First Colombian multicentric newborn screening for congenital toxoplasmosis

Aims

To determine the incidence of congenital toxoplasmosis in Colombian newborns from 19 hospital or maternal child health services from seven different cities of five natural geographic regions (Caribbean, Central, Andean, Amazonia and Eastern).

Materials and Methods

We collected 15,333 samples from umbilical cord blood between the period of March 2009 to May 2010 in 19 different hospitals and maternal-child health services from seven different cities. We applied an IgM ELISA assay (Vircell, Spain) to determine the frequency of IgM anti Toxoplasma. The results in blood cord samples were confirmed either by western blot and repeated ELISA IgM assay. In a sub-sample of 1,613 children that were negative by the anti-Toxoplasma IgM assay, the frequency of specific anti-Toxoplasma IgA by the ISAGA assay was determined. All children with positive samples by IgM, IgA, clinical diagnosis or treatment during pregnancy were recalled for confirmatory tests after day 10 of life.

Results

61 positive samples for specific IgM (0.39%) and 9 positives for IgA (0.5%) were found. 143 questionnaires were positive for a clinical diagnosis or treatment for toxoplasmosis during pregnancy. 109 out of the 218 children that had some of the criteria for postnatal confirmatory tests were followed. Congenital toxoplasmosis infection was confirmed in 15 children: 7 were symptomatic, and three of them died before the first month of life (20% of lethality). A significant correlation was found between a high incidence of markers for congenital toxoplasmosis and higher mean annual rainfall for the city.

Conclusions

Incidence for congenital toxoplasmosis is significantly different between hospitals or maternal child health services from different cities in Colombia. Mean annual rainfall was correlated with incidence of congenital toxoplasmosis.     

Refinement of the mouse model of congenital toxoplasmosis

The goals of the present investigation, focusing on the BALB/c mouse model of congenital toxoplasmosis, were: (1) to find a method to determine pregnancy in the mouse. The method has 100% sensitivity and 72% specificity; (2) to test congenital transmission during the chronic stage of toxoplasmosis. This occurred in 2 of 10 mice tested; (3) to investigate the relationship between the infective dose and the rate of congenital transmission. This was not demonstrated for doses of 10(2) to 10(3) bradyzoites and oocysts of Prugniaud, M3 and M7741 strains, with transmission rates of 3 of 8 to 6 of 10 mice inoculated; (4) to determine homologous and heterologous protection. Homologous protection was demonstrated with Prugniaud cysts, and heterologous protection was found between ME-49 and M3 cysts. This finding is consistent with the uniform natural protection against congenital toxoplasmosis seen in immune women and ewes.     

Murine neonatal infection provides an efficient model for congenital ocular toxoplasmosis

Congenital infection is one of the most serious settings of infection with the apicomplexan parasite Toxoplasma gondii. Ocular diseases, such as retinochoroiditis, are the most common sequels of such infection in utero. However, while numerous studies have investigated the physiopathology of acquired toxoplasmosis, congenital infection has been largely neglected so far. Here, we establish a mouse model of congenital ocular toxoplasmosis. Parasite load and ocular pathology have been followed for the first 4 weeks of life. Ocular infection developed slowly compared to cerebral infection. Even after 4 weeks, not all eyes were infected and ocular parasite load was low. Therefore, we evaluated a scheme of neonatal infection to overcome problems associated with congenital infection. Development of infection and physiopathology was similar, but at a higher, more reliable rate. In summary, we have established a valuable model of neonatal ocular toxoplasmosis, which facilitates the research of the underlying physiopathological mechanisms and new diagnostic approaches of this pathology.     

Maternal smoking habits and congenital malformations: a population study.

Maternal smoking habits in 67 609 singleton pregnancies were examined. The overall incidence of congenital malformations was 2.8% in both non-smokers and smokers. On analysing congenital defects according to individual systems there was no significant difference in the incidence of malformations according to the number of cigarettes smoked, except for neural tube defects. Further analysis, taking social class into account, showed that neural tube defects were less common in non-smokers in social classes I and II. This study suggests that maternal smoking does not have teratogenic effects in the offspring, except in the case of neural tube defects, where the effect is at most modest.     

