Pronounced interplay between intrinsic phase-coexistence and octahedral tilt magnitude in hole-doped lanthanum cuprates.

Definitive understanding of superconductivity and its interplay with structural symmetry in the hole-doped lanthanum cuprates remains elusive. The suppression of superconductivity around 1/8th doping maintains particular focus, often attributed to charge-density waves (CDWs) ordering in the low-temperature tetragonal (LTT) phase. Central to many investigations into this interplay is the thesis that La1.875Ba0.125CuO4 and particularly La1.675Eu0.2Sr0.125CuO4 present model systems of purely LTT structure at low temperature. However, combining single-crystal and high-resolution powder X-ray diffraction, we find these to exhibit significant, intrinsic coexistence of LTT and low-temperature orthorhombic domains, typically associated with superconductivity, even at 10 K. Our two-phase models reveal substantially greater tilting of CuO6 octahedra in the LTT phase, markedly buckling the CuO2 planes. This would couple significantly to band narrowing, potentially indicating a picture of electronically driven phase segregation, reminiscent of optimally doped manganites. These results call for reassessment of many experiments seeking to elucidate structural and electronic interplay at 1/8 doping.

Distance to water source and altitude in relation to active trachoma in Rombo district, Tanzania.

OBJECTIVES: To investigate the relationship between distance to water source, altitude and active trachoma in children in Rombo district, Tanzania. METHODS: In each of Rombo's 64 villages, 10 balozis (groups of 8-40 households) were selected at random and all resident children aged 1-9 years were examined for clinical signs of active trachoma. The households of these children and village water sources were mapped using differentially corrected global positioning system data to determine each household's altitude and distance to the nearest water supply. RESULTS: We examined 12 415 children and diagnosed 1171 cases of active trachoma (weighted prevalence=9.1%, 95% CI: 8.0, 10.2%). Active trachoma prevalence ranged from 0% to 33.7% across villages. Increasing distance to the nearest water source was significantly associated with rising trachoma prevalence (age-adjusted odds ratio for infection (OR) for highest quartile compared to lowest=3.56, 95% CI 2.47, 5.14, P for trend <0.0001). Altitude was significantly inversely associated with trachoma prevalence (age-adjusted OR for highest quartile compared to lowest=0.55, 95% CI 0.41, 0.75, P for trend <0.0001). These associations remained significant after adjustment in multivariate analysis. CONCLUSIONS: Trachoma is endemic in Rombo district, although the prevalence varies considerably between villages. Spatial mapping is a useful method for analysing risk factors for active trachoma.

A randomised controlled trial of azithromycin following surgery for trachomatous trichiasis in the Gambia.

BACKGROUND/AIM: Trachomatous trichiasis frequently returns following surgery. Several factors may promote recurrence: preoperative disease severity, surgeon ability, surgical procedure, healing responses, and infection. This study investigates whether enhanced control of infection, both of Chlamydia trachomatis and other bacteria, with azithromycin can improve surgical outcome in a trachoma control programme. METHODS: Individuals with trachomatous trichiasis were examined and operated. After surgery patients were randomised to the azithromycin or control group. The azithromycin group and children in their household were given a dose of azithromycin. Antibiotic treatment was repeated at 6 months. All patients were reassessed at 6 months and 12 months. Samples were collected for C trachomatis polymerase chain reaction and general microbiology at each examination. RESULTS: 451 patients were enrolled. 426 (94%) were reassessed at 1 year, of whom 176 (41.3%) had one or more lashes touching the eye and 84 (19.7%) had five or more lashes. There was no difference in trichiasis recurrence between the azithromycin and control group. Recurrent trichiasis was significantly associated with more severe preoperative trichiasis, bacterial infection, and severe conjunctival inflammation at 12 months. Significant variability in outcome was found between surgeons. Visual acuity and symptoms significantly improved following surgery. CONCLUSION: In this setting, with a low prevalence of active trachoma, azithromycin did not improve the outcome of trichiasis surgery conducted by a trachoma control programme. Audit of trichiasis surgery should be routine.

Long term outcome of trichiasis surgery in the Gambia.

BACKGROUND: Trichiasis surgery is believed to reduce the risk of losing vision from trachoma. There are limited data on the long term outcome of surgery and its effect on vision and corneal opacification. Similarly, the determinants of failure are not well understood. METHODS: A cohort of people in the Gambia who had undergone surgery for trachomatous trichiasis 3-4 years earlier was re-assessed. They were examined clinically and the conjunctiva was sampled for Chlamydia trachomatis polymerase chain reaction (PCR) and general bacterial culture. RESULTS: In total, 141/162 people were re-examined. Recurrent trichiasis was found in 89/214 (41.6%) operated eyes and 52 (24.3%) eyes had five or more lashes touching the globe. Corneal opacification improved in 36 of 78 previously affected eyes. There was a general deterioration in visual acuity between surgery and follow up, which was greater if new corneal opacification developed or trichiasis returned. Recurrent trichiasis was associated with severe conjunctival inflammation and bacterial infection. C trachomatis was detected in only one individual. CONCLUSIONS: Recurrent trichiasis following surgery is a common potentially sight threatening problem. Some improvement in the cornea can occur following surgery and the rate of visual loss tended to be less in those without recurrent trichiasis. The role of conjunctival inflammation and bacterial infection needs to be investigated further. Follow up of patients is advised to identify individuals needing additional surgical treatment.

Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci.

Experimental evidence implicates interferon gamma (IFNgamma) in protection from and resolution of chlamydial infection. Conversely, interleukin 10 (IL10) is associated with susceptibility and persistence of infection and pathology. We studied genetic variation within the IL10 and IFNgamma loci in relation to the risk of developing severe complications of human ocular Chlamydia trachomatis infection. A total of 651 Gambian subjects with scarring trachoma, of whom 307 also had potentially blinding trichiasis and pair-matched controls with normal eyelids, were screened for associations between single-nucleotide polymorphisms (SNPs), SNP haplotypes and the risk of disease. MassEXTEND (Sequenom) and MALDI-TOF mass spectrometry were used for detection and analysis of SNPs and the programs PHASE and SNPHAP used to infer haplotypes from population genetic data. Multivariate conditional logistic regression analysis identified IL10 and IFNgamma SNP haplotypes associated with increased risk of both trachomatous scarring and trichiasis. SNPs in putative IFNgamma and IL10 regulatory regions lay within the disease-associated haplotypes. The IFNgamma +874A allele, previously linked to lower IFNgamma production, lies in the IFNgamma risk haplotype and was more common among cases than controls, but not significantly so. The promoter IL10-1082G allele, previously associated with high IL10 expression, is in both susceptibility and resistance haplotypes.

An index of community ocular Chlamydia trachomatis load for control of trachoma.

Quantitative PCR (Q-PCR) technology has recently been applied to the measurement of ocular loads of Chlamydia trachomatis. We present an index called the community ocular C. trachomatis load (COCTL) which is similar to the community microfilarial load (CMFL) of onchocerciasis. Our index has the advantage of being scale-independent so that, for example, percentage changes are the same whether calculated per eye swab or per Q-PCR capillary. The COCTL for a population or subgroup is formed by adding the arbitrary concentration of 1 organism per ml to each individual Q-PCR quantification, calculating the geometric mean, and finally subtracting 1 per ml again. The use of the COCTL is illustrated in a study of trachoma in northern Tanzania. The COCTL is higher in people with clinical trachoma than those without (5.8 organisms per swab vs. 0.1), and in children aged six months to ten years than in the overall population (1.1 vs. 0.4). The COCTL index is potentially useful for sentinel sites, operational research and calibration of clinical measures of trachoma.

The household distribution of trachoma in a Tanzanian village: an application of GIS to the study of trachoma.

The distribution of active trachoma in Kahe Mpya, Tanzania, an endemic village of approximately 1000 people, was mapped spatially and analysed for associated risk factors and evidence of clustering. An association between distance to water source and active disease was demonstrated, although this was reduced after accounting for the lack of independence between cases in the same household. Significant clustering of active trachoma within households was demonstrated, adding support to the hypothesized importance of intra-familial transmission. The spatial distribution of trachoma was analysed using the spatial scan statistic, and evidence of clustering of active trachoma cases detected. Understanding the distribution of the disease has implications for understanding the dynamics of transmission and therefore appropriate control activities. The demonstrated spatial clustering suggests inter-familial as well as intra-familial transmission of infection may be common in this setting. The association between active trachoma and geographical information system (GIS) measured distance to water may be relevant for planning control measures.

Flies and Helicobacter pylori infection.

Houseflies have been proposed to be a reservoir and vector for Helicobacter pylori. We assessed the effect of insecticide spraying in villages in The Gambia on H. pylori infection in young children. Effective control of flies did not prevent infection with H. pylori.

