Delta Opioid Receptor-Mediated Antidepressant-Like Effects of Diprenorphine in Mice.

Major depressive disorder is a highly common disorder, with a lifetime prevalence in the United States of approximately 21%. Traditional antidepressant treatments are limited by a delayed onset of action and minimal efficacy in some patients. Ketamine is effective and fast-acting, but there are concerns over its abuse liability. Thus, there is a need for safe, fast-acting antidepressant drugs. The opioid buprenorphine shows promise but also has abuse liability due to its mu-agonist component. Preclinical evidence indicates that the delta-opioid system contributes to mood disorders, and delta-opioid agonists are effective in preclinical models of depression- and anxiety-like states. In this study, we test the hypothesis that the mu-opioid antagonist diprenorphine by virtue of its partial delta opioid agonist activity may offer a beneficial profile for an antidepressant medication without abuse liability. Diprenorphine was confirmed to bind with high affinity to all three opioid receptors, and functional experiments for G protein activation verified diprenorphine to be a partial agonist at delta- and kappa-opioid receptors and a mu-antagonist. Studies in C57BL/6 mice demonstrated that an acute dose of diprenorphine produced antidepressant-like effects in the tail suspension test and the novelty-induced hypophagia test that were inhibited in the presence of the delta-selective antagonist, naltrindole. Diprenorphine did not produce convulsions, a side effect of many delta agonists but rather inhibited convulsions caused by the full delta agonist SNC80; however, diprenorphine did potentiate pentylenetetrazole-induced convulsions. Diprenorphine, and compounds with a similar pharmacological profile, may provide efficient and safe rapidly acting antidepressants. SIGNIFICANCE STATEMENT: The management of major depressive disorder, particularly treatment-resistant depression, is a significant unmet medical need. Here we show that the opioid diprenorphine, a compound with mu-opioid receptor antagonist activity and delta- and kappa-opioid receptor partial agonist activities, has rapid onset antidepressant-like activity in animal models. Diprenorphine and compounds with a similar pharmacological profile to diprenorphine should be explored as novel antidepressant drugs.

The Buprenorphine Analogue BU10119 Attenuates Drug-Primed and Stress-Induced Cocaine Reinstatement in Mice.

There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The µ-opioid receptor (MOPr) partial agonist buprenorphine alone or in combination with naltrexone has been shown to reduce cocaine-positive urine tests and cocaine seeking in rodents. However, there are concerns over the abuse liability of buprenorphine. Buprenorphine's partial agonist and antagonist activity at the nociception receptor (NOPr) and κ-opioid receptor (KOPr), respectively, may contribute to its ability to inhibit cocaine seeking. Thus, we hypothesized that a buprenorphine derivative that exhibits antagonist activity at MOPr and KOPr with enhanced agonist activity at the NOPr could provide a more effective treatment. Here we compare the pharmacology of buprenorphine and two analogs, BU10119 and BU12004, in assays for antinociception and for cocaine- and stress-primed reinstatement in the conditioned place preference paradigm. In vitro and in vivo assays showed that BU10119 acts as an antagonist at MOPr, KOPr, and δ-opioid receptor (DOPr) and a partial agonist at NOPr, whereas BU12004 showed MOPr partial agonist activity and DOPr, KOPr, and NOPr antagonism. BU10119 and buprenorphine but not BU12004 lessened cocaine-primed reinstatement. In contrast, BU10119, BU12004, and buprenorphine blocked stress-primed reinstatement. The selective NOPr agonist SCH221510 but not naloxone decreased cocaine-primed reinstatement. Together, these findings are consistent with the concept that NOPr agonism contributes to the ability of BU10119 and buprenorphine to attenuate reinstatement of cocaine-conditioned place preference in mice. The findings support the development of buprenorphine analogs lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction. SIGNIFICANCE STATEMENT: There are no Food and Drug Administration-approved medications for cocaine use disorder. Buprenorphine has shown promise as a treatment for cocaine relapse prevention; however, there are concerns over the abuse liability of buprenorphine. Here we show a buprenorphine analogue, BU10119, which lacks µ-opioid receptor agonism and inhibits cocaine-primed and stress-primed reinstatement in a conditioned place-preference paradigm. The results suggest the development of BU10119 for the management of relapse to cocaine seeking.

In vivo modeling of docosahexaenoic acid and eicosapentaenoic acid-mediated inhibition of both platelet function and accumulation in arterial thrombi.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with a variety of cellular alterations that mitigate cardiovascular disease. However, pinpointing the positive therapeutic effects is challenging due to inconsistent clinical trial results and overly simplistic in vitro studies. Here we aimed to develop realistic models of n-3 PUFA effects on platelet function so that preclinical results can better align with and predict clinical outcomes. Human platelets incubated with the n-3 PUFAs docosahexaenoic acid and eicosapentaenoic acid were stimulated with agonist combinations mirroring distinct regions of a growing thrombus. Platelet responses were then monitored in a number of ex-vivo functional assays. Furthermore, intravital microscopy was used to monitor arterial thrombosis and fibrin deposition in mice fed an n-3 PUFA-enriched diet. We found that n-3 PUFA treatment had minimal effects on many basic ex-vivo measures of platelet function using agonist combinations. However, n-3 PUFA treatment delayed platelet-derived thrombin generation in both humans and mice. This impaired thrombin production paralleled a reduced platelet accumulation within thrombi formed in either small arterioles or larger arteries of mice fed an n-3 PUFA-enriched diet, without impacting P-selectin exposure. Despite an apparent lack of robust effects in many ex-vivo assays of platelet function, increased exposure to n-3 PUFAs reduces platelet-mediated thrombin generation and attenuates elements of thrombus formation. These data support the cardioprotective value of-3 PUFAs and strongly suggest that they modify elements of platelet function in vivo.

In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains.

S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 ß-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the first set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all ≤1 µg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of ≥8 µg/ml. In the second set, the MIC values of S-649266 were ≤4 µg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of ≤2 µg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 µg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.

In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria.

OBJECTIVES: S-649266 is a parenteral siderophore cephalosporin antibiotic with a catechol moiety on its side chain. The in vitro antimicrobial activity of S-649266 against non-fermenting Gram-negative bacteria was evaluated and compared with the activities of meropenem, levofloxacin, cefepime, ceftazidime and piperacillin/tazobactam. METHODS: MIC values of S-649266 were determined in Mueller-Hinton broth or Iso-Sensitest broth supplemented with apo-transferrin. RESULTS: S-649266 showed potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-ß-lactamase-producing P. aeruginosa. MIC90s of S-649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type ß-lactamases, and P. aeruginosa producing metallo-ß-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively. CONCLUSIONS: S-649266 is a novel antibiotic with potent in vitro activity against a range of non-fermenting Gram-negative bacteria, including MDR strains.

Dissection of complex adult traits in a mouse synthetic population.

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modest-sized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Victimization of Peruvian adolescents and health risk behaviors: Young Lives cohort.

BACKGROUND: While extensive research has been conducted on bullying and victimization in western countries, research is lacking in low- and middle-income settings. This study focused on bullying victimization in Peru. It explored the relationship between the caregiver's perception of child victimization and the child's view of selected negative experiences occurring with other children their age. Also, the study examined the association between victimization and adolescent health risk behaviors. METHODS: This study used data from 675 children participating in the Peru cohort of the Young Lives study. Children and caregivers were interviewed in 2002 when children were 8 years of age and again in 2009 when children were 15 years of age. Measures of victimization included perceptions from children and caregivers while measures of health risk behaviors included cigarette smoking, alcohol drinking, and sexual relations among adolescents. RESULTS: Caregivers identified 85 (12.6%) children bullied at ages 8 and 15, 235 (34.8%) bullied at age 8 only, 61 (9.0%) bullied at age 15 only, and 294 (43.6%) not bullied at either age. Children who were bullied at both ages compared with all other children were 1.58 (95% CI 1.00-2.50) times more likely to smoke cigarettes, 1.57 (1.04-2.38) times more likely to drink alcohol, and 2.17 (1.41-3.33) times more likely to have ever had a sexual relationship, after adjusting for gender. The caregiver's assessment of child victimization was significantly associated with child reported bullying from other children their age. Child reported victimization was significantly associated with increased risky behaviors in some cases. CONCLUSION: Long-term victimization from bullying is more strongly associated than less frequent victimization with increased risk of cigarette smoking, alcohol drinking, and sexual relations at age 15. Hence, programs focused on helping children learn how to mitigate and prevent bullying consistently over time may also help reduce risky adolescent health behaviors such as smoking, alcohol consumption, and sexual activity.

Sexting among Peruvian adolescents.

BACKGROUND: Sexting (sexual messaging via mobile devices) among adolescents may result in increased risky sexual practices, psychological distress and in some cases, suicide. There is very little research on sexting in developing nations, such as Peru. In particular, little is known about gender differences in the correlates of sexting. The purpose of this study was to determine the sexting prevalence and correlates of sexting among adolescent boys and girls in Cusco, Peru. METHODS: The study sample comprised 949 high school aged adolescents from Cusco, Peru. Adolescents responded to questions about demographics, sexting behavior, and risk/protective factors. Separate regression models were constructed to compare correlates of sexting for boys and sexting for girls. RESULTS: Twenty percent of the sample reported engaging in at least one instance of sexting. Boys reported higher rates of sexting than girls (35.17% vs. 13.19%, p = 0.000). Significant correlates for girls' sexting included having been cyberbullied and parental factors. For boys, hypertexting, fighting, parental factors, and parental rules about sexting were significant. CONCLUSIONS: Peruvian health officials with an interest in reducing the effects of sexