Browsing by Subject "Infant"
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Item Open Access A Longitudinal Cohort Study of Malaria Exposure and Changing Serostatus in a Malaria Endemic Area of Rural Tanzania(Malaria Journal, 2017-08-02) Simmons, RA; Mboera, L; Stresman, A; Turner, E; Kramer, R; Drakeley, C; O'Meara, WPBackground
Measurements of anti-malarial antibodies are increasingly used as a proxy of transmission intensity. Most serological surveys are based on the use of cross-sectional data that, when age-stratified, approximates historical patterns of transmission within a population. Comparatively few studies leverage longitudinal data to explicitly relate individual infection events with subsequent antibody responses.Methods
The occurrence of seroconversion and seroreversion events for two Plasmodium falciparum asexual stage antigens (MSP-1 and AMA-1) was examined using three annual measurements of 691 individuals from a cohort of individuals in a malaria-endemic area of rural east-central Tanzania. Mixed-effect logistic regression models were employed to determine factors associated with changes in serostatus over time.Results
While the expected population-level relationship between seroprevalence and disease incidence was observed, on an individual level the relationship between individual infections and the antibody response was complex. MSP-1 antibody responses were more dynamic in response to the occurrence and resolution of infection events than AMA-1, while the latter was more correlated with consecutive infections. The MSP-1 antibody response to an observed infection seemed to decay faster over time than the corresponding AMA-1 response. Surprisingly, there was no evidence of an age effect on the occurrence of a conversion or reversion event.Conclusions
While the population-level results concur with previously published sero-epidemiological surveys, the individual-level results highlight the more complex relationship between detected infections and antibody dynamics than can be analysed using cross-sectional data. The longitudinal analysis of serological data may provide a powerful tool for teasing apart the complex relationship between infection events and the corresponding immune response, thereby improving the ability to rapidly assess the success or failure of malaria control programmes.Item Open Access A Multicountry Molecular Analysis of Salmonella enterica Serovar Typhi With Reduced Susceptibility to Ciprofloxacin in Sub-Saharan Africa.(Clin Infect Dis, 2016-03-15) Al-Emran, Hassan M; Eibach, Daniel; Krumkamp, Ralf; Ali, Mohammad; Baker, Stephen; Biggs, Holly M; Bjerregaard-Andersen, Morten; Breiman, Robert F; Clemens, John D; Crump, John A; Cruz Espinoza, Ligia Maria; Deerin, Jessica; Dekker, Denise Myriam; Gassama Sow, Amy; Hertz, Julian T; Im, Justin; Ibrango, Samuel; von Kalckreuth, Vera; Kabore, Leon Parfait; Konings, Frank; Løfberg, Sandra Valborg; Meyer, Christian G; Mintz, Eric D; Montgomery, Joel M; Olack, Beatrice; Pak, Gi Deok; Panzner, Ursula; Park, Se Eun; Razafindrabe, Jean Luco Tsiriniaina; Rabezanahary, Henintsoa; Rakotondrainiarivelo, Jean Philibert; Rakotozandrindrainy, Raphaël; Raminosoa, Tiana Mirana; Schütt-Gerowitt, Heidi; Sampo, Emmanuel; Soura, Abdramane Bassiahi; Tall, Adama; Warren, Michelle; Wierzba, Thomas F; May, Jürgen; Marks, FlorianBACKGROUND: Salmonella enterica serovar Typhi is a predominant cause of bloodstream infections in sub-Saharan Africa (SSA). Increasing numbers of S. Typhi with resistance to ciprofloxacin have been reported from different parts of the world. However, data from SSA are limited. In this study, we aimed to measure the ciprofloxacin susceptibility of S. Typhi isolated from patients with febrile illness in SSA. METHODS: Febrile patients from 9 sites within 6 countries in SSA with a body temperature of ≥38.0°C were enrolled in this study. Blood samples were obtained for bacterial culture, and Salmonella isolates were identified biochemically and confirmed by multiplex polymerase chain reaction (PCR). Antimicrobial susceptibility of all Salmonella isolates was performed by disk diffusion test, and minimum inhibitory concentrations (MICs) against ciprofloxacin were measured by Etest. All Salmonella isolates with reduced susceptibility to ciprofloxacin (MIC > 0.06 µg/mL) were screened for mutations in quinolone resistance-determining regions in target genes, and the presence of