Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

Maternal Smoking and Congenital Heart Defects, National Birth Defects Prevention Study, 1997-2011.

OBJECTIVES: To assess associations between maternal smoking and congenital heart defects (CHDs) in offspring. STUDY DESIGN: We performed a retrospective case-control study using data for cases of CHD (n = 8339) and nonmalformed controls (n = 11 020) from all years (1997-2011) of the National Birth Defects Prevention Study. Maternal self-reported smoking 1 month before through 3 months after conception was evaluated as a binary (none, any) and categorical (light, medium, heavy) exposure. Multivariable logistic regression was used to estimate aOR and 95% CIs. Stratified analyses were performed for septal defects according to maternal age, prepregnancy body mass index, and maternal race/ethnicity. RESULTS: Multiple CHDs displayed modest associations with any level of maternal periconceptional smoking independent of potential confounders; the strongest associations were for aggregated septal defects (OR, 1.5; 95% CI, 1.3-1.7), tricuspid atresia (OR, 1.7; 95% CI, 1.0-2.7), and double outlet right ventricle (DORV) (OR, 1.5; 95% CI, 1.1-2.1). Tricuspid atresia and DORV also displayed dose-response relationships. Among heavy smokers, the highest odds were again observed for tricuspid atresia (aOR 3.0; 95% CI, 1.5-6.1) and DORV (aOR 1.5; 95% CI, 1.1-2.2). Heavy smokers ≥35 years old more frequently had a child with a septal defect when compared with similarly aged nonsmokers (aOR 2.3; 95% CI, 1.4-3.9). CONCLUSIONS: Maternal periconceptional smoking is most strongly associated with septal defects, tricuspid atresia, and DORV; the risk for septal defects is modified by maternal age.

Interaction of maternal medication use with ambient heat exposure on congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Maternal exposure to weather-related extreme heat events (EHEs) has been associated with congenital heart defects (CHDs) in offspring. Certain medications may affect an individual's physiologic responses to EHEs. We evaluated whether thermoregulation-related medications modified associations between maternal EHE exposure and CHDs. METHODS: We linked geocoded residence data from the U.S. National Birth Defects Prevention Study, a population-based case-control study, to summertime EHE exposures. An EHE was defined using the 90th percentile of daily maximum temperature (EHE90) for each of six climate regions during postconceptional weeks 3-8. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between EHE90 and the risk of CHDs were estimated by strata of maternal thermoregulation-related medication use and climate region. Interaction effects were evaluated on multiplicative and additive scales. RESULTS: Over 45% of participants reported thermoregulation-related medication use during the critical period of cardiogenesis. Overall, these medications did not significantly modify the association between EHEs and CHDs. Still, medications that alter central thermoregulation increased aORs (95% CI) of EHE90 from 0.73 (0.41, 1.30) among non-users to 5.09 (1.20, 21.67) among users in the Southwest region, U.S. This effect modification was statistically significant on the multiplicative (P = 0.03) and additive scales, with an interaction contrast ratio (95% CI) of 1.64 (0.26, 3.02). CONCLUSION: No significant interaction was found for the maternal use of thermoregulation-related medications with EHEs on CHDs in general, while medications altering central thermoregulation significantly modified the association between EHEs and CHDs in Southwest U.S. This finding deserves further research.

Effectiveness of preoxygenation by conventional face mask versus non-invasive ventilation in morbidly obese patients: measurable by the oxygen-reserve index?

Preoxygenation is a crucial manoeuvre for patients' safety, particularly for morbidly obese patients due to their reduced pulmonary reserve and increased risk for difficult airway situations. The oxygen reserve index (ORI™) was recently introduced as a new parameter of multiple wavelength pulse oximetry and has been advocated to allow assessment of hyperoxia [quantified by the resulting arterial oxygen partial pressure (PaO2)]. This study investigates if ORI can be used to evaluate the impact of two different preoxygenation manoeuvres on the grade of hyperoxia. Two preoxygenation manoeuvres were sequentially evaluated in 41 morbidly obese patients: First, breathing 100% oxygen for 5 min via standard face mask. Second, after achieving a second baseline, 5 min of non-invasive ventilation (NIV) with 100% oxygen. The effect of preoxygenation on ORI compared to PaO2 was evaluated and whether differences in the two preoxygenation manoeuvres can be monitored by ORI. Overall correlation of PaO2 and ORI was significant (Spearman-Rho coefficient of correlation 0.818, p < 0.001). However, ORI could not differentiate between the two preoxygenation manoeuvres although the PaO2 values for NIV preoxygenation were significantly higher compared to standard preoxygenation (median 505 mmHg (M1) vs. 550 mmHg (M3); p < 0.0001). In contrast, ORI values did not differ significantly (median 0.39 (M1) vs. 0.38 (M3); p = 0.758). Absolute values of ORI cannot be used to assess effectiveness of a preoxygenation procedure in bariatric patients, mainly because its range of discrimination is considerably lower than the high ranges of PaO2 attained by adequate preoxygenation. Trial registration German Clinical Trials Register: DRKS00025023 (retrospectively registered on April 16th, 2021).

Evaluation of ThT augmentation and RLS inner filter effect caused by highly fluorescent coumarin derivative and establishing it as true inhibitor of amyloid fibrillation.

Screening of inhibitors that slow down or suppress amyloid fibrils formation relies on some simple but sensitive spectroscopy techniques. Thioflavin T (ThT) fluorescence assay is one of the most common, amyloid specific and sensitive method. However, if an inhibitor is itself fluorescent in the ThT fluorescence range, its screening becomes complicated and require complementary assays. One of such molecules, 6, 7-dihydroxycoumarin (6, 7-DHC, also known as aesculetin, esculetin, and cichorigenin) is fluorescent in the ThT emission range and absorbs in the ThT excitation range. Therefore, it can produce a subtractive effect attributed to primary inner filter effect and/or additive effect due to its self-fluorescence in ThT assay. Our study shows that 6, 7-DHC produces an additive effect in ThT fluorescence, which is minimized at high concentration of ThT and decrease in ThT fluorescence is solely due to its inhibitory effect against HSA fibrillation. These ThT fluorescence-based results are verified through other complementary assays, such as Rayleigh and dynamic light scattering and amyloid-specific Congo red binding assay. Furthermore, hydrophobicity reduction is studied through Nile red (NR) and kinetics through far-UV circular dichroism (far-UV CD) in place of the most commonly employed ThT assay owing to extremely high fluorescence of 6, 7-DHC during initial incubation period.

Fear of COVID-19 and workplace phobia among Pakistani doctors: A survey study.

BACKGROUND: The novel coronavirus disease-2019 (COVID-19) has seriously affected the lives of millions of people across the world. It has also heavily burdened healthcare professionals and the virus poses serious risks for their personal and professional lives. Therefore, the present study examined the associations between fear of COVID-19 and workplace phobia among doctors in Pakistan during the COVID-19 pandemic. METHODS: An online survey was conducted among 421 doctors in Pakistan between April 10 and May 25, 2020. The Workplace Phobia Scale (WPS) and the Fear of COVID-19 Scale (FCV-19S) were the main psychometric instruments used in this study. RESULTS: There was a significant positive relationship between fear of COVID-19 and workplace panic anxiety and workplace avoidance behavior. Significantly higher fear of COVID-19 was found among (i) females compared to males, (ii) doctors with 5 years or less of work experience compared to those with more than 5 years, and (iii) postgraduate trainees compared with other ranks. Two groups (doctors who were above 30 years old and postgraduate trainees) were found to have higher levels of workplace phobia compared to their counterparts. Doctors with severe levels of fear of COVID-19 had significantly higher levels of workplace panic anxiety and workplace avoidance behavior. CONCLUSIONS: Fear of COVID-19 was significantly associated with workplace phobia which may negatively affect doctors' performance. Therefore, important steps are needed to protect doctors' health by providing sufficient resources to allay their fears and anxieties which consequently help them in carrying out their frontline duties in response to the COVID-19 pandemic.

Measurement invariance of the Phubbing Scale across 20 countries.

