Journal Articles
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Item Antibiotic Use In Utero and Early Life and Risk of Chronic Childhood Conditions in New Zealand: Protocol for a Data Linkage Retrospective Cohort Study(JMIR Publications, 2025-02-28) Ram S; Corbin M; 't Mannetje A; Eng A; Kvalsig A; Baker M; Douwes JBackground: The incidence of many common chronic childhood conditions has increased globally in the past few decades, which has been suggested to be potentially attributed to antibiotic overuse leading to dysbiosis in the gut microbiome. Objective: This linkage study will assess the role of antibiotic use in utero and in early life in the development of type 1 diabetes (T1D), attention-deficit/hyperactive disorder (ADHD), and inflammatory bowel disease. Methods: The study design involves several retrospective cohort studies using linked administrative health and social data from Statistics New Zealand’s Integrated Data Infrastructure. It uses data from all children who were born in New Zealand between October 2005 and December 2010 (N=334,204) and their mothers. Children’s antibiotic use is identified for 4 time periods (at pregnancy, at ≤1 year, at ≤2 years, and at ≤5 years), and the development of T1D, ADHD, and inflammatory bowel disease is measured from the end of the antibiotic use periods until death, emigration, or the end of the follow-up period (2021), whichever came first. Children who emigrated or died before the end of the antibiotic use period are excluded. Cox proportional hazards regression models are used while adjusting for a range of potential confounders. Results: As of September 2024, data linkage has been completed, involving the integration of antibiotic exposure and outcome variables for 315,789 children. Preliminary analyses show that both prenatal and early life antibiotic consumption is associated with T1D. Full analyses for all 3 outcomes will be completed by the end of 2025. Conclusions: This series of linked cohort studies using detailed, complete, and systematically collected antibiotic prescription data will provide critical new knowledge regarding the role of antibiotics in the development of common chronic childhood conditions. Thus, this study has the potential to contribute to the development of primary prevention strategies through, for example, targeted changes in antibiotic use.Item Case-Control Study of Congenital Anomalies: Study Methods and Nonresponse Bias Assessment.(Wiley Periodicals LLC, 2025-02-20) Eng A; Mannetje AT; Ellison-Loschmann L; Borman B; Cheng S; Lawlor DA; Douwes J; Pearce NBACKGROUND: To describe the methods of a congenital anomalies case-control study conducted in New Zealand, discuss the encountered methodological difficulties, and evaluate the potential for nonresponse bias. METHODS: The potential cases (n = 2710) were New Zealand live births in 2007-2009 randomly selected from the New Zealand Congenital Anomalies Registry. The potential controls (n = 2989) included live births identified from the Maternity and Newborn Information System, frequency matched to cases by the child's year of birth and sex. Mothers were invited to complete an interview covering demographic, lifestyle, and environmental factors. Response probabilities for case and control mothers were evaluated in relation to maternal age, deprivation, occupation, and ethnicity, available from the Electoral Roll, and inverse probability weights (IPWs) for participation were calculated. Odds ratios (ORs) for key demographic and selected risk factors were estimated through unconditional logistic regression, with and without IPW. RESULTS: A total of 652 (24%) of case mothers and 505 (17%) of control mothers completed the interview. Younger and more deprived mothers were underrepresented among the participants, particularly for controls, resulting in inflated ORs of associations with congenital anomalies for younger age, Māori ethnicity, deprivation, and risk factors under study, such as blue-collar occupations and smoking, indicative of nonresponse bias. Nonresponse bias was minimized through IPW, resulting in ORs and exposure prevalence estimates similar to those based on the prerecruitment sample. CONCLUSIONS: Attaining high participation rates was difficult in this study that was conducted in new mothers, particularly for the controls. The resulting nonresponse bias was minimized through IPW.Item Campylobacter colonization and undernutrition in infants in rural eastern Ethiopia - a longitudinal community-based birth cohort study.