Maternal panic disorder and congenital abnormalities: a population-based case-control study

BACKGROUND: Maternal panic disorder in pregnancy is the most common manifestation of anxiety disorders in Hungary. The association between panic disorder during pregnancy and structural birth defects, i.e., congenital abnormalities, was studied. METHODS: The prevalence of maternal panic disorder in cases with different congenital abnormalities was compared to that of matched controls in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of 22,843 cases with congenital abnormalities, 210 (0.9%) had mothers with panic disorder during pregnancy compared to 187 (0.5%) of 38,151 controls (adjusted prevalence odds ratio [POR] 1.6; 95% CI, 1.3-2.0). Specific groups of congenital abnormalities were also assessed versus controls. Cases with isolated cleft lip with or without cleft palate (CL/P) (adjusted POR, 3.4; 95% CI, 1.3-9.0) and multiple congenital abnormalities (adjusted POR, 3.0; 95% CI, 1.2-7.2) were more likely to have had mothers with panic disorder during the study pregnancy. Notably, among mothers with panic disorders, the associations were found only in offspring of untreated mothers. CONCLUSIONS: A higher rate of isolated CL/P and multiple congenital abnormalities may be caused by the direct biological effect of panic disorder or by the interaction of maternal panic disorder and lifestyle factors. Antipanic drug treatment seems to have a protective effect for isolated CL/P and multiple congenital abnormalities. Birth Defects Research (Part A), 2006.     

Maternal alpha-fetoprotein screening: two years' experience in a low-risk district.

Over a two-year period, 3479 pregnant women in the Kings'' Lynn Health District were screened for neural tube defects by estimation of maternal serum alpha-fetoprotein. Most pregnancies were scanned by sonar for fetal maturity. Eight women had fetuses with open neural tube defects; four with anencephaly were associated with very high alpha-fetoprotein values. Of the four with open neural tube defects without anencephaly, only one was detected by screening and confirmed after amniocentesis. One other had a raised serum alpha-fetoprotein but a normal amniotic fluid value. The other two affected fetuses were missed. This disappointing outcome was attributed to the poor predictive value of alpha-fetoprotein in detecting open neural tube defects (anencephaly apart) rather than to errors in its estimation or in assessment of fetal maturity by sonar scan. We question the validity of screening, particularly in areas of intermediate or low incidence.     

Maternal serum alpha-fetoprotein screening: report of a Canadian pilot project.

A pilot project of maternal serum alpha-fetoprotein (MSAFP) screening was carried out in Ontario from 1982 to 1985 to examine the feasibility and acceptability of screening a prenatal population for open fetal neural tube defects. A total of 8140 patients at low genetic risk were screened. Patient acceptance was excellent. Blood samples were taken at 16 to 18 weeks'' gestation. If the MSAFP level was elevated, the assay was repeated and an ultrasound examination performed. Amniocentesis was offered to 67 women with unexplained persistently elevated levels. The outcome of pregnancy was known in 7473 patients (91.8%). Seven of nine known open fetal neural tube defects were detected. All were confirmed, and no unaffected fetuses were aborted on the basis of the screening results. The rates of perinatal death (6.7%), intrauterine growth retardation (11.7%) and prematurity (23.3%) were significantly higher among the patients with unexplained elevated MSAFP levels than among those with normal levels (p less than 0.001). Of 20 patients with unexplained low levels, 10 subsequently had spontaneous abortions and 10 gave birth to term appropriate-for-gestational-age infants. Seven of nine patients who gave birth to infants with autosomal trisomy had MSAFP values below the median. The findings indicate that MSAFP screening is feasible, accurate and acceptable in a low-risk area.     

Universal precautions to prevent HIV transmission to health care workers: an economic analysis.

The universal precautions recommended by the US Centers for Disease Control (CDC), Atlanta, for the prevention of HIV (human immunodeficiency virus) transmission to health care workers are widely accepted, despite little documentation of their effectiveness and efficiency. We reviewed the evidence on the risk of HIV transmission to hospital workers and the effectiveness of the universal precautions. We also evaluated the costs of implementing the recommendations in a 450-bed acute care teaching hospital in Hamilton, Ont. On the basis of aggregated results from six prospective studies the risk of HIV seroconversion among hospital workers after a needlestick injury involving a patient known to have AIDS (acquired immune deficiency syndrome) is 0.36% (upper 95% confidence limit 0.67%); the risk after skin and mucous membrane exposure to blood or other body fluids of AIDS patients is 0% (upper 95% confidence limit 0.38%). We estimated that 0.038 cases of HIV seroconversion would be prevented annually in the study hospital if the CDC recommendations were followed. The incremental cost of implementing the universal precautions was estimated to be about $315,000 per year, or over $8 million per case of HIV seroconversion prevented. If all HIV-infected workers were assumed to have AIDS within 10 years of infection the of the program would be about $565,000 per life-year saved. When less conservative, more probable assumptions were applied the best estimate of the implementation cost was $128,862,000 per case of HIV seroconversion prevented. The universal precautions implemented in the study hospital were not found to be efficacious or cost-effective. To minimize the already small risk of HIV transmission in hospitals the sources of risk of percutaneous injury should be better defined and the design of percutaneous lines, needles and surgical equipment as well as techniques improved. Preventive measures recommended on the basis of demonstrated efficacy and aimed at routes of exposure that represent true risk are needed.     

