Impact of anti-Hib conjugate vaccine on the incidence of Haemophilus influenzae meningitis in Brazil's Federal District: results of a three-year follow-up]

INTRODUCTION: Type b Haemophilus influenzae (Hib) continues to be an important causative agent of various infectious processes, and its encapsulated strains cause invasive disease. In some aboriginal populations, the incidence of Hib infections in children under five is greater than 400 per 100,000. In the seventies and eighties, vaccines against Hib were developed after antibodies against the capsular component were identified. The objective of this paper was to estimate the impact that the vaccine against Hib has had in Brazil's Federal District since it was introduced in March of 1998. METHODS: Using population-based data obtained from Brazil's Federal District's Ministry of Health's Surveillance System, rates of incidence of meningitis during the three years that preceded and that followed the introduction of the anti-Hib vaccine were compared. Comparisons were also drawn between changes in the trends observed. RESULTS: A comparison of the data from the two periods showed a decrease of approximately 90% in the incidence of Hib meningitis, but no concomitant decrease in other forms of bacterial meningitis was noted. There was also a proportional increase in the number of cases among infants 6 months of age and under due to a drop in the incidence of the disease in children older than 6 months. CONCLUSION: As a result of the introduction of the conjugated anti-Hib vaccine in Brazil's Federal District, the incidence of Hib meningitis among children 7 months to 35 months of age dropped from 168 per 100,000 to 15 per 100,000 (91.1%).     

Neuromeningeal enterovirus infections in Tunisia: epidemiology, clinical presentation, and outcome of 26 pediatric cases

Non-polio enteroviruses are the most common identified cause of viral neuromeningeal infections following the introduction of the mumps and polio vaccines. OBJECTIVE: The aim of this study was to describe the epidemiology, clinical presentation, and the outcome of enteroviral infections of the CNS. METHOD AND PATIENTS: We performed a prospective study on 41 children admitted for viral neuromeningeal infections in the pediatric department of Monastir between December 2001 and November 2002. Enteroviruses were detected from cerebrospinal fluid by RT-PCR. RESULTS: This study showed that enteroviruses were responsible for 63.4% of the infections. The mean age of patients was 6.1 years. Aseptic meningitis was diagnosed in 14 cases and encephalitis in 10. The most frequent symptom was fever (61.5%), followed by seizures (42.3%), and confusion (23%). On follow-up, all patients with meningitis had recovered without sequels. Neurological complications in patients with encephalitis were epilepsy (3 cases), cerebral palsy (2 cases), and mental retardation (1 case). CONCLUSION: This study confirmed that enteroviruses were the most common cause of viral infections of the CNS. Common use of RT-PCR can have a significant impact on the outcome of patients with enterovirus infections.     

Viral meningitis in child care center staff and parents: an outbreak of echovirus 30 infections.

OBJECTIVE: A report of five cases of viral meningitis among adults with children enrolled in a child care center prompted an investigation of risk factors for viral transmission from children to adult household members. METHODS: To determine recent echovirus 30 (E30) infections, the authors conducted a serologic survey. To determine risk factors for infection among adult household members, they conducted a retrospective cohort study using written questionnaires. RESULTS: Recent E30 infections were found in 84% of children tested, 57% of adult household members tested, and 47% of staff members tested. Infected adults were more likely than infected children to have clinical meningitis. Among adult household members, changing diapers was a risk factor for recent infection. Women who changed > or = 90 diapers per month had a higher infection rate than women who changed fewer diapers; in contrast, men who changed > or = 90 diapers per month had a lower infection rate than men who changed fewer diapers. Handwashing was protective: there was a negative correlation between handwashing after diaper changes and E30 infection among adults with infected children in diapers. CONCLUSIONS: Because child care centers can be a source of enteroviral infections among adult household members, adults with viral meningitis should be questioned about their children's day care or preschool attendance. The importance of handwashing should be stressed to adults with children in day care.     