plasmid-mediated quinolone resistance (PMQR) genes was assessed by PCR. RESULTS: A total of 8161 blood cultures were performed, and 100 (1.2%) S. Typhi, 2 (<0.1%) Salmonella enterica serovar Paratyphi A, and 27 (0.3%) nontyphoid Salmonella (NTS) were isolated. Multidrug-resistant S. Typhi were isolated in Kenya (79% [n = 38]) and Tanzania (89% [n = 8]) only. Reduced ciprofloxacin-susceptible (22% [n = 11]) S. Typhi were isolated only in Kenya. Among those 11 isolates, all had a Glu133Gly mutation in the gyrA gene combined with either a gyrA (Ser83Phe) or gyrB mutation (Ser464Phe). One Salmonella Paratyphi A isolate with reduced susceptibility to ciprofloxacin was found in Senegal, with 1 mutation in gyrA (Ser83Phe) and a second mutation in parC (Ser57Phe). Mutations in the parE gene and PMQR genes were not detected in any isolate. CONCLUSIONS: Salmonella Typhi with reduced susceptibility to ciprofloxacin was not distributed homogenously throughout SSA. Its prevalence was very high in Kenya, and was not observed in other study countries. Continuous monitoring of antimicrobial susceptibility is required to follow the potential spread of antimicrobial-resistant isolates throughout SSA.Item Open Access A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014-03) Parikh, Suhag H; Mendizabal, Adam; Benjamin, Cara L; Komanduri, Krishna V; Antony, Jeyaraj; Petrovic, Aleksandra; Hale, Gregory; Driscoll, Timothy A; Martin, Paul L; Page, Kristin M; Flickinger, Ketti; Moffet, Jerelyn; Niedzwiecki, Donna; Kurtzberg, Joanne; Szabolcs, PaulReduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).Item Open Access A prospective neurosurgical registry evaluating the clinical care of traumatic brain injury patients presenting to Mulago National Referral Hospital in Uganda.(PloS one, 2017-01) Kuo, Benjamin J; Vaca, Silvia D; Vissoci, Joao Ricardo Nickenig; Staton, Catherine A; Xu, Linda; Muhumuza, Michael; Ssenyonjo, Hussein; Mukasa, John; Kiryabwire, Joel; Nanjula, Lydia; Muhumuza, Christine; Rice, Henry E; Grant, Gerald A; Haglund, Michael MBackground
Traumatic Brain Injury (TBI) is disproportionally concentrated in low- and middle-income countries (LMICs), with the odds of dying from TBI in Uganda more than 4 times higher than in high income countries (HICs). The objectives of this study are to describe the processes of care and determine risk factors predictive of poor outcomes for TBI patients presenting to Mulago National Referral Hospital (MNRH), Kampala, Uganda.Methods
We used a prospective neurosurgical registry based on Research Electronic Data Capture (REDCap) to systematically collect variables spanning 8 categories. Univariate and multivariate analysis were conducted to determine significant predictors of mortality.Results
563 TBI patients were enrolled from 1 June- 30 November 2016. 102 patients (18%) received surgery, 29 patients (5.1%) intended for surgery failed to receive it, and 251 patients (45%) received non-operative management. Overall mortality was 9.6%, which ranged from 4.7% for mild and moderate TBI to 55% for severe TBI patients with GCS 3-5. Within each TBI severity category, mortality differed by management pathway. Variables predictive of mortality were TBI severity, more than one intracranial bleed, failure to receive surgery, high dependency unit admission, ventilator support outside of surgery, and hospital arrival delayed by more than 4 hours.Conclusions
The overall mortality rate of 9.6% in Uganda for TBI is high, and likely underestimates the true TBI mortality. Furthermore, the wide-ranging mortality (3-82%), high ICU fatality, and negative impact of care delays suggest shortcomings with the current triaging practices. Lack of surgical intervention when needed was highly predictive of mortality in TBI patients. Further research into the determinants of surgical interventions, quality of step-up care, and prolonged care delays are needed to better understand the complex interplay of variables that affect patient outcome. These insights guide the development of future interventions and resource allocation to improve patient outcomes.Item Open Access A randomized controlled trial of standard versus intensified tuberculosis diagnostics on treatment decisions by physicians in Northern Tanzania.