (median 3%, 0–9%) (p n = 29/36, 81% vs n = 4/9, 54%) (p

Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36–330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.

ObjectiveTo understand community seroprevalence of SARS-CoV-2 in children and adolescents. This is vital to understanding the susceptibility of this cohort to COVID-19 and to inform public health policy for disease control such as immunisation.DesignWe conducted a community-based cross-sectional seroprevalence study in participants aged 0–18 years old recruiting from seven regions in England between October 2019 and June 2021 and collecting extensive demographic and symptom data. Serum samples were tested for antibodies against SARS-CoV-2 spike and nucleocapsid proteins using Roche assays processed at UK Health Security Agency laboratories. Prevalence estimates were calculated for six time periods and were standardised by age group, ethnicity and National Health Service region.ResultsPost-first wave (June–August 2020), the (anti-spike IgG) adjusted seroprevalence was 5.2%, varying from 0.9% (participants 10–14 years old) to 9.5% (participants 5–9 years old). By April–June 2021, this had increased to 19.9%, varying from 13.9% (participants 0–4 years old) to 32.7% (participants 15–18 years old). Minority ethnic groups had higher risk of SARS-CoV-2 seropositivity than white participants (OR 1.4, 95% CI 1.0 to 2.0), after adjusting for sex, age, region, time period, deprivation and urban/rural geography. In children ConclusionsApproximately one-third of participants aged 15–18 years old had evidence of antibodies against SARS-CoV-2 prior to the introduction of widespread vaccination. These data demonstrate that ethnic background is independently associated with risk of SARS-CoV-2 infection in children.Trial registration numberNCT04061382.

Background Cases of human monkeypox are rarely seen outside of west and central Africa. There are few data regarding viral kinetics or the duration of viral shedding and no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for treatment of smallpox and have demonstrated efficacy against monkeypox in animals. Our aim was to describe the longitudinal clinical course of monkeypox in a high-income setting, coupled with viral dynamics, and any adverse events related to novel antiviral therapies. Methods In this retrospective observational study, we report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox who were diagnosed in the UK between 2018 and 2021, identified through retrospective case-note review. This study included all patients who were managed in dedicated high consequence infectious diseases (HCID) centres in Liverpool, London, and Newcastle, coordinated via a national HCID network. Findings We reviewed all cases since the inception of the HCID (airborne) network between Aug 15, 2018, and Sept 10, 2021, identifying seven patients. Of the seven patients, four were men and three were women. Three acquired monkeypox in the UK: one patient was a health-care worker who acquired the virus nosocomially, and one patient who acquired the virus abroad transmitted it to an adult and child within their household cluster. Notable disease features included viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and one patient had a monkeypox virus PCR-positive deep tissue abscess. Five patients spent more than 3 weeks (range 22–39 days) in isolation due to prolonged PCR positivity. Three patients were treated with brincidofovir (200 mg once a week orally), all of whom developed elevated liver enzymes resulting in cessation of therapy. One patient was treated with tecovirimat (600 mg twice daily for 2 weeks orally), experienced no adverse effects, and had a shorter duration of viral shedding and illness (10 days hospitalisation) compared with the other six patients. One patient experienced a mild relapse 6 weeks after hospital discharge. Interpretation Human monkeypox poses unique challenges, even to well resourced health-care systems with HCID networks. Prolonged upper respiratory tract viral DNA shedding after skin lesion resolution challenged current infection prevention and control guidance. There is an urgent need for prospective studies of antivirals for this disease.

Non-tuberculous mycobacteria (sometimes known as atypical mycobacteria) are environmental mycobacteria found throughout the world in soil, dust, water, foodstuffs and other animals. They are defined simply in contrast to those mycobacteria which cause tuberculosis or leprosy, but a small number of species are considered to be human pathogens in their own right and the incidence of human infections has increased in recent decades. Characterised by their relative resistance to many classes of antibiotics, sometimes including those used to treat tuberculosis, non-tuberculous mycobacteria can cause a wide range of diseases in children, including lymphadenitis, skin and soft tissue infections, respiratory infections and disseminated infections. Diagnosis relies on a high index of clinical suspicion, collection of appropriate samples for culture on specialised media, and is now augmented by evolving molecular techniques. Treatment often involves surgical debridement and complex multi-drug regimens taken over many months, particularly in those children with underlying respiratory or immunological illnesses. Controlled clinical trials to identify optimal combinations of anti-mycobacterial drugs for use by such patients are desperately needed to treat these emerging infections.