玉溪市5岁以下婴幼儿病毒性腹泻危险因素调查

目的探讨5岁以下婴幼儿病毒性腹泻的危险因素,为婴幼儿腹泻病的防控提供科学依据。方法采用1∶1配对对照研究方法,对玉溪市2015年哨点医院收治的5岁以下病毒性腹泻儿童进行问卷调查,并经过logistic回归分析影响5岁以下婴幼儿病毒性腹泻的因素。结果 112例病例中,男女性别比为1.87∶1,平均年龄(13.72±6.25)个月,最小为45天。多因素logistic回归分析结果显示:接种疫苗是婴幼儿病毒性腹泻的保护因素,餐具没有消毒(OR=3.52,95%CI:3.07,6.40)、婴幼儿饭前没有洗手(OR=1.67,95%CI:1.18,2.33)、婴幼儿便后没有洗手(OR=1.14,95%CI:1.09,2.60)以及室内有苍蝇(OR=3.40,95%CI:1.38,6.41)是婴幼儿病毒性腹泻的危险因素。结论接种疫苗是婴幼儿病毒性腹泻的保护因素,不良卫生习惯、较差生活环境增加了婴幼儿病毒性腹泻发生的危险性。为有效控制婴幼儿腹泻的发病率,大力开展健康教育和健康促进,接种疫苗,养成良好卫生行为。     

Efficacy of meat and iron-fortified commercial cereal to prevent iron depletion in cow milk-fed infants 6 to 12 months of age: a randomized controlled trial

OBJECTIVE: To determine whether utilization of iron from infant cereal and pureed meat was sufficient to prevent iron depletion and/or anaemia in infants 6 to 12 months old fed whole cow milk (WCM) as their primary milk source. DESIGN: Six-month-old infants were randomized into a treatment group (n = 43) receiving iron-fortified infant cereal (10.2 mg iron), pureed meat (0.75-1.7 mg iron) and WCM for six months or a control group (n = 54) receiving no dietary intervention. Haemoglobin < 110 g/L or ferritin < 10 micrograms/L (measured bi-monthly), confirmed in a second blood sample, defined end-points. RESULTS: Proportion reaching end-point was similar between the treatment (3/43) and control infants (5/54) (p = 0.66). Infants not complying with the protocol were at greater risk of reaching end-point (p = 0.0002). Change in haemoglobin and ferritin across age was similar in both groups. CONCLUSIONS: Iron deficiency is not a concern in WCM-fed infants after six months of age if iron-containing complementary foods are concurrently ingested.     

Epidemiology of invasive Haemophilus influenzae infections in England and Wales in the pre-vaccination era (1990-2).

This survey defined the pattern of invasive Haemophilus influenzae infections during 1990-2 in six regions in England and Wales during the pre-vaccination era providing a baseline against which any changes in patterns of disease due to the introduction of the Haemophilus influenzae type b vaccination programme can be monitored. A total of 946 cases of invasive Haemophilus influenzae were recorded during the survey period of which almost 90% were due to type b and most of the remainder were non-typeable. Type b infections occurred predominantly in children less than 5 years of age (88%) with the highest attack rate in male infants in the 6-11 month age group. Diagnostic category varied with both age and serotype; meningitis was the commonest presentation overall but pneumonia and bacteraemia were more common in adults and non-typeable isolates. Mortality was highest in neonates and the elderly (over 65 years of age) who were more likely to have an underlying predisposing condition than older children and adults. Children under 5 years of age had a higher case fatality rate for non-typeable than for type b infections. Ampicillin resistance was 15% and there were no cefotaxime resistant type b isolates.     

