Machine-learned modeling of PM2.5 exposures in rural Lao PDR.

This study presents a machine-learning-enhanced method of modeling PM2.5 personal exposures in a data-scarce, rural, solid fuel use context. Data collected during a cookstove (Africa Clean Energy (ACE)-1 solar-battery-powered stove) intervention program in rural Lao PDR are presented and leveraged to explore advanced techniques for predicting personal exposures to particulate matter with aerodynamic diameter smaller than 2.5 µm (PM2.5). Mean 48-h PM2.5 exposure concentrations for female cooks were measured for the pre- and post-intervention periods (the "Before" and "After" periods, respectively) as 123 µg/m3 and 81 µg/m3. Mean 48-h PM2.5 kitchen air pollution ("KAP") concentrations were measured at 462 µg/m3 Before and 124 µg/m3 After. Application of machine learning and ensemble modeling demonstrated cross-validated personal exposure predictions that were modest at the individual level but reasonably strong at the group level, with the best models producing an observed vs. predicted r2 between 0.26 and 0.31 (r2 = 0.49 when using a smaller, un-imputed dataset) and mean Before estimates of 119-120 µg/m3 and After estimates of 86-88 µg/m3. This offered improvement over one typical method of predicting exposure - using a kitchen exposure factor (the ratio of exposure to KAP)- which demonstrated an r2 ~ 0.03 and poorly estimated group average values. The results of these analyses highlight areas of methodological improvement for future exposure assessments of household air pollution and provide evidence for researchers to explore the advantages of further incorporating machine learning methods into similar research across wider geographic and cultural contexts.

Movers and stayers: how residential selection contributes to the association between female body mass index and neighborhood characteristics.

BACKGROUND/OBJECTIVES: To examine how a woman's current body mass index (BMI) is associated with nonrandom residential migration that is based on the average BMI of her origin and destination neighborhoods. SUBJECTS/METHODS: Among women having at least two children, all birth certificates from Salt Lake county from 1989 to 2010 (n=34 010) were used to obtain prepregnancy weights before the first and second births, residential location and sociodemographic information. Census data were used for measures of walkability of neighborhoods. RESULTS: After adjustments for age, education, race/ethnicity and marital status, obese women living in the leanest neighborhoods are found to be three times more likely (odds ratio (OR)=3.03, 95% confidence interval (CI) 2.06-4.47) to move to the heaviest neighborhoods relative to women with healthy weight (BMI between 18 and 25 kg m(-2)). Conversely, obese women in the heaviest neighborhoods are 60% less likely (OR=0.39, 95% CI 0.22-0.69) to move to the leanest neighborhoods relative to healthy weight women. Indicators of relatively greater walkability (older housing, greater proportion of residents who walk to work) and higher median family income characterize leaner neighborhoods. CONCLUSIONS: The findings are consistent with the hypothesis that nonrandom selection into and out of neighborhoods accounts for some of the association between BMI and neighborhood characteristics.

Maternal and neonatal outcomes for pregnancies before and after gastric bypass surgery.

BACKGROUND: Interaction between maternal obesity, intrauterine environment and adverse clinical outcomes of newborns has been described. METHODS: Using statewide birth certificate data, this retrospective, matched-control cohort study compared paired birth weights and complications of infants born to women before and after Roux-en-Y gastric bypass surgery (RYGB) and to matched obese non-operated women in several different groups. Women who had given birth to a child before and after RYGB (group 1; n=295 matches) and women with pregnancies after RYGB (group 2; n=764 matches) were matched to non-operated women based on age, body mass index (BMI) prior to both pregnancy and RYGB, mother's race, year of mother/s birth, date of infant births and birth order. In addition, birth weights of 13 143 live births before and/or after RYGB of their mothers (n=5819) were compared (group 3). RESULTS: Odds ratios (ORs) for having a large-for-gestational-age (LGA) neonate were significantly less after RYGB than for non-surgical mothers: ORs for groups 1 and 2 were 0.19 (0.08-0.38) and 0.33 (0.21-0.51), respectively. In contrast, ORs in all three groups for risk of having a small for gestational age (SGA) neonate were greater for RYGB mothers compared to non-surgical mothers (ORs were 2.16 (1.00-5.04); 2.16 (1.43-3.32); and 2.25 (1.89-2.69), respectively). Neonatal complications were not different for group 1 RYGB and non-surgical women for the first pregnancy following RYGB. Pregnancy-induced hypertension and gestational diabetes were significantly lower for the first pregnancy of mothers following RYGB compared to matched pregnancies of non-surgical mothers. CONCLUSION: Women who had undergone RYGB not only had lower risk for having an LGA neonate compared to BMI-matched mothers, but also had significantly higher risk for delivering an SGA neonate following RYGB. RYGB women were less likely than non-operated women to have pregnancy-related hypertension and diabetes.

Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah.

BACKGROUND: Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood. AIM: To quantify the risk of CRC in first-degree (FDR), second-degree (SDR) and first cousin (FC) relatives of individuals with CRC, stratified by subsite in the colorectum and age at diagnosis. METHODS: Colorectal cancers diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age and gender-matched CRC-free controls were selected to form the comparison group for determining CRC risk in relatives using Cox regression analysis. RESULTS: Of the 18,208 index patients diagnosed with CRC, 6584 (36.2%) were located in the proximal colon, 5986 (32.9%) in the distal colon and 5638 (31%) in the rectum. The elevated risk of CRC in relatives was similar in analysis stratified for CRC colorectal subsites in the index cases. FDR had similarly elevated risk of all site CRC, whether the index patient had cancer in the proximal colon [hazards ratio (HR): 1.85; 95% CI: 1.70-2.02], distal colon (HR: 1.90; 95% CI: 1.73-2.08) or rectum (HR: 1.83; 95% CI: 1.66-2.02) compared to relatives of controls. This risk was consistently greater for FDR when cases developed CRC below the age of 60 years. CONCLUSIONS: Relatives of CRC patients have a similarly elevated risk of CRC regardless of colonic tumour subsite in the index patient, and it is greatest for relatives of younger age index cases.

A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation.

We describe a three generation family in whom multiple individuals are variably affected due to a PHOX2B non-polyalanine repeat mutation. This family demonstrates extreme phenotypic variability and autosomal dominant transmission over three generations not previously reported in the wider literature. Novel findings also inclue a history of recurrent second trimester miscarriage. Pediatr Pulmonol. 2014; 49:E140-E143. © 2014 Wiley Periodicals, Inc.

Genetic risk factors in two Utah pedigrees at high risk for suicide.

We have used unique population-based data resources to identify 22 high-risk extended pedigrees that show clustering of suicide over twice that expected from demographically adjusted incidence rates. In this initial study of genetic risk factors, we focused on two high-risk pedigrees. In the first of these (pedigree 12), 10/19 (53%) of the related suicides were female, and the average age at death was 30.95. In the second (pedigree 5), 7/51 (14%) of the suicides were female and the average age at death was 36.90. Six decedents in pedigree 12 and nine in pedigree 5 were genotyped with the Illumina HumanExome BeadChip. Genotypes were analyzed using the Variant Annotation, Analysis, and Search program package that computes likelihoods of risk variants using the functional impact of the DNA variation, aggregative scoring of multiple variants across each gene and pedigree structure. We prioritized variants that were: (1) shared across pedigree members, (2) rare in other Utah suicides not related to these pedigrees, (3) < or = 5% in genotyping data from 398 other Utah population controls and (4) < or = 5% frequency in publicly available sequence data from 1358 controls and/or in dbSNP. Results included several membrane protein genes (ANO5, and TMEM141 for pedigree 12 and FAM38A and HRCT1 for pedigree 5). Other genes with known neuronal involvement and/or previous associations with psychiatric conditions were also identified, including NFKB1, CASP9, PLXNB1 and PDE11A in pedigree 12, and THOC1, and AUTS2 in pedigree 5. Although the study is limited to variants included on the HumanExome BeadChip, these findings warrant further exploration, and demonstrate the utility of this high-risk pedigree resource to identify potential genes or gene pathways for future development of targeted interventions.

Household fuels, low birth weight, and neonatal death in India: the separate impacts of biomass, kerosene, and coal.

