Genetically predicted selenium concentrations and thyroid function: A two-sample Mendelian randomization study.

OBJECTIVE: The impact of selenium (Se) on human thyroid function remains unclear, with inconsistent results from recent epidemiological studies. Moreover, the observed associations are prone to bias due to potential confounding and reverse causation. Mendelian randomization (MR) analysis facilitates the large minimization of biases produced by environmental and lifestyle influences, providing unconfounded estimates of causal effects using instrumental variables. We aim to examine the association between Se concentrations and human thyroid function using a two-sample MR analysis. DESIGN AND METHODS: Genetic instruments for Se concentrations, including toenail and blood (TAB) and blood Se concentrations, were identified from a genome-wide association study (GWAS) of blood Se (n = 5477) and toenail Se levels (n = 4162). GWAS summary statistics on thyroid phenotypes were downloaded from the ThyroidOmics consortium, including thyroid-stimulating hormone (TSH) (n = 54,288), free thyroxin (FT4) (n = 49,269), hypo (n = 53,423), and hyperthyroidism (n = 51,823). The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with the weighted median and the mode-based method. RESULTS: Genetically determined TAB Se was negatively associated with FT4 (ß = -.067; 95% confidence interval [CI] = -0.106, -0.028; p = 0.001) using the IVW analyses, as well in the additional analyses using the weighted median and weighted-mode methods. No evidence in heterogeneity, pleiotropy or outlier single-nucleotide polymorphisms was detected (all p > 0.05). Suggestive casual association between increased genetically determined TAB Se concentrations and decreased hypothyroidism risk was found by the IVW method (odds ratio [OR] = 0.847; 95% CI = 0.728, 0.985; p = 0.031). The causal effect of TAB Se on FT4 was observed in women (ß = -.076; 95% CI = -0.129, -0.024; p = 0.004). However, the influence of genetically determined higher Se concentrations on TSH levels and hyperthyroidism revealed insignificance in the primary and sensitivity analyses. CONCLUSIONS: The present MR study indicated that high Se concentration enable the decreasing of FT4 levels, and the effects of Se concentrations on FT4 remain sex-specific.

Educational attainment and offspring birth weight: A bidirectional Mendelian randomization study.

Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW. Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BW were estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome. Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BW was 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10-3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis. Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI.

Off-Label, but on-Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy.

Many drugs are still prescribed off-label to the pediatric population. Although off-label drug use not supported by high level of evidence is potentially harmful, a comprehensive overview of the quality of the evidence pertaining off-label drug use in children is lacking. The Dutch Pediatric Formulary (DPF) provides best evidence-based dosing guidelines for drugs used in children. For each drug-indication-age group combination-together compiling one record-we scored the highest available level of evidence: labeled use, systematic review or meta-analysis, randomized controlled trial (RCT), comparative research, noncomparative research, or consensus-based expert opinions. For records based on selected guidelines, the original sources were not reviewed. These records were scored as guideline. A total of 774 drugs were analyzed comprising a total of 6,426 records. Of all off-label records (n = 2,718), 14% were supported by high quality evidence (4% meta-analysis or systematic reviews, 10% RCTs of high quality), 20% by comparative research, 14% by noncomparative research, 37% by consensus-based expert opinions, and 15% by selected guidelines. Fifty-eight percent of all records were authorized, increasing with age from 30% in preterm neonates (n = 110) up to 64% in adolescents (n = 1,630). Many have advocated that off-label use is only justified when supported by a high level of evidence. We show that this prerequisite would seriously limit available drug treatment for children as the underlying evidence is low across ages and drug classes. Our data identify the drugs and therapeutic areas for which evidence is clearly missing and could drive the global research agenda.

Associations between seasonal ambient air pollution and adverse perinatal outcomes: a retrospective cohort study in Wenzhou, China.

Prenatal exposure to ambient air pollution has been associated with adverse perinatal outcomes in previous studies. However, few studies have examined the interaction between air pollution and the season of conception on term low birth weight (TLBW) or macrosomia. Birth registry data of singleton live births in Wenzhou, China, between January 2015 and December 2016 were accessed from the Wenzhou Maternal and Child Health Information Management platform, and data on the ambient air pollutants in Wenzhou were obtained from the Chinese Air Quality Online Monitoring and Analysis Platform. Single-/two-pollutant binary logistic regression models were used to assess the associations between ambient air pollutants (PM2.5, PM10, NO2, SO2, and O3) and TLBW/macrosomia, further exploring whether the season of conception interacts with air pollution to impact birth weight. Finally, 213,959 term newborns were selected, including 2452 (1.1%) infants with TLBW and 13,173 (6.1%) infants with macrosomia. In the single-/two-pollutant models, we observed an increased risk of TLBW associated with maternal exposure to PM2.5, PM10, SO2, and NO2 during the entire pregnancy, especially in the 2nd trimester. Maternal exposure to O3 during the 1st trimester was associated with increased macrosomia risk, and O3 exposure during the 3rd trimester was associated with increased TLBW risk. Pregnant women who conceive in the warm season may experience a more adverse ambient air environment that is related to the risks of TLBW. These findings add to the evidence suggesting that air pollution and the season of conception may have synergistic effects on adverse perinatal outcomes, especially TLBW. Further prospective cohort studies are needed to validate our results.

Decreased Risk of Dementia Among Patients With Traumatic Brain Injury Receiving Acupuncture Treatment: A Population-Based Retrospective Cohort Study.

OBJECTIVE: We conducted a longitudinal cohort study comparing the effect of acupuncture on the risk of dementia in Taiwanese individuals with traumatic brain injury (TBI). DESIGN AND PARTICIPANTS: A national health insurance database was used to identify 15 440 newly diagnosed TBI patients 20 to 70 years old between 1998 and 2007. Of the identified patients, 6308 received acupuncture following the onset of TBI (acupuncture users) and 9132 patients did not receive acupuncture (nonacupuncture users). MEASURES: All enrollees were followed until the end of 2012 to record incident cases of dementia. A Cox proportional hazards regression model was used to compute adjusted hazard ratios for the relationship of acupuncture use with dementia. RESULTS: During the follow-up period, 249 acupuncture users and 810 nonacupuncture users developed dementia, corresponding to incidence rates of 6.11 and 9.64 per 1000 person-years, respectively. Use of acupuncture was significantly associated with a lower risk of dementia. Those who received more than 5 sessions of acupuncture benefited most from it. CONCLUSIONS: Adding acupuncture to the clinical management of patients with TBI may benefit these patients by decreasing their risk of developing dementia.

[Correlation between end-tidal carbon dioxide and partial pressure of arterial carbon dioxide in ventilated newborns].

OBJECTIVE: To study the correlation between end-tidal carbon dioxide (PetCO2) and partial pressure of arterial carbon dioxide (PaCO2) in ventilated newborns. METHODS: Thirty-one ventilated newborn underwent mainstream PetCO2 monitoring; meanwhile, arterial blood gas analysis was performed. The correlation and consistency between PetCO2 and PaCO2 were assessed. RESULTS: A total of 85 end-tidal and arterial CO2 pairs were obtained from 31 ventilated newborns. The mean PetCO2 (41±10 mm Hg) was significantly lower than the corresponding mean PaCO2 (46±11 mm Hg) (P<0.01). There was a significant positive correlation between PetCO2 and PaCO2 (r=0.92, P<0.01). The overall PetCO2 bias was 5.1±4.3 mm Hg (95% limits of consistency, -3.3 to 13.6 mmHg), and 5% (4/85) of the points were beyond the 95%CI. When the oxygenation index (OI) was less than 300 mm Hg (n=48), there was a significant positive correlation between PetCO2 and PaCO2 (r=0.85, P<0.01); the PetCO2 bias was 5.9±4.3 mm Hg (95% limits of consistency, -2.6 to 14.5 mm Hg), and 4.2% (2/48) of the points were beyond the 95%CI. When the OI was more than 300 mm Hg (n=37), there was also a significant positive correlation between PetCO2 and PaCO2 (r=0.91, P<0.01); the PetCO2 bias was 4.1±4.1 mm Hg (95% limits of consistency, -3.9 to 12.1 mm Hg), and 5% (2/37) of the points were beyond the 95%CI. CONCLUSIONS: There is a good correlation and consistency between PetCO2 and PaCO2 in ventilated newborns.

[Feasibility study for limited filamentous bulking under low dissolved oxygen at different operation regimes].

Limited filamentous bulking under low dissolved oxygen (DO) is a new technology for energy saving and high quality effluent. In order to investigate the feasibility of this technology, four sequence batch reactors (SBRs) were occupied to operate at different regimes to stimulate different processes under low DO (0.5 mg/L). Sludge settleability, floc structure, pollutant removal and aerated energy consumption were investigated. The results showed that limited filamentous bulking under low DO was hard to realize in the single-stage aerobic reactors for they were prone to bulking severely, while it could be achieved stably in the pre-denitrification reactors when the feed length was between 60 and 90 minutes. Compared with normal sludge at the same DO, limited filamentous bulking sludge acquired by low DO displayed its high energy-saving effect. In addition, the specific ammonia consumption rate of limited filamentous bulking sludge was about 2 times higher than the one of normal sludge. On the contrary, the total nitrogen removal efficiency was lower. Further analysis indicated that stable limited sludge bulking could be achieved in a good alternative anoxic/anaerobic/aerobic condition without too high organic loading.

Energy saving achieved by limited filamentous bulking sludge under low dissolved oxygen.

Limited filamentous bulking caused by low dissolved oxygen (DO) was proposed to establish a low energy consumption wastewater treatment system. This method for energy saving was derived from two full-scale field observations, which showed pollutants removal would be enhanced and energy consumption could be reduced by at least 10% using limited filamentous bulking. Furthermore, preliminary investigation including the abundance evaluation and the identification of filamentous bacteria demonstrated that the limited filamentous bulking could be repeated steadily in a lab-scale anoxic-oxic reactor fed with domestic wastewater. The sludge loss did not occur in the secondary clarifier, while COD and total nitrogen removal efficiencies were improved by controlling DO for optimal filamentous bacterial population. Suspended solids in effluent were negligible and turbidity was lower than 2 NTU, which were distinctly lower than those under no bulking. Theoretical and experimental results indicated the aeration consumption could be saved by the application of limited filamentous bulking.

[Energy saving achieved by limited filamentous bulking under low dissolved oxygen: experimental validation in A/O process].

Preliminary studies had been conducted to determine the correctness of the theory and technique of energy saving achieved by limited filamentous bulking under low DO using a lab-scale A/O reactor with real domestic wastewater as the influent. The results showed that SVI could be maintained 150-230 mL/g and sludge settleability would not become very poor under the condition of low DO. During the period of limited filamentous bulking, COD and total nitrogen removal efficiencies were improved, and distinct simultaneous nitrification and denitrification (SND) was achieved, while ammonia removal efficiency would slightly decline with decreasing of DO, compared with the period of good settleability sludge under high DO. COD, ammonia and total nitrogen removal efficiencies were 86%, 70% and 63%, respectively. It was found that about 10%-25% nitrogen would be removed by SND based on the mass balance of nitrogen. Besides, SS in the effluent was almost negligible and the effluent turbidity was lower than 3 NTU. Significantly, aeration consumptions would be decreased by 17% under the condition with DO of 0.5 mg/L compared with 2.0 mg/L according to theoretical calculation of air requirements to keep different DO levels, which was about 57% in lab-scale reactor correspondingly.

[Dynamic change in respiratory mechanic dynamics and its clinical significance during mechanical ventilation in hyaline membrane disease of children].

OBJECTIVE: To explore the characteristics of changes in respiratory mechanic dynamics and clinical significance in hyaline membrane disease (HMD) under mechanical ventilation. METHODS: One hundred and twenty-six newborns with HMD undergoing mechanical ventilation were divided into two groups: complication group with 43 cases and no-complication group with 83 cases. The blood gases and indices of respiratory mechanic dynamics were monitored 2, 24, 48 and 72 hours after the first ventilation and before the first weaning from ventilation. RESULTS: Pulmonary compliance [(0.55+/-0.10) ml.cm H(2)O(-1).kg(-1), (0.43+/-0.10) ml.cm H(2)O(-1).kg(-1)] and minute volume [MV, (0.65+/-0.10) L/min, (0.62+/-0.30) L/min] were elevated compared with that after ventilation for 2-72 hours, however the oxygenation index [OI, (10.2+/-1.9)mm Hg vs. (13.6+/-4.3) mm Hg] significantly lower. The compliance and MV in no-complication group were higher than that in complication group 24 and 48 hours after ventilation. There were no differences in the airway resistance and lung inflation index between two groups. The pulmonary compliance was negatively correlated with OI (r=-0.208, P<0.01) and corrected with MV (r=0.218, P<0.01). In no-complication group, all cases ventilation was weaned successfully at once in all the patients,and their mean compliance and MV were (0.55+/-0.10) ml.cm H(2)O(-1).kg(-1) and (0.65+/-0.20) L/min respectively. However, in complication group, weaning failed 38 patients, their mean compliance and MV were (1.03+/-0.30) ml.cm H(2)O(-1).kg(-1) and (0. 33+/-0.30) L/min respectively. CONCLUSION: Respiratory mechanic dynamics monitoring is beneficial in evaluating the severity of hyaline membrane disease and complications, guiding mechanical ventilation management and weaning.

[Correlation between mannose-binding lectin gene codon 54 polymorphism and susceptibility of Kawasaki disease].