Group day care and the risk of serious infectious illnesses

Group day care attendance has been associated with an increased risk of infectious illnesses. With the exception of illnesses caused by Haemophilus influenzae type b (H. influenzae) and Neisseria Meningitidis (N. meningitidis), most studies have examined relatively mild illnesses. A matched case-control study was conducted to study the association between group day care attendance and serious infectious illnesses (requiring hospitalization). Cases were children aged 3 months to 59 months hospitalized for an infectious illness at Yale-New Haven Hospital from June 1984 through November 1986. Each case was matched to a control by date of birth and regular pediatrician, and their parents were interviewed. Data from 193 matched pairs were analyzed using conditional logistic regression. The matched odds ratio (OR) for the association between group day care attendance and serious infectious illness was 1.39 (95% confidence interval (CI) 0.87-2.20). For pairs in which the case had an H. influenzae infection (n = 46), the odds ratio was 8.00 (95% CI 1.00-63.85), and for N. meningitidis (n = 9) the odds ratio was 2.00 (95% CI 0.39-10.27). In the remaining 138 pairs, the odds ratio was 1.27 (95% CI 0.76-2.12). In infants less than 12 months of age (n = 64) the odds ratio for group day care and illnesses (excluding H. influenzae and N. meningitidis) was 1.66 (95% CI 0.73-3.80) and it was 1.06 (95% CI 0.55-2.05) for older children (n = 74). The data suggested an association between day care attendance and invasive bacterial infections other than H. influenza and N. meningitidis, OR = 2.00 (95% CI 0.81-4.94) but not for local bacterial infections, OR = 1.00 (95% CI 0.25-4.00) or infections of presumed viral etiology, OR = 1.00 (95% CI 0.49-2.05). Important predictors of serious infections (excluding H. influenzae and N. meningitidis) were passive smoking (OR = 3.96, 95% CI 2.16-7.24) and sharing a bedroom (OR = 2.31, 95% CI 1.23-4.33). These findings do not suggest that group day care attendance poses a large risk of serious infections (other than H. influenzae or N. meningitidis) to young children; however, at least one preventable factor, passive smoking, may.     

Impact of Tdap vaccine during pregnancy on the incidence of pertussis in children under one year in Brazil – A time series analysis

Pertussis is a globally distributed infectious disease that is a significant cause of morbidity and mortality, especially in infants who are too young to be immunized. This disease is common in childhood, and when it occurs during the first few months of life, it leads to hospitalization and, sometimes, death. Brazil has adopted the strategy of maternal immunization against pertussis in late 2014. This study aims to analyze public data on the disease to determine whether there was an impact on the disease burden following the introduction of the vaccine Tdap in pregnant women and its magnitude. We performed a time-series analysis of the incidence of pertussis between October 2010 and January 2019. We stratified the population of interest into three groups: infants aged less than two months old, infants aged two to six months, and infants aged six months to one year, according to Brazil's vaccination schedule. We found a protective effect of maternal vaccination in all age groups, more prominent on the first group. Before the intervention, infants under two months had a higher risk of getting pertussis in comparison with infants two to six months old (HR 1.15, CI 95%: 1.11–1.19). After the intervention, age under two months is a protective factor compared with two to six months (HR 0.90, CI 95%: 0.82–0.98). The pertussis incidence reduced in all age groups and all Brazil's Regions.     

7. Dynamics of multiple Plasmodium falciparum infections in infants in a highly endemic area of Tanzania

The force of infection and recovery rate for malaria in infants in a highly endemic area of Tanzania were analysed using polymerase chain reaction-restriction fragment length polymorphism genotyping of the Plasmodium falciparum msp2 locus in 99 paired blood samples. Overall, new genotypes were acquired at a rate of 0·064 per day, and the average duration of infections was estimated to be 23 d. The highest recovery rates were in children under 4 months of age. The higher susceptibility of infants to clinical malaria in comparison with older children, in areas of very high transmission, may be largely a consequence of the short duration of infections which precludes the establishment of concomitant immunity. The high turnover of infections also implies that infection prevalence and multiplicity approach an equilibrium even in very young children, and calls into question the use of infant conversion rates as a measure of transmission intensity.     

Meningococcal disease from the public health policy perspective

The incidence and serogroup distribution of meningococcal disease vary by country and over time. In the United States, the annual incidence has been 0.5-1.1/100,000 or about 1400-2800 cases annually with the highest incidence being in infants less than six months of age [1]. Given the availability of conjugate vaccines against serogroups A, C, W-135 and Y and the possible future availability of a group B vaccine, there is now the potential to effectively control meningococcal disease globally. The question then arises as to how public health policy can best serve this goal. MCV-D (Menactra) is not immunogenic in the first six months of life. For this reason, it has been proposed that immunization with this vaccine begin at nine months of age with a second dose at 12 months. This proposal would rely upon indirect or "herd protection" to protect young infants with the highest disease incidence. A second vaccine, MCV-CRM (Menveo), is immunogenic in the first months of life and is under consideration by the FDA for use in infants two months of age and older. MCV-CRM could provide direct protection of this high risk group, but three primary doses plus a toddler booster are required for this approach. In developing public health recommendations to protect infants, policy makers must weigh the additional cost of immunizing with four doses versus the possibility that relying on herd protection using a lower cost immunization schedule beginning at nine months of age may leave young infants unprotected. Optimal control of meningococcal disease will require both the public will and public policy to best serve this goal. The decision as to what ages to target and which schedules to use should not only take into account the cost of the program, but also the severity of the disease and the high level public concern regarding meningococcal disease.     

Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal.

A randomized, double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age) and infants aged 1-6 months who received a large, oral dose of vitamin A (15,000 retinol equivalents (RE) (50,000 IU) and 30,000 RE (100,000 IU), respectively) or placebo (75 RE (250 IU) and 150 RE (500 IU), respectively) in oil. Infants (vitamin A group, n = 1461; controls, n = 1379) were assessed for vomiting, loose stools, fever, and irritability during the 24 hours before and after dosing. Fontanelles were palpated 24 hours after dosing. Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE. Compared with controls the older infants who ingested 30,000 RE had a 1.6% excess rate of vomiting (95% confidence interval (CI): 0.2-3.0%) and a 0.5% excess rate (95% CI: -0.1 to 1.1%) in the occurrence of bulging fontanelles. There were no other significant differences in the older infants. The controlled, periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants; a 30,000 RE dose is associated with a minimum risk of transient, acute side-effects.     

Seroprevalence of Varicella-Zoster virus IgG antibodies in Swiss children during the first 16 months of age

QUESTION UNDER STUDY: To investigate the persistence of maternal IgG antibodies against Varicella-Zoster virus (VZV) in infants and young children. METHODS: Serum specimens of children aged 0-16 months who had been hospitalized in our institution between 1994 and 1999 were identified from our routine serum collection. Exclusion criteria were: preterm delivery (<37 gestational weeks); suspected varicella infection or presence of exanthema of unknown etiology at time of serum collection; transfusion of blood products during 6 months preceding serum collection; foreign born mother; and previous VZV immunization. Serotesting for IgG antibodies against VZV was performed by use of a commercially available ELISA kit. RESULTS: Two hundred and fifty three serum specimens from 240 patients were analyzed. Age distribution of patients at time of specimen collection was: 0-3 months: n=57; >3-6 months: n=47; >6-9 months: n=47; >9-12 months: n=48; >12-16 months: n=54. Seroprevalence rates for IgG antibodies against VZV in the different age groups were 90% (0-3 months), 38% (>3-6 months); 0% (>6-9 and >9-12 months); and 7% (>12-16 months). CONCLUSIONS: Our results demonstrate high levels of passively acquired humoral immunity against varicella in Swiss infants during the first 3 months of life. Beyond the first 3 months of life IgG antibodies against VZV are lacking in the majority of patients and between 6 and 12 months of age all specimens tested were negative. Beyond the first year of life antibodies against varicella were detected in four samples, probably due to previous VZV infection. In accordance with current recommendations, VZV vaccination should ideally be administered to children 9 months of age and older, although our data indicate that successful immunization may be possible at earlier age (6 months onwards) in certain circumstances.     

Characteristics of the inhibition of interferon-alpha/beta production after crystalline nickel sulfide exposure.

Murine L-929 cells were treated with crystalline nickel sulfide (NiS), washed, and then exposed to polyriboinosinic-polyribocytidylic acid (Poly I:C) to induce interferon-alpha/beta (IFN-alpha/beta). Addition of crystalline NiS at different time points, from 24 hr prior to IFN induction (pretreatment) up to 12 hr after IFN induction, resulted in significant inhibition of IFN-alpha/beta production. In addition, 24-hr pretreatment of L-929 cells with crystalline NiS resulted in significantly decreased production of IFN-alpha/beta even 120 hr after addition of IFN inducer. IFN-alpha/beta at a known concentration was titered by means of a viral plaque reduction assay in crystalline NiS-treated L-929 cell cultures. Crystalline NiS did not show a significant inhibitory effect on the antiviral activity of IFN on L-929 cells as compared to controls. The results described here suggest that NiS has a rapid and a long-lasting inhibitory activity on the production of IFN-alpha/beta.     

