Predictors of TB disease in HIV-exposed children from Southern Africa.

BACKGROUND: P1041 was a randomised, placebo-controlled isoniazid prophylaxis trial in South Africa. We studied predictors for TB in HIV-exposed children participating in the P1041 trial.METHODS: We included data from entry until Week 108. Predictors considered were type of housing, overcrowding, age, sex, ethnicity, tobacco exposure, weight-for-age percentile Z-score (WAZ), CD4%, viral load (VL), antiretroviral therapy (ART) and number of household smokers.RESULTS: Of 543 HIV-positive (HIV+) and 808 HIV-exposed uninfected (HEU) infants at entry, median age was 96 days (interquartile range: 92-105). Of 1,351 caregivers, 125 (9%) had a smoking history, and 62/1,351 reported current smoking. In 594/1,351 (44%) households, there was at least one smoker. Smoking caregivers consumed 1-5 cigarettes daily. In the HIV+ cohort, significant baseline TB predictors after adjusting covariates were as follows: WAZ (adjusted hazard ratio [aHR] 0.76, P = 0.002) and log10 HIV RNA copies/ml (aHR 1.50, P = 0.009). Higher CD4% (aHR 0.88, P = 0.002) and ART (aHR 0.50, P = 0.006) were protective. In the HEU cohort, smoking exposure was associated with reduced TB-free survival on univariate analysis, but not after adjustment in the multivariate model.CONCLUSION: Low WAZ and high VL were strong predictors of TB disease or death. Rising CD4 percentage and being on ART were protective in the HIV+ cohort.

A targeted response to the COVID-19 pandemic: analysing effectiveness of remote consultations for triage and management of routine dermatology referrals.

During the UK's COVID-19 pandemic lockdown there was national guidance to suspend routine dermatology work. As a consequence, over 800 patient appointments in a district general dermatology department were temporarily suspended. Remote consultations were carried out to triage and manage referrals, via telephone or video consultations. Data were prospectively recorded on 488 patient interactions. Outcomes included advice/treatment, discharge, surgery or clinic review; 25% of patients were either uncontactable or their problem had resolved. Over a third of referrals were discharged with advice/treatment initiated remotely; 56% of referred dermatoses required further clinical review; 25% of lesion referrals were booked directly to surgery. This process was time-intensive for the clinicians involved, and triage mechanisms could be improved. Sufficient referral information allows remote diagnosis; implementation of management plans and appropriate discharge of patients. This process has been shown to be feasible, and may be a temporary solution for other COVID-19 impacted dermatology departments.

Source case identification in HIV-exposed infants and tuberculosis diagnosis in an isoniazid prevention study.

BACKGROUND: Identifying source cases of children exposed to tuberculosis (TB) is challenging. We examined the time-point of obtaining contact information of TB source cases in human immunodeficiency virus (HIV) infected and HIV-exposed uninfected (HEU) children in a randomised, placebo-controlled trial of pre-exposure to isoniazid prophylaxis. METHODS: A total of 543 HIV-infected and 808 HEU infants without TB exposure aged 3-4 months were enrolled between 2004 and 2008. At 3-monthly follow-up, infants were evaluated for TB and care givers were asked about new TB exposure. RESULTS: In total, 128 cases of TB disease and 40 deaths were recorded among 19% (105/543) of the HIV-infected and 8% (63/808) of the HEU children; 229 TB contact occasions were reported in 205/1351 (15%) children, of which 83% (189/229) were in the household. Of the 189 household contacts, 108 (53%) underwent microbiological evaluations; 81% (87/108) were positive. HIV-infected and HEU infants had similar frequencies of TB contact: in 48% of infants with definite TB, 58% with probable TB and 43% with possible TB. Of 128 children diagnosed with TB, a TB contact was identified for 59. Of these, 29/59 (49%) were identified at or after the child's TB diagnosis. CONCLUSION: TB source cases are often identified at or after a child's TB diagnosis. More effort is required for earlier detection.