(BMC Infect Dis, 2014-02-20) Reddy, Elizabeth A; Njau, Boniface N; Morpeth, Susan C; Lancaster, Kathryn E; Tribble, Alison C; Maro, Venance P; Msuya, Levina J; Morrissey, Anne B; Kibiki, Gibson S; Thielman, Nathan M; Cunningham, Coleen K; Schimana, Werner; Shao, John F; Chow, Shein-Chung; Stout, Jason E; Crump, John A; Bartlett, John A; Hamilton, Carol DBACKGROUND: Routine tuberculosis culture remains unavailable in many high-burden areas, including Tanzania. This study sought to determine the impact of providing mycobacterial culture results over standard of care [unconcentrated acid-fast (AFB) smears] on management of persons with suspected tuberculosis. METHODS: Adults and children with suspected tuberculosis were randomized to standard (direct AFB smear only) or intensified (concentrated AFB smear and tuberculosis culture) diagnostics and followed for 8 weeks. The primary endpoint was appropriate treatment (i.e. antituberculosis therapy for those with tuberculosis, no antituberculous therapy for those without tuberculosis). RESULTS: Seventy participants were randomized to standard (n = 37, 53%) or intensive (n = 33, 47%) diagnostics. At 8 weeks, 100% (n = 22) of participants in follow up randomized to intensive diagnostics were receiving appropriate care, vs. 22 (88%) of 25 participants randomized to standard diagnostics (p = 0.14). Overall, 18 (26%) participants died; antituberculosis therapy was associated with lower mortality (9% who received antiuberculosis treatment died vs. 26% who did not, p = 0.04). CONCLUSIONS: Under field conditions in a high burden setting, the impact of intensified diagnostics was blunted by high early mortality. Enhanced availability of rapid diagnostics must be linked to earlier access to care for outcomes to improve.Item Open Access A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome.(Haematologica, 2017-06) Shekhovtsova, Zhanna; Bonfim, Carmem; Ruggeri, Annalisa; Nichele, Samantha; Page, Kristin; AlSeraihy, Amal; Barriga, Francisco; de Toledo Codina, José Sánchez; Veys, Paul; Boelens, Jaap Jan; Mellgren, Karin; Bittencourt, Henrique; O'Brien, Tracey; Shaw, Peter J; Chybicka, Alicja; Volt, Fernanda; Giannotti, Federica; Gluckman, Eliane; Kurtzberg, Joanne; Gennery, Andrew R; Rocha, Vanderson; Eurocord, Cord Blood Committee of Cellular Therapy and Immunobiology Working Party of the EBMT, Federal University of Parana, Duke University Medical Center and Inborn Errors Working Party of the EBMTWiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes two phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome; however, the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. The median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores [2 (23%), 3 (30%), 4 (23%) and 5 (19%)]. Most patients underwent HLA-mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. The cumulative incidence of neutrophil recovery at day 60 was 89% and that of grade II-IV acute graft-versus-host disease at day 100 was 38%. The use of methotrexate for graft-versus-host disease prophylaxis delayed engraftment (P=0.02), but decreased acute graft-versus-host disease (P=0.03). At 5 years, overall survival and event-free survival rates were 75% and 70%, respectively. The estimated 5-year event-free survival rates were 83%, 73% and 55% for patients with a clinical score of 2, 4-5 and 3, respectively. In multivariate analysis, age <2 years at the time of the umbilical cord blood transplant and a clinical phenotype of X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be better in patients transplanted after 2007 (P=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor.Item Open Access Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.(PLoS One, 2013) Banugaria, Suhrad G; Prater, Sean N; Patel, Trusha T; Dearmey, Stephanie M; Milleson, Christie; Sheets, Kathryn B; Bali, Deeksha S; Rehder, Catherine W; Raiman, Julian AJ; Wang, Raymond A; Labarthe, Francois; Charrow, Joel; Harmatz, Paul; Chakraborty, Pranesh; Rosenberg, Amy S; Kishnani, Priya SOBJECTIVE: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. METHODS: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. RESULTS: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. CONCLUSIONS: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.Item Open Access Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis.(The Lancet. Haematology, 2017-07) Eapen, Mary; Wang, Tao; Veys, Paul A; Boelens, Jaap J; St Martin, Andrew; Spellman, Stephen; Bonfim, Carmem Sales; Brady, Colleen; Cant, Andrew J; Dalle, Jean-Hugues; Davies, Stella M; Freeman, John; Hsu, Katherine C; Fleischhauer, Katharina; Kenzey, Chantal; Kurtzberg, Joanne; Michel, Gerard; Orchard, Paul J; Paviglianiti, Annalisa; Rocha, Vanderson; Veneris, Michael R; Volt, Fernanda; Wynn, Robert; Lee, Stephanie J; Horowitz, Mary M; Gluckman, Eliane; Ruggeri, AnnalisaBackground
