Homicide, Inequality, and Climate: Untangling the Relationships.

Researchers debate the causal connections between homicide, inequality, and temperature. This study examines these relationships globally based on country-level data. A new measure of inequality is introduced that provides a more granular measure of inequality patterns than commonly used metrics. The approach allows estimation of risk sensitive decision-making that helps to explain how class impacts violence under different climate conditions. The results indicate that homicide rates are higher when poorer segments of populations are disproportionately influenced by temperature, middle class segments are influenced by inequality, and the wealthy are influenced by middle and impoverished class dynamics.

Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug.

Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

Development and Validation of a Lateral Flow Immunoassay Test Kit for Dual Detection of Casein and ß-Lactoglobulin Residues.

Allergies to cow's milk are very common and can present as life-threatening anaphylaxis. Consequently, food labeling legislation mandates that foods containing milk residues, including casein and/or ß-lactoglobulin, provide an indication of such on the product label. Because contamination with either component independent of the other can occur during food manufacturing, effective allergen management measures for containment of milk residues necessitates the use of dual screening methods. To assist the food industry in improving food safety practices, we have developed a rapid lateral flow immunoassay test kit that reliably reports both residues down to 0.01 µg per swab and 0.1 ppm of protein for foods. The assay utilizes both sandwich and competitive format test lines and is specific for bovine milk residues. Selectivity testing using a panel of matrices with potentially interfering substances, including commonly used sanitizing agents, indicated reduction in the limit of detection by one-to fourfold. With food, residues were easily detected in all cow's milk-based foods tested, but goat and sheep milk residues were not detected. Specificity analysis revealed no cross-reactivity with common commodities, with the exception of kidney beans when present at high concentrations (> 1%). The development of a highly sensitive and rapid test method capable of detecting trace amounts of casein and/or ß-lactoglobulin should aid food manufacturers and regulatory agencies in monitoring for milk allergens in environmental and food samples.

Mediating effects of body composition between physical activity and body esteem in Hong Kong adolescents: a structural equation modeling approach.

This study investigated the mediating role of body mass index (BMI) in the relationship between physical activity and body esteem in adolescents. Nine hundred and five Hong Kong Chinese students aged 12-18 years participated in a cross-sectional study in 2007. Students' BMI was computed as an indicator of their body composition. Their physical activity level and body esteem were examined using the Physical Activity Rating for Children and Youth (PARCY) and Body Esteem Scale (BES), respectively. Structural equation modelling was used to investigate the mediating effects of BMI and physical activity in predicting body esteem, with stratification by sex. The overall fit of the hypothesized models was satisfactory in boys (NFI = 0.94; NNFI = 0.88; CFI = 0.95; RMSEA = 0.07) and girls (NFI = 0.89; NNFI = 0.77; CFI = 0.91; RMSEA = 0.11). When BMI was considered as a mediator, higher physical activity had a significant negative total effect on body esteem in boys, but not in girls. The indirect effect of higher physical activity on body esteem via BMI was positive in boys, but negative in girls. CONCLUSIONS: Regular physical activity may help overweight adolescents, especially boys, improve their body esteem. Kinesiologists and health professionals could explore the use of physical activity prescriptions for weight management, aiming at body esteem improvement in community health programs for adolescents. WHAT IS KNOWN: Among Western adolescents, negative body esteem is more pervasive in girls than in boys. There are consistent findings of the association between higher body mass index and lower body esteem in adolescents, but the association between physical activity and body esteem are equivocal. WHAT IS NEW: A negative association between body mass index and body esteem was found in both Hong Kong adolescent boys and girls. The indirect effect of physical activity on body esteem via body mass index was positive in Hong Kong adolescent boys, but negative in girls.

A Novel Immunoassay Test System for Detection of Modified Allergen Residues Present in Almond-, Cashew-, Coconut-, Hazelnut-, and Soy-Based Nondairy Beverages.