Background Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. Objectives This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. Methods We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. Results Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. Conclusions The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Knowledge regarding the prevalence, clinical features and etiology of pediatric influenza-like illness (ILI) remains limited in African settings. Furthermore, it is likely that many children presenting with ILI receive antibiotics unnecessarily. More data are required to develop antimicrobial stewardship practice and guide effective vaccine strategies. We undertook a 1-year prospective study of ILI in the Gambia.Children5 years of age presenting with ILI from March 2018 to March 2019 were recruited. Clinical and antibiotic prescribing data were collected. Nasopharyngeal swabs were collected and analyzed for 12 respiratory viruses using a multiplex polymerase chain reaction.From a total of 735 ILI episodes, 530 (72.1%) nasopharyngeal swabs were positive for ≥1 virus. Of these, 36.7% were positive for rhinovirus, 14.7% for respiratory syncytial virus, 8.4% for influenza and 7.2% for human metapneumovirus. Compared with children6 months of age, influenza was more common in 6- to 23-month-old children [odd ratio (OR): 5.68; 95% confidence interval (CI): 1.72-18.76; P = 0.004]. Respiratory syncytial virus and human metapneumovirus were associated with low peripheral oxygen saturations (OR: 2.13; 95% CI: 1.23-3.69; P = 0.007; and OR: 2.44; 95% CI: 1.13-5.27; P = 0.023, respectively). Antibiotics were prescribed in 78.3% of all ILI cases.A broad range of viruses are responsible for pediatric ILI in the Gambia. Refined treatment guidelines, improved diagnostic capacity and vaccines to prevent respiratory viruses will all play a role in reducing antimicrobial use for these cases.

Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC—busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC—treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8–99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8–25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7–100.0%) and 79% (55–91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαβ-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

Background Antibiotic resistance is a major problem in every region of the globe and Sub-Saharan Africa (SSA) is no exception. Several systematic reviews have addressed the prevalence of resistant organisms but few have examined the underlying causes in this region. This systematic review of qualitative literature aims to highlight barriers and facilitators to antimicrobial stewardship in SSA. Methods A literature search of Embase and MEDLINE(R) was carried out. Studies were included if they were in English, conducted in SSA, and reported qualitative data on the barriers and facilitators of antimicrobial stewardship or on attitudes towards resistance promoting behaviours. Studies were screened with a simple critical appraisal tool. Secondary constructs were extracted and coded into concepts, which were then reviewed and grouped into themes in light of the complete dataset. Results The literature search yielded 169 results, of which 14 studies from 11 countries were included in the final analysis. No studies were excluded as a result of the critical appraisal. Eight concepts emerged from initial coding, which were consolidated into five major themes: ineffective regulation, health system factors, clinical governance, patient factors and lack of resources. The ineffective regulation theme highlighted the balance between tightening drugstore regulation, reducing over-the-counter sale of antibiotics, and maintaining access to medicines for rural communities. Meanwhile, health system factors explored the tension between antimicrobial stewardship and the need of pharmacy workers to maintain profitable businesses. Additionally, a lack of resources, actions by patients and the day-to-day challenges of providing healthcare were shown to directly impede antimicrobial stewardship and exacerbate other factors which promote resistance. Conclusion Antibiotic resistance in SSA is a multi-faceted issue and while limited resources contribute to the problem they should be viewed in the context of other factors. We identify several contextual factors that affect resistance and stewardship that should be considered by policy makers when planning interventions. This literature base is also incomplete, with only 11 nations accounted for and many studies being confined to regions within countries, so more research is needed. Specifically, further studies on implementing stewardship interventions, successful or not, would be beneficial to inform future efforts.

Chronic lung disease (CLD) is common in individuals living with perinatally acquired HIV (PA-HIV) in southern/eastern Africa. Most of the UK PA-HIV population are African. We conducted a case-note review of CLD in 3 UK PA-HIV cohorts (n = 98). Bronchiectasis or obliterative bronchiolitis occurred in 8.1% of patients and ring/tramline opacities occurred in 19.2% of patients on chest radiograph. There may be unrecognized and underdiagnosed CLD among PA-HIV in the UK.