Cutaneous ulcers in a returning traveller: a rare case of imported diphtheria in the UK.

We describe a case of cutaneous diphtheria in the UK, presenting as lower leg ulcers in a returning traveller, and discuss the epidemiology, significance and public health implications of this disease and the therapeutic options available. A 65-year-old woman presented with a 6-week history of multiple ulcers appearing on her legs following a holiday in Kenya. Culture of biopsy tissue grew Corynebacterium diphtheriae. A cascade of therapeutic and public health interventions followed, many of which were terminated once the isolate was confirmed as nontoxigenic. Cutaneous diphtheria is a rare, notifiable disease in the UK, but is common in tropical countries, and is most often seen in the West as a traveller's disease. Corynebacteria are common skin commensals, and without appropriate clinical details, laboratories may not recognize C. diphtheriae/Corynebacterium ulcerans. This is likely to have led to under-reporting and under-recognition of the condition.

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.

Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ≥1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.

Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study.

The United Kingdom Childhood Cancer Study was designed to examine the relation between childhood cancer and preceding exposure to infectious diseases. The authors analyzed the relation between diagnosis (1991-1996) of acute lymphoblastic leukemia (ALL) at ages 2-5 years and clinically diagnosed infections in infancy. Almost all study children (96% of both cases and controls) were taken to a general practitioner for a non-immunization-associated visit at least once before their first birthday. Children diagnosed with ALL had significantly more clinically diagnosed infectious episodes in infancy than did controls; the average number of episodes was 3.6 (95% confidence interval (CI): 3.3, 3.9) versus 3.1 (95% CI: 2.9, 3.2). This case-control difference was most apparent in the neonatal period (< or =1 month); 18% of controls and 24% of ALL cases were diagnosed with at least one infection (odds ratio = 1.4, 95% CI: 1.1, 1.9; p < 0.05). Cases who had more than one neonatal infectious episode tended to be diagnosed with ALL at a comparatively young age; the mean age at ALL diagnosis was 37.7 months for cases with two or more episodes versus 45.3 months for cases with only one episode or none (p < 0.01). These findings support the hypothesis that a dysregulated immune response to infection in the first few months of life promotes transition to overt ALL later in childhood.

Factors associated with HIV prevalence in a pre-partum cohort of Zambian women.

An ongoing study of mother-to-child human herpes virus-8 (HHV-8) transmission in Zambian women (n = 3160) allowed us to examine the association of medical injections with HIV serostatus while simultaneously accounting for other factors known to be correlated with HIV prevalence. Multi-method data collection included structured interviews, medical record abstraction, clinical examinations, and biological measures. Medically administered intramuscular or intravenous injections in the past five years (but not blood transfusions) were overwhelmingly correlated with HIV prevalence, exceeding the contribution of sexual behaviours in a multivariable logistic regression. Statistically significant associations with HIV also were found for some demographic variables, sexual behaviours, alcohol use, and sexually transmitted diseases (STD). The results confirmed that iatrogenic needle exposure, sexual behaviour, demographic factors, substance use, and STD history are all implicated in Zambian women's HIV+ status. However, the disproportionate association of medical injection history with HIV highlights the need to investigate further and prospectively the role of health-care injection in sub-Saharan Africa's HIV epidemic.

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial.

Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event-free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0.0007). Event-free survival was significantly improved with dexamethasone (84.2% vs. 75.6% at 5 years; P = 0.01), with no evidence of differing effects in any subgroup of patients. The use of 6.5 mg/m(2) dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk-groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.

Relationships between perinatal and maternal characteristics and hepatoblastoma: a report from the UKCCS.