The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation.Methods
We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model.Findings
Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 107 cells per kg compared with 21 × 107 cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality.Interpretation
These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.Funding
National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.Item Open Access Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.(Bone marrow transplantation, 2012-03) Mynarek, M; Tolar, J; Albert, MH; Escolar, ML; Boelens, JJ; Cowan, MJ; Finnegan, N; Glomstein, A; Jacobsohn, DA; Kühl, JS; Yabe, H; Kurtzberg, J; Malm, D; Orchard, PJ; Klein, C; Lücke, T; Sykora, K-WAlpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.Item Open Access Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014-02) Kurtzberg, Joanne; Prockop, Susan; Teira, Pierre; Bittencourt, Henrique; Lewis, Victor; Chan, Ka Wah; Horn, Biljana; Yu, Lolie; Talano, Julie-An; Nemecek, Eneida; Mills, Charles R; Chaudhury, SonaliSevere steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation.Item Open Access Analyses of pediatric isolates of Cryptococcus neoformans from South Africa.(J Clin Microbiol, 2011-01) Miglia, Kathleen J; Govender, Nelesh P; Rossouw, Jenny; Meiring, Susan; Mitchell, Thomas G; Group for Enteric, Respiratory and Meningeal Disease Surveillance in South AfricaCompared to the incidence in adults, cryptococcosis is inexplicably rare among children, even in sub-Saharan Africa, which has the highest prevalence of coinfection with HIV and Cryptococcus neoformans. To explore any mycological basis for this age-related difference in the incidence of cryptococcosis, we investigated isolates of C. neoformans recovered from pediatric and adult patients during a 2-year period in South Africa. From reports to the Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA), we reviewed all cases of cryptococcosis in 2005 and 2006. We analyzed one isolate of C. neoformans from each of 82 pediatric patients (<15 years of age) and determined the multilocus sequence type (ST), mating type, ploidy, and allelic profile. This sample included isolates of all three molecular types of serotype A or C. neoformans var. grubii (molecular types VNI, VNII, and VNB) and one AD hybrid. Seventy-seven (94%) of the strains possessed the MATα mating type allele, and five were MATa. Seventy-five (91%) were haploid, and seven were diploid. A total of 24 different STs were identified. The ratios of each mating type and the proportion of haploids were comparable to those for the isolates that were obtained from 86 adult patients during the same period. Notably, the most prevalent pediatric ST was significantly associated with male patients. Overall, these pediatric isolates exhibited high genotypic diversity. They included a relatively large percentage of diploids and the rarely reported MATa mating type.Item Open Access Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.(Clinical epigenetics, 2023-09) Kadalayil, Latha; Alam, Md Zahangir; White, Cory Haley; Ghantous, Akram; Walton, Esther; Gruzieva, Olena; Merid, Simon Kebede; Kumar, Ashish; Roy, Ritu P; Solomon, Olivia; Huen, Karen; Eskenazi, Brenda; Rzehak, Peter; Grote, Veit; Langhendries, Jean-Paul; Verduci, Elvira; Ferre, Natalia; Gruszfeld, Darek; Gao, Lu; Guan, Weihua; Zeng, Xuehuo; Schisterman, Enrique F; Dou, John F; Bakulski, Kelly M; Feinberg, Jason I; Soomro, Munawar Hussain; Pesce, Giancarlo; Baiz, Nour; Isaevska, Elena; Plusquin, Michelle; Vafeiadi, Marina; Roumeliotaki, Theano; Langie, Sabine AS; Standaert, Arnout; Allard, Catherine; Perron, Patrice; Bouchard, Luigi; van Meel, Evelien R; Felix, Janine F; Jaddoe, Vincent WV; Yousefi, Paul D; Ramlau-Hansen, Cecilia H; Relton, Caroline L; Tobi, Elmar W; Starling, Anne P; Yang, Ivana V; Llambrich, Maria; Santorelli, Gillian; Lepeule, Johanna; Salas, Lucas A; Bustamante, Mariona; Ewart, Susan L; Zhang, Hongmei; Karmaus, Wilfried; Röder, Stefan; Zenclussen, Ana Claudia; Jin, Jianping; Nystad, Wenche; Page, Christian M; Magnus, Maria; Jima, Dereje D; Hoyo, Cathrine; Maguire, Rachel