不同夜间喂养终止时间对婴幼儿生长发育的影响

目的探讨不同夜间喂养终止时间对婴幼儿生长发育的影响。方法选取2017年1月至2018年1月于余姚市妇幼保健院足月出生并纳入儿童保健系统管理的418例婴幼儿为研究对象,根据在6月龄后是否继续夜间喂养分为继续组(n=270)和终止组(n=148),比较两组婴幼儿30月龄时身高、体重、超重肥胖发生率以及龋齿患病率。结果两组婴幼儿30月龄时,继续组身高显著低于终止组,继续组超重以及超重肥胖发生率显著高于终止组,差异均具有统计学意义(t/χ²值分别为6.283、5.279、8.173,均P<0.05);两组婴幼儿体重以及肥胖发生率比较差异无统计学意义(均P>0.05);418例研究对象中,53例出现龋齿,龋齿患病率为12.68%,继续组的龋齿患病率以及龋齿数均显著高于终止组,差异具有统计学意义(t/χ²值分别为7.392、5.283,均P<0.05)。结论6月龄后继续夜间喂养会严重影响婴幼儿的生长发育,显著增加超重肥胖率以及龋齿的患病风险。     

Paediatric hospitalizations due to whooping cough in Spain (1997–2017)

This epidemiological survey estimates the burden of whooping cough in infants up to 12 months old in Spain during a twenty-one-year period (1997–2017). The survey was conducted by reviewing data from the Spanish Surveillance System for Hospital Data. All hospitalizations due to whooping cough for infants, reported during the 1997–2017 period, were analysed. Codes were selected from the International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes 033.0–033.9. To explore the latest national outbreak and the implementation of vaccination in pregnant women, analyses were stratified to compare the following periods: 1997–2010, 2011–2015 and 2016–2017. A total of 13,352 hospital discharges for whooping cough in infants up to 12 months old were reported. A total of 6850 discharges in the period 1997–2010, 5271 in the period 2011–2015 and 1231 in 2016–2017 were identified. The annual hospitalization rate prior to 2011 was 131.02 cases per 100,000 infants; in 2011–2015, the rate was significantly higher (250.13 cases per 100,000 infants) and in 2016–2017 it decreased (157.69 cases per 100,000 infants). Most of the cases (n = 11,446) occurred in infants under 4 months of age, with hospitalization rates of 328.80, 670.81 and 385.84 cases per 100,000 infants up to 4 months of age in the periods 1997–2010, 2011–2015 and 2016–17, respectively. Thirty-four deaths occurred in the period 1997–2010, 36 in the period 2011–2015 and 4 in 2016–2017. All of the deaths occurred in infants under 4 months old. The case fatality rate did not vary significantly across the study periods. Whooping cough infections concentrate in infants up to 4 months of age in Spain. Public health measures such as vaccination of pregnant women, caregivers, health care professionals and relatives, especially young parents, could reduce the hospitalization burden during the current outbreak.     

早期喂养方式对2岁以下婴幼儿肥胖的影响

目的:观察分析早期喂养方式对2岁以下婴幼儿肥胖的影响,总结临床意义。方法:选取我院2010年10月至2011年10月接受体检的2岁以下婴幼儿240例,按照0～4个月喂养方式的差异分为A组(母乳喂养)131例和B组(人工喂养)109例,观察比较两组婴幼儿在不同月龄的肥胖、超重+肥胖发生率。结果:两组在月龄为18个月时肥胖率与12、24个月时超重+肥胖发生率比较有显著差异(P<0.05),具有统计学意义。结论:婴儿期尤其是婴儿早期实行母乳喂养,能够有效预防2岁以下婴幼儿肥胖发生值得大力提倡。     

Nosocomial rotavirus infections in a pediatric unit: surveillance during four successive winters

The incidence of rotavirus and RSV outbreaks during winter seasons leads to overcrowding of pediatric units in the Paris area, and increases the risk of viral nosocomial infections in hospitalized young infants. OBJECTIVE: The aim of this study was to measure the incidence of rotavirus nosocomial infections in children less than 2 years of age during 4 consecutive winters. METHODS: All infants admitted in the pediatric unit during the winter were prospectively screened for rotavirus with a stools exam. All children with negative stools examination on admission but developing diarrhea after 2 days of hospitalization underwent a new screening test for rotavirus in stools. RESULTS: During the 4 consecutive winters, the global incidence of nosocomial rotavirus infection was 13.9% (12.7 to 15.9%). Asymptomatic carriage of rotavirus was detected in 3% of admitted infants. The risk of nosocomial rotavirus infection increases with young age and the length of hospital stay. CONCLUSION: The incidence of nosocomial rotavirus infections was high in this unit. It is related to overcrowding due to coincidence of diarrhea and bronchiolitis outbreaks in the Paris area and to the young age of hospitalized patients.     

