Additional file 1: Table S1. of Low cigarette smoking prevalence in peri-urban Peru: results from a population-based study of tobacco use by self-report and urine cotinine

Comparison of cotinine subsample against balance of parent sample. Table S2. Comparison of those lost to follow up against those who completed follow up. Table S3. Estimates of smoking prevalence with 95% confidence intervals of smoking stratified by age, sex, and site. Table S4. Differences in estimates of daily smoking stratified by time between survey and urine sample. Table S5. Prevalence and means of chronic disease symptoms at baseline and 40 month follow up. (DOCX 25 kb

Association of traffic air pollution and rhinitis quality of life in Peruvian children with asthma

<div><p>Background</p><p>Air pollution exposure may contribute to rhinoconjunctivitis morbidity in children with underlying airways disease. Prior studies have not assessed rhinoconjunctivitis-related quality of life (QOL) in children with asthma chronically exposed to air pollution.</p><p>Methods</p><p>Children ages 9–19 years with asthma from peri-urban Peru, self-reporting rhinoconjunctivitis symptoms (n = 484), were administered the Rhinoconjunctivitis QOL Questionnaire (RQLQ) at repeated intervals over one year, with scores dichotomized into bothered (>0) and not bothered (= 0). Individual weekly exposures to particulate matter<2.5μm (PM_2.5) and its black carbon (BC) component were estimated by inverse distance weighted methods. Generalized estimating equations, adjusting for covariates, estimated associations of PM_2.5 and BC with QOL.</p><p>Results</p><p>Participants were on average 13 years old, 55% female, and majority were atopic (77%). Mean (SD) PM_2.5 and BC concentrations were 21(3.2) μg/m3 and 4.4(1.5) μg/m3, respectively. In adjusted multi-pollutant models, each 10μg/m3 increase in PM_2.5 was associated with increased odds of worse rhinoconjunctivitis QOL (OR;[95% CI]: 1.83;[1.33,2.52]). A 10% increase in the BC proportion was associated with higher rhinitis burden (OR;[95% CI]: 1.80;[1.22,2.66]), while increases in the non-BC component of PM did not significantly impact rhinoconjunctivitis QOL. Associations were similar regardless of atopy.</p><p>Conclusion</p><p>Higher PM2.5 and BC exposure is associated with worse rhinitis QOL among asthmatic children.</p></div

Unadjusted and adjusted¹ single and multipollutant logistic regression analyses evaluating the association of PM_2.5 and black carbon with rhinoconjunctivitis quality of life in young children and adolescents residing in Pampas and Villa, Peru.

<p>Unadjusted and adjusted¹ single and multipollutant logistic regression analyses evaluating the association of PM_2.5 and black carbon with rhinoconjunctivitis quality of life in young children and adolescents residing in Pampas and Villa, Peru.</p

Baseline demographic and clinical characteristics of asthmatic children overall and by site.

<p>Baseline demographic and clinical characteristics of asthmatic children overall and by site.</p

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer

A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure–activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound <b>49</b> achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds <b>36</b> and <b>49</b> show favorable potency and PK characteristics in preclinical species indicative of suitability for further development