We examined the impact of maternal use of different household cooking fuels in India on low birth weight (LBW<2500g), and neonatal mortality (death within 28 days of birth). Using cross-sectional data from India's National Family Health Survey (NFHS-3), we separately analyzed the prevalence of these two outcomes in households utilizing three types of high-pollution fuels for cooking - biomass, coal, and kerosene - using low-pollution fuels (gas and biogas) as the comparison "control" group. Taking socioeconomic and child-specific factors into account, we employed logistic regression to examine the impact of fuel use on fetal and infant health. The results indicate that household use of high-pollution fuels is significantly associated with increased odds of LBW and neonatal death. Compared to households using cleaner fuels (in which the mean birth weight is 2901g), the primary use of coal, kerosene, and biomass fuels is associated with significant decreases in mean birth weight (of -110g for coal, -107g for kerosene, and -78g for biomass). Kerosene and biomass fuel use are also associated with increased risk of LBW (p<0.05). Results suggest that increased risk of neonatal death is strongly associated with household use of coal (OR 18.54; 95% CI: 6.31-54.45), and perhaps with kerosene (OR 2.30; 95% CI: 0.95-5.55). Biomass is associated with increased risk of neonatal death among infants born to women with no more than primary education (OR 7.56; 95% CI: 2.40-23.80). These results are consistent with a growing literature showing health impacts of household air pollution from these fuels.

Early origins of longevity: prenatal exposures to food shortage among early Utah pioneers.

Undernutrition during critical or sensitive prenatal periods may 'program' the fetus for increased chronic disease and mortality in later life. Using birth cohorts that were or were not exposed to severe food shortage in Utah in the mid-19th century, this study examines how in utero exposure to undernutrition is associated with mortality after age 50. The Utah Population Database is used to identify 1392 prenatally exposed individuals and 29,022 individuals from subsequent, unexposed birth cohorts. Gompertz hazards with parametric frailty show that males born between April and June of the famine period (and hence exposed during critical periods in utero during the winter months) have higher mortality risks compared with post-famine cohorts. Alternative Cox non-proportional hazard models suggest that females born during the same period have higher initial mortality risks (starting at age 50) that decline over time creating a mortality crossover with unexposed women at approximately age 70, a result not found for men. An ancillary sibling analysis that uses shared frailty survival models to compare individuals with prenatal exposure to undernutrition to their younger (post-famine) same-sex siblings finds no significant differences in adult mortality for males but the pattern for females support the findings from the previous analysis. Although findings are sensitive to model choice, this study presents evidence that is consistent with an association between undernutrition in utero and adult mortality, shows that effects may be sensitive to the duration and gestational period of exposure, and illustrates the differential exposure effects between genders.

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation.

Roux-en-Y gastric bypass (RYGB) surgery has been shown to decrease consummatory responsiveness of rats to high sucrose concentrations, and genetic deletion of glucagon-like peptide-1 receptors (GLP-1R) has been shown to decrease consummatory responsiveness of mice to low-sucrose concentrations. Here we assessed the effects of RYGB and pharmacological GLP-1R modulation on sucrose licking by chow-fed rats in a brief-access test that assessed consummatory and appetitive behaviors. Rats were tested while fasted presurgically and postsurgically and while nondeprived postsurgically and 5 h after intraperitoneal injections with the GLP-1R antagonist exendin-3(9-39) (30 µg/kg), agonist exendin-4 (1 µg/kg), and vehicle in 30-min sessions during which a sucrose concentration series (0.01-1.0 M) was presented in 10-s trials. Other rats were tested postsurgically or 15 min after peptide or vehicle injection while fasted and while nondeprived. Independent of food-deprivation state, sucrose experience, or GLP-1R modulation, RYGB rats took 1.5-3× as many trials as sham-operated rats, indicating increased appetitive behavior. Under nondeprived conditions, RYGB rats with presurgical sucrose experience licked more to sucrose relative to water compared with sham-operated rats. Exendin-4 and exendin-3(9-39) impacted 0.3 M sucrose intake in a one-bottle test, but never interacted with surgical group to affect brief-access responding. Unlike prior reports in both clearly obese and relatively leaner rats given RYGB and in GLP-1R knockout mice, we found that neither RYGB nor GLP-1R blockade decreased consummatory responsiveness to sucrose in our less obese chow-fed rats. Collectively, these results highlight the fact that changes in taste-driven motivated behavior to sucrose after RYGB and/or GLP-1R modulation are very model and measure dependent.

The use of genes for performance enhancement: doping or therapy?

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such ‘gene doping’, exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping.

The use of genes for performance enhancement: doping or therapy?

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such 'gene doping', exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping.

Awareness in children: a secondary analysis of five cohort studies.

Five recent cohort studies have shown a frequency of awareness in paediatric anaesthesia of between 0.2% and 1.2%, but they were not individually large enough to identify risk factors. This study pooled raw data from these five studies to identify factors associated with awareness in children. The outcome of awareness was taken as the cases judged to be most likely awareness cases in each study. Logistic regression was used to identify awareness-associated factors. A combined sample of 4486 anaesthetics revealed 33 cases of awareness. Unadjusted analysis demonstrated weak evidence that nitrous oxide used as an anaesthetic maintenance adjunct was associated with awareness (OR 2.04 (95% CI 0.97-4.33), p=0.06), and some evidence that use of a tracheal tube was associated with awareness (OR 2.78 (95% CI 1.11-6.94), p=0.03). Multivariable regression analysis revealed that nitrous oxide maintenance and use of a tracheal tube were independently associated with awareness (nitrous oxide, OR 2.4 (95% CI 1.08-5.32), p=0.03; tracheal tube, OR 3.0 (95% CI 1.20-7.56), p=0.02).

Audit of initial use of the ultrasound-guided transversus abdominis plane block in children.

The extent of dermatomal block post transversus abdominis plane block is described in adults as T7-L1; other authors argue extent above T10 is infrequent (supra-iliac 20 ml injection). A paediatric guideline recommends this block for upper and lower abdominal surgery using 0.2 ml/kg. We aimed (through prospective audit) to document the multi-level block achieved with ultrasound-guided transversus abdominis plane block in children having abdominal surgery, during a departmental training period. Data included patient, anaesthetic and surgical details, transversus abdominis plane block characteristics (anterior supra-iliac injections) and dermatomal blockade to ice. Twenty-seven children received 38 blocks performed by 58% consultant and 42% trainee operators (90% novices): 16 unilateral/11 bilateral for umbilical (1), inguinal (13), laparoscopic (8) and laparotomy (5) surgery. Dermatomal assessment for 35 blocks (mean local anaesthetic volume 0.4 ml/kg [SD 0.2]) revealed the median blockade achieved was 3 dermatomes (interquartile range 3 to 4) involving T10 to L1 in 75% of patients. Eight blocks (six patients) also involved T8 and T9, following 0.31 to 0.81 ml/kg. One patient (3% of assessed blocks) had no block to ice at 60 minutes, but required no postoperative analgesia. Ultrasound-guided transversus abdominis plane blocks performed by supra-iliac approach and novice operators produced lower abdominal sensory blockade in children of usually 3 to 4 dermatomes, and should be offered for lower abdominal surgery only, as only 25% had upper abdominal block extension. The optimal local anaesthetic dose/volume, duration of effect and utility for these blocks in relation to peripheral and neuraxial blockade needs clarification.

Relative potencies of bupivacaine, levobupivacaine, and ropivacaine for neonatal spinal anaesthesia.

BACKGROUND: Comparing the relative potency of new local anaesthetics such as levobupivacaine and ropivacaine with bupivacaine by the minimum local analgesic concentration model has not been described for neonatal spinal anaesthesia. This information is important to compare agents and to determine the most effective spinal dose. METHODS: We performed a two-stage study to determine the ED50, the ED95, and the relative analgesic potency of isobaric spinal bupivacaine, levobupivacaine, and ropivacaine in infants. In phase 1, 81 infants were randomized in a Dixon-Massey study to describe the minimum local analgesic dose. In phase 2, a further 70 patients were randomly allocated to receive spinal anaesthesia with doses in the upper dose-response range to define the ED95. RESULTS: The ED50 doses for bupivacaine, levobupivacaine, and ropivacaine were estimated by isotonic regression to be 0.30 mg kg(-1) [95% confidence interval (CI) 0.25-0.43], 0.55 mg kg(-1) (0.50-0.64), and 0.50 mg kg(-1) (0.43-0.64), respectively. The ED(95), respectively, of bupivacaine, levobupivacaine, and ropivacaine were 0.96 mg kg(-1) (95% CI 0.83-0.98), 1.18 mg kg(-1) (1.05-1.22), and 0.99 mg kg(-1) (0.73-1.50). The relative potency ratios at the ED(50) were bupivacaine:levobupivacaine 0.55 (95% CI 0.39-0.88), bupivacaine:ropivacaine 0.61 (0.41-1.00), and levobupivacaine:ropivacaine 1.09 (0.84-1.45). CONCLUSIONS: Appropriate doses for infant spinal anaesthesia are 1 mg kg(-1) of isobaric 0.5% bupivacaine and ropivacaine and 1.2 mg kg(-1) of isobaric 0.5% levobupivacaine.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