Within the context of a national population-based case-control study--the United Kingdom Childhood Cancer Study (UKCCS)--we aimed to explore relationships between perinatal and maternal factors and childhood hepatic tumours, for participants with data available from medical records. 26/28 children with hepatic tumours (22/24 hepatoblastomas, 4/4 hepatocellular carcinomas (HCC)) and 4753 age- and sex-matched controls were included. Polyhydramnios was associated with 0.9% of control pregnancies and 13.6% of case pregnancies (Odds Ratio (OR)=28.64, 95% Confidence Interval (CI)=6.94-118.21, P<0.0001); eclampsia or severe pre-eclampsia complicated the pregnancies of 16.7% of mothers whose children developed hepatoblastoma compared with 0.5% of control pregnancies (OR=52.50, 95% CI=10.75-257.05, P<0.0001). Three children with hepatoblastoma weighed <1500 g at birth, two of whom weighed <1000 g (OR for birthweight <1500 g=69.00, 95% CI=11.98-397.17, P<0.0001). Of children with hepatoblastoma, 50% (11/22) had records of congenital anomalies, as did two of their mothers. Three mothers of children with hepatoblastoma had diagnoses of cancer--two of papillary carcinoma of the thyroid and one of acute lymphoblastic leukaemia (ALL). Paediatricians and others should be alert to the possibility of familial or genetic syndromes in children with hepatoblastomas. Potential links between maternal pre-eclampsia, low birthweight and subsequent malignancy merit further investigation. Hepatoblastoma is an extremely rare childhood tumour, but understanding the mechanism(s) underlying severe pre-eclampsia and eclampsia may also shed light on factors that contribute to the development of hepatoblastoma.

Epidemiological characteristics of human herpesvirus-8 infection in a large population of antenatal women in Zambia.

Comprehensive data describing epidemiological characteristics of the human herpesvirus-8 or Kaposi's sarcoma-associated herpesvirus (HHV-8 or KSHV) infection among pregnant women in a central sub-Saharan Africa are not available. This study determined virus prevalence estimates and the risk factors associated with HHV-8 infection. Cross-sectional, enrollment visit data were analyzed from a prospective cohort study of perinatal transmission of HHV-8 in Lusaka, Zambia. Exposure data were obtained via structured interview, physical examination, medical chart review, and laboratory testing. Among 3,160 antenatal women serologically screened for HHV-8 between September 1998 and October 2000, 40.2% were seropositive. The HHV-8 positive women were more likely to be co-infected with HIV-1 than those who were HHV-8 negative (34% vs. 26%; P < 0.0001). Of 154 variables evaluated by logistic regression analyses, only three risk factors, have emerged as independent predictors of HHV-8 positive serology: diagnosis of genital warts, HIV-1 co-infection and primary education. The association of HHV-8 infection with genital warts and HIV-1 co-infection suggests heterosexual transmission of HHV-8. HIV-1 infection may also act as a marker for particular behaviors, which could be sexual in nature, that are associated with both HIV-1 and HHV-8 transmission. Since HHV-8 facilitates development of AIDS-related Kaposi's sarcoma (KS), the results of this study could be utilized to identify specific population groups of pregnant women who are at increased risk for this disease.

Incidental memory and navigation in panoramic virtual reality for electronic commerce.

Recently much effort has been dedicated to designing and implementing World Wide Web sites for virtual shopping and e-commerce. Despite this effort, relatively little empirical work has been done to determine the effectiveness with which different site designs sell products. We report three experiments in which participants were asked to search for products in various experimental e-commerce sites. Across the experiments participants were asked to search in either QTVR (QuickTime Virtual Reality), hypertext, or pictorially rich hypertext environments; they were then tested for their ability to recall the products seen and to recognize product locations. The experiments demonstrated that when using QTVR (Experiments 1, 2, and 3) or pictorial environments (Experiment 2), participants retained more information about products that were incidental to their goals. In two of the experiments it was shown that participants navigated more efficiently when using a QTVR environment. The costs and benefits of using 3D virtual environments for on-line shops are discussed. Actual or potential applications of this research include support for the development of e-commerce design guidelines.

Lateralized cognitive deficits in children following cerebellar lesions.