Objective To explore parent’s experiences and views relating to their use of children’s emergency healthcare services during the Covid-19 pandemic. Design Qualitative telephone interview study using in-depth interviews, based on the principles of grounded theory. Recorded, transcribed verbatim, managed in NVivo version 12, analysed by thematic analysis. Setting North East England, United Kingdom. Participants Parents of children aged 0-8 years. Findings Three major themes emerged from the interview data: Risk to children and families, Sources of Information, and Making Healthcare-seeking Decisions. These themes encompassed a range of intellectual and emotional responses in the way that parents interpreted information related to Covid-19, and their sense of responsibility towards family and wider society. Conclusions Together these themes aid understanding of the changes in paediatric emergency department attendances reported in the early months of the Covid-19 pandemic in the UK. The analysis suggests that public health messaging directed at those seeking urgent care for children may be inadequate and lead to adverse consequences, the impacts of which require further study and refinement. What is known about the subject Following lockdown, there was a substantial reduction in the number of children taken to unscheduled medical care across the country Delays in presentation can impact on children’s health It is not known what parents’ views are on accessing emergency health services in a pandemic situation What this study adds Parents had to weigh up a number of information sources before deciding on whether to take their child to hospital Public health messaging directed at those seeking urgent care for children may lead to a reduction in use of emergency healthcare services Future lockdowns should implement focussed strategies, optimising use of emergency healthcare services, whilst avoiding harm.

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.

Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell–replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell–depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αβ (TCRαβ)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαβ/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged 5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαβ/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.

Maccari et al. identify a physiological population of highly proliferative CD38+CD45RA+, IL-10–producing TCRαβ+ T cells. They can be CD4+, CD8+, or double-negative and are controlled by FAS and CTLA4, while their survival is enhanced by mTOR and STAT3 signals., The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET− expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease., Graphical Abstract

Predictors of Paediatric Influenza-like-Illness Severity During the COVID-19 Pandemic*George James Porter1 and Stephen Owens2,3Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, United Kingdom.Department of Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.Population Health Sciences Institute, Newcastle University, Framlington Place, Newcastle Upon Tyne, United Kingdom.*Indicates the corresponding author, correspondence to: g.porter2@newcastle.ac.ukWord Count: 807Respiratory viral illness is a common cause of paediatric admission in the UK. It is estimated that In an average winter in the UK, 2.4% of children under five will have a respiratory illness attributable to Influenza A alone.(1) Despite the importance of viral respiratory infection, the predictive value of symptoms, co-morbidities and viral isolation are debated.(2) For example, in an American study of 241 children presenting to hospital with influenza-like-illness (ILI) the risk of severe complications was only increased by neurological/neuromuscular disease.(3) Meanwhile, a similar British study analysing 265 paediatric H1N1-positive ILI patients each with 2 virus-negative ILI controls found that chronic lung disease, cerebral palsy, chest retractions, tachycardia, dehydration and oxygen requirement predicted adverse outcome across the two groups.(4)The ongoing COVID-19 pandemic has shown that surges of acute respiratory infections must be planned for by the health service. Therefore, clearer definition of the early indicators of high-risk patients could be of considerable benefit regarding resource allocation and risk stratification. Equally, few studies have taken into account demographic data (including age and ethnicity), co-morbidities and symptoms and signs at presentation simultaneously.(5) We therefore conducted a retrospective study to help identify the predictors of severity of ILI in the North East of England during the height of the coronavirus pandemic.We defined ILI as the presence of fever ≥37.8oC and one other upper respiratory symptom. A cohort of children hospitalised with ILI in Newcastle-Upon-Tyne hospitals between 01/03/2020 and 05/05/2020 was identified from trust records. Information on symptoms at presentation, past medical history, demographics and outcomes was extracted. Disease severity was approximated by admission length, oxygen usage and intensive care unit (ITU) admission. Regression modelling identified variables which impacted these outcomes.

Children’s attendances in paediatric emergency departments have fallen precipitously in North East England and elsewhere in recent months. We analysed data from 3 hospitals to understand which children were not being brought during the COVID-19 ‘lockdown’. In our population there is no evidence of a disproportionate impact on children belonging to vulnerable sociodemographic groups and no obvious change in illness acuity among those children still attending. However we noted a marked reduction in infectious disease presentations which might reflect one positive impact of enhanced social distancing on child health. More granular data describing the ‘collateral damage’ of the COVID-19 pandemic to children’s clinical services are needed to plan for the mitigation of its continuing effects.What is known on this topicPresentations to paediatric emergency departments in Europe and the United States have reduced dramatically during the COVID-19 pandemic ‘lockdown’.What this paper adds boxThis is the first paper to show that reduced attendance was proportionate across different deprivation and ethnicity groups.We show that presentations of children with infectious diseases reduced more than those with other conditions or trauma.There was no change in admission rates, taken as a broad indicator of illness acuity at presentation among the population still attending paediatric emergency departments.