(Frontiers Media S.A., 2025-01-07) Chen D; McKune SL; Yang Y; Usmane IA; Ahmed IA; Amin JK; Ibrahim AM; Seran AJ; Shaik N; Ojeda A; Hassen BM; Deblais L; Ahmedo BU; Hassen KA; Bhrane M; Li X; Singh N; Roba KT; French NP; Rajashekara G; Manary MJ; Hassen JY; Havelaar AH; CAGED Research TeamBackground: Campylobacter is associated with environmental enteric dysfunction (EED) and malnutrition in children. Campylobacter infection could be a linchpin between livestock fecal exposure and health outcomes in low-resource smallholder settings. Methods: We followed a birth cohort of 106 infants in rural smallholder households in eastern Ethiopia up to 13 months of age. We measured anthropometry, surveyed sociodemographic determinants, and collected stool and urine samples. A short survey was conducted during monthly visits, infant stool samples were collected, and Campylobacter spp. was quantified using genus-specific qPCR. In month 13, we collected stool and urine samples to assay for EED biomarkers. We employed regression analyses to assess the associations of household determinants with Campylobacter colonization, EED, and growth faltering. Results: The Campylobacter load in infant stools increased with age. The mean length-for-age Z-score (LAZ) decreased from −0.45 at 3–4 months of age to −2.06 at 13 months, while the prevalence of stunting increased from 3 to 51%. The prevalence of EED at 13 months of age was 56%. A higher Campylobacter load was associated with more frequent diarrhea. Prelacteal feeding significantly increased Campylobacter load in the first month of life. Over the whole follow-up period, Campylobacter load was increased by keeping chickens unconfined at home and unsanitary disposal of infant stools while decreased by mothers’ handwashing with soap. Longitudinally, Campylobacter load was positively associated with food insecurity, introduction of complementary foods, and raw milk consumption. There were no significant associations between Campylobacter load, EED, and LAZ. Conclusion: This study found that most determinants associated with increased Campylobacter infection were related to suboptimal feeding practices and hygiene. The findings related to livestock-associated risks were inconclusive. Although stunting, EED, and Campylobacter prevalence rates all increased to high levels by the end of the first year of life, no significant association between them was identified. While additional research is needed to investigate whether findings from this study are replicable in other populations, community efforts to improve infant and young child feeding practices and food hygiene, and water, sanitation, and hygiene (WaSH) at the household level, could reduce (cross-)contamination at the point of exposure.Item Differences in Compositions of Gut Bacterial Populations and Bacteriophages in 5-11 Year-Olds Born Preterm Compared to Full Term(Frontiers Media S.A., 2020-06-16) Jayasinghe TN; Vatanen T; Chiavaroli V; Jayan S; McKenzie EJ; Adriaenssens E; Derraik JGB; Ekblad C; Schierding W; Battin MR; Thorstensen EB; Cameron-Smith D; Forbes-Blom E; Hofman PL; Roy NC; Tannock GW; Vickers MH; Cutfield WS; O'Sullivan JM; Shkoporov APreterm infants are exposed to major perinatal, post-natal, and early infancy events that could impact on the gut microbiome. These events include infection, steroid and antibiotic exposure, parenteral nutrition, necrotizing enterocolitis, and stress. Studies have shown that there are differences in the gut microbiome during the early months of life in preterm infants. We hypothesized that differences in the gut microbial composition and metabolites in children born very preterm persist into mid-childhood. Participants were healthy prepubertal children aged 5-11 years who were born very preterm (≤32 weeks of gestation; n = 51) or at term (37-41 weeks; n = 50). We recorded the gestational age, birth weight, mode of feeding, mode of birth, age, sex, and the current height and weight of our cohort. We performed a multi'omics [i.e., 16S rRNA amplicon and shotgun metagenomic sequencing, SPME-GCMS (solid-phase microextraction followed by gas chromatography-mass spectrometry)] analysis to investigate the structure and function of the fecal microbiome (as a proxy of the gut microbiota) in our cross-sectional cohort. Children born very preterm were younger (7.8 vs. 8.3 years; p = 0.034), shorter [height-standard deviation score (SDS) 0.31 vs. 0.92; p = 0.0006) and leaner [BMI (body mass index) SDS -0.20 vs. 0.29; p < 0.0001] than the term group. Children born very preterm had higher fecal calprotectin levels, decreased fecal phage richness, lower plasma arginine, lower fecal branched-chain amino acids and higher fecal volatile (i.e., 3-methyl-butanoic acid, butyrolactone, butanoic acid and pentanoic acid) profiles. The bacterial microbiomes did not differ between preterm and term groups. We speculate that the observed very preterm-specific changes were established in early infancy and may impact on the capacity of the very preterm children to respond to environmental changes.Item Ileal Digestibility of Nitrogen and Amino Acids in Human Milk and an Infant Formula as Determined in Neonatal Minipiglets(Elsevier Inc. on behalf of American Society for Nutrition, 2023-04) Charton E; Henry G; Cahu A; Le Gouar Y; Dahirel P; Moughan PJ; Montoya CA; Bellanger A; Dupont D; Le Huërou-Luron I; Deglaire ABACKGROUND: Infant formula (IF) has to provide at least the same amount of amino acids (AAs) as human milk (HM). AA digestibility in HM and IF was not studied extensively, with no data available for tryptophan digestibility. OBJECTIVES: The present study aimed to measure the true ileal digestibility (TID) of total nitrogen and AAs in HM and IF to estimate AA bioavailability using Yucatan mini-piglets as an infant model. METHODS: Twenty-four 19-day-old piglets (males and females) received either HM or IF for 6 days or a protein-free diet for 3 days, with cobalt-EDTA as an indigestible marker. Diets were fed hourly over 6 h before euthanasia and digesta collection. Total N, AA, and marker contents in diets and digesta were measured to determine the TID. Unidimensional statistical analyses were conducted. RESULTS: Dietary N content was not different between HM and IF, while true protein was lower in HM (-4 g/L) due to a 7-fold higher non-protein N content in HM. The TID of total N was lower (P < 0.001) for HM (91.3 ± 1.24%) than for IF (98.0 ± 0.810%), while the TID of amino acid nitrogen (AAN) was not different (average of 97.4 ± 0.655%, P = 0.272). HM and IF had similar (P > 0.05) TID for most of the AAs including tryptophan (96.7 ± 0.950%, P = 0.079), except for some AAs (lysine, phenylalanine, threonine, valine, alanine, proline, and serine), with small significant difference (P < 0.05). The first limiting AA was the aromatic AAs, and the digestible indispensable AA score (DIAAS) was higher for HM (DIAASHM = 101) than for IF (DIAASIF = 83). CONCLUSION: HM, compared to IF, had a lower TID for total N only, whereas the TID of AAN and most AAs, including Trp, was high and similar. A larger proportion of non-protein N is transferred to the microbiota with HM, which is of physiological relevance, although this fraction is poorly considered for IF manufacturing.Item Birth weight and prematurity with lung function at ~17.5 years: "Children of 1997" birth cohort.(Springer Nature Limited, 2020-01-15) He B; Kwok MK; Au Yeung SL; Lin SL; Leung JYY; Hui LL; Li AM; Leung GM; Schooling CMWe aimed to determine if prematurity and lower birth weight are associated with poorer lung function in a non-western developed setting with less marked confounding by socioeconomic position. Using multivariable linear regression in Hong Kong's "Children of 1997" birth cohort, adjusted associations of prematurity and birth weight with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75%) at ~17.5 years were assessed. Associations for birth weight were stronger in boys for FEV1 (boys: 0.31 L, 95% confidence interval (CI) 0.24 to 0.38, girls: 0.18 L, 95% CI 0.12 to 0.25), FVC (boys: 0.36 L, 95% CI 0.27 to 0.44, girls: 0.22 L, 95% CI 0.15 to 0.28) and FEF25-75% (boys: 0.35 L, 95% CI 0.21 to 0.49, girls: 0.22 L, 95% CI 0.09 to 0.34) adjusted for age, socioeconomic position and infant and maternal characteristics. Similarly adjusted, preterm birth (compared to full-term birth) was associated with lower FEV1/FVC and FEF25-75%. Thus, associations of lower birth weight, especially in boys, and prematurity with poorer lung function at 17.5 years were found. Identifying underlying mechanism might contribute to the improvement of pulmonary health and the prevention of adult respiratory illness.Item Severe weather events and cryptosporidiosis in Aotearoa New Zealand: A case series of space-time clusters.