RESUMEN
Accurate genome replication is essential for all life and a key mechanism of disease prevention, underpinned by the ability of cells to respond to replicative stress (RS) and protect replication forks. These responses rely on the formation of Replication Protein A (RPA)-single stranded (ss) DNA complexes, yet this process remains largely uncharacterized. Here, we establish that actin nucleation-promoting factors (NPFs) associate with replication forks, promote efficient DNA replication and facilitate association of RPA with ssDNA at sites of RS. Accordingly, their loss leads to deprotection of ssDNA at perturbed forks, impaired ATR activation, global replication defects and fork collapse. Supplying an excess of RPA restores RPA foci formation and fork protection, suggesting a chaperoning role for actin nucleators (ANs) (i.e. Arp2/3, DIAPH1) and NPFs (i.e, WASp, N-WASp) in regulating RPA availability upon RS. We also discover that ß-actin interacts with RPA directly in vitro, and in vivo a hyper-depolymerizing ß-actin mutant displays a heightened association with RPA and the same dysfunctional replication phenotypes as loss of ANs/NPFs, which contrasts with the phenotype of a hyper-polymerizing ß-actin mutant. Thus, we identify components of actin polymerization pathways that are essential for preventing ectopic nucleolytic degradation of perturbed forks by modulating RPA activity.
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Actinas , Replicación del ADN , Actinas/genética , Proteína de Replicación A/genética , Proteína de Replicación A/metabolismo , ADN de Cadena Simple/genética , Chaperonas Moleculares/genéticaRESUMEN
OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.
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Antivirales , Infecciones por Citomegalovirus , Ganciclovir , Pérdida Auditiva Sensorineural , Valganciclovir , Humanos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/complicaciones , Valganciclovir/uso terapéutico , Valganciclovir/administración & dosificación , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/virología , Pérdida Auditiva Sensorineural/etiología , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Masculino , Femenino , Método Doble Ciego , Lactante , Administración Oral , Ganciclovir/análogos & derivados , Ganciclovir/uso terapéutico , Ganciclovir/administración & dosificación , Preescolar , Resultado del Tratamiento , Carga Viral , Recién NacidoRESUMEN
Protracted bacterial bronchitis (PBB) causes chronic wet cough for which seasonal azithromycin is increasingly used to reduce exacerbations. We investigated the impact of seasonal azithromycin on antimicrobial resistance and the nasopharyngeal microbiome. In an observational cohort study, 50 children with PBB were enrolled over two consecutive winters; 25/50 at study entry were designated on clinical grounds to take azithromycin over the winter months and 25/50 were not. Serial nasopharyngeal swabs were collected during the study period (12-20 months) and cultured bacterial isolates were assessed for antimicrobial susceptibility. 16S rRNA-based sequencing was performed on a subset of samples. Irrespective of azithromycin usage, high levels of azithromycin resistance were found; 73% of bacteria from swabs in the azithromycin group vs. 69% in the comparison group. Resistance was predominantly driven by azithromycin-resistant S. pneumoniae, yet these isolates were mostly erythromycin susceptible. Analysis of 16S rRNA-based sequencing revealed a reduction in within-sample diversity in response to azithromycin, but only in samples of children actively taking azithromycin at the time of swab collection. Actively taking azithromycin at the time of swab collection significantly contributed to dissimilarity in bacterial community composition. The discrepancy between laboratory detection of azithromycin and erythromycin resistance in the S. pneumoniae isolates requires further investigation. Seasonal azithromycin for PBB did not promote antimicrobial resistance over the study period, but did perturb the microbiome.
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Infecciones Bacterianas , Bronquitis Crónica , Microbiota , Niño , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Azitromicina/farmacología , Azitromicina/uso terapéutico , Bacterias/genética , Infecciones Bacterianas/tratamiento farmacológico , Enfermedad Crónica , Tos/tratamiento farmacológico , Farmacorresistencia Bacteriana , Eritromicina , ARN Ribosómico 16S/genética , Estaciones del Año , Streptococcus pneumoniaeRESUMEN
BACKGROUND: In adults, anti-tumor necrosis factor-α (TNF-α) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited. METHODS: Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. RESULTS: Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified: Crohn's disease (n = 8; 42%) and juvenile idiopathic arthritis (n = 6; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-γ release assay) was performed in 15 patients before commencing anti-TNF-α therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR, 7.1-20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR, 46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. CONCLUSIONS: LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low-TB-prevalence settings.