This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation–based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD.

Purpose To assess the impact of childhood epilepsy on social transitioning outcomes for young people with epilepsy (YPWE) living in Tanzania, and to explore influences on these outcomes. Methods At six years from baseline, we followed up 84 YPWE and 79 age- sex- and village- matched controls recruited into a case-control study of childhood epilepsy in rural northern Tanzania. Data were collected from interviews with young people and their carers using a structured questionnaire. Perceived stigma was evaluated using the Kilifi Stigma Score and functional disability using the Barthel Index (BI). The effects of age, gender, functional disability and stigma on selected markers of social transitioning (education, employment and relationships) were estimated using multivariable modelling. Results Fewer YPWE than controls were in an intimate relationship (42.3% vs. 76.9%) or in education or paid employment (33.3% vs. 91.1%) and they reported elevated perceived stigma scores (27.4% vs. 3.8%). Among YPWE, a positive education or employment outcome was predicted by a lower seizure frequency (adjusted OR 3.79) and a higher BI score (adj. OR 12.12); a positive relationship outcome was predicted by a higher BI score (adj. OR 45.86) and being male (adj. OR 8.55). Conclusion YPWE were more likely to experience adverse employment, educational and relationship outcomes in the transition to adult life than controls, with the greatest disadvantage experienced by females, those with greater functional disability and those with poorer seizure control. Markers of social transitioning should be included in any prospective evaluation of interventions designed to support these groups.

AimsTo evaluate the provision of recommended medical equipment on forensic psychiatric inpatient wards in Mersey Care's secure division, as outlined by the Care Quality Commission (CQC) in their 2019 guidance “Brief Guide: Physical Healthcare In Mental Health Settings”. It has been documented that people with severe and enduring mental illness are at risk of dying on average 15 to 20 years earlier than people without, two thirds of which are due to avoidable physical illnesses. It was our aim to use these data to improve the provision of physical healthcare equipment on the wards of Mersey Care's secure division, in turn allowing for the safe assessment of patients in the acute setting, and the monitoring their chronic health conditions.MethodWe conducted a closed loop, two cycle audit of all forensic inpatient wards in Mersey Care's secure division measuring the provision of physical health equipment against the CQC's 2019 guidance. The intervention was to present our findings and implement physical health equipment boxes in the clinic rooms on the wards. Low, medium, high, and secure learning disability (LD) wards were audited, with a control sample of non-secure wards (addiction, old age, general adult, and LD non-secure) in the initial cycle for comparison.ResultOn initial audit, the mean availability of equipment across the secure division was 66% (range 50.9%-88.9%), and 75% across our sample of wards in the non-secure divisions (range 61.1%-88.9%). Following the intervention in the secure units, the mean availability increased to 73.5% (range 72.2%-77.8%). The mean percentage increase in equipment availability following intervention was 12.5% (range -12.5% to 41.8%).ConclusionFollowing the intervention, the re-audit conducted found an overall improvement with 73.5% of recommended equipment available. Despite this improvement in equipment availability in the secure unit wards, the equipment is still less available than on the non-secure control wards. Due to this, further intervention and another re-audit have been planned. In the second cycle, significant items such as disposable gloves, pulse oximeters, sphygmomanometers, thermometers and stethoscopes were available across all wards. This was an improvement from the initial audit and allows for the safe assessment of patients in the acute setting.

Objective Educational outcomes for young people with epilepsy (YPE) in Hai District, Tanzania, are poor, as is commonly observed elsewhere in Sub-Saharan Africa. The reasons for this finding are not well understood, though stigma arising from supernatural concepts of epilepsy is frequently cited as a barrier to YPE accessing education. In this study, we aimed to explore the reasons why many YPE in Tanzania experience poor access to education, and elicit ways in which education could be improved for YPE according to teachers, parents and YPE. Methods Ten focus group discussions with teachers were organized in Hai schools between March and May 2016. The themes arising from these discussions were identified, coded, analyzed and tested in semi-structured interviews with 19 YPE and 17 parents identified from a prevalent cohort of YPE identified in 2009. Results Behavioral problems and learning difficulties were cited as the main barriers to education for YPE. Other barriers included parental stigmatization, teachers' inadequate seizure management, and limited access to specialist schools. Teachers perceived that parents and YPE believe in spiritual etiology and traditional management for epilepsy. However, the majority of teachers, parents, and YPE cited biological etiology and management options, although understanding of epilepsy etiology and management could be improved amongst all groups. Significance A multidimensional approach is needed to improve educational access, and hence outcomes, for YPE. Widespread community education is needed to improve knowledge of epilepsy etiology and management. Teachers require seizure management training, and parents need help to recognize YPE's right to education. Educational needs assessments would help to identify YPE requiring specialist schooling, and access to this could be improved. These interventions will likely reduce stigma, ensure appropriate academic and pastoral care at school, and thus enable YPE to attend, and succeed, in education.

