Challenges to delivery of isoniazid preventive therapy in a cohort of children exposed to tuberculosis in Timor-Leste.

OBJECTIVES: To evaluate the number and geographic location of children aged <5 years exposed to sputum smear-positive tuberculosis (TB) in Timor-Leste, to determine the proportion evaluated for isoniazid preventive therapy (IPT) and to review the programmatic challenges present in delivering IPT to this cohort. METHODS: A total of 256 consecutive sputum smear-positive TB index cases diagnosed at Bairo Pite Clinic between August 2013 and July 2014 were interviewed about places of residence and household contacts <5 years of age in the 3 months preceding diagnosis. Attendance of these contacts for screening and the outcome of screening were recorded prospectively. RESULTS: The majority (225 of 256, 88%) of index cases resided in Dili, but 73 of 225 (32%) of these also had a second address outside the capital. A total of 255 contacts were identified; 172 of 255 (67%) of whom lived in Dili district and 83 of 255 (33%) of whom resided in remote districts. Only 66 of 255 (26%) contacts attended for evaluation for IPT, of whom 46 of 255 (18%) started IPT and nine of 255 (3.5%) were diagnosed with TB. Attendance was significantly less likely when the index case was not the parent of the child contact. CONCLUSIONS: Sputum smear-positive pulmonary TB cases frequently result in household exposure of children <5 years in Timor-Leste, and provision of IPT is suboptimal. Contacts are located in diverse and distant locations. Further studies to delineate access barriers to IPT and review programmatic models that will facilitate IPT scale up in Timor-Leste are needed.

Trends in the epidemiology of invasive Haemophilus influenzae disease in Queensland, Australia from 2000 to 2013: what is the impact of an increase in invasive non-typable H. influenzae (NTHi)?

Following the introduction of vaccination against Haemophilus influenzae type b (Hib), cases of invasive encapsulated Hib disease have decreased markedly. This study aimed to examine subsequent epidemiological trends in invasive H. influenzae disease in Queensland, Australia and in particular, assess the clinical impact and public health implications of invasive non-typable H. influenzae (NTHi) strains. A multicentre retrospective study was conducted from July 2000 to June 2013. Databases of major laboratories in Queensland including Queensland Forensic and Scientific Services (jurisdictional referral laboratory for isolate typing) were examined to identify cases. Demographic, infection site, Indigenous status, serotype, and mortality data were collected. In total, 737 invasive isolates were identified, of which 586 (79·5%) were serotyped. Hib, NTHi and encapsulated non-b strains, respectively, constituted 12·1%, 69·1% and 18·8% of isolates. The predominant encapsulated non-b strains were f (45·5%) and a (27·3%) serotypes. Of isolates causing meningitis, 48·9% were NTHi, 14·9% Hib, 14·9% Hie, 10·6% Hif, 6·4% Hia and 4·3% were untyped. During the study period, there was an increase in the incidence of invasive NTHi disease (P = 0·007) with seasonal peaks in winter and spring (P 0·001) and Hib (P = 0·039) than non-Indigenous patients. In Queensland, invasive H. influenzae disease is now predominantly encountered in adults and most commonly caused by NTHi strains with demonstrated pathogenicity extending to otherwise young or immunocompetent individuals. Routine public health notification of these strains is recommended and recent available immunization options should be considered.

The tangled web of non-canonical Wnt signalling in neural migration.

In all multicellular animals, successful embryogenesis is dependent on the ability of cells to detect the status of the local environment and respond appropriately. The nature of the extracellular environment is communicated to the intracellular compartment by ligand/receptor interactions at the cell surface. The Wnt canonical and non-canonical signalling pathways are found in the most primitive metazoans, and they play an essential role in the most fundamental developmental processes in all multicellular organisms. Vertebrates have expanded the number of Wnts and Frizzled receptors and have additionally evolved novel Wnt receptor families (Ryk, Ror). The multiplicity of potential interactions between Wnts, their receptors and downstream effectors has exponentially increased the complexity of the signal transduction network. Signalling through each of the Wnt pathways, as well as crosstalk between them, plays a critical role in the establishment of the complex architecture of the vertebrate central nervous system. In this review, we explore the signalling networks triggered by non-canonical Wnt/receptor interactions, focussing on the emerging roles of the non-conventional Wnt receptors Ryk and Ror. We describe the role of these pathways in neural tube formation and axon guidance where Wnt signalling controls tissue polarity, coordinated cell migration and axon guidance via remodelling of the cytoskeleton.