(Cambridge University Press, 2024-04-15) Grout L; Hales S; Baker MG; French N; Wilson NOccurrence of cryptosporidiosis has been associated with weather conditions in many settings internationally. We explored statistical clusters of human cryptosporidiosis and their relationship with severe weather events in New Zealand (NZ). Notified cases of cryptosporidiosis from 1997 to 2015 were obtained from the national surveillance system. Retrospective space-time permutation was used to identify statistical clusters. Cluster data were compared to severe weather events in a national database. SaTScan analysis detected 38 statistically significant cryptosporidiosis clusters. Around a third (34.2%, 13/38) of these clusters showed temporal and spatial alignment with severe weather events. Of these, nearly half (46.2%, 6/13) occurred in the spring. Only five (38%, 5/13) of these clusters corresponded to a previously reported cryptosporidiosis outbreak. This study provides additional evidence that severe weather events may contribute to the development of some cryptosporidiosis clusters. Further research on this association is needed as rainfall intensity is projected to rise in NZ due to climate change. The findings also provide further arguments for upgrading the quality of drinking water sources to minimize contamination with pathogens from runoff from livestock agriculture.Item Ruminant Milk-Derived Extracellular Vesicles: A Nutritional and Therapeutic Opportunity?(MDPI (Basel, Switzerland), 2021-07-22) Ong SL; Blenkiron C; Haines S; Acevedo-Fani A; Leite JAS; Zempleni J; Anderson RC; McCann MJ; Chassard CMilk has been shown to contain a specific fraction of extracellular particles that are reported to resist digestion and are purposefully packaged with lipids, proteins, and nucleic acids to exert specific biological effects. These findings suggest that these particles may have a role in the quality of infant nutrition, particularly in the early phase of life when many of the foundations of an infant's potential for health and overall wellness are established. However, much of the current research focuses on human or cow milk only, and there is a knowledge gap in how milk from other species, which may be more commonly consumed in different regions, could also have these reported biological effects. Our review provides a summary of the studies into the extracellular particle fraction of milk from a wider range of ruminants and pseudo-ruminants, focusing on how this fraction is isolated and characterised, the stability and uptake of the fraction, and the reported biological effects of these fractions in a range of model systems. As the individual composition of milk from different species is known to differ, we propose that the extracellular particle fraction of milk from non-traditional and minority species may also have important and distinct biological properties that warrant further study.Item Prevalence and Load of the Campylobacter Genus in Infants and Associated Household Contacts in Rural Eastern Ethiopia: a Longitudinal Study from the Campylobacter Genomics and Environmental Enteric Dysfunction (CAGED) Project(American Society for Microbiology, 2023-07-26) Deblais L; Ojeda A; Brhane M; Mummed B; Hassen KA; Ahmedo BU; Weldesenbet YD; Amin JK; Ahmed IA; Usmane IA; Yusuf EA; Seran AJ; Abrahim FI; Game HT; Mummed BA; Usmail MM; Umer KA; Dawid MM; Gebreyes W; French N; Hassen JY; Roba KT; Mohammed A; Yimer G; Saleem C; Chen D; Singh N; Manary MJ; McKune SL; Havelaar AH; Rajashekara G; Elkins CAIn our previous cross-sectional study, multiple species of Campylobacter were detected (88%) in stool samples from children (12 to 14 months of age) in rural eastern Ethiopia. This study assessed the temporal fecal carriage of Campylobacter in infants and identified putative reservoirs associated with these infections in infants from the same region. The prevalence and load of Campylobacter were determined using genus-specific real-time PCR. Stool samples from 106 infants (n = 1,073) were collected monthly from birth until 376 days of age (DOA). Human stool samples (mothers and siblings), livestock feces (cattle, chickens, goats, and sheep), and environmental samples (soil and drinking water) from the 106 households were collected twice per household (n = 1,644). Campylobacter was most prevalent in livestock feces (goats, 99%; sheep, 98%; cattle, 99%; chickens, 93%), followed by human stool samples (siblings, 91%; mothers, 83%; infants, 64%) and environmental samples (soil, 58%; drinking water, 43%). The prevalence of Campylobacter in infant stool samples significantly increased with age, from 30% at 27 DOA to 89% at 360 