A growing number of plant-based milk substitutes have become commercially available, providing an array of options for consumers with dietary restrictions. Though several of these products rival cow's milk in terms of their nutritional profiles, beverages prepared with soy and tree nuts can be a significant concern to consumers because of potential contamination with food allergens. Adding to this concern is the fact that allergen residues from plant-based beverages are modified during manufacturing, thereby decreasing the sensitivity of antibody-based detection methods. Consequently, many commercially available allergen detection kits are less effective for allergens derived from nondairy milk substitutes. To address this limitation, we developed a panel of polyclonal antibodies directed against the modified proteins present in almond, cashew, coconut, hazelnut, and soy milks and incorporated them into rapid lateral flow immunoassay tests configured in both sandwich and competitive format. The tests had robust detection capabilities when used with a panel of various brand-name products, with a sensitivity of 1 ppm and selectivity values of 3 to 5 ppm in nondairy beverages. Minimal cross-reactivity to extracts prepared from common commodities was observed. The development of a highly sensitive and rapid test specifically designed to detect trace quantities of highly modified allergen residues in plant-based, dairy-free beverages will aid food manufacturers and regulatory agencies in monitoring products for these modified allergens when testing environmental and food samples.

Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.

Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan (160, 32, or 6 mg/kg per day by mouth), whereas liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Because DILI has become a significant public health problem, drug safety could be improved if preclinical toxicology studies were performed using humanized TK-NOG.

Metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling.

Although metformin hepatic distribution is critical to pharmacological activity, the drug is cleared by urinary excretion. Metformin hepatobiliary disposition was studied in rodents representative of clinical pharmacokinetics to elucidate why metformin is not appreciably eliminated in bile. On average, 1.0% ± 0.1% of the metformin oral dose was present in the liver (liver/plasma ratio = 4.5 ± 0.6) over a pharmacologically relevant dose and time range in mice (10-300 mg/kg; 1.5-2.5 hours; T(max) = 1.4 ± 0.5; bioavailability > 59%). Distribution to the kidneys was not markedly higher, which contained 0.87% ± 0.08% of the oral dose (kidney/plasma ratio = 11.9 ± 1.1). However, only 0.11% ± 0.02% of the intravenous and bioavailable oral dose was recovered in bile, suggesting that biliary excretion is not the only route of clearance for hepatic metformin. Consistent with negligible biliary excretion, pharmacokinetics were unaffected by bile duct cannulation, proving the effective absence of enterohepatic cycling. In single-pass liver perfusion studies, 2.4% ± 0.3% of the perfused metformin dose was distributed to the liver, which underwent >300-fold greater sinusoidal than biliary excretion during the subsequent drug-free washout perfusion (74.0% ± 39.3% versus 0.222% ± 0.003% recovery of hepatic metformin in perfusate versus bile, respectively). These studies demonstrate that despite similar magnitude of metformin liver and kidney distribution, metformin biliary excretion is negligible due to predominant sinusoidal efflux from the liver.

Characteristics of overdose and non-overdose suicide attempts in a multi-ethnic Asian society.

BACKGROUND: Overdosing is an accessible method adopted by people attempting suicide in city settings. AIMS: This study aimed to compare the trends and characteristics of people attempting suicide by drug overdose and by other methods in Singapore. METHODS: This study examined the medical records of 628 patients who were admitted to a university hospital in Singapore, between January 2004 and December 2006. Patients were classified as overdose and non-overdose persons attempting suicide for comparisons of demographic and suicidal characteristics. Logistic regression was used to determine the odds ratios of various factors associated with self-perceived lethality of the suicide attempt. Patterns of monthly and weekly variations in the frequencies of suicide attempts were also analyzed. RESULTS: The percentages of Chinese people was higher in the non-overdose group (71.5% vs. 62.9%), while the percentages of Malay and Indian people were higher in the overdose group (31.6% vs. 18.5%). The female gender (OR=0.36, p=0.04) and admission of suicide intention (OR=7.11, p<0.001) were significantly associated with higher perceived lethality of the suicide method in the non-overdose group. Suicide attempts occurred more frequently between May and November, and on Tuesdays. CONCLUSIONS: Gender and ethnic differences between overdose and non-overdose people attempting suicide were found. Temporal variations of suicidal cases were also noted.

Views on the peer review system of biomedical journals: an online survey of academics from high-ranking universities.