Background Our centre performed the first ex-vivo T-lymphocyte depleted (TCD) haploidentical allograft in 1987 in a child with PID. Different TCD methods have been used including CAMPATH-1M TCD marrow (n=34), CD34+ selected marrow (CD34-S, n=34), CD3/CD19 TCD PBSC (n=7), and CD3-TCRαβ/CD19 TCD PBSC (αβ-TCD, n=30)). This study aimed to examine transplant outcomes according to different methods in children with PID. Methods Between Jan 1987 and Mar 2019, 105 PID patients underwent first TCD allograft and were included in the study. Thirteen patients who received gene-modified add-back T cells were excluded. The main outcomes of interest were OS, EFS and graft failure. An event was defined as death, graft failure or second procedures for slipping chimerism. Other endpoints were neutrophil engraftment, GvHD, immune reconstitution and donor chimerism. Log-rank test was used to compare OS and EFS according to TCD methods. Cumulative incidences (CI) graft failure was calculated using a competing risk analysis, considering death as a competing event. Multilevel mixed effects modelling was performed for the longitudinal analysis of immune reconstitution and CAMPATH-1M was used as a reference group. Results Donors were haploidentical donor (n=84, 83%), MUD/MFD (n=9, 9%) and MMFD/MMUD (n=8, 8%). 94% received conditioning. Thirteen (12%) patients had aGvHD, of whom 3 had grade III-IV. None had cGvHD. The cause of death changed from predominantly infection (18/25, 72%) in CAMPATH-IM and CD34-S to non-infectious causes in all 6 deaths in CD3/CD19 and αβ-TCD. Analysis by TCD methods revealed a 5-year OS of 58% (95% CI, 40-73%) for CAMPATH-1M, 68% (49-81%) for CD34-S, 69% (22-91%) for CD3/CD19 TCD and 83% (61-93%) for (αβ-TCD (p=0.24). Age was a significant predictor of OS for non-SCID PID (p=0.02). The corresponding EFS was 46% (29-62%) for CAMPATH-1M, 47% (30-62%) for CD34-S, 69% (95% CI, 22-91%) for CD3/CD19 TCD and 83% (61-93%) for αβ-TCD (p=0.04) (Fig 1B) The CI of graft failure reduced significantly, from 29% (14-61%) for CAMPATH-1M, to 19% (95%CI, 8-45%) for CD34-S, 17% (2-18%) for CD3/CD19 TCD and none had graft failure in αβ-TCD (p=0.002) (Figure 1C). CD4+ lymphocytes were significantly higher in CD34-S at months 4 (p=0.02), 5 (p=0.01), and 6 (p=0.006) post-HCT and at month 4 (p=0.04) post-HCT in αβ-TCD when compared to CAMPATH-1M (Fig 1D). The median donor myeloid chimerism at last follow-up was higher in newer TCD; 100% (range, 0-100%) for αβ-TCD, 93% (0-100%) for CD3/CD 19 depletion, 6% (0 -49%) for CD34-S, 20% (0-100%) for CAMPATH-1M (p Conclusions Outcomes after CD3+TCR αβ/CD19+ depletion are superior to previously used TCD methods. In an experienced centre it is a safe alternative procedure and enables a wide spectrum of PID to be transplanted. The result has led to evolution of donor hierarchy in our centre.

Recent advances in conceptualizing structures of influence in education policymaking have emphasized the role of nongovernmental actors working in networks to promote their agendas. These useful in...

