Latent variable modeling to develop a robust proxy for sensitive behaviors: application to latrine use behavior and its association with sanitation access in a middle-income country.

BACKGROUND: Globally, diarrhea is a leading cause of child morbidity and mortality. Although latrines are integral for reducing enteric pathogen transmission, several studies have shown no evidence that latrine ownership improved child health. There are a number of explanations for these results. One explanation is that latrine access does not equate to latrine use. Latrine use, however, is difficult to accurately ascertain, as defecation behavior is often stigmatized. To address this measurement issue, we measure latrine use as a latent variable, indicated by a suite of psychosocial variables. METHODS: We administered a survey of 16 defecation-related psychosocial questions to 251 individuals living in rural Ecuador. We applied latent class analysis (LCA) to these data to model the probability of latrine use as a latent variable. To account for uncertainty in predicted latent class membership, we used a pseudo-class approach to impute five different probabilities of latrine use for each respondent. Via regression modeling, we tested the association between household sanitation and each imputed latrine use variable. RESULTS: The optimal model presented strong evidence of two latent classes (entropy = 0.86): consistent users (78%) and inconsistent users (22%), predicted by 5 of our 16 psychosocial variables. There was no evidence of an association between the probability of latrine use, predicted from the LCA, and household access to basic sanitation (OR = 1.1, 95% CI = 0.6-2.1). This suggests that home access to a sanitation facility may not ensure the use of the facility for every family member at all times. CONCLUSION: Effective implementation and evaluation of sanitation programs requires accurate measurement of latrine use. Psychosocial variables, such as norms, perceptions, and attitudes may provide robust proxy-measures. Future longitudinal studies will help to strengthen the use of these surrogate measures, as many of these factors may be subject to secular trends. Additionally, subgroup analyses will elucidate how our  proxy indicators of latrine defecation vary by individual-level characteristics.

Norovirus outbreaks: a systematic review of commonly implicated transmission routes and vehicles.

Causal mechanisms of norovirus outbreaks are often not revealed. Understanding the transmission route (e.g. foodborne, waterborne, or environmental) and vehicle (e.g. shellfish or recreational water) of a norovirus outbreak, however, is of great public health importance; this information can facilitate interventions for an ongoing outbreak and regulatory action to limit future outbreaks. Towards this goal, we conducted a systematic review to examine whether published outbreak information was associated with the implicated transmission route or vehicle. Genogroup distribution was associated with transmission route and food vehicle, but attack rate and the presence of GII.4 strain were not associated with transmission route, food vehicle, or water vehicle. Attack rate, genogroup distribution, and GII.4 strain distribution also varied by other outbreak characteristics (e.g. setting, season, hemisphere). These relationships suggest that different genogroups exploit different environmental conditions and thereby can be used to predict the likelihood of various transmission routes or vehicles.

Heterogeneity in norovirus shedding duration affects community risk.

Norovirus is a common cause of gastroenteritis in all ages. Typical infections cause viral shedding periods of days to weeks, but some individuals can shed for months or years. Most norovirus risk models do not include these long-shedding individuals, and may therefore underestimate risk. We reviewed the literature for norovirus-shedding duration data and stratified these data into two distributions: regular shedding (mean 14-16 days) and long shedding (mean 105-136 days). These distributions were used to inform a norovirus transmission model that predicts the impact of long shedders. Our transmission model predicts that this subpopulation increases the outbreak potential (measured by the reproductive number) by 50-80%, the probability of an outbreak by 33%, the severity of transmission (measured by the attack rate) by 20%, and transmission duration by 100%. Characterizing and understanding shedding duration heterogeneity can provide insights into community transmission that can be useful in mitigating norovirus risk.

The epidemiology of published norovirus outbreaks: a review of risk factors associated with attack rate and genogroup.

The purpose of this study was to examine global epidemiological trends in human norovirus (NoV) outbreaks by transmission route and setting, and describe relationships between these characteristics, viral attack rates, and the occurrence of genogroup I (GI) or genogroup II (GII) strains in outbreaks. We analysed data from 902 reverse transcriptase-polymerase chain reaction-confirmed, human NoV outbreaks abstracted from a systematic review of articles published from 1993 to 2011 and indexed under the terms 'norovirus' and 'outbreak'. Multivariate regression analyses demonstrated that foodservice and winter outbreaks were significantly associated with higher attack rates. Foodborne and waterborne outbreaks were associated with multiple strains (GI+GII). Waterborne outbreaks were significantly associated with GI strains, while healthcare-related and winter outbreaks were associated with GII strains. These results identify important trends for epidemic NoV detection, prevention, and control.

C1q PRECIPITINS IN THE SERA OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER HYPOCOMPLEMENTEMIC STATES: CHARACTERIZATION OF HIGH AND LOW MOLECULAR WEIGHT TYPES.