L; Kvist, Tuomas; Czamara, Darina; Räikkönen, Katri; Gong, Tong; Ullemar, Vilhelmina; Rifas-Shiman, Sheryl L; Oken, Emily; Almqvist, Catarina; Karlsson, Robert; Lahti, Jari; Murphy, Susan K; Håberg, Siri E; London, Stephanie; Herberth, Gunda; Arshad, Hasan; Sunyer, Jordi; Grazuleviciene, Regina; Dabelea, Dana; Steegers-Theunissen, Régine PM; Nohr, Ellen A; Sørensen, Thorkild IA; Duijts, Liesbeth; Hivert, Marie-France; Nelen, Vera; Popovic, Maja; Kogevinas, Manolis; Nawrot, Tim S; Herceg, Zdenko; Annesi-Maesano, Isabella; Fallin, M Daniele; Yeung, Edwina; Breton, Carrie V; Koletzko, Berthold; Holland, Nina; Wiemels, Joseph L; Melén, Erik; Sharp, Gemma C; Silver, Matt J; Rezwan, Faisal I; Holloway, John WBackground
Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.Methods
We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.Results
We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).Conclusions
In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.Item Open Access Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study.(Blood, 2013-09) Locatelli, Franco; Crotta, Alessandro; Ruggeri, Annalisa; Eapen, Mary; Wagner, John E; Macmillan, Margaret L; Zecca, Marco; Kurtzberg, Joanne; Bonfim, Carmem; Vora, Ajay; Díaz de Heredia, Cristina; Teague, Lochie; Stein, Jerry; O'Brien, Tracey A; Bittencourt, Henrique; Madureira, Adrienne; Strahm, Brigitte; Peters, Christina; Niemeyer, Charlotte; Gluckman, Eliane; Rocha, VandersonWe retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 × 10(7)/kg (range, 1.7-27.6 × 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted.Item Open Access Analysis of the equity of emergency medical services: a cross-sectional survey in Chongqing city.(Int J Equity Health, 2015-12-21) Liu, Yalan; Jiang, Yi; Tang, Shenglan; Qiu, Jingfu; Zhong, Xiaoni; Wang, YangBACKGROUND: Due to reform of the economic system and the even distribution of available wealth, emergency medical services (EMS) experienced greater risks in equity. This study aimed to assess the equity of EMS needs, utilisation, and distribution of related resources, and to provide evidence for policy-makers to improve such services in Chongqing city, China. METHODS: Five emergency needs variables (mortality rate of maternal, neonatal, cerebrovascular, cardiovascular, injury and poisoning) from the death surveillance, and two utilisation variables (emergency room visits and rate of utilisation) were collected from Chongqing Health Statistical Year Book 2008 to 2012. We used a concentration index (CI) to assess equality in the distribution of needs and utilisation among three areas with different per-head gross domestic product (GDP). In each area, we randomly chose two districts as sample areas and selected all the medical institutions with emergency services as subjects. We used the Gini coefficient (G) to measure equity in population and geographic distribution of facilities and human resources related EMS. RESULTS: Maternal-caused (CI: range -0.213 to -0.096) and neonatal-caused (CI: range -0.161 to -0.046)deaths declined in 2008-12, which focusing mainly on the less developed area. The maternal deaths were less equitably distributed than neonatal, and the gaps between areas gradually become more noticeable. For cerebrovascular (CI: range 0.106 to 0.455), cardiovascular (CI: range 0.101 to 0.329), injury and poisoning (CI: range 0.001 to 0.301) deaths, we documented a steady improvement of mortality; the overall equity of these mortalities was lower than those of maternal and neonatal mortalities, but distinct decreases were seen over time. The patients in developed area were more likely to use EMS (CI: range 0.296 to 0.423) than those in less developed area, and the CI increased over the 5-year period, suggesting that gaps in equity were increasing. The population distribution of facilities, physicians and nurses (G: range 0.2 to 0.3) was relatively equitable; the geographic distribution (G: range 0.4 to 0.5) showed a big gap between areas. CONCLUSIONS: In Chongqing city, equity of needs, utilization, and resources allocation of EMS is low, and the provision of such services has not met the needs of patients. To narrow the gap of equity, improvement in the capability of EMS to decrease cerebrovascular, cardiovascular, injury and poisoning cases, should be regarded as a top priority. In poor areas, allocation of facilities and human resources needs to be improved, and the economy should also be enhanced.Item Open Access Antibiotic overuse for acute respiratory tract infections in Sri Lanka: a qualitative study of outpatients and their physicians.