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Tuberculosis Latente , Tuberculosis , Adolescente , Adulto , Niño , Humanos , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Necrosis , Estudios Retrospectivos , Prueba de Tuberculina , Tuberculosis/epidemiología , Factor de Necrosis Tumoral alfaRESUMEN
Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.
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ADN Ligasas/deficiencia , ADN Ligasas/genética , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Leucopenia/genética , Trombocitopenia/genética , Anomalías Múltiples/genética , Inmunidad Adaptativa , Adolescente , Línea Celular , Niño , Preescolar , ADN Ligasa (ATP) , Exoma , Femenino , Retardo del Crecimiento Fetal/etiología , Variación Genética , Genotipo , Heterocigoto , Humanos , Lactante , Masculino , Microcefalia/genética , Neoplasias/genética , Síndrome de Nijmegen/genética , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , SíndromeRESUMEN
Accurate genome replication is essential for all life and a key mechanism of disease prevention, underpinned by the ability of cells to respond to replicative stress (RS) and protect replication forks. These responses rely on the formation of Replication Protein A (RPA)-single stranded (ss) DNA complexes, yet this process remains largely uncharacterized. Here we establish that actin nucleation-promoting factors (NPFs) associate with replication forks, promote efficient DNA replication and facilitate association of RPA with ssDNA at sites of RS. Accordingly, their loss leads to deprotection of ssDNA at perturbed forks, impaired ATR activation, global replication defects and fork collapse. Supplying an excess of RPA restores RPA foci formation and fork protection, suggesting a chaperoning role for actin nucleators (ANs) (i.e., Arp2/3, DIAPH1) and NPFs (i.e, WASp, N-WASp) in regulating RPA availability upon RS. We also discover that ß-actin interacts with RPA directly in vitro , and in vivo a hyper-depolymerizing ß-actin mutant displays a heightened association with RPA and the same dysfunctional replication phenotypes as loss of ANs/NPFs, which contrasts with the phenotype of a hyper-polymerizing ß-actin mutant. Thus, we identify components of actin polymerization pathways that are essential for preventing ectopic nucleolytic degradation of perturbed forks by modulating RPA activity.
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Background: Pediatric inflammatory multisystem syndrome temporarily associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PIMS-TS) is an acute complication of previous SARS-CoV-2 exposure. The relationship between inflammatory markers and anti-inflammatory medication in PIMS-TS is unknown. We retrospectively investigated the relationship between demographics, biomarkers, treatment, and length of stay (LOS) in this novel disease. Methods: We reviewed the case notes and blood tests of all patients who met the Royal College of Paediatrics and Child Health diagnostic criteria for PIMS-TS at a large tertiary center in the United Kingdom. Biomarker trajectories were modeled using log linear mixed effects, and factors affecting LOS in hospital were evaluated using multiple regression. Results: Between March 2020 and May 2022, a total of 56 patients attended Sheffield Children's Hospital with PIMS-TS, 70% male. Mean age was 7.4 ± 3.7 years and mean LOS 8.7 ± 4.5 days with 50% requiring intensive care and 20% requiring inotropes. Older males had shorter LOS than younger males (P = 0.04), not seen in females. Treatment included intravenous glucocorticoids in 93%, intravenous immunoglobulins (IVIG) in 77%, Anakinra in 11%, and infliximab in 1.8%. Biomarkers correlated poorly with trajectories that peaked at different times. C-reactive protein peaked first after median 1.3 days postadmission; while LFT's and neutrophils peaked after 3 days. Age had a large effect on some biomarkers, with older children having larger troponin and ferritin, and lower lymphocytes and platelets. Cumulative dose of glucocorticoids and IVIG had a statistically significant effect on some biomarkers, but effect size was small. Conclusions: The heterogenous nature of PIMS-TS highlights the importance of a multidisciplinary approach. Worse inflammatory markers in older children within our cohort may be an indication of a different disease process occurring at different ages. Future work to investigate the association between age and troponin and ferritin in hyperinflammatory states is warranted.