BACKGROUND: Peer review is the major method used by biomedical journals for making the decision of publishing an article. This cross-sectional survey assesses views concerning the review system of biomedical journals among academics globally. METHODS: A total of 28,009 biomedical academics from high-ranking universities listed by the 2009 Times Higher Education Quacquarelli Symonds (THE-QS) World University Rankings were contacted by email between March 2010 and August 2010. 1,340 completed an online survey which focused on their academic background, negative experiences and views on biomedical journal peer review and the results were compared among basic scientists, clinicians and clinician scientists. RESULTS: Fewer than half of the respondents agreed that the peer review systems of biomedical journals were fair (48.4%), scientific (47.5%), or transparent (25.1%). Nevertheless, 58.2% of the respondents agreed that authors should remain anonymous and 64.4% agreed that reviewers should not be disclosed. Most, (67.7%) agreed to the establishment of an appeal system. The proportion of native English-speaking respondents who agreed that the "peer review system is fair" was significantly higher than for non-native respondents (p = 0.02). Similarly, the proportion of clinicians stating that the "peer review system is fair" was significantly higher than that for basic scientists and clinician-scientists (p = 0.004). For females, (ß = -0.1, p = 0.03), the frequency of encountering personal attacks in reviewers' comments (ß = -0.1, p = 0.002) and the frequency of imposition of unnecessary references by reviewers (ß = -0.06, p = 0.04) were independently and inversely associated with agreement that "the peer review system is fair". CONCLUSION: Academics are divided on the issue of whether the biomedical journal peer review system is fair, scientific and transparent. A majority of academics agreed with the double-blind peer review and to the establishment of an appeal system. Female academics, experience of personal attacks and imposition of unnecessary references by reviewers were related to disagreement about fairness of the peer review system of biomedical journals.

Enhancing peptide ligand binding to vascular endothelial growth factor by covalent bond formation.

Formation of a stable covalent bond between a synthetic probe molecule and a specific site on a target protein has many potential applications in biomedical science. For example, the properties of probes used as receptor-imaging ligands may be improved by increasing their residence time on the targeted receptor. Among the more interesting cases are peptide ligands, the strongest of which typically bind to receptors with micromolar dissociation constants, and which may depend on processes other than simple binding to provide images. The side chains of cysteine, histidine, or lysine are attractive for chemical attachment to improve binding to a receptor protein, and a system based on acryloyl probes attaching to engineered cysteine provides excellent positron emission tomographic images in animal models (Wei et al. (2008) J. Nucl. Med. 49, 1828-1835). In nature, lysine is a more common but less reactive residue than cysteine, making it an interesting challenge to modify. To seek practically useful cross-linking yields with naturally occurring lysine side chains, we have explored not only acryloyl but also other reactive linkers with different chemical properties. We employed a peptide-VEGF model system to discover that a 19mer peptide ligand, which carried a lysine-tagged dinitrofluorobenzene group, became attached stably and with good yield to a unique lysine residue on human vascular endothelial growth factor (VEGF), even in the presence of 70% fetal bovine serum. The same peptide carrying acryloyl and related Michael acceptors gave low yields of attachment to VEGF, as did the chloroacetyl peptide.

The associations of asthma symptoms with active and passive smoking in Hong Kong adolescents.

BACKGROUND: Tobacco smoke has detrimental effects on the respiratory system. This study investigated the associations of active and passive smoking with asthma symptoms in Hong Kong adolescents. METHODS: A total of 6,494 Hong Kong secondary school students, with a mean ± SD age of 15.0 ± 1.21 years, participated in the Health Related Behavior General Survey in 2000-2001. They reported their demographic factors (sex, age, housing type, district of living), lifestyles (smoking, drinking, extracurricular sports, eating), and asthma symptoms (exercise-induced bronchospasm [EIB] and nocturnal cough) in the questionnaire. In addition, number of smoking parents (none/one/both) and presence of a smoking best friend (yes/no) were assessed. Logistic regression models were used to determine the odds ratios (OR) of frequently having the asthma symptoms for different smoking status of students, parents, and best friend, with adjustment for demographic factors and lifestyles. RESULTS: The prevalence of former, light, and heavy smokers was 17.5%, 7.7%, and 1.0%, respectively. Moreover, 35.1% of the participants had one and 3.8% had 2 parents who smoked. Heavy smokers were more likely to experience EIB with OR (95% CI) of 2.27 (1.30-3.97) and nocturnal cough with OR (95% CI) of 3.45 (1.52-7.81), as well as both symptoms with OR (95% CI) = 4.69 (1.88-11.73) when compared to those who never smoked. The corresponding OR (95% CI) for having at least one smoking parent and a smoking best friend was 1.45 (1.17-1.81), 1.61 (1.06-2.42), and 2.43 (1.37-4.31), when compared with those without a parent or best friend who smoked. CONCLUSIONS: Adolescents who are heavy smokers and having parents and a best friend who smoke are more likely than others to have asthma symptoms. Both active and passive smoking are related to asthma symptoms in adolescents.

Smoking of parents and best friend--independent and combined effects on adolescent smoking and intention to initiate and quit smoking.

INTRODUCTION: This study investigates the independent and combined effects of smoking of parents and best friend on smoking and the intention to initiate or quit smoking in adolescents. METHODS: In this school-based survey, 6,553 Hong Kong students aged 13-18 reported their demographic characteristics, smoking status of themselves, parents, and best friend; and intention to smoke (initiation among never-smokers and reinitiation among ex-smokers) or quit smoking among current smokers. Logistic regression yielded adjusted odds ratios (AORs) of student smoking (current/ever) and intention to smoke or quit smoking for parental (paternal/maternal/both parents vs. none) and best friend (yes vs. no) smoking. RESULTS: Parental smoking and having a smoking best friend were associated with adolescent current smoking, ever smoking, and intention to initiate smoking. Having a smoking best friend was also associated with reinitiating and quitting smoking. The AORs (95% CI) of current smoking for having a smoking best friend, in addition to smoking father, mother, or both were 19.14 (14.36-25.51), 20.38 (12.42-33.43), and 24.18 (15.89-36.77). The respective AORs of ever smoking were 8.30 (6.74-10.22), 8.92 (5.63-14.12), and 11.99 (8.05-17.87). CONCLUSIONS: Parental smoking and best friend smoking have independent effects on adolescent smoking behaviors. Their combined effects on current and ever smoking were particularly large. Smoking prevention programs should pay special attention to adolescents with both best friend and parents who smoke.

Efflux transport is an important determinant of ethinylestradiol glucuronide and ethinylestradiol sulfate pharmacokinetics.

17α-ethinylestradiol (EE) undergoes extensive conjugation to 17α-ethinylestradiol-3-O-glucuronide (EEG) and 17α-ethinylestradiol-3-O-sulfate (EES). Thus, oral contraceptive drug-drug interaction (DDI) studies usually characterize metabolite pharmacokinetics, with changes typically attributed to modulation of metabolism. EE passively diffuses through plasma membranes, but its conjugates are hydrophilic and require active transport. Unlike EE metabolism, EEG and EES transport has not been explored in vivo as a potential mechanism of DDIs. Recent in vitro studies demonstrated that EEG is transported by multidrug resistance-associated protein (MRP) 2 and MRP3 and EES is a breast cancer resistance protein (BCRP) substrate. In the study presented here, pharmacokinetics of EE and conjugates were studied in TR⁻ rats, which lack Mrp2, have marginal hepatic Bcrp expression, and overexpress hepatic Mrp3. EE pharmacokinetics in TR⁻ rats were comparable to wild type; however, EEG and EES systemic exposures were altered markedly. EEG exposure was greatly increased: 20-fold and >100-fold after intravenous and oral EE administration, respectively. In contrast, EES exposure was lower in TR⁻ rats: 65% decreased (intravenously) and 83% decreased (orally). In intestinal and liver perfusions, EE intestinal permeability and metabolism and hepatic clearance were unchanged in TR⁻ rats; however, secretion of EEG into intestinal lumen was halved, EEG was not detected in TR⁻ bile, and EES biliary excretion was 98% decreased. After oral EE administration to Mrp2- and Bcrp-knockout mice, EEG exposure increased 46- and 2-fold, respectively, whereas EES concentrations were decreased modestly. In conclusion, altered efflux transport resulted in major alterations of EEG and EES pharmacokinetics, highlighting transport as a potential site of DDIs with EE conjugates.

Chemically modified antibodies as diagnostic imaging agents.

Notable new applications of antibodies for imaging involve genetically extracting the essential molecular recognition properties of an antibody, and in some cases enhancing them by mutation, before protein expression. The classic paradigm of intravenous administration of a labeled antibody to image not only its target but also its metabolism can be improved on. Protocols involving molecular targeting with an engineered unlabeled protein derived from an antibody, followed by capture of a small probe molecule that provides a signal, are being developed to a high level of utility. This is accompanied by new strategies for probe capture such as irreversible binding, incorporation of engineered enzyme active sites, and antibody-ligand systems that generate a signal only upon binding or uptake.

Secular trends of sports participation, sedentary activity and physical self-perceptions in Hong Kong adolescents, 1995-2000.