Precipitin reactions of C1q in gel diffusion proved useful in detecting unknown complexes containing gamma-globulin in the sera of patients with SLE. Using this method low molecular weight C1q reactants also have been detected in a number of sera from patients with SLE as well as other diseases. Both the circulating complexes and the unidentified low molecular weight reactants are associated with disease activity and in vivo complement depression. In some sera from patients with SLE, circulating complexes as detectable by C1q precipitation were closely associated with cryoprecipitins and an active nephritic process. Evidence is presented that both rheumatoid factors and C1q interact with circulating complexes in these patients and that the interaction is related to cryoprecipitation. The demonstration of the same rheumatoid factors in the cryoprecipitates and in the renal glomerular deposits suggests that rheumatoid factors have a special significance in the presence of circulating complexes.

Predictability of oppositional defiant disorder and symptom dimensions in children and adolescents with ADHD combined type.

BACKGROUND: Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making. METHOD: Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5-17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses. RESULTS: ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension. CONCLUSIONS: The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADHD.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

An inhibitor of the binding of thyroid hormones to serum proteins is present in extrathyroidal tissues.

Extrathyroidal tissues of man and the rat contain a potent inhibitor of the binding of thyroid hormones to serum proteins and to an anion-exchange resin. The inhibitor is heat-labile and nondialyzable. It acts by reducing the binding affinity of thyroid hormones to serum proteins, not by reducing the number of binding sites. The tissue inhibitor is similar in several characteristics to an inhibitor described previously in the serum of some critically ill patients, suggesting that the tissue inhibitor may leak into the circulation in severe illnesses.

Coronary artery perforations in the contemporary interventional era.

BACKGROUND: Coronary perforations represent a serious complication of percutaneous coronary intervention (PCI). METHODS: We performed a retrospective analysis of documented coronary perforations at Massachusetts General Hospital from 2000 to 2008. Medical records review and detailed angiographic analysis were performed in all patients. RESULTS: Sixty-eight cases of coronary perforation were identified from a total of 14,281 PCIs from March 2000 to March 2008 representing an overall incidence of 0.48%. The study cohort was predominantly male (61.8%), mean age 71+/-11 years with 78% representing acute cases (unstable angina: 36.8%, NSTEMI: 30.9%, STEMI: 10.3%). Coronary artery perforation occurred as a complication of wire manipulation in 45 patients (66.2%) with 88.9% of this group being hydrophilic wires, of coronary stenting in 11 (16.2%), of angioplasty alone in 6 (8.8%), and of rotational atherectomy in 8 (11.8%). The perforation was sealed with an angioplasty balloon alone in 16 patients (23.5%), and with stents in 14 patients (20.6%) (covered stents: 11.8% and noncovered stents: 8.8%). Emergency CABG was performed in 2 patients (2.9%). Five patients (7.4%) developed periprocedural MI. The in-hospital mortality rate was 5.9% in the study cohort. CONCLUSION: Coronary artery perforation as a complication of PCI is still rare as demonstrated in our series with an incidence of 0.48%. The predominant cause of coronary perforations in the current era of PCI is wire injury.

Impacts of small-scale chicken farming activity on antimicrobial-resistant Escherichia coli carriage in backyard chickens and children in rural Ecuador.

The emergence, spread, and persistence of antimicrobial resistance (AMR) remains a pressing global concern. Increased promotion of commercial small-scale agriculture within low-resource settings has facilitated an increased use in antimicrobials as growth promoters globally, creating antimicrobial-resistant animal reservoirs. We conducted a longitudinal field study in rural Ecuador to monitor the AMR of Escherichia coli populations from backyard chickens and children at three sample periods with approximately 2-month intervals (February, April, and June 2017). We assessed AMR to 12 antibiotics using generalized linear mixed effects models (GLMM). We also sampled and assessed AMR to the same 12 antibiotics in one-day-old broiler chickens purchased from local venders. One-day-old broiler chickens showed lower AMR at sample period 1 compared to sample period 2 (for 9 of the 12 antibiotics tested); increases in AMR between sample periods 2 and 3 were minimal. Two months prior to the first sample period (December 2016) there was no broiler farming activity due to a regional collapse followed by a peak in annual farming in February 2017. Between sample periods 1 and 2, we observed significant increases in AMR to 6 of the 12 antibiotics in children and to 4 of the 12 antibiotics in backyard chickens. These findings suggest that the recent increase in farming, and the observed increase of AMR in the one-day old broilers, may have caused the increase in AMR in backyard chickens and children. Small-scale farming dynamics could play an important role in the spread of AMR in low- and middle-income countries.

Association of ADHD with genetic variants in the 5'-region of the dopamine transporter gene: evidence for allelic heterogeneity.

Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder.

Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases.

Differential dopamine receptor D4 allele association with ADHD dependent of proband season of birth.

Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.

Dynamics affecting the risk of silent circulation when oral polio vaccination is stopped.

Waning immunity could allow transmission of polioviruses without causing poliomyelitis by promoting silent circulation (SC). Undetected SC when oral polio vaccine (OPV) use is stopped could cause difficult to control epidemics. Little is known about waning. To develop theory about what generates SC, we modeled a range of waning patterns. We varied both OPV and wild polio virus (WPV) transmissibility, the time from beginning vaccination to reaching low polio levels, and the infection to paralysis ratio (IPR). There was longer SC when waning continued over time rather than stopping after a few years, when WPV transmissibility was higher or OPV transmissibility was lower, and when the IPR was higher. These interacted in a way that makes recent emergence of prolonged SC a possibility. As the time to reach low infection levels increased, vaccine rates needed to eliminate polio increased and a threshold was passed where prolonged low-level SC emerged. These phenomena were caused by increased contributions to the force of infection from reinfections. The resulting SC occurs at low levels that would be difficult to detect using environmental surveillance. For all waning patterns, modest levels of vaccination of adults shortened SC. Previous modeling studies may have missed these phenomena because (1) they used models with no or very short duration waning and (2) they fit models to paralytic polio case counts. Our analyses show that polio case counts cannot predict SC because nearly identical polio case count patterns can be generated by a range of waning patterns that generate different patterns of SC. We conclude that the possibility of prolonged SC is real but unquantified, that vaccinating modest fractions of adults could reduce SC risk, and that joint analysis of acute flaccid paralysis and environmental surveillance data can help assess SC risks and ensure low risks before stopping OPV.

First Complete Genome Sequences of Zika Virus Isolated from Febrile Patient Sera in Ecuador.

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, EcEs062_16 and EcEs089_16, isolated from the sera of febrile patients in Esmeraldas City, in the northern coastal province of Esmeraldas, Ecuador, in April 2016. These are the first complete ZIKV genomes to be reported from Ecuador.

Afternoon continuous plasma levels of 3-methoxy-4-hydroxyphenylglycol and age. Distinctive biologic subgroups of endogenous depression?

Afternoon continuous plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were first shown to be a good representation of the mean 24-hour plasma level of MHPG in 18 normal subjects. Then, after the stability of the procedure was tested and retested, the afternoon continuous test for plasma MHPG levels was performed in 57 normal subjects and 42 endogenously depressed patients. A significant correlation between plasma MHPG levels and age was found in normal subjects and depressive patients. When the variable of age was taken into account, a distinct pattern of increasing plasma MHPG levels with age--the "MHPG per age"--was found in the depressed patients, especially the women, who could be divided into high or low MHPG per age groups. There was almost no association between plasma levels of MHPG or MHPG per age values and clinical symptoms, and the two biologic subgroups did not differ clinically.

Usefulness of synovial fluid analysis in the evaluation of joint effusions. Use of threshold analysis and likelihood ratios to assess a diagnostic test.

This study applied threshold analysis and likelihood ratios to determine the usefulness of a diagnostic test. Eleven staff rheumatologists or rheumatology fellows provided probability estimates for the most likely diagnoses both before and after synovial fluid analyses were performed on 180 patients with joint effusions. They also indicated whether the planned therapy was altered by the test results. The therapeutic thresholds and log likelihood ratios were derived for the six most frequent diagnoses. Synovial fluid analysis was most useful for patients likely to have gout, pseudogout, or infectious arthritis. The derived therapeutic thresholds were consistent with recommended medical practice, for example, with a lower threshold for possible septic arthritis (20%) than for possible gout (65%). This study demonstrates that threshold analysis and likelihood ratios can be used to assess the clinical contribution of diagnostic tests.

Antibodies to blood-brain barrier bind selectively to brain capillary endothelial lateral membranes and to a 46K protein.

To begin elucidating the biochemical basis of the polarized membrane features of the blood-brain barrier (BBB), a series of immunochemical and immunoperoxidase studies were initiated with bovine brain microvessels that make up the BBB in vivo. A rabbit antiserum was prepared against isolated bovine brain BBB plasma membranes. The bovine microvessel plasma membranes were radioiodinated with chloramine-T, and the antiserum selectively immunoprecipitated a 46K protein. The antibodies directed against the 46K protein were quantitatively absorbed with bovine brain capillaries but not with rat kidney or liver powder. Only the capillaries of brain reacted with the rat kidney-absorbed antiserum in immunoperoxidase studies of ethanol-fixed, 8-micron sections of bovine brain cortex, whereas the capillaries in heart, liver, and kidney did not react. This antiserum also strongly illuminated the lateral membranes of isolated bovine brain capillary endothelial cells grown in primary tissue culture. These studies provide evidence for a polarized distribution of a surface antigen in bovine brain capillary endothelial cells that is not present in capillary endothelia of liver, heart, or kidney. The correlation of the immunoperoxidase and immunoprecipitation techniques suggests that a candidate for the asymmetrically distributed surface antigen in the BBB is the 46K protein. The relationship between the 46K protein and the composition of BBB tight junctions remains to be determined.

Introduction to clinical economics: assessment of cancer therapies.

Recent changes in the health care environment have led to the assessment of the costs and benefits of cancer treatment as criteria for the evaluation of new cancer therapies. The methodological framework for these assessments is provided by the field of clinical economics, a discipline that combines the techniques from clinical medicine, economics, epidemiology, and biostatistics. This article reviews the concepts of clinical economics and issues related to economic analysis of new therapies. This type of information is increasingly important to patients, clinicians, and health policy decision makers to help assure patients' access to effective cancer therapies.