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COVID-19 , Femenino , Humanos , Masculino , Niño , Adolescente , Preescolar , Glucocorticoides , Inmunoglobulinas Intravenosas , Estudios Retrospectivos , SARS-CoV-2 , Antiinflamatorios , Biomarcadores , Ferritinas , Hospitales PediátricosRESUMEN
BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.
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Angioedemas Hereditarios , Humanos , Femenino , Masculino , Angioedemas Hereditarios/epidemiología , Angioedemas Hereditarios/tratamiento farmacológico , Proteína Inhibidora del Complemento C1/uso terapéutico , Danazol/uso terapéutico , Reino Unido/epidemiología , Encuestas y CuestionariosRESUMEN
SARS-CoV-2 infections in children are generally asymptomatic or mild and rarely progress to severe disease and hospitalization. Why this is so remains unclear. Here we explore the potential for protection due to pre-existing cross-reactive seasonal coronavirus antibodies and compare the rate of antibody decline for nucleocapsid and spike protein in serum and oral fluid against SARS-CoV-2 within the pediatric population. No differences in seasonal coronaviruses antibody concentrations were found at baseline between cases and controls, suggesting no protective effect from pre-existing immunity against seasonal coronaviruses. Antibodies against seasonal betacoronaviruses were boosted in response to SARS-CoV-2 infection. In serum, anti-nucleocapsid antibodies fell below the threshold of positivity more quickly than anti-spike protein antibodies. These findings add to our understanding of protection against infection with SARS-CoV-2 within the pediatric population, which is important when considering pediatric SARS-CoV-2 immunization policies.
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Antibacterianos/sangre , Dermatitis Atópica/sangre , Dermatitis Atópica/complicaciones , Erupción Variceliforme de Kaposi/sangre , Erupción Variceliforme de Kaposi/etiología , Péptidos/sangre , Vitamina D/sangre , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proyectos PilotoRESUMEN
OBJECTIVE: To 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. DESIGN: We 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. RESULTS: Post-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 <10 years, there were no symptoms or symptom clusters that reliably predicted seropositivity. Overall, 48% of seropositive participants with complete questionnaire data recalled no symptoms between February 2020 and their study visit. CONCLUSIONS: Approximately 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 NUMBER: NCT04061382.
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BACKGROUND AND OBJECTIVES: Long-term prophylactic antibiotics are often used to prevent bacterial infections. However, supporting evidence for this is not always robust. Including parents in decisions relating to medication is key to medicines optimisation. Parental concern regarding medication is a major determinant of poor adherence. This study explores parental experiences of having a child prescribed prophylactic antibiotics and how that affects their antibiotic use behaviour. METHODS: We conducted a prospective, single-centre, exploratory, qualitative study at Sheffield Children's Hospital. Through 15 interviews, involving 18 participants, we explored parental 'lived experiences' and attitudes towards azithromycin prophylaxis prescribed for various respiratory conditions. Thematic analysis was conducted. RESULTS: The overriding factor influencing parental decisions about the uptake of antibiotic prophylaxis is wanting their child to be well now. The main concern voiced by parents is that of antibiotic resistance given their children are high users of antibiotics. This is however seen as a problem for the future, not the present. Preparing families adequately helps prevent practical difficulties relating to medication. Facilitating 'normalisation' of prophylaxis through daily routines and minimising disruption to the family environment may reduce parental anxiety, promote adherence and result in easing of potential restrictions to the child's daily activities. CONCLUSION: Grounded in our deeper understanding, we propose a behavioural model that describes phases parents go through while having a child on prophylactic antibiotics. Time invested in holistically addressing the parental experience and having an awareness of potential issues parents face, may facilitate medication adherence, reduce anxieties and improve doctor-parent relationships.