Maternal serum alpha-fetoprotein screening activities of state health agencies: a survey.

Maternal serum alpha-fetoprotein (MSAFP) screening has been demonstrated to be cost-effective on a population basis and is becoming standard practice. The American Society of Human Genetics has twice published policy statements to define the essential elements of a quality screening program. The present study reviewed the impact of these policy statements on state public-health agencies with respect to regulation or provision of MSAFP screening in their jurisdictions. With a few exceptions, states have not elected to play a major role in provision or regulation of this test. There is need to address issues of funding, standards, and data collection in a collaborative effort, if policy statements on genetic services are to be translated into effective state population screening.     

Fitness of Toxoplasma gondii is not related to DHFR single-nucleotide polymorphism during congenital toxoplasmosis

Factors that regulate the pathogenesis of Toxoplasma gondii in humans are poorly understood. When acquired during pregnancy, toxoplasmosis can be disastrous, leading to fetal loss or conversely to subclinical disease. In congenitally infected infants, evolution is highly unpredictable. Genotype based virulence patterns have been described in mice, but in humans this classification does not correlate with the gravity of the disease. Mutations on DHFR-TS loci have recently been reported to confer T. gondii fitness cost. In this study, we investigated the relationship between the virulence of the parasite, as measured by clinical outcome in the fetus or newborn, fitness, as measured by parasitic load in amniotic fluid, and allelic polymorphism in DHFR. Six cases of severe congenital toxoplasmosis and 23 cases of mild congenital infections were included in the study. Quantitative PCR was performed to evaluate total T. gondii DNA load in amniotic fluid and detection of mutations was carried out with a LightCycler using hybridisation probes. Parasitic load was significantly higher in severe infections than in mild diseases. Among isolates from severe or non-severe cases of congenital toxoplasmosis, no polymorphism could be detected at loci 36, 83 or 245 of the DHFR gene. The virulent RH strain presented the same melting temperature as the non-virulent PRU strain for codons 36, 83 and 245. Only mutated clones, M2M3 and M2M4 with allelic replacement at these positions, displayed different profiles allowing a clear distinction between wild and mutant types. We concluded that the DHFR gene mutations we investigated do not regulate T. gondii fitness in humans.     

Screening to prevent renal failure in insulin dependent diabetic patients: an economic evaluation.

OBJECTIVE: To examine the conditions necessary to make screening for microalbuminuria in patients with insulin dependent diabetes mellitus cost effective. DESIGN: This economic evaluation compared two strategies designed to prevent the development of end stage renal disease in patients with insulin dependent diabetes with disease for five years. Strategy A, screening for microalbuminuria as currently recommended, was compared with strategy B, a protocol in which patients were screened for hypertension and macroproteinuria. INTERVENTION: Patients identified in both strategies were treated with an angiotensin converting enzyme inhibitor. SETTING: Computer simulation. MAIN OUTCOME MEASURES: Strategy costs and quality adjusted life years (QALYs). RESULTS: The model predicted that strategy A would produce an additional 0.00967 QALYs at a present value cost of $261.53 (1990 US$) per patient (or an incremental cost/QALY of $27,041.69) over strategy B. The incremental cost/QALY for strategy A over B was sensitive to several variables. If the positive predictive value of screening for microalbuminuria (impact of false label and unnecessary treatment) is < 0.72, the effect of treatment to delay progression from microalbuminuria to macroproteinuria is < 1.6 years, the cumulative incidence of diabetic nephropathy falls to < 20%, or > 64% of patients demonstrate hypertension at the onset of microalbuminuria, then the incremental costs/QALY will exceed $75,000. CONCLUSION: Whether microalbuminuria surveillance in this population is cost effective requires more information. Being aware of the costs, recommendation pitfalls, and gaps in our knowledge should help focus our efforts to provide cost effective care to this population.     