OBJECTIVE: Human mannose-binding lectin (MBL) is a C-type serum lectin synthesized by the liver as an acute-phase protein. MBL can bind to glycoproteins terminated with mannose and N-acetylglucosamine present in the cell walls on a variety of microorganisms. Therefore, MBL appears to play an important role in the immune system. Low levels of MBL in human have been associated with a susceptibility to recurrent infections. MBL deficiency and low serum MBL levels are strongly associated with the presence of three point mutations at codon 52, 54 and 57 of exon 1 in the human MBL gene, and in Chinese population, the codon-54 mutation occurs at a frequency of 0.11 - 0.17. The data suggested that MBL insufficiency might also predispose to the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The possibility that Kawasaki disease (KD) is an infectious disease has been discussed and investigated for decades, in light of the implication that infections are involved in the pathogenesis of KD. It has been suggested that MBL insufficiency might predispose to the occurrence of KD. This study was aimed to investigate the genetic association of MBL codon-54 polymorphism in patients with KD, and to investigate possible associations with clinical manifestations of the disease. METHODS: There were 95 patients with KD and 160 healthy subjects in the study. The genotype of MBL gene 54 codon was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Clinical characteristics and biochemical examination were also performed. RESULTS: The genotype frequency of heterozygote (GGC/GAC) was significantly higher in KD group than that in healthy subjects (45.2% vs 25.0%, P < 0.01), and the allele frequency of GAC mutation was also higher in KD patients than that in control group (0.258 vs 0.138, P < 0.01). The variant allele (GAC) was markedly associated with KD (OR = 2.18, 95% CI = 1.38 approximately 3.44, P < 0.05). But there was no significant difference in the allele frequency of GAC between patients with and without coronary artery lesion (CAL) in KD cases (0.281 vs 0.246, P > 0.05). In addition, in cases of KD, more patients carrying the variant allele (GAC) had episodes of upper respiratory or gastrointestinal infections prior to the onset of KD than wild homozygotes (P < 0.01). CONCLUSION: The codon 54 polymorphism of MBL gene was associated with KD. It is possible that MBL gene codon 54 mutation might be related to the pathogenesis of KD.

[The correlation between Kawasaki disease and polymorphisms of Tumor necrosis factor alpha and interleukin-10 gene promoter].

OBJECTIVE: Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects coronary artery. It has been suggested that proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) are key players during acute KD. Recently, the polymorphisms relative to major transcriptional start site of TNF-alpha and IL-10 gene were shown to influence the level of TNF-alpha and IL-10 production in vitro. This study was aimed to investigate the genetic association of TNF-alpha and IL-10 promoter polymorphisms in juvenile patients of Han nationality with KD, and to investigate the possible associations with clinical manifestations of the disease. METHODS: Four polymorphism sites of TNF-alpha and IL-10 gene promoter regions from 96 children with KD were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). One hundred and sixty age-matched normal children of the Han nationality were used as control. All patients accepted Doppler echocardiography examination in order to differentiate coronary artery lesions. RESULTS: There was significant difference in allele frequencies of -308 (A/G) site of the TNF-alpha gene between children of the Han nationality and those of Japanese and Caucasian in America. There were significant differences in the allele frequencies of -1082 (G/A), -819 (C/T) and -592 (A/C) of IL-10 gene between children of the Han nationality and their British Counterparts (P < 0.01). There was no significant difference in allele frequencies of -308 (A/G) site of TNF-alpha gene between children with KD and normal controls. There was no significant difference in the haplotypes and the allele frequencies of the above three sites of IL-10 between the two groups. However, when clinical features were examined, the genotype frequency of TNF-alpha-308A was significantly higher in IVIG-resistant KD patients than that of TNF-alpha-308G genotype (67% vs 5%, chi(c)(2) = 90.48, P < 0.01). The genotype of TNF-alpha-308A was closely associated with IVIG-resistant KD (P < 0.01, relative risk 42.25, 95% confidence interval 15.81-112.88). The haplotype frequency of IL-10 -1082A/-819T/-592A was also higher in patients with coronary artery lesion (CAL) caused by KD than those of Non-ATA haplotype (52% vs 20%, chi(2) = 18.36, P < 0.01). The haplotypes of IL-10 -1082A/-819T/-592A was significantly associated with CAL caused by KD (P < 0.01, relative risk 4.26, 95% confidence interval 2.20-8.25). CONCLUSION: The genotype of TNF-alpha-308A is one of the important factors that probably influence the therapeutic effect of KD. The haplotypes (-1082/-819/-592) of IL-10 gene promoter might be related to the pathogenesis of coronary artery complication of KD and -1082A/-819T/-592A haplotypes might be regarded as a genetic marker of risk factor for coronary artery lesion in KD.