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Antibacterianos/uso terapéutico , Profilaxis Antibiótica/psicología , Infecciones Bacterianas/prevención & control , Padres/psicología , Infecciones del Sistema Respiratorio/prevención & control , Adulto , Anciano , Ansiedad/prevención & control , Ansiedad/psicología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Niño , Preescolar , Toma de Decisiones , Femenino , Humanos , Masculino , Cumplimiento de la Medicación/psicología , Persona de Mediana Edad , Padres/educación , Estudios Prospectivos , Investigación Cualitativa , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/inmunología , Prevención Secundaria/métodos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Non-Langerhans cell histiocytosis in the absence of cutaneous or other organ involvement is very rare. A Caucasian boy age 3 years 11 months presented with episodes of recurrent right-side seizures over 2 weeks. Brain CT and MR imaging showed a single enhancing left frontal lobe lesion. Stereotactic biopsy was performed and histological examination showed diffuse infiltrate of macrophages with foamy cytoplasm. Four months later there was recurrence of seizure activity despite anti-epileptic medication and a repeat MR scan showed a persistent enhancing lesion in the left frontal lobe. Histological examination of the resection specimen resembled juvenile xanthogranuloma (JXG) involving the central nervous system. In the absence of skin lesions a diagnosis of non-Langerhans cell histiocytosis was made. The child made a full recovery following surgery with resolution of his symptoms.
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Encefalopatías/patología , Lóbulo Frontal/patología , Histiocitosis de Células no Langerhans/patología , Imagen por Resonancia Magnética , Preescolar , Humanos , MasculinoRESUMEN
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.
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Infecciones por VIH , Enfermedades Pulmonares , Adolescente , Adulto , Antirretrovirales/uso terapéutico , Niño , Enfermedad Crónica , Inglaterra , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/epidemiología , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.
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Síndromes de Inmunodeficiencia/patología , Inflamación/patología , Receptores de Interleucina-6/deficiencia , Adolescente , Adulto , Niño , Preescolar , Femenino , Células HEK293 , Humanos , Recién Nacido , Masculino , Receptores de Interleucina-6/metabolismoRESUMEN
BACKGROUND: Tuberculosis is the most common serious co-infection in people living with HIV worldwide, but little is known about its incidence in HIV-infected children living in high-resource settings with low tuberculosis prevalence. We aimed to assess the incidence and prevalence of tuberculosis in children with HIV living in the UK and Ireland to understand rates, risk factors, and outcomes of the disease in this group. METHODS: We did an analysis of children enrolled in CHIPS, an observational multicentre cohort of children receiving HIV care in the UK and Ireland. We assessed characteristics and prevalence of tuberculosis at baseline, measured incidence of disease through the follow-up period using the CHIPS database, and calculated associated risk factors in these children with multivariable logistic and Cox regression models. FINDINGS: Between Jan 1, 1996, to Sept 18, 2014, data for 1848 children with 14â761 years of follow-up were reported to CHIPS. 57 (3%) children were diagnosed with tuberculosis: 29 children had tuberculosis at presentation (prevalent tuberculosis) and 29 had the disease diagnosed during follow-up (incident tuberculosis), including one child with recurrent tuberculosis events. Median age at diagnosis was 9 years (IQR 5-12). 25 (43%) children had pulmonary tuberculosis, 24 (41%) had extrapulmonary tuberculosis with or without pulmonary involvement, and the remainder (n=9; 16%) had unspecified-site tuberculosis. The overall incidence rate for the follow-up period was 196 cases per 100â000 person-years (95% CI 137-283). In our multivariable model, tuberculosis at presentation was associated with more severe WHO immunological stage at baseline (odds ratio 0·25, 95% CI 0·08-0·74; p=0·0331; for none vs severe) and being born abroad (odds ratio 0·28, 0·10-0·73; p=0·0036; for UK and Ireland vs abroad). Incident tuberculosis was associated with time-updated more severe WHO immunological stage (hazard ratio 0·15, 95% CI 0·06-0·41; p=0·0056; for none vs severe) and older age at baseline (1·11, 0·47-2·63; p=0·0027; for age >10 years vs 5-9 years). INTERPRETATION: Tuberculosis rates in HIV-infected children in the UK and Ireland were higher than those reported in the general paediatric population. Further study is warranted of tuberculosis screening and preventive treatment for children at high-risk of this disease to avoid morbidity and mortality in this population. FUNDING: NHS England, PENTA Foundation.