(BMC Fam Pract, 2018-03-01) Tillekeratne, L Gayani; Bodinayake, Champica K; Dabrera, Thushani; Nagahawatte, Ajith; Arachchi, Wasantha Kodikara; Sooriyaarachchi, Anoji; Stewart, Kearsley; Watt, Melissa; Østbye, Truls; Woods, Christopher WBACKGROUND: Acute respiratory tract infections (ARTIs) are a common reason for antibiotic overuse worldwide. We previously showed that over 80% of outpatients presenting to a tertiary care hospital in Sri Lanka with influenza-like illness received antibiotic prescriptions, although almost half were later confirmed to have influenza. The purpose of this qualitative study was to assess Sri Lankan patients' and physicians' attitudes towards ARTI diagnosis and treatment. METHODS: Semi-structured interviews were conducted with 50 outpatients with ARTIs and five physicians in the Outpatient Department (OPD) at a large, public tertiary care hospital in southern Sri Lanka. Interviews were audio-recorded, transcribed, and analyzed for themes related to ARTI diagnosis and treatment. RESULTS: Patients frequently sought ARTI care in the public sector due to the receipt of free care and the perception that government hospitals carried a sense of responsibility for patients' health. Patients reported multiple medical visits for their illnesses of short duration and many indicated that they were seeking care in the OPD while at the hospital for another reason. While patients generally expected to receive medication prescriptions at their visit, most patients were not specifically seeking an antibiotic prescription. However, more than 70% of patients received antibiotic prescriptions at their OPD visit. Physicians incorrectly perceived that patients desired antibiotics or "capsules," a common formulation of antibiotics dispensed in this outpatient setting, and cited patient demand as an important cause of antibiotic overuse. Physicians also indicated that high patient volume and fear of bacterial superinfection drove antibiotic overuse. CONCLUSIONS: Patients in this study were seeking medication prescriptions for their ARTIs, but physicians incorrectly perceived that antibiotic prescriptions were desired. High patient volume and fear of bacterial superinfection were also important factors in antibiotic overuse. Training of physicians regarding guideline-concordant management and dealing with diagnostic uncertainty, education of patients regarding ARTI etiology and management, and systematic changes in the public outpatient care structure may help decrease unnecessary antibiotic prescriptions for ARTIs in this setting.Item Open Access Arrhythmias Requiring ECMO in Infants Without Structural Congenital Heart Disease.(Pediatric cardiology, 2022-04) Well, Andrew; Fenrich, Arnold; Shmorhun, Daniel; Stromberg, Daniel; Lavinghousez, Preston; Beckerman, Ziv; Fraser, Charles D; Mery, Carlos MArrhythmias account for 55 per 100,000 patient evaluations in pediatric emergency departments. Most arrhythmias in children are amenable to medical management or cardioversion. Rarely, arrhythmias lead to significant hemodynamic instability requiring extracorporeal membrane oxygenation (ECMO) support. This study seeks to evaluate children under 1 year of age with a structurally normal heart requiring ECMO for an arrhythmia. This is a retrospective review of the Extracorporeal Life Support Organization Registry. All patients less than 1 year of age between 2009 and 2019 with a diagnosis of arrhythmia and without a diagnosis of structural heart malformation were included. Demographics, clinical characteristics, and outcomes were assessed with descriptive statistics and univariate and multivariable analyses. A total of 140 eligible patients were identified from the dataset. The most common arrhythmia was supraventricular tachycardia (SVT) in 70 (50%) patients. ECMO complications occurred in 106 (76.3%) patients and survival to discharge was achieved in 120 (85.7%) patients. In-hospital mortality was associated with neuromuscular blockade prior to ECMO [aOR 10.0 (95% CI 2.95-41.56), p < 0.001], neurologic ECMO complication [aOR 28.1 (95% CI 6.6-155.1), p < 0.001], and race with white race being protective [aOR 0.13, (95% CI 0.02-0.21), p = 0.002]. Similar survival and complication rates were found in subgroup analysis of SVT arrhythmias alone. Arrhythmias necessitating ECMO support in infants without structural congenital heart disease is a rare occurrence. However, survival to hospital discharge is favorable at greater than 85%. Given the favorable survival, earlier and more aggressive utilization of ECMO may result in improved outcomes.Item Open Access Assessing risk of breast cancer in an ethnically South-East Asia population (results of a multiple ethnic groups study).(BMC cancer, 2012-11-19) Gao, Fei; Machin, David; Chow, Khuan-Yew; Sim, Yu-Fan; Duffy, Stephen W; Matchar, David B; Goh, Chien-Hui; Chia, Kee-SengBackground
Gail and others developed a model (GAIL) using age-at-menarche, age-at-birth of first live child, number of previous benign breast biopsy examinations, and number of first-degree-relatives with breast cancer as well as baseline age-specific breast cancer risks for predicting the 5-year risk of invasive breast cancer for Caucasian women. However, the validity of the model for projecting risk in South-East Asian women is uncertain. We evaluated GAIL and attempted to improve its performance for Singapore women of Chinese, Malay and Indian origins.Methods
Data from the Singapore Breast Screening Programme (SBSP) are used. Motivated by lower breast cancer incidence in many Asian countries, we utilised race-specific invasive breast cancer and other cause mortality rates for Singapore women to produce GAIL-SBSP. By using risk factor information from a nested case-control study within SBSP, alternative models incorporating fewer then additional risk factors were determined. Their accuracy was assessed by comparing the expected cases (E) with the observed (O) by the ratio (E/O) and 95% confidence interval (CI) and the respective concordance statistics estimated.Results
From 28,883 women, GAIL-SBSP predicted 241.83 cases during the 5-year follow-up while 241 were reported (E/O=1.00, CI=0.88 to 1.14). Except for women who had two or more first-degree-relatives with breast cancer, satisfactory prediction was present in almost all risk categories. This agreement was reflected in Chinese and Malay, but not in Indian women. We also found that a simplified model (S-GAIL-SBSP) including only age-at-menarche, age-at-birth of first live child and number of first-degree-relatives performed similarly with associated concordance statistics of 0.5997. Taking account of body mass index and parity did not improve the calibration of S-GAIL-SBSP.Conclusions
GAIL can be refined by using national race-specific invasive breast cancer rates and mortality rates for causes other than breast cancer. A revised model containing only three variables (S-GAIL-SBSP) provides a simpler approach for projecting absolute risk of invasive breast cancer in South-East Asia women. Nevertheless its role in counseling the individual women regarding their risk of breast cancer remains problematical and needs to be validated in independent data.Item Open Access Assessment of Macular Microvasculature in Healthy Eyes of Infants and Children Using OCT Angiography.(Ophthalmology, 2019-12) Hsu, S Tammy; Ngo, Hoan T; Stinnett, Sandra S; Cheung, Nathan L; House, Robert J; Kelly, Michael P; Chen, Xi; Enyedi, Laura B; Prakalapakorn, S Grace; Materin, Miguel A; El-Dairi, Mays A; Jaffe, Glenn J; Freedman, Sharon F; Toth, Cynthia A; Vajzovic, LejlaPURPOSE:To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). DESIGN:Prospective cross-sectional study. PARTICIPANTS:One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks-17 years) treated at the Duke University Eye Center. METHODS:We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. MAIN OUTCOME MEASURES:The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. RESULTS:The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm2; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). CONCLUSIONS:Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.Item Open Access Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1.