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Background Angiomatoid Fibrous Histiocytoma mimicking Systemic JIA via mutation-driven IL-6 production: Angiomatoid Fibrous Histiocytoma (AFH) is a rare tumour associated with mutation-driven production of Interleukin-6 (IL-6) which causes a systemic inflammatory picture similar to Systemic Juvenile Idiopathic Arthritis (sJIA). Objectives A previously well 6-year old girl was referred with 6 weeks of abdominal pain, nausea, weight loss, night sweats, & lethargy. Examination was unremarkable apart from a 2cm lump in the right popliteal fossa. This had been reported on USS 2 months earlier, at an external hospital, to be a Sebaceous cyst. There was no rash, organomegaly, lymphadenopathy, or synovitis. She had persistent recurrent fevers of >39C, but not in the classical quotidian pattern of sJIA. Methods Bloods showed persistent Hb 600, ESR >100, & CRP >200. Autoantibody & full infection screens were negative. Urine HMMA:creatinine ratio was minimally raised at 7.2 (normal 1.8 - 5) Faecal calprotectin, upper & lower GI endoscopy were normal. Bone-Marrow Aspiration was reported as being highly reactive but with no malignancy seen. Whole-body STIR MRI was reported as normal, but repeat localised USS &MRI of the knee showed a 27x18x21mm well circumscribed, mixed cystic/solid lesion with marked vascularity. The lesion was then biopsied, and subsequently excised Plasma IL-6 levels were significantly elevated at 46.7pg/ml (normal range: 0-2), but normalised after excision. TNF and IL1b levels were normal Results Initial biopsy and FISH analysis confirmed the diagnosis of AFH with an abnormal EWSR1 signal pattern and classical EWSR1-CREB1 fusion. She went on to have a full excision, and staging investigations were negative. AFH is rare ( In >90% of cases AFH is associated with a characteristic translocation: t(2:22) (q33:q12). This forms the fusion gene EWSR1-CREB1 which in turn leads to continuous activation of CREB1. The promoter region of IL-6 has a CREB1 binding site thus causing IL-6 over-production and leading to the paraneoplastic syndrome. Conclusion Paraneoplastic immune dysregulation is a rare, but important cause of symptoms often otherwise associated with rheumatic diseases. Careful physical examination, and liaison with oncology teams, is needed, particularly before treatment with steroids or IL-6 inhibitors such as Tocilizumab are considered Disclosure of Interests: Mark Friswell: None declared, Stephen Owens Consultant for: paid a consultancy fee by Chimerix to act as an advisor on a study of adenovirus in transplant patients, Gail Halliday: None declared

Infection with SARS-CoV-2 does not, thankfully, appear to be harming children in great numbers at this point of the COVID-19 pandemic.1 Concerns have however been raised that necessary social distancing and particularly ‘lockdown’ measures are having negative, often unintended, consequences for the health and well-being of babies, children and young people. These consequences have been termed ‘collateral damage’,2 and it has been argued that measures to control the COVID-19 pandemic are likely to cause a ‘secondary pandemic’ of child neglect and abuse.3 The Children’s Commissioner for England has raised concerns within government that children are at increased risk of abuse and neglect during the pandemic, while household stress is high, families are confined to the home and usual societal …

Introduction Studies focusing on post-HCT AIC in large cohorts of patients transplanted for primary immunodeficiency (PID) are lacking. Objectives We conducted a retrospective analysis of incidence, risk factors, outcome of post-HCT AIC in children with PID and B-cell function following rituximab treatment. Methods Between January 1987-December 2018, 502 PID patients who underwent first HCT for PID at our center were included. Cumulative incidence (CI) of post-HCT AIC was calculated using a competing risk analysis, considering death as a competing event. Fine-and-Gray test was used to identify risk factors of AIC. The selected variables: gender, age at HCT, indication for HCT (SCID versus non-SCID PID), pre-HCT AIC, donor type, donor-recipient ABO matching, stem cell source, ex-vivo T-cell depletion (TCD), stem cell doses, conditioning regimen, serotherapy, GvHD prophylaxis, acute GvHD, chronic GvHD and viraemia. B-lymphocyte immune reconstitution kinetics was compared between surviving patients with post-HCT AIC without rituximab (n=18), post-HCT treated with rituximab (n=12) and controls (n=24). Results 36 (CI, 9%) developed post-HCT AIC, with median onset at 6.5 months (2.5 months - 18.2 years). On univariate analysis, pre-HCT AIC (Fig. A), mismatched donor, alemtuzumab (Fig. B), ATG, acute GvHD (Fig. C) and chronic GvHD were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (p=0.02) was independently associated with post-HCT AIC. Corticosteroid and high-dose IVIg (2gm/kg) achieved remission in 50% (n=18), additional rituximab led to remission in 25% (n=9), and the remaining 25% were treated with various modalities including sirolimus (n=5), bortezomib (n=3), mycophenolate mofetil (n=2), splenectomy (n=2), and second HCT (n=3). The mortality of post-HCT AIC reduced from 25% (4/16) prior to 2011 to 5% (1/20) after 2011. The median follow-up of 5.8 years (0.4-29.1) showed that 26 of 30 survivors (87%) were in complete remission, 4 (13%) were in remission with sirolimus and low dose steroid. Of 12 survivors who were treated with rituximab, immunoglobulin substitution was discontinued in 7 (52%), and 5 (48%) required on-going IVIg replacement. The median interval between HCT and rituximab was 1.95 years (0.96-19.9) in patients who were IVIg dependent and 0.73 (0.30-2.3) in patients who were IVIg-free on last follow-up (p=0.17). B-lymphocyte immune reconstitution kinetics was significant slowly in patients with post-AIC with/without rituximab (Fig. D). Conclusions 5-year CI of post-HCT AIC in children with PID was 9% and there is risk of very late onset post-HCT AIC in patients with Artemis and RAG1 mutations, and activated PI3 delta syndrome. Alemtuzumab pk study might play a role in reducing the incidence of post-HCT AIC. Sirolimus is an effective steroid-sparing immunomodulator in refractory/frequently relapsing post-HCT AIC.