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Fármacos Anti-VIH/uso terapéutico , Coinfección/epidemiología , Infecciones por VIH/epidemiología , Tamizaje Masivo/organización & administración , Tuberculosis/epidemiología , Recuento de Linfocito CD4 , Niño , Coinfección/inmunología , Coinfección/fisiopatología , Inglaterra/epidemiología , Femenino , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Humanos , Incidencia , Irlanda/epidemiología , Masculino , Prevalencia , Factores de Riesgo , Tuberculosis/inmunología , Tuberculosis/fisiopatología , Tuberculosis/prevención & controlRESUMEN
We report a case of accidental cutaneous burns caused by salbutamol metered dose inhaler. A 9-year-old boy underwent dental extraction at a children's hospital and was incidentally noted to have burn injuries on dorsum of both hands. On questioning, the boy revealed that a few days ago his 14-year-old brother, who is an asthmatic, playfully sprayed his salbutamol metered dose inhaler on the back of both his hands with the inhaler's mouth piece being in direct contact with the patient's skin. On examination, there was a rectangular area of erythema with superficial peeling on the dorsum of both hands, the dimensions of which exactly matched those of the inhaler's mouthpiece. It is possible that the injury could have been a chemical burn from the pharmaceutical/preservative/propellant aerosol or due to the physical effect of severe cooling of the skin or mechanical abrasive effect of the aerosol blasts or a combination of some or all the above mechanisms. This case highlights the importance of informing children and parents of the potentially hazardous consequences of misusing a metered dose inhaler.
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A 11-year-old girl presented with a subcutaneous lesion on the forehead, thought to be an implantation dermoid cyst. Microscopic examination revealed an onchocercoma. Microfilariae were found in the blood indicating a co-infection with Mansonella perstans. This case demonstrates the diagnostic difficulties of a parasitic co-infection uncommonly encountered in Europe.
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Mansonella/patogenicidad , Mansoneliasis/diagnóstico , Onchocerca/patogenicidad , Oncocercosis/diagnóstico , Animales , Niño , Quiste Dermoide/diagnóstico , Quiste Dermoide/patología , Diagnóstico Diferencial , Femenino , Frente/parasitología , Frente/patología , Humanos , Mansoneliasis/patología , Oncocercosis/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The relative invasiveness rates (attack rates) of Streptococcus pneumoniae of different capsular serotypes in children are not known. Estimates of capsular serotype invasiveness (designated "invasive odds ratios") that are based on cross-sectional prevalence carriage data have been published, but these estimates could be biased by variation in the duration of carriage. METHODS: The relative attack rates of invasive pneumococci were measured using national UK surveillance data on invasive pneumococcal disease (IPD) incidence and data on incidence of pneumococcal acquisition from longitudinal studies of nasopharyngeal pneumococcal carriage. RESULTS: We found significant differences in capsular serotype-specific attack rates. For example, capsular serotypes 4, 14, 7F, 9V, and 18C were associated with rates of >20 IPD cases/100,000 acquisitions, whereas capsular serotypes 23F, 6A, 19F, 16F, 6B, and 15B/C were associated with <10 IPD cases/100,000 acquisitions. There was an inverse relationship between duration of carriage and attack rate by capsular serotype (P<.0001). Attack rates were significantly correlated with invasive odds ratios (P<.0001). CONCLUSIONS: The capsular serotype is a major determinant of both pneumococcal duration of carriage and attack rate. Published invasive odds ratios are a reliable and practical method of determining capsular serotype invasiveness and will be valuable for investigating and characterizing emerging capsular serotypes in the context of conjugate vaccination.