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.

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.

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.

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.

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.

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.

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.

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.

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.

Co-transmission of conduct problems with attention-deficit/hyperactivity disorder: familial evidence for a distinct disorder.

Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as > or =4 on the SDQ conduct-subscale, and T > or = 65, on Conners' oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59-9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6-5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

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.

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.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Associations between water-treatment methods and diarrhoea in HIV-positive individuals.

This manuscript extends our previously published work (based on data from one clinic) on the association between three drinking water-treatment modalities (boiling, filtering, and bottling) and diarrhoeal disease in HIV-positive persons by incorporating data from two additional clinics collected in the following year. We conducted a cross-sectional survey of drinking water patterns, medication usage, and episodes of diarrhoea among HIV-positive persons attending clinics associated with the San Francisco Community Consortium. We present combined results from our previously published work in one clinic (n = 226) with data from these two additional clinics (n = 458). In this combined analysis we employed logistic regression and marginal structural modelling of the data. The relative risk of diarrhoea for 'always' vs. 'never' drinking boiled water was 0.68 (95% CI 0.45-1.04) and for 'always' vs. 'never' drinking bottled water was 1.22 (95 % CI 0.82-1.82). Drinking filtered water was unrelated to diarrhoea (1.03 (95% CI 0.78, 1.35) for 'always' vs. 'never' drinking filtered water]. Adjustment for confounding did not have any notable effect on the point estimates (0.61, 1.35 and 0.98 for boiled, bottled, and filtered water respectively, as defined above). The risk of diarrhoea was lower among those consuming boiled water but this finding was not statistically significant. Because of these findings, the importance of diarrhoea in immunocompromised individuals, and the limitations of cross-sectional data further prospective investigations of water consumption and diarrhoea among HIV-positive individuals are needed.

The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA).

One particular candidate gene, the dopamine D4 receptor (DRD4), has been the focus of intense study regarding ADHD since the original investigation by La Hoste et al, an observation confirmed by a recent metaanalysis. However, two previous studies from Israel failed to observe this association. We have now recruited an additional sample and, overall, in the combined sample of 178 triads we observe using the transmission disequilibrium test, preferential transmission of the short allele. Additionally, we now report the effect of the DRD4 repeat region on the Test Of Variables of Attention (TOVA), a widely used computerized continuous performance test. Probands with the short exon III repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. Intriguingly, a 'dose effect' was observed. Increasing repeat size is accompanied by a reduced number of errors of commission and a significant difference is observed between the 2 vs 7 repeats. On the whole, our results lend credence to the notion that the relationship between the DRD4 receptor and ADHD is complex and may be reflecting linkage disequilibrium between the 7 or long DRD4 exon III repeats and a 'true' risk allele in this gene or a neighboring locus.

Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA).

Monoamine oxidase A (MAO A) is located on the X chromosome and metabolizes biogenic amines including dopamine, norepinephrine and serotonin. A functional promoter-region polymorphism of this gene has been described that has been studied in a number of mental illnesses but not in attention deficit hyperactivity disorder (ADHD). In the current study, we examined the MAO A promoter-region polymorphism initially in 133 triads and observed preferential transmission of the long alleles from 74 heterozygote mothers to ADHD probands (chi(2) = 4.37, P = 0.036, df = 1). We also examined the role of this polymorphism in a computerized continuous performance test, the TOVA. Significant differences were observed on errors of commission (chi(2) = 7.021, P = 0.008) and patients carrying the long MAO A allele made significantly more such errors. Errors of commission are a measure of impulsivity. However, following Ritalin (methylphenidate) administration the association between this polymorphism and errors of commission was markedly attenuated and no longer significant at the P < 0.05 level. We also analyzed the provisional association by the case-control design. A significant difference in allele frequency was observed between 110 male probands vs 202 male controls (Pearson chi(2) = 7.94, P = 0.047). Similarly results were obtained when 19 female probands were compared to female controls (genotype chi(2) = 21.28; P = 0.0032, 3 df and allele chi(2) = 30.88, P= 0.0007, 2 df). All three complementary approaches employed (family-based, case-control and quantitative trait design) suggest a role for the MAO A promoter-region polymorphism in conferring risk for ADHD in our patient population.