(J Virol, 2015-10) Pollara, Justin; McGuire, Erin; Fouda, Genevieve G; Rountree, Wes; Eudailey, Josh; Overman, R Glenn; Seaton, Kelly E; Deal, Aaron; Edwards, R Whitney; Tegha, Gerald; Kamwendo, Deborah; Kumwenda, Jacob; Nelson, Julie AE; Liao, Hua-Xin; Brinkley, Christie; Denny, Thomas N; Ochsenbauer, Christina; Ellington, Sascha; King, Caroline C; Jamieson, Denise J; van der Horst, Charles; Kourtis, Athena P; Tomaras, Georgia D; Ferrari, Guido; Permar, Sallie RUNLABELLED: Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants do not contract HIV-1 postnatally, even in the absence of maternal antiretroviral therapy. This suggests that immune factors in breast milk of HIV-1-infected mothers help to limit vertical transmission. We compared the HIV-1 envelope-specific breast milk and plasma antibody responses of clade C HIV-1-infected postnatally transmitting and nontransmitting mothers in the control arm of the Malawi-based Breastfeeding Antiretrovirals and Nutrition Study using multivariable logistic regression modeling. We found no association between milk or plasma neutralization activity, antibody-dependent cell-mediated cytotoxicity, or HIV-1 envelope-specific IgG responses and postnatal transmission risk. While the envelope-specific breast milk and plasma IgA responses also did not reach significance in predicting postnatal transmission risk in the primary model after correction for multiple comparisons, subsequent exploratory analysis using two distinct assay methodologies demonstrated that the magnitudes of breast milk total and secretory IgA responses against a consensus HIV-1 envelope gp140 (B.con env03) were associated with reduced postnatal transmission risk. These results suggest a protective role for mucosal HIV-1 envelope-specific IgA responses in the context of postnatal virus transmission. This finding supports further investigations into the mechanisms by which mucosal IgA reduces risk of HIV-1 transmission via breast milk and into immune interventions aimed at enhancing this response. IMPORTANCE: Infants born to HIV-1-infected mothers are repeatedly exposed to the virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in the breast milk of HIV-1-infected mothers help to limit transmission. We compared the antibody responses in plasma and breast milk of HIV-1-transmitting and -nontransmitting mothers to identify responses that correlated with reduced risk of postnatal HIV-1 transmission. We found that neither plasma nor breast milk IgG antibody responses were associated with risk of HIV-1 transmission. In contrast, the magnitudes of the breast milk IgA and secretory IgA responses against HIV-1 envelope proteins were associated with reduced risk of postnatal HIV-1 transmission. The results of this study support further investigations of the mechanisms by which mucosal IgA may reduce the risk of HIV-1 transmission via breastfeeding and the development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation.Item Open Access Association of maternal depression and hypothyroidism with infant gastroschisis: a population-based cohort study in Canada.(Scientific reports, 2023-05) Liu, Shiliang; Claude, Hughes; Yong, Shin Jie; Chen, DunjinGastroschisis has increased globally over recent decades, and this increase has not been explained by identified risk factors. We conducted a population-based study of infants born in Canada, 2004-2020. We used "winter" months (i.e., September through June) and northern areas of residence as indicators of less sunlight/less active lifestyle, while "summer" (i.e., July and August) and southern areas were considered as reference. Rate of gastroschisis for infants conceived in winter (3.4 per 10,000) was higher than for infants conceived in summer (2.2 per 10,000; p < 0.001). Exposure to winter, and northern area, hypothyroidism, substance or tobacco uses and depressive disorder were initially identified as risk factors for gastroschisis. There was a significant interaction between women < 24 years of age and 2-month conception intervals (rate ratio (RR): 1.42 (95% confidence interval [CI] 1.19-1.70). The association of maternal depression (mean ratio 2.19, 95% CI 0.87-3.50, p = 0.001) with infant gastroschisis was mediated by hypothyroidism (mean ratio 1.04, 95% CI 1.01-1.07, p < 0.001), whereas substance use, hypothyroidism, tobacco smoking and gestational diabetes showed 5.5-, 3.1-, 2.7-, and 1.2-fold associations, respectively, with maternal depression. In contrast to the summer conception interval of low gastroschisis risk, an elevated risk of gastroschisis spans the other ten months in association with higher levels of stress adaptation, thermoregulation and metabolism, reproduction, and growth effector hormones. Our findings suggest that periconception depression with mediation by hypothyroidism, may play a causal role in offspring gastroschisis.