Mobile phone addiction is a robust phenomenon observed throughout the world. The social aspect of mobile phone use is crucial; therefore, phubbing is a part of the mobile phone addiction phenomenon. Phubbing is defined as ignoring an interlocutor by glancing at one's mobile phone during a face-to-face conversation. The main aim of this study was to investigate how the Phubbing Scale (containing 10 items) might vary across countries, and between genders. Data were collected in 20 countries: Belarus, Brazil, China, Croatia, Ecuador, India, Israel, Italy, Netherlands, Pakistan, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, Turkey, UK, Ukraine and USA. The mean age across the sample (N = 7696, 65.8% women, 34.2% men) was 25.32 years (SD = 9.50). The cross-cultural invariance of the scale was investigated using multigroup confirmatory factor analyses (MGCFA) as well as the invariance analyses. Additionally, data from each country were assessed individually via confirmatory factor analyses (CFAs). We obtained two factors, based on only eight of the items: (a) communication disturbances and (b) phone obsession. The 8 items Phubbing Scale.

Amyloid Oligomers, Protofibrils and Fibrils.

Amyloid diseases are of major concern all over the world due to a number of factors including: (i) aging population, (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multi-targeting small molecules as therapeutic options. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia/cell dysfunction. Here, in this chapter, we have described the recent scenario of amyloid diseases with a great deal of information about the structural features of oligomers, protofibrils and fibrils. Also, comprehensive details have been provided to differentiate the degree of toxicity associated with prefibrillar aggregates. Moreover, a review of the technologies that aid characterisation of oligomer, protofibrils and fibrils as well as various inhibition strategies to overcome protein fibrillation are also discussed.

Stabilizing proteins to prevent conformational changes required for amyloid fibril formation.

Amyloid fibrillation is associated with several human maladies, such as Alzheimer's, Parkinson's, Huntington's diseases, prions, amyotrophic lateral sclerosis, and type 2 diabetes diseases. Gaining insights into the mechanism of amyloid fibril formation and exploring novel approaches to fibrillation inhibition are crucial for preventing amyloid diseases. Here, we hypothesized that ligands capable of stabilizing the native state of query proteins might prevent protein unfolding, which, in turn, may reduce the propensity of proteins to form amyloid fibrils. We demonstrated the efficient inhibition of amyloid formation of the human serum albumin (HSA) (up to 85%) and human insulin (up to 80%) by a nonsteroidal anti-inflammatory drug, ibuprofen (IBFN). IBFN significantly increases the conformational stability of both HSA and insulin, as confirmed by differential scanning calorimetry (DSC). Moreover, increasing concentration of IBFN boosts its amyloid inhibitory propensity in a linear fashion by influencing the nucleation phase as assayed by thioflavin T fluorescence, transmission electron microscopy, and dynamic light scattering. Furthermore, circular dichroism analysis supported the DSC results, showing that IBFN binds to the native state of proteins and almost completely prevents their tendency to lose secondary and tertiary structures. Cell toxicity assay confirms that species formed in the presence of IBFN are less toxic to neuronal cells (SH-SY5Y). These results demonstrate the feasibility of using a small molecule to stabilize the native state of proteins, thereby preventing the amyloidogenic conformational changes, which appear to be the common link in several human amyloid diseases.

Two-dimensional systolic speckle tracking echocardiography provides a noninvasive aid in the identification of acute pediatric heart transplant rejection.

BACKGROUND: Acute rejection is an important cause of morbidity and mortality in the pediatric heart transplant (HT) population. A reliable noninvasive method for diagnosis of clinical rejection could substantially reduce these negative outcomes. OBJECTIVE: Evaluate left ventricular (LV) global longitudinal strain (GLS), and global circumferential strain (GCS) as early noninvasive indicators of acute pediatric HT rejection. METHODS: An 18-month prospective cohort study involving 61 patients evaluated absolute change in peak global systolic strain (GLS and GCS) from enrollment (baseline) to next planned clinical encounter (follow-up) or rejection. Acute rejection defined as a biopsy of grade ≥ 2R or treatment with enhanced immunosuppression by the transplant team, blinded to strain analysis. Two patient cohorts three months post HT without evidence of rejection at enrollment were identified. The study cohort experienced rejection. The control cohort remained free from rejection on follow-up. Two-way analysis of variance (ANOVA) models evaluated change in GLS and GCS by cohort group and time. RESULTS: Applying exclusion criteria, 51 patients enrolled in the control cohort and 10 in the study cohort. The study cohort's mean GLS declined 33% from baseline to rejection (P < .001) and mean GCS declined 16.6% (P = .021). No significant change from baseline to follow-up was seen in the control cohort. A threshold absolute GLS value of 16.1% identified acute rejection with 100% sensitivity and 98% specificity (Likelihood Ratio, [LR] 51). CONCLUSION: Noninvasive global longitudinal strain was sensitive and specific in the identification of acute clinical rejection in pediatric HT recipients.