Invasive group A streptococcal disease in children in Queensland.

The epidemiology and clinical features of invasive group A streptococcal (iGAS) disease in Queensland children was investigated in response to anecdotal evidence of an increase in frequency and severity of this condition. A retrospective review of clinical records of all cases of iGAS disease notified to Queensland Health aged 0-18 years during a 5-year period was conducted. The annualized incidence of iGAS was 3·5/100,000 for the total population aged 0-18 and 13·2/100,000 for the Indigenous population of similar age. The annualized incidence was highest in Indigenous infants but no increase in frequency or severity of iGAS infections was observed. Findings included an increased prevalence in Indigenous children particularly in those aged <1 year, a significant male preponderance, lack of seasonal variation and an association with blunt trauma. Further studies are required to confirm and investigate these findings and to define specific risk factors in high-risk groups.

First outbreak of PVL-positive nonmultiresistant MRSA in a neonatal ICU in Australia: comparison of MALDI-TOF and SNP-plus-binary gene typing.

The purpose of this brief report is to describe the first outbreak of a community-associated nonmultiresistant and PVL-positive MRSA strain (CC30) in a neonatal intensive care unit in Australia. The utility of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) for microbial typing is compared with single nucleotide polymorphism (SNP) plus binary gene analysis. The composite correlation index analysis of the MALDI-TOF-MS data demonstrated the similar inter-strain relatedness found with the SNP-plus-binary gene typing used to confirm the outbreak. The evolving spread of MRSA emphasizes the importance of surveillance, infection control vigilance and the ongoing investigation of rapid typing methods for MRSA.

Paediatric tuberculosis in Queensland, Australia: overrepresentation of cross-border and Indigenous children.

SETTING: Queensland, Australia. BACKGROUND: Understanding paediatric tuberculosis (TB) is important, as children with TB typically reflect recent community transmission. Children pose unique diagnostic challenges and are at risk of developing severe disseminated infection. OBJECTIVE: To describe the epidemiology, presentation and outcomes of children with TB disease in Queensland. DESIGN: This is a retrospective case series of children diagnosed with TB aged 0-16 years notified in 2005-2014. Data collected in the Queensland Notifiable Conditions System were extracted and analysed. RESULTS: Of 127 children diagnosed with TB, 16 were Australian-born (including 12 Indigenous Queenslanders), 41 were overseas-born permanent and temporary residents and 70 were cross-border Papua New Guinea (PNG) children; 88 children had pulmonary disease (with/without other sites) and 39 had extra-pulmonary disease only, with lymph node TB the predominant extra-pulmonary site; 70.1% of children had laboratory confirmation; and 14 cross-border children had multidrug-resistant TB. Treatment outcomes among children residing in Australia were good (100% among Australian-born and 97.2% among permanent and temporary residents), but they were less favourable among PNG children diagnosed in the Torres Strait Protected Zone (76.6%). CONCLUSION: Queensland has unique challenges in TB control, with a high proportion of cross-border diagnoses and over-representation of Indigenous children. Vigilance is needed given the wide spectrum of clinical presentation, particularly in high-risk communities.

Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis.

Zellweger syndrome (ZS) is a peroxisome biogenesis disorder that involves significant neuropathology, the molecular basis of which is still poorly understood. Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population. Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes, as well as increased levels of mitochondrial superoxide and membrane depolarization; this phenotype was rescued by antioxidant treatment. Significant oxidative damage to neurons in brain was indicated by products of lipid and DNA oxidation. Similar overall changes were observed for glial cells. In toto, these findings suggest that mitochondrial oxidative stress and aberrant mitochondrial dynamics are associated with the neuropathology arising from PEX13 deficiency.