Paediatric infections: prevention of transmission and disease--implications for adults

Congenital and neonatal viral infections usually display their acute manifestations in highly recognisable ways, for example, congenital rubella, cytomegalovirus (CMV), varicella, human immunodeficiency (HIV) and herpes simplex virus (HSV) infection. By contrast, congenital hepatitis B virus (HBV) infection may go undetected for years. Some of these are preventable, but what is not immediately apparent is that the long-term consequences are being prevented as well. The long-term consequences of congenital and neonatal infections include endocrine, immunological and cardiovascular disease, deafness, visual problems, intellectual handicap and cerebral palsy. With the survival of HIV-infected infants into adulthood the long-term consequences will soon be described. Maternally and neonatally transmitted HBV infection predisposes to carriage, liver cirrhosis and hepatocellular carcinoma in young adults. Neonatal HBV vaccination prevents adult cancer. Acquired viral infections may predispose to subsequent lung disease, malabsorption, fertility problems or neurological disability. In the prevention of acquired rubella, varicella, HBV, influenza, poliovirus, measles and hepatitis A, one should mention the added bonus of preventing secondary cases by preventing transmission from infants and children to other children and adults. Preventing paediatric HSV, HBV and HIV infection in females may even be preventing subsequent transmission to future generations. Turning to paediatric bacterial infections, vaccinating infants and young children against pertussis could not only prevent transmission to older children and adults but also break the cycle, which then transmits from adults back to infants and young children. There is evidence that disease in older age groups, including adults, has been prevented by virtue of herd immunity from paediatric vaccination, e.g. Neisseria meningitidis Group C and Streptococcus pneumoniae. The add-on benefits for other generations, including for adults, arising from the prevention of paediatric infections are considerable.     

Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial

OBJECTIVE: To examine the effect of nucleotide (NT)-supplemented cow's milk-based formula on growth and biochemical indices of immune function in healthy infants. DESIGN: Randomized controlled trial (RCT) of formula-fed term infants allocated to control formula with an innate level of NT at 10 mg/l (n = 102), or formula fortified with NT at 33.5 mg/l (n = 98). A parallel group of 125 breastfed infants followed the same protocol as a reference. OUTCOME MEASURES: Growth was assessed at enrolment, 7 weeks, 4 months and 7 months of age. Natural killer cell activity, cytokine production and lymphocyte subpopulations were assessed at 7 weeks of age. Antibody responses to diphtheria toxoid, tetanus toxoid and Haemophilus influenzae type b (Hib) immunizations were measured at 7 months of age. RESULTS: NT supplementation did not influence the growth of formula fed infants or any markers of immunity measured at 7 weeks of age. Antibody responses to tetanus toxoid were higher in the NT-supplemented group (n = 68) compared with the control group (n = 70) at 7 months of age (median (5th, 95% percentile): 1.57(0.42, 3.43) vs 1.01(0.41, 4.66) IU/ml, P < 0.03). A difference between treatments was seen in response to diphtheria toxoid but this effect disappeared when adjusted for hepatitis B immunization at birth. There was no effect of treatment on antibody responses to Hib immunization. CONCLUSIONS: Supplementation of formulas with NT at 33.5 mg/l resulted in a modest improvement in antibody response consistent with RCTs that used higher levels of NT supplementation. Whether this translates to clinical benefits in well-nourished infants requires further study. SPONSORSHIP: Supported by a grant from Wyeth Nutrition. Dr Makrides was supported by an RD Wright Fellowship from the National Health and Medical Research Council of Australia and Dr Gibson was partially supported by the MS McLeod Research Trust and a Senior Research Fellowship from the National Health and Medical Research Council of Australia.