Lymphatic filariasis in the Karonga district of northern Malawi: a prevalence survey.

In Malawi, two main foci of lymphatic filariasis (LF) are known to exist: one in the south, in the Shire valley, and the other in the north, along the Songwe River, on the border with Tanzania. There have been no formal surveys in the Songwe area since the 1960s but an opportunity arose in 2000-2001 to map LF in this area, in the context of a leprosy survey that formed part of the follow-up of a large leprosy and tuberculosis vaccine trial. Overall 687 immunochromatographic (ICT) tests were carried out. Wuchereria bancrofti antigenaemia was found in > 25% of adults in each of the 12 villages sampled (four in the Songwe area and eight in the rest of the Karonga district), with village prevalences varying from 28%-58%. Of the 685 adult male residents of the Songwe area who were each given full-body clinical examinations, 80 (11.7%) were identified as cases of hydrocele. Lymphoedema was found in seven (1.0%) of these adult males and in 29 (3.7%) of the 769 adult female residents of the Songwe area who were also examined. Microfilariae were detected in 33 (30.8%) of the 107 thick smears of night-blood samples that were made from individuals with positive ICT cards. The W. bancrofti infection focus in Karonga district is therefore wider than was previously known. This has important implications for the implementation and eventual impact of LF-control activities in this area.

Design and analysis issues in cluster-randomized trials of interventions against infectious diseases.

This paper discusses the application of the cluster-randomized trial (CRT) design to evaluate the effectiveness of interventions against infectious diseases. In addition to the usual rationale for this design, there are a number of other advantages that are peculiar to the study of infectious diseases. In particular, CRTs are able to measure the overall effect of an intervention at the population level, capturing both the direct effect of an intervention on an individual's susceptibility to infection, and also the indirect effects due to changes in risks of transmission to other individuals, or to the mass effect or 'herd immunity' resulting from intervening in a large proportion of the population. We briefly review published CRTs of interventions against infectious diseases, most of which have been conducted in the developing countries where such diseases predominate. The focus is on trials in which communities or other large groupings are randomized, and in which impacts on infectious disease incidence or mortality are assessed. We then discuss three issues that are of special relevance to CRTs of infectious diseases. First, issues relating to the definition and size of clusters; secondly, the role of matching or stratification, and the choice of matching factors; and thirdly, the definition of direct and indirect effects of intervention, and methods of assessing these components in a CRT. We conclude by outlining some areas for future research.

Bacterial, viral and parasitic aetiology of paediatric diarrhoea in the highlands of Papua New Guinea.

Enteropathogens and clinical features associated with diarrhoea were investigated in 1526 children admitted over a 5-year period to the paediatric ward of a hospital in the highlands of Papua New Guinea. Overall, a recognized pathogen was isolated from 39 per cent of the children admitted with diarrhoea. The most commonly isolated agents were rotavirus (23 per cent), Shigella spp. (13 per cent), Campylobacter spp. (12 per cent), Cryptosporidium parvum (10 per cent) and enteropathogenic Escherichia coli (8 per cent). The clearest clinical associations were rotavirus with vomiting, and Shigella with blood and pus in the stool. A control series of children admitted with other complaints was also included, and the odds ratios for diarrhoea for the above five pathogens were 18.2, 9.6, 3.7, 2.2, and 1.6, respectively.

Wuchereria bancrofti infection and disease in a rural area of Papua New Guinea.

The relation between infection and disease in lymphatic filariasis is still imperfectly understood. This paper presents baseline data on microfilaraemia, oedema and acute episodes from a drug trial against bancroftian filariasis in Papua New Guinea. Among 2,187 people with data on these manifestations, 1,144 were microfilaraemic, 78 had leg oedema, 356 had acute episodes and 919 were negative for all three. All possible combinations of the three manifestations were observed. The relationships between microfilaraemia and disease are found to be time-dependent. Microfilaraemia is a positive risk factor for leg oedema at lower ages, but a negative one at higher ages. Acute disease over a whole year is found to be positively associated with a point estimate of microfilaraemia. However, when considering incidence within a month of the time of the blood sample, a curvilinear relationship is found and people with low but positive microfilarial counts have the lowest incidence. Possible explanations for these findings are discussed.

Towards eliminating lymphatic filariasis in Papua New Guinea: impact of annual single-dose mass treatment on transmission of Wuchereria bancrofti in East Sepik Province.