Gender comparisons and prevalence of child abuse and post-traumatic stress disorder symptoms in adolescents.

OBJECTIVE: To identify the gender differences, prevalence and cross association of abuse and post-traumatic stress disorder symptoms in school-going adolescents. METHODS: The cross-sectional study was conducted in four government schools of Lahore, Pakistan, from February to June 2016, and comprised students aged 11-18 years who were selected through simple random sampling technique. The Child Abuse Scale: Adolescent Version and Hopkins Symptoms Checklist were used to measure the gender differences, prevalence and cross-association of abuse and post traumatic stress disorder symptoms. SPSS 22 was used to analyse data. RESULTS: There were 478 participants with a mean age of 15.18}1.45 years. Of the total, 247(52%) subjects were males and 231(48%) were females. The overall, 130(27%) male respondents reported significantly high abuse than 101(21%) female adolescents (p=0.032). However, 113(23%) females scored significantly high on physical and emotional sub-scales of abuse than 98(21%) males (p=0.031). No significant gender differences in the prevalence of sexual abuse were observed (p=0.431). On post-traumatic stress disorder symptoms, 140(29%) females demonstrated high scores than 102(21%) males (p=0.008). Association of child abuse with post-traumatic stress disorder symptoms was also significant (p=0.008) as 133(28%) subjects reporting high abuse also exhibited high symptoms of post-traumatic stress disorder. CONCLUSIONS: Significant association of abuse with post-traumatic stress disorder symptoms emphasise the need for early identification and timely management of abuse and post traumatic stress disorder symptoms in adolescents.

Capreomycin inhibits the initiation of amyloid fibrillation and suppresses amyloid induced cell toxicity.

Protein aggregation and amyloid fibrillation are responsible for several serious pathological conditions (like type II diabetes, Alzheimer's and Parkinson's diseases etc.) and protein drugs ineffectiveness. Therefore, a molecule that can inhibit the amyloid fibrillation and potentially clear amyloid fibrils is of great therapeutic value. In this manuscript, we investigated the antiamyloidogenic, fibril disaggregating, as well as cell protective effect of an anti-tuberculosis drug, Capreomycin (CN). Aggregation kinetics data, as monitored by ThT fluorescence, inferred that CN retards the insulin amyloid fibrillation by primarily targeting the fibril elongation step with little effect on lag time. Increasing the dose of CN boosted its inhibitory potency. Strikingly, CN arrested the growth of fibrils when added during the elongation phase, and disaggregated mature insulin fibrils. Our Circular Dichroism (CD) results showed that, although CN is not able to maintain the alpha helical structure of protein during fibrillation, reduces the formation of beta sheet rich structure. Furthermore, Dynamic Light Scattering (DLS) and Transmission Electronic Microscopy (TEM) analysis confirmed that CN treated samples exhibited different size distribution and morphology, respectively. In addition, molecular docking results revealed that CN interacts with insulin through hydrophobic interactions as well as hydrogen bonding, and the Hemolytic assay confirmed the non-hemolytic activity of CN on human RBCs. For future research, this study may assist in the rational designing of molecules against amyloid formation.

Rationalising the use of cardiac catheterisation before Glenn completion.

Previous studies have shown that cardiac MRI can be used to evaluate the suitability for infants to undergo the Glenn operation after having undergone the Norwood procedure. We sought to analyse our institutional data retrospectively to identify whether such a policy would be advisable in the current era. We reviewed patients who underwent the Norwood procedure between 1 January, 2006 and 1 January, 2016. All patients undergoing evaluation for the Glenn procedure received clinical evaluation, echocardiography, and cardiac catheterisation. A total of 179 patients were identified; 154 patients (86%) survived to undergo cardiac catheterisation as part of evaluation for the Glenn, and all who were evaluated did not eventually receive the Glenn. Using said algorithm, if cardiac MRI or CT were to be used to rationalise the use of catheterisation, 26 of 154 patients would have required catheterisation after cross-sectional imaging identified vascular obstruction; 83 of 154 patients would have received cross-sectional imaging only; and 45 of 154 would have had catheterisation only. All cases that required intervention, excluding aortopulmonary collaterals, and all cases that were not suitable to progress would have been correctly identified using clinical and echocardiographic criteria in addition to cardiac cross-sectional imaging to rationalise the use of catheterisation. Thus, in cases with acceptable clinical, echocardiographic, and angiographic findings, the additional haemodynamic information from catheterisation is rarely of use for decision-making, and interventions can largely be predicted by angiographic imaging modalities.