BACKGROUND: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. METHODS: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM). RESULTS: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. CONCLUSIONS: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe?

Sebaceous glands are intriguing glands that are found throughout the human body except on the palms of the hands and soles of the feet. The true function of these glands has yet to be determined, but there are several theories, including antioxidant effects, antibacterial effects, and transport of pheromones. Sebaceous glands produce lipids that are involved in the pathogenesis of one of the most prevalent diseases of adolescence, acne. Although the majority of lipids produced by the sebaceous gland are also produced in other areas of the body, there are two that are characteristic of the sebaceous gland, wax esters and squalene. This review seeks to present an update on the physiology of the sebaceous glands, with particular emphasis on the production of sebaceous lipids.

Lung function and symptoms among indigenous Mayan women exposed to high levels of indoor air pollution.

SETTING: Indoor air pollution from burning of biomass fuel in open fires is a known risk factor for chronic obstructive pulmonary disease (COPD) in developing countries. OBJECTIVE: To estimate the prevalence of respiratory symptoms and lung function among women in rural Guatemala and to describe the methods and practical issues associated with the assessment of respiratory health. DESIGN: Information about respiratory symptoms, lung function and individual measurement of exposure was collected cross-sectionally among 350 Mayan-Indian women aged 15-50 years who used traditional open fires. RESULTS: These women, exposed to indoor air pollution since birth, had a relatively high prevalence of cough (22.6%), phlegm (15.1%), wheeze (25.1%) and tightness in the chest (31.4%). Respiratory symptoms were positively associated with exposure levels. Lung function was higher than the most feasible reference population (average above predicted forced expiratory volume in 1 s [FEV(1)] +4.5% and forced vital capacity [FVC] +4.2%). Only one woman had a FEV(1)/FVC ratio lower than 70%. CONCLUSIONS: According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, almost one third of these young non-smoking women were at risk (stage 0) of developing COPD. The methodological issues encountered during the study highlight the importance of standardising approaches to local adaptation of established questionnaires to study respiratory health in rural areas of developing countries.

Introduction and audit of intravenous paracetamol at a tertiary paediatric teaching hospital.

Although intravenous (i.v.) paracetamol is an attractive analgesic, there is little information on its paediatric use. During an introduction phase with limited prescribing rights, an audit was performed to assess its use and cost impact at a tertiary paediatric centre. Patients receiving IV paracetamol prescribed by two pain specialists for restricted indications had their medical records retrospectively reviewed for age, weight, diagnosis, indications/dose for IV (and other route) paracetamol/other analgesics/antiemetics, vomiting/oral intake and liver function tests if performed. One-hundred-and-twenty-one children and five neonates received 1216 (median 8 each) doses of paracetamol IV Audited expenditure for IV paracetamol was 3.9 times the rectal alternative ($3435 vs. $875). Indications were appropriate, with 97% of patients nil oral, 41% vomiting, 17% having rectal route replaced and 3% avoiding parenteral morphine. Only five patients received incorrect dosing: three through prescription errors and two as guideline deviations; none were considered dangerous. No liver function test derangements could be directly attributed to paracetamol. This data facilitated our application to extend prescribing rights for IVparacetamol within our institution. As there is limited information or local experience with the use of IVparacetamol in paediatric settings in Australia, our data may be of use to other centres considering the introduction of the IV form of this agent.