The impact of annual single-dose community-wide treatment on the transmission of Wuchereria bancrofti was investigated in 5 villages in the East Sepik Province where pretreatment prevalence of microfilaraemia ranged from 34% to 73%. Anopheles punctulatus and An. koliensis were the only carriers of the parasite. 3 villages received diethylcarbamazine citrate (DEC) in combination with ivermectin (IVR) and 2 received DEC alone. The rate and intensity of microfilaraemia were both reduced in all 5 villages. Reduction in prevalence was between 43% and 67% in the DEC+IVR study villages and between 24% and 27% in the DEC alone villages. Density was reduced by between 81% and 95% in the DEC+IVR villages and between 69% and 74% in the DEC alone villages. Breaks in perennial transmission (failure to detect infective mosquitoes in four or more consecutive monthly collections) occurred in all 3 communities treated with DEC+IVR. Transmission was almost completely interrupted in 2 villages, where infective mosquitoes were not detected during 11 of the 12 months following treatment. We concluded that repeated annual single-dose community-wide treatment with DEC+IVR could lead to complete interruption of transmission and ultimately elimination of lymphatic filariasis.

Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival.

Field studies were carried out to determine the impact of mass human treatment with ivermectin on the survival of anthropophagic mosquitoes of the Anopheles punctulatus complex (Diptera: Culicidae), the vectors of lymphatic filariasis and malaria in Papua New Guinea. In a village where mass treatment had been given, using 400 microg/kg ivermectin plus 6 mg/kg diethylcarbamazine citrate (DEC), we performed pre- and post-treatment collections of freshly blood-engorged mosquitoes from the same nine bedrooms. All blood-fed mosquitoes collected less than 4 days after mass treatment died within 9 days, whereas 67% of those collected before treatment survived for >9 days. Comparison (using the log-rank test) of the survival curves for mosquitoes collected (i) before treatment, (ii)<4 days after treatment, and (iii) 28 days after treatment, showed the survival rate of group (ii) to be significantly lower than the other two (chi2=176, df=2, P<0.0001). Pre- and post-treatment all-night landing catches showed no reduction in human biting rates in the experimental village. In another village, where people were mass treated with ivermectin (400 microg/kg) only, the survival rates of freshly blood-engorged An. punctulatus collected from bedroom resting-sites less than 1 day after treatment, were compared to similar collections carried out at the same time in a nearby village where people were not treated with ivermectin. The 48-h survival rate for the ivermectin-treated village was 31% compared to 94% for the other; this difference was highly significant (chi2=32.42, df=1, P<0.0001). Mosquitoes fed 2 months post-treatment with DEC or collected 38 days post-treatment with ivermectin had normal survival rates. We conclude that the duration of the systemic lethal effect of ivermectin on mosquitoes is insufficient to be of epidemiological significance in filariasis control programmes that are based on biannual and annual single-dose treatments, but might reduce vectorial capacity sufficiently to block epidemics of dengue or even malaria.

Acute disease episodes in a Wuchereria bancrofti-endemic area of Papua New Guinea.

Acute disease episodes of Bancroftian filariasis were monitored prospectively in a rural area of Papua New Guinea. The frequency and duration of episodes were recorded for the leg, arm, scrotum, and breast. A very high incidence of acute disease was observed; 0.31 episodes per person-year in the leg alone. Incidence generally increased with age, except in the breast, where episodes were concentrated in the reproductive age range. Males had slightly higher incidence than females in the leg and arm. Chronic disease was strongly associated with acute disease incidence in all locations. Microfilaremia had a statistically significant association with acute disease in the leg, arm, and breast, but not the scrotum. This study again demonstrates the high burden of acute manifestations of lymphatic filariasis, and provides new information on risk factors, which may lead to better understanding of etiology and control prospects.

The effect of pregnancy on Wuchereria bancrofti microfilarial load in humans.

As part of a drug trial against bancroftian filariasis in the East Sepik Province of Papua New Guinea we measured the pre-treatment microfilarial densities of 2219 individuals. Mean levels generally increased with age in both sexes, with a tendency to plateau at the highest ages. However, there was a reduction among women of approximately reproductive age. Allowing for the tendency for aggregation to decrease with age, this reduction was statistically significant. However, a comparison of pregnant women and controls showed no evidence that the reduction is specifically related to pregnancy. Moreover, a simple differential equation model of microfilarial acquisition and loss suggests that age-specific patterns of exposure are also unlikely to be solely responsible. Therefore, we suggest that the observed reduction in microfilarial intensity may result from hormonal changes associated with female reproduction, possibly in combination with other factors.