ObjectiveTo raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation.MethodsCase report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature.ResultsWe present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function.ConclusionsOur case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.

Malaria, as a key disease of poverty, was singled out for special attention in the Millennium Project of 2000. Recent data suggest that malaria incidence and mortality are now declining all over the world. While these figures are cause for celebration, they must be interpreted carefully and with caution, particularly in relation to Africa. There are daunting challenges ahead for those working to achieve malaria eradication, not least of which is the poor quality of the data on which the work is based. In the absence of an affordable and fully effective vaccine, international funding for malaria control needs to be escalated still further. The money is essential to pay for universal access to a set of simple and proven interventions which would save the lives of millions of children over the next 15 years.

The largest and most complex Ebola epidemic in history is believed to have started with the infection of a 2-year-old boy in South-eastern Guinea in late 2013. Within a year, thousands of children and their families had contracted the virus, many had died and many more were orphaned. We reflect on our experiences of volunteering at the Kerry Town Ebola Treatment Centre in Sierra Leone between January and February 2015, where we were deployed to care for just a few of these children as part of the Save The Children team.

Journal of Infection - In Press.Proof corrected by the author Available online since vendredi 9 septembre 2016

Periconceptional supplementation could extend the period over which maternal and fetal nutrition is improved,\ud but there are many challenges facing early-life intervention studies. Periconceptional trials differ from pregnancy\ud supplementation trials, not only because of the very early or pre-gestational timing of nutrient exposure but also\ud because they generate subsidiary information on participants who remain non-pregnant. The methodological\ud challenges are more complex although, if well designed, they provide opportunities to evaluate concurrent\ud hypotheses related to the health of non-pregnant women, especially nulliparous adolescents. This review examines\ud the framework of published and ongoing randomised trial designs. Four cohorts typically arise from the\ud periconceptional trial design — two of which are non-pregnant and two are pregnant — and this structure\ud provides assessment options related to pre-pregnant, maternal, pregnancy and fetal outcomes. Conceptually the\ud initial decision for single or micronutrient intervention is central — as is the choice of dosage and content — in\ud order to establish a comparative framework across trials, improve standardisation, and facilitate interpretation of\ud mechanistic hypotheses. Other trial features considered in the review include: measurement options for baseline\ud and outcome assessments; adherence to long-term supplementation; sample size considerations in relation to\ud duration of nutrient supplementation; cohort size for non-pregnant and pregnant cohorts as the latter is influenced\ud by parity selection; integrating qualitative studies and data management issues. Emphasis is given to low resource\ud settings where high infection rates and the possibility of nutrient-infection interactions may require appropriate\ud safety monitoring. The focus is on pragmatic issues that may help investigators planning a periconceptional trial.