AIM: To assess the 5-year secular changes in sports participation, sedentary activity, and physical self-perceptions among Hong Kong adolescents. METHODS: A total of 2932 and 5692 secondary students, aged 13-18 participated in the Health Related Behavior General (HRBG) Survey in 1995-1996 and 2000-2001, respectively. Extracurricular sports participation at least weekly or as a team member (none, 1-2 events, 3 or more events), sedentary activities (0-1 h/day, 2 h/day or more) including television/video watching and homework were assessed. Additionally, physical self-perceptions, physical fitness (fit/very fit, moderately fit, unfit/very unfit) and body weight (intention to lose weight, satisfied, intention to gain weight) were reported. Secular trends of sports participation, and sedentary activities and physical self-perceptions were assessed. RESULTS: During the 5 years, the prevalence of sports participation (at least weekly or membership) decreased significantly in boys. The prevalence of both TV/video watching and homework for at least 2 h/day increased significantly in both sexes. The prevalence of being unfit/very unfit increased significantly in girls. No significant secular difference in weight perception was observed for both sexes. CONCLUSIONS: Sports participation decreased and sedentary activities increased during the 5-year period. Physical self-perceptions did not change significantly, except an increase in being physically unfit was observed in girls.

Health-related physical fitness and weight status in Hong Kong adolescents.

BACKGROUND: This study was designed to investigate the relation between health-related physical fitness and weight status in Hong Kong adolescents. METHODS: 3,204 students aged 12-18 years participated in the Hong Kong Student Obesity Surveillance (HKSOS) project in 2006-2007. Anthropometric measures (height, weight) and health-related fitness (push-up, sit-up, sit-and-reach, 9-minute run) were assessed. Body mass index (BMI) was computed to classify participants into normal weight, underweight (Grade I, II/III), overweight, and obese groups. The associations of health-related physical fitness with BMI and weight status were examined by partial correlation coefficients and analysis of covariance, respectively. RESULTS: More boys than girls were overweight or obese (18.0% vs 8.7%), but more girls than boys were underweight (22.3% vs 16.7%). Boys performed significantly (P < 0.001) better in sit-up (38.8 vs 31.6 times/min) and 9-minute run (1632.1 vs 1353.2 m), but poorer in sit-and-reach (27.4 vs 32.2 cm) than girls. All four physical fitness tests were significantly positively correlated with each other in both sexes, and BMI was only weakly correlated with sit up and sit-and-reach tests in boys. Decreasing performance (P for trend < 0.05) was observed from normal weight to overweight and obese for push-up, sit-up, and 9-minute run in both sexes. From normal weight to Grade I and Grade II/III underweight, decreasing performance (P for trend < 0.05) for sit-up and sit-and-reach in both sexes and for push-up in boys was observed. CONCLUSIONS: The relations between BMI and health-related physical fitness in adolescents were non-linear. Overweight/obese and underweight adolescents had poorer performance in push-up and sit-up tests than normal weight adolescents. Different aspects of health-related physical fitness may serve as immediate indicators of potential health risks for underweight and overweight adolescents.

Predicting oral absorption of drugs: a case study with a novel class of antimicrobial agents.

PURPOSE: The purpose of this work was to evaluate an oral absorption prediction model, maximum absorbable dose (MAD), which predicts a theoretical dose of drug that could be absorbed across rat intestine based on consideration of intestinal permeability, solute solubility, intestinal volume, and residence time. METHODS: In the present study, Caco-2 cell permeability, as a surrogate for rat intestinal permeability, and aqueous solubility were measured for 27 oxazolidinones. The oxazolidinones are a novel class of potential antibacterial agents currently under investigation. These values were used to estimate MAD for each of the compounds. Finally, these predicted values were compared to previously measured bioavailability data in the rat in order to estimate oral absorption properties. RESULTS: A reasonably good correlation between predicted dose absorbed and bioavailability was observed for most of the compounds. In a few cases involving relatively insoluble compounds, absorption was underestimated. For these compounds while aqueous solubility was low. solubility in 5% polysorbate 80 was significantly higher, a solvent possibly more representative of the small intestinal lumen. CONCLUSIONS: These results suggest that MAD may be useful for prioritizing early discovery candidates with respect to oral absorption potential. In the case of compounds with poor aqueous solubility, additional factors may have to be considered such as solubility in the intestinal lumen.