An epidemiological study of prevalence and comorbidity of obsessive compulsive disorder symptoms (SOCD) and stress in Pakistani Adults.

OBJECTIVE: To investigate the prevalence and comorbidity of subclinical obsessive compulsive disorder (SOCD) symptoms and stress across gender, marital and employment statuses. METHODS: A cross-sectional research was conducted from December, 2016 to March 2017 at two universities of cosmopolitan city Lahore. Two self-report scales measuring SOCD symptoms and stress were used to collect data from 377 adults selected through simple random sampling technique, proportionately distributed across gender, marital and employment status. RESULTS: From the total sample, 52% reported low level of stress and 48% faced high level of stress. Significant differences in prevalence were observed across marital and employment statuses whereas for men and women, it was observed same (24%). Comorbidity of high level of SOCD symptoms and high level of stress was seen 34%. CONCLUSION: Significant prevalence and comorbidity exists between SOCD symptoms and stress and more studies addressing diverse population are needed.

Equity in the use of public services for mother and newborn child health care in Pakistan: a utilization incidence analysis.

BACKGROUND: Poor maternal and infant health indicators are mostly concentrated among low income households in Pakistan and health care expenditures - especially on medical emergencies - are the most common income shocks experienced by the poor. Public investments in health are therefore considered as pro-poor interventions by the government of Pakistan. This study employs nationally representative household data for Pakistan for 2007-08 and 2010-11 to investigate whether benefits from publicly financed services on Mother and Newborn Child Health (MNCH) are effectively captured by the poor in terms of service utilization. METHODS: The study conducts a Utilization Incidence Analysis of the use of public health services for MNCH in Pakistan. For this purpose, the utilization shares of households, ranked by economic status, are computed. The concentration curves are plotted and their dominance is tested against an equal distribution and Lorenz curves to determine whether the distribution is pro-poor and progressive. RESULTS: Although the shares of bottom income groups in the utilization of most services for MNCH have increased between 2007 and 2011, the utilization of some services such as post-natal consultation; institutional maternal delivery; and Tetanus Toxoid injections for pregnant women remains pro-rich in 2011. The utilization of pre-natal consultation, especially through lady health workers and visitors; the use of Family Panning Units; and immunization services is somewhat evenly distributed. The use of Basic Health Units (BHUs) is found to be pro-poor. The provincial analysis reveals that the province of Baluchistan depicts an unusually high level of inequity in the distribution of utilization benefits from almost all public health services. Finally, in terms of progressivity, public spending on all health services analyzed in the study is found to be progressive at the national level implying that investment in MNCH has the potential to redistribute income from rich to the poor. CONCLUSION: To target the poor effectively, the study recommends expanding the network of BHUs as well as basic reproductive and child health care services. The outreach of health facilities in Baluchistan need to be expanded while targeting the poor effectively by mitigating various access costs that prevent them from using public health services.

Impact of emotional maltreatment on self esteem among adolescents.

OBJECTIVE: To investigate the impact of emotional maltreatment on self-esteem among adolescents, and to see if gender makes a difference in this context. METHODS: The cross-sectional study was conducted from January to April 2014, and comprised adolescents in the age range of 14 to 18 years who were selected using purposive sampling from various government and private schools and colleges of Sargodha, Punjab. The questionnaire on seven dimensions of emotional maltreatment at home and Rosenberg self-esteem scale were used. RESULTS: There were 400 subjects; 200(50%) boys and as many girls. The overall mean age was 16.14±1.36 years (range: 14-18 years). Correlation coefficient indicated significant negative relationship between emotional maltreatment and self-esteem (degrading r= -0.33, p<0.01; exploitation r= -0.30, p< 0.01; isolating r=-0.36, p<0.01; ignoring r= -0.32, p<0.01; rejecting r=-0.43, p< 0.01; and terrorizing r= -0.35, p<0.01) among students. Emotional maltreatment strongly predicted negative self-esteem (isolating?= -0.12, p<0.05; and rejecting ?= -0.30, p< 0.001) among adolescents. Findings indicated significant gender differences in degrading component of emotional maltreatment and self-esteem. CONCLUSIONS: Emotional maltreatment strongly predicted negative self-esteem among adolescents. Gender was a significant factor in the domain of degrading.

Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use.

BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious birth defects, occurring in 8 to 10 of every 1000 live births in the United States. Epidemiologic studies have reported an association between CHDs and maternal smoking, but it remains unknown how genes impact the susceptibility of offspring to CHDs in the presence of maternal tobacco use. METHODS: Using data from 403 case- and 219 control-parental triads enrolled in the National Birth Defects Prevention Study between 1998 and 2008, we investigated the association between CHDs and maternal and infant genetic variants involved in the tobacco metabolism and DNA repair pathways among mothers who smoked prenatally. RESULTS: The maternal genotypes of single nucleotide polymorphisms in the excision repair cross-complementation group 1 (ERCC1), poly (ADP-ribose) polymerase 2 (PARP2), and ERCC5 genes were identified to be significantly associated with the occurrence of CHDs in the presence of maternal tobacco use. Our analysis also revealed a moderate association between the infant genotypes of polymorphisms in the O-sialoglycoprotein endopeptidase (OSGEP) gene and increased risk of CHDs among mothers who smoked. CONCLUSION: Our study provides evidence that maternal and infant polymorphisms within the ERCC1, PARP2, ERCC5, and OSGEP genes are associated with CHD risk in the presence of maternal tobacco use. These results may provide insight into the susceptibility of having a pregnancy affected by CHDs among women who smoke.

Maternal occupational pesticide exposure and risk of congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent. METHODS: We examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Potential pesticide exposure from 1 month before conception through the first trimester of pregnancy was assigned by an expert-guided task-exposure matrix and job history details self-reported by mothers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect (OR = 1.8; 95% CI, 1.3-2.7, 40 exposed cases); both insecticides and herbicides and hypoplastic left heart syndrome (OR = 5.1; 95% CI, 1.7-15.3, 4 exposed cases), as well as pulmonary valve stenosis (OR = 3.6; 95% CI, 1.3-10.1, 5 exposed cases); and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF) (OR = 2.2; 95% CI, 1.2-4.0, 13 exposed cases). CONCLUSION: Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations.

Alternative repair strategies for ductal-dependent tetralogy of fallot and short-term postoperative outcomes, a multicenter analysis.

Our aim was to evaluate postoperative morbidity and mortality following initial intervention, comparing primary repair versus palliative shunt in the setting of ductal-dependent tetralogy of Fallot. When neonatal surgical intervention is required, controversy and cross-center variability exists with regard to surgical strategy. The multicenter Pediatric Health Information System database was queried to identify patients with TOF and ductal-dependent physiology, excluding pulmonary atresia. Eight hundred forty-five patients were included-349 (41.3%) underwent primary complete repair, while 496 (58.7%) underwent initial palliation. Palliated patients had significantly higher comorbid diagnoses of genetic syndrome and coronary artery anomalies. Primary complete repair patients had significantly increased morbidity across a number of variables compared to shunt palliation, but mortality rate was equal (6%). Second-stage complete repair was analyzed for 285 of palliated patients, with median inter-stage duration of 231 days (175-322 days). In comparison to primary complete repairs, second-stage repairs had significantly decreased morbidity and mortality. However, cumulative morbidity was higher for the staged patients. Median adjusted billed charges were lower for primary complete repair ($363,554) compared to staged repair ($428,109). For ductal-dependent TOF, there is no difference in postoperative mortality following the initial surgery (6%) whether management involves primary repair or palliative shunt. Although delaying complete repair by performing a palliative shunt is associated with a shift of much of the morbidity burden to outside of the newborn period, there is greater total postoperative morbidity and resource utilization associated with the staged approach.