Identification of homo- and heteromeric interactions between members of the breast carcinoma-associated D52 protein family using the yeast two-hybrid system.

The hD52 gene was originally identified through its elevated expression level in human breast carcinoma. Cloning of D52 homologues from other species has indicated that D52 may play roles in calcium-mediated signal transduction and cell proliferation. Two human homologues of hD52, hD53 and hD54, have also been identified, demonstrating the existence of a novel gene/protein family. Since D52-like protein sequences are all predicted to contain a coiled-coil domain, we used the yeast two-hybrid system and glutathione S-transferase pull-down assays to investigate whether homo- and/or heteromeric interactions occur between D52-like proteins. Analyses of yeast strains co-transfected with paired D52-like constructs indicated that D52-like fusion proteins interact in homo- and heteromeric fashions through their predicted coiled-coil domains. Similarly, extensive two-hybrid screenings of a human breast carcinoma expression library identified hD53 and hD52 as potential interactors for both hD52 and hD53 baits. Thus, D52-like proteins appear to exert and/or regulate their activities through specific interactions with other D52-like proteins, which in turn may be intrinsic to potential roles of these molecules in controlling cell proliferation.

Cloning of a third member of the D52 gene family indicates alternative coding sequence usage in D52-like transcripts.

D52 proteins are emerging as signalling molecules which may be regulators of cell proliferation. Having previously reported the existence of the human D52 gene family, comprising the hD52 and hD53 genes expressed in human breast carcinoma, we report the identification of a novel human gene hD54 (TPD52L2), which represents a third D52 gene family member. In situ mapping placed the hD54 gene on human chromosome 20q13.2-q13.3, a localization distinct from those of both hD52 and hD53 genes. The identified hD54 cDNAs predicted three hD54 isoforms, suggesting that alternatively-spliced transcripts may be produced from D52-like genes. This was confirmed by directly sequencing reverse transcriptase-polymerase chain reaction (RT-PCR) products amplified from D52-like gene transcripts expressed in developing and adult rat tissues, and by performing sequence analyses of the expressed sequence tag divisions of nucleotide databases. Alternative splicing of sequences encoding two regions, termed ins2 and ins3, was identified in one or more D52-like genes, with these alternative splicing events being differentially regulated. The functional consequences of alternative splicing were examined by characterizing the protein-protein interactions mediated by a truncated hD53 isoform within the yeast two-hybrid system. This hD53 isoform displayed altered interaction capabilities with respect to those of full-length hD53, suggesting that alternative splicing within the D52 gene family functions in part to alter the protein-protein interaction capabilities of encoded isoforms.

VRE in the Republic of Ireland: clinical significance, characteristics and molecular similarity of isolates.

There have been increasing reports worldwide of vancomycin resistant enterococci (VRE) since they were first noted over ten years ago. This study sought to investigate the clinical significance of VRE in Ireland and to compare the phenotypic, genotypic and molecular characteristics of isolates recovered from patients in different institutions. The relative contribution of inter-hospital transmission of strains to the dissemination of VRE in Ireland was assessed. Hospital surveillance for VRE is not well established in Ireland. The organism has been detected in seven hospitals. Detection has been predominantly in oncology inpatients in large tertiary referral hospitals in the Dublin metropolitan area in whom strains generally represent asymptomatic gastrointestinal tract colonization. The predominant species is E. faecium with the Van A resistance phenotype. Twenty-seven (87) of 31 isolates from one unit were shown to be of the same or closely related strain as were 10 (63%) of 16 from another unit, indicating significant nosocomial transmission within institutions. There was no evidence for inter-hospital transmission of VRE. VRE is established in Ireland and nosocomial transmission readily occurs. Regular surveillance for VRE is indicated in high-risk populations in large institutions, specific risk factors for the acquisition of VRE need to be defined and optimal control and preventative strategies need to he instituted to detect and preempt the spread of this organism.

Paediatric HIV infection in the Republic of Ireland and the need for antenatal screening.

Thirty-seven HIV-infected children have been identified in the Republic of Ireland since 1985. Only 12 (32%) of 37 were followed prospectively from birth. Median age at diagnosis was 18 months (4 weeks to 8 years). In 32 (86%) of 37 cases, HIV infection was acquired as a result of transmission from mother to infant with intravenous drug use (IVDU) the most frequent risk factor for maternal acquisition of HIV. Of these 32 children, median maternal age at delivery was 24 (interquartile range (IQR) 23-26) years with median gestation at delivery 40 (IQR 38-40) weeks. Mode of delivery was by vaginal delivery in all 29 (91%) cases where mode of delivery is known. Only 2 infants were breastfed. Seven children have died at a median age of 9 (0.8-9.6) years. As of July 1997, 12 children have AIDS, 14 have symptomatic disease without AIDS and 3 are asymptomatic. Median age at AIDS diagnosis was 2.6 (0.1-6.5) years. Median survival time post-AIDS diagnosis was 6.5 (1.8-8.3) years. Of 29 living children, 24 mothers and 14 fathers are HIV infected and only 14 children live with both parents. Childhood HIV infection has had a significant personal, social and financial impact on both Irish families and society in general. More effective measures to control HIV infection among intravenous drug users are needed. Antenatal detection of HIV-infected mothers is paramount as vertical transmission can be successfully prevented and morbidity and death can be prevented in the infected infant.

A multi-dimensional model of groupwork for adolescent girls who have been sexually abused.

This paper describes a treatment approach for sexually abused adolescent girls using a group work model. The model incorporates three treatment modalities: a skills component, a psychotherapeutic component, and an educative component. The group ran for 16 sessions over a 6-month period and each girl was assessed prior to joining the group. The girls were again assessed at the end of treatment and a 6-months follow-up; all of them showed improvement on self-statements (outcome) and on behavioral measures assessed by others (follow-up). Girls who had been sexually abused demonstrated difficulties in many areas of their lives following abuse. These problems related to their feelings of guilt and helplessness in relation to both themselves and their abuser. Sexually abused children often have poor knowledge of sexual matters and demonstrate confusion over their own body image. Using a multidimensional model the problems following abuse can be addressed.

Perinatal transmission of HIV and diagnosis of HIV infection in infants: a review.

Paediatric HIV infection has become a major burden on families, communities and health services worldwide. The vast majority of children now acquire HIV as a result of mother to infant (vertical) transmission. Recent major advances have occurred following the greater understanding of the risk factors for perinatal transmission and the role of antiretroviral therapy in preventing transmission. Now that interruption of vertical transmission is possible, early identification of HIV-infected pregnant women is critical. As of June 1997, HIV infection has been diagnosed in 37 children under 15 yrs of age in the Republic of Ireland; 32 as a result of maternal to infant transmission. The exact timing of HIV transmission during pregnancy is unclear but it is estimated that 60-70 per cent of infants may be infected at the time of delivery with approximately 30 per cent infected earlier in gestation. Vertical transmission rates vary from 15-40 per cent in different global areas. Antenatal and perinatal zidovudine treatment can reduce this rate by 60-70 per cent. Risk factors for the vertical transmission of HIV-1 are multifactorial. These factors include maternal disease status, in particular maternal viral load, route of delivery, duration of membrane rupture, presence of obstetric complications and infant feeding practices. Definitive diagnosis of HIV infection in infancy has been difficult in the past. Direct viral detection methods now allow the reliable diagnosis of HIV infection in the first few months of life. The most effective intervention to reduce perinatal HIV infection will be the better identification of HIV positive pregnant women with the subsequent introduction of measures to interrupt vertical transmission of HIV.