Background: Maternal micronutrient deficiencies are commonly associated with clinical indicators of placental dysfunction.Objective: We tested the hypothesis that periconceptional multiple-micronutrient supplementation (MMS) affects placental function.Design: We conducted a double-blind, randomized, placebo-controlled trial of MMS in 17- to 45-y-old Gambian women who were menstruating regularly and within the previous 3 mo. Eligible subjects were pre–randomly assigned to supplementation with the UNICEF/WHO/United Nations University multiple micronutrient preparation (UNIMMAP) or placebo on recruitment and until they reached their first antenatal check-up or for 1 y if they failed to conceive. Primary outcome measures were midgestational indexes of utero-placental vascular-endothelial function [ratio of plasminogen-activator inhibitor (PAI) 1 to PAI-2 and mean uterine-artery resistance index (UtARI)] and placental active transport capacity at delivery [fetal to maternal measles antibody (MMA) ratio].Results: We recruited 1156 women who yielded 415 pregnancies, of which 376 met all of the inclusion criteria. With adjustment for gestational age at sampling, there were no differences in PAI-1 to PAI-2 or MMA ratios between trial arms, but there was a 0.02-unit reduction in UtARI between 18 and 32 wk of gestation (95% CI: −0.03, −0.00; P = 0.040) in women taking UNIMMAP.Conclusions: Placental vascular function was modifiable by periconceptional micronutrient supplementation. However, the effect was small and supplementation did not further affect other variables of placental function. This trial was registered at www.controlled-trials.com as ISRCTN 13687662.

Background/Objectives: The use of multimicronutrient (MMN) supplementation to reduce the burden of anaemia in nonpregnant women of reproductive age has been little studied, particularly in Africa. The objective of the study was to evaluate haematological outcomes in non-pregnant, rural Gambian women of reproductive age, receiving daily MMN supplements for 1 year. Subjects/Methods: The study in 293 women aged from 17 to 45 years old was nested within a double-blind, randomized placebo-controlled trial of periconceptional MMN supplementation [ISRCTN 13687662], using the United Nations International Multiple Micronutrient Preparation (UNIMMAP), received daily for 1 year or until conception. Red cell parameters and free erythrocyte protoporphyrin concentration were measured at baseline and after 12 months in those women who did not conceive. Results: Anaemic women (haemoglobin concentration

Objectives Control of infectious diseases in developing countries often requires using drugs that are contraindicated during pregnancy. Avoiding inadvertent exposure to drugs involves women (a) recognising pregnancy early, (b) disclosing the pregnancy to health workers and (c) using medicines in an informed manner. We explored these factors to inform and improve the process by which health workers provide care and treatment to pregnant women. Design Qualitative study. Setting The Gambia. Population Rural women and men. Methods We conducted 41 interviews and 16 focus group discussions with women, adolescents, men and traditional birth attendants (TBAs). Main outcome measure Pregnancy disclosure. Results Most women recognised early signs and symptoms of pregnancy and believed other people could easily do so. To avoid gossip, women hid their pregnancies and delayed antenatal care, even though husbands and TBAs insisted on attendance. Women acutely ill in early pregnancy hoped health workers would recognise pregnancy without explicit disclosure. Women said that they knew, and sought to avoid, some contraindicated drugs, but their knowledge was rudimentary. Health workers stressed the benefits, not the risks of prescribed drugs. Conclusions Despite public health and clinical benefits of preventing and treating pregnancy infections, women were ill informed and pressurised into taking drugs. These ethical issues should be more widely addressed.

In Africa, approximately 25 million pregnant women are at risk of Plasmodium falciparum infection each year, one in four has evidence of placental involvement and up to half of these may be associated with low birth weight outcomes. In infected pregnant women, the placenta is an ideal site for the accumulation of the parasites, and this reduces in extent in subsequent pregnancies. Recent data indicate that terminal alpha 2,3 sialic acid-dependent routes are central to the efficient invasion of erythrocytes with P. falciparum, however, the role in placental malaria of sialylated, or other glycoconjugates, on syncytiotrophoblast has not previously been assessed. Placental biopsies from Zambian women showed the Neu5Ac(g.2,6)Gal/GalNAc sequences bound by the lectin from Sambucus nigra (SNA-1) to have greatly increased expression on microvillous membranes in samples with chronic P.falciparum infection showing, by electronic image analysis, a significant trend (p = 0.002) compared to samples with past or no infection. This suggests a specific placental membrane response to falciparum malaria. Expression of alpha 2,6-linked sialic acid, demonstrated by the binding of SNA-1, has been associated with intercellular repulsion in tissues from patients with cancer, and such repulsion resulting from increased alpha 2,6 sialylation of chorionic villi could influence intervillous placental parasite density. Sialic acid expression should be examined in placental malaria to identify if this is a malaria-specific phenomenon, and to determine its relation to placental inflammation and pregnancy outcomes. (c) 2008 Elsevier Ltd. All rights reserved