The aim of this preliminary study was to examine the developing cognitive profiles of children with cerebellar tumours in a consecutive series of clinical patients. MRI and longitudinal intellectual profiles were obtained on seven children (two females, five males; mean age 3 years at diagnosis; mean age 7 years at first assessment). Tumours in three of the children were astrocytomas; of the remaining tumours, two were medulloblastomas, one low-grade glioma, and one ependymoma. In right-handed children, we observed an association between greater damage to right cerebellar structures and a plateauing in verbal and/or literacy skills. In contrast, greater damage to left cerebellar structures was associated with delayed or impaired non-verbal/spatial skills. Long-term cognitive development of the children studied tentatively supports a role for the cerebellum in learning/development. These findings suggest that lateralized cerebellar damage may selectively impair the development of cognitive functions subserved by the contralateral cerebral hemisphere and, in addition, that all children with cerebellar lesions in early childhood should routinely undergo long-term monitoring of their intellectual development.

Effect of prenatal zidovudine on disease progression in perinatally HIV-1-infected infants.

OBJECTIVE: To determine the influence of prenatal zidovudine (ZDV) prophylaxis on the course of HIV- 1 infection in children by comparing the clinical outcome of infants born to HIV- 1-seropositive mothers who did versus those who did not receive ZDV during pregnancy. METHODS: Medical records of HIV-1-seropositive mothers and their infants were reviewed retrospectively. Participants were divided according to maternal ZDV use: no ZDV (n = 152); ZDV (n = 139). The main outcome measure was rapid disease progression (RPD) in the infant, defined as occurrence of a category C disease or AIDS-related death before 18 months of age. RESULTS: HIV vertical transmission rates were significantly different (no ZDV versus ZDV: 22.3% versus 12.2%; p = .034). Among infected infants, the RPD rate was 29.4% in the no ZDV group compared with 70.6% in the ZDV group (p = .012), and prematurity was significantly associated with a higher risk of RPD (p = .027). CONCLUSIONS: The rate of RPD was significantly higher among perinatally infected infants born to HIV-infected mothers treated with ZDV than among infected infants born to untreated mothers. The decreased proportion of infected infants with nonrapid disease progression in the former group might be related to the ability of ZDV to block intrapartum transmission preferentially and also to nonrapid disease progression resulting from intrapartum transmission.

Gram-negative bacillary bacteremia in human immunodeficiency virus type 1-infected children.

BACKGROUND: HIV-infected children are particularly susceptible to serious bacterial infections including Gram-negative bacillary bacteremia (GNB). However, the information available on GNB in these children is limited. METHODS: Retrospective review of hospital charts of HIV-infected children with GNB diagnosed between 1980 and 1997. The association between bacteremic episodes, degree of immunosuppression, HIV severity, medical treatment and clinical outcome was assessed. RESULTS: Of 680 HIV-infected children, 72 (10.6%) had 95 episodes of GNB. Statistical analyses were restricted to data from the first episode. The mean age (+/-SD) at diagnosis of GNB was 2.5 +/- 2.7 years (median, 1.6). The predominant organisms were Pseudomonas aeruginosa (26.4%), nontyphoidal Salmonella (15.3%), Escherichia coli (15.3%) and Haemophilus influenzae (12.5%). The relative frequency, per 5-year interval, of P. aeruginosa bacteremia steadily increased from 13% during 1980 through 1984 to 56% during 1995 through 1997. There were no cases of H. influenzae bacteremia after January 1, 1990. Eighty percent of GNB developed in children with AIDS and 72.2% developed in those with severe immunosuppression. Hypogamma-globulinemia and neutropenia were present in only 4.9 and 10.4% of first episodes, respectively. The overall case-fatality rate of GNB was 43.0%, and in children younger than 12 months it was 54.2%. CONCLUSIONS: A diagnosis of AIDS and/or severe immunosuppression was associated with increased risk of GNB, especially among younger children. Because of the high mortality of GNB, a broad spectrum antimicrobial therapy that effectively covers these organisms should be promptly instituted when bacteremia is suspected in HIV-infected children.