Physicochemical screening for chemical stabilizer of erythropoietin to prevent its aggregation

Recombinant protein aggregation is a problematic issue and can provoke immunological response. The aim of this study was to analyze the stability of erythropoietin (EPO), as a therapeutic protein expressed in mammalian cells, in the presence of different chemicals and find a specific stabilizer for EPO. The effects of several chemicals, including mannitol, betaine, trehalose, taurine, linoleic acid, beta-cyclodextrin, copper sulfate, spermidine, maltose, maltodextrin, sucrose, dextran, beta-alanine, myo-inositol, and cysteine, on protein stabilization through the thermally induced aggregation of EPO were monitored. Based on the results of turbidity assay for thermal aggregation, three different patterns were observed for protein stability of active pharmaceutical ingredient of EPO, namely, accelerated, dose-dependent, and inhibitory behaviors for aggregate formation due to treatment with spermidine, mannitol, and betaine, respectively. According to circular dichroism outcomes, EPO treatment with betaine and spermidine resulted in different helical contents of the secondary structure. Dynamic light scattering experiments indicated that treating EPO with betaine resulted in less protein aggregation due to freeze and thaw stresses. Betaine was able to stabilize EPO and inhibit its aggregation, as opposed to spermidine that induced protein aggregation.     

Why and how to support screening strategies to prevent sudden death in athletes

Sudden death in athletes occurs because of the existence of hidden cardiovascular disorders which, during effort, may jeopardize the electrical stability of the heart, triggering ventricular tachycardia and/or fibrillation. Apart from rare conditions of ion channel diseases in the setting of a structurally normal heart, in which the disorder may be easily diagnosed on basal or stress test ECG, cardiac abnormalities at risk of causing sudden death may affect the aorta (Marfan syndrome), the coronary arteries (congenital coronary artery anomalies, premature coronary atherosclerosis), the myocardium (hypertrophic and arrhythmogenic cardiomyopathy), the valves (bicuspid aortic valve, mitral valve prolapse) and the conduction system (pre-excitation syndromes). These structural heart disorders may be detected by ECG and/or echo. The employment of these tools at pre-participation screening can help to identify concealed anomalies, which may play a major role in early diagnosis, risk stratification, and prevention of sudden death.     

Effectiveness and economic evaluation of a nurse delivered home exercise programme to prevent falls. 1: Randomised controlled trial

ObjectivesTo assess the effectiveness of a trained district nurse individually prescribing a home based exercise programme to reduce falls and injuries in elderly people and to estimate the cost effectiveness of the programme.DesignRandomised controlled trial with one year''s follow up.SettingCommunity health service at a New Zealand hospital.Participants240 women and men aged 75 years and older.Intervention121 participants received the exercise programme (exercise group) and 119 received usual care (control group); 90% (211 of 233) completed the trial.ResultsFalls were reduced by 46% (incidence rate ratio 0.54, 95% confidence interval 0.32 to 0.90). Five hospital admissions were due to injuries caused by falls in the control group and none in the exercise group. The programme cost $NZ1803 (£523) (at 1998 prices) per fall prevented for delivering the programme and $NZ155 per fall prevented when hospital costs averted were considered.ConclusionA home exercise programme, previously shown to be successful when delivered by a physiotherapist, was also effective in reducing falls when delivered by a trained nurse from within a home health service. Serious injuries and hospital admissions due to falls were also reduced. The programme was cost effective in participants aged 80 years and older compared with younger participants.

What is already known on this topic

Falls are the costliest type of injury among elderly people, and the healthcare costs increase with frequency of falls and severity of injuriesAn exercise programme delivered by a physiotherapist was successful in reducing falls and moderate injuries in elderly people

What this study adds

An exercise programme to prevent falls in elderly people worked well when delivered by a district nurse from a home health service in the suburbs of a large cityResearchers, public health administrators, and health practitioners can work together to benefit elderly people in the community     

Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes

Background

Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients'' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.

Methods and Findings

Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm³ and 3,610.14 mm³ for CA125 and between 0.21 mm³ and 131.51 mm³ for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm³ and 1.52 × 10⁶ mm³ for CA125 and between 27 mm³ and 3.45 × 10⁵ mm³ for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.

Conclusions

This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.