DOA (1% increase/day in the odds of being colonized) (P < 0.001). The Campylobacter load increased linearly (P < 0.001) with age from 2.95 logs at 25 DOA to 4.13 logs at 360 DOA. Within a household, the Campylobacter load in infant stool samples was positively correlated with the load in mother stool samples (r2 = 0.18) and soil collected inside the house (r2 = 0.36), which were in turn both correlated with Campylobacter loads in chicken and cattle feces (0.60 < r2 < 0.63) (P < 0.01). In conclusion, a high proportion of infants are infected with Campylobacter in eastern Ethiopia, and contact with the mother and contaminated soil may be associated with early infections. IMPORTANCE A high Campylobacter prevalence during early childhood has been associated with environmental enteric dysfunction (EED) and stunting, especially in low-resource settings. Our previous study demonstrated that Campylobacter was frequently found (88%) in children from eastern Ethiopia; however, little is known about potential Campylobacter reservoirs and transmission pathways leading to infection of infants by Campylobacter during early growth. In the longitudinal study presented here, Campylobacter was frequently detected in infants within the 106 surveyed households from eastern Ethiopia, and the prevalence was age dependent. Furthermore, preliminary analyses highlighted the potential role of the mother, soil, and livestock in the transmission of Campylobacter to the infant. Further work will explore the species and genetic composition of Campylobacter in infants and putative reservoirs using PCR and whole-genome and metagenomic sequencing. The findings from these studies can lead to the development of interventions to minimize the risk of transmission of Campylobacter to infants and, potentially, EED and stunting.Item Hauora Māori - Māori health: a right to equal outcomes in primary care.(BioMed Central Ltd, 2024-02-27) Sheridan N; Jansen RM; Harwood M; Love T; Kenealy T; Primary Care Models Study GroupBackground For more than a century, Māori have experienced poorer health than non-Māori. In 2019 an independent Tribunal found the Government had breached Te Tiriti o Waitangi by “failing to design and administer the current primary health care system to actively address persistent Māori health inequities”. Many Māori (44%) have unmet needs for primary care. Seven models of primary care were identified by the funders and the research team, including Māori-owned practices. We hypothesised patient health outcomes for Māori would differ between models of care. Methods Cross-sectional primary care data were analysed at 30 September 2018. National datasets were linked to general practices at patient level, to measure associations between practice characteristics and patient health outcomes. Primary outcomes: polypharmacy (≥ 55 years), HbA1c testing, child immunisations, ambulatory sensitive hospitalisations (0–14, 45–64 years) and emergency department attendances. Regressions include only Māori patients, across all models of care. Results A total of 660,752 Māori patients were enrolled in 924 practices with 124,854 in 65 Māori-owned practices. Māori practices had: no significant association with HbA1c testing, ambulatory sensitive hospitalisations or ED attendances, and a significant association with lower polypharmacy (3.7% points) and lower childhood immunisations (13.4% points). Māori practices had higher rates of cervical smear and cardiovascular risk assessment, lower rates of HbA1c tests, and more nurse (46%) and doctor (8%) time (FTE) with patients. The average Māori practice had 52% Māori patients compared to 12% across all practices. Māori practices enrolled a higher percentage of children and young people, five times more patients in high deprivation areas, and patients with more multimorbidity. More Māori patients lived rurally (21.5% vs 15%), with a greater distance to the nearest ED. Māori patients were more likely to be dispensed antibiotics or tramadol. Conclusions Māori practices are an expression of autonomy in the face of enduring health system failure. Apart from lower immunisation rates, health outcomes were not different from other models of care, despite patients having higher health risk profiles. Across all models, primary care need was unmet for many Māori, despite increased clinical input. Funding must support under-resourced Māori practices and ensure accountability for the health outcomes of Māori patients in all models of general practice.