Mother-to-child transmission of human immunodeficiency virus (HIV) in Ireland: a prospective study.

Symptomatic HIV infection was first diagnosed in an Irish child in 1985. A prospective study was initiated to determine the vertical transmission rate (VTR) of HIV and the average age of infant seroreversion and to monitor clinical, immunologic and virologic evidence for HIV infection in seroreverters. Ninety three HIV positive infants have been prospectively identified since 1985. The predominant underlying maternal risk factor for HIV infection is intravenous drug use (IVDU) (96 per cent). Of 93 infants, median gestational age was 40 weeks and median birth weight 3125 grams. Ninety-four per cent of infants were bottle fed. Currently 72 (77 per cent) infants are uninfected, 12 (13 per cent) are infected, 4 (4.5 per cent) are indeterminate and 5 (5.5 per cent) have been lost to follow up. The intermediate estimate of vertical transmission rate (VTR) is 14.3 per cent. The median age at documented seroreversion was 12 months. There are no significant differences between infected and non-infected children in male/female ratio, gestational age, mode of delivery or birth weight. Strategies to reduce the transmission of HIV among drug users in combination with routine antenatal screening and antiretroviral prophylaxis of vertical transmission are all measures which can reduce HIV infection in our children.

Childhood needlestick injuries in the Dublin metropolitan area.

Childhood needlestick injuries and other risk exposures outside of hospital are becoming increasingly common. A retrospective review of casenotes to ascertain the incidence, epidemiology and adequacy of management and follow-up of exposures in the Dublin metropolitan area revealed 52 cases between July 1995 and October 1996. Median age of children was 7.4 years. Most occurred in inner city areas with a recognised high prevalence of i.v. drug use. Only 2 high-risk exposures were identified. On presentation all cases received Hepatitis B vaccination and 56% received Hepatitis B immunoglobulin. Following Hepatitis B virus, Hepatitis C virus and Human immunodeficiency virus testing, no seroconversions have been identified to date in 9 children with completed tests. General follow-up and Hepatitis B immunisation when initiated were not always complete. Standardised management protocols and wider availability of counselling are recommended.

Perinatal outcome following conservative management of mid-trimester pre-labour rupture of the membranes.

OBJECTIVE: To assess perinatal outcome and the effect of antenatal steroid use following conservative management of 86 consecutive singleton pregnancies complicated by pre-labour rupture of membranes (ROM) in the mid-trimester (13-26 weeks; mean 22.8 weeks). METHODOLOGY: Review of obstetric and neonatal case notes between 1 January 1990 and 31 December 1993. RESULTS: The duration of ruptured membranes (latent period) ranged from 1.25 to 105 days (mean 23.8 days; median 14 days) and was inversely related to gestational age at ROM. There was clinical evidence of chorioamnionitis in 39.5% with placental histological changes consistent with chorioamnionitis in 76.6%. All infants were delivered before 33 weeks gestation (mean 26 weeks). Overall, the mortality rate was 43.0% but 62.5% in infants with ROM before 24 completed weeks gestation. Adverse outcome (defined as death, severe intraventricular haemorrhage (IVH) or periventricular leucomalacia (PVL)) occurred in 46.5% and was significantly related to both gestation at delivery and gestation at ROM. In the group (n = 40) with ROM before 24 weeks gestation, adverse outcome occurred in 65% and was inversely related to gestation at ROM independent of gestation at delivery. Antenatal steroid administration resulted in less adverse outcome independent of gestation at delivery (OR 0.31; 95% CI (0.09-0.98; P = 0.046)). CONCLUSION: From the neonatal perspective conservative management is justified for pregnancies with ROM at or after 24 weeks gestation; in this group the use of antenatal steroids prior to delivery may improve perinatal outcome. A poor outcome is associated with ROM that occurs before 24 weeks gestation.

Glycopeptide prescribing in an Australian tertiary paediatric hospital.

OBJECTIVE: To assess the extent and appropriateness of glycopeptide use in a tertiary Australian Paediatric hospital. METHODOLOGY: A retrospective analysis of prescriptions during a six-month period between July 1999 and January 2000. Medical records were examined and prescribing practices compared with the recommendations of the Hospital Infectious Control Practices Advisory Committee (HICPAC) and the Infectious Diseases Society of America (IDSA). RESULTS: Fifty-one patients were identified who received a total of 98 glycopeptide prescriptions. The Haematology/ Oncology unit prescribed 71/98 (72.4%). 68/98 (69.4%) patients received vancomycin, 9/98 (9.2%) received teicoplanin and 21/98 (21.4%) a combination of both. 81/98 (82.7%) had central venous catheters and 69/98 (70.4%) were immunocompromised. 48/98 (49%) prescriptions were for empiric treatment with 38/98 (38.8%) for prophylaxis and 11/98 (12.2%) therapeutic. 19/98 (19.4%) prescriptions were deemed appropriate, 6 (6.1%) by HICPAC criteria, and a further 13 (13.3%) by IDSA or other criteria. Of 19 prescriptions started appropriately, only 7/17 (41.1%) were continued appropriately beyond 48 h. Appropriate cultures were taken before prescription in 93.3% of cases. Dose was appropriate in 91/98 (92.9%) and frequency appropriate in all cases. The cost of inappropriate prescribing was approximately $9500. DISCUSSION: A high rate of inappropriate glycopeptide prescribing was evident in this paediatric population. Inappropriate prescribing existed across all subspecialties. Use was primarily for empiric therapy and prophylaxis in young children with an oncology diagnosis. A number of situations existed where glycopeptide prescription was felt appropriate despite not being included in HICPAC/IDSA guidelines. Areas with high rates of inappropriate prescribing were identified and will be targeted for education and intervention. Audit of practice continues.

Glycopeptide prescribing in a tertiary referral paediatric hospital and applicability of hospital infection control practices advisory committee (HICPAC) guidelines to children.

UNLABELLED: This study was undertaken to investigate the frequency of, indications for and appropriateness of glycopeptide prescription in a paediatric tertiary referral hospital and to assess the usefulness of the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines. A prospective audit of all systemic glycopeptide prescriptions over a 2-month period was undertaken. Clinical and microbiological data were recorded. Of 2810 hospital admissions, systemic IV glycopeptides were prescribed on 57 occasions to 50 patients, 30 (52.6%) for vancomycin and 27 (47.4%) for teicoplanin. Prescriptions were for 34 males and 23 females aged from 2 weeks to 11 years (mean 15 months; median 9 months). Median hospital stay was 50 days. Glycopeptides were given to the following patient groups: cardiology 7 (12%), prophylaxis for cardiac surgery 11 (19%), post-cardiac surgery 1 (1.8%), oncology 14 (24.6%), post-gastrointestinal tract surgical 8 (14%), general surgical 9 (15. 8%) and medical 7 (12.3%). Twenty three children (41.8%) had central lines in situ. Reason for use of glycopeptide was therapeutic in 7 (12.3%), empiric in 38 (66.7%), and as prophylaxis in 12 (21.1%). Eight (14%) prescriptions met strict HICPAC criteria, but a further 22 (39%) prescriptions were considered appropriate in this high-risk population. Glycopeptides were chosen appropriately for cardiac surgery prophylaxis in a further 10 (18%) but timing and duration of use in this group was inappropriate. Of all prescriptions, use was empiric in 38 (76%) and appropriate cultures were obtained at the time of commencement in only 13 (34%) of these. Glycopeptides were not used for routine surgical prophylaxis or for first-line empiric treatment of febrile neutropenia. CONCLUSIONS: The strict implementation of HICPAC guidelines may not always be appropriate for children at risk of beta-lactam resistant gram-positive infections. Hospital guidelines need to be tailored to the patient population and microbial susceptibility patterns of each institution. Appropriate cultures should be obtained at the time glycopeptide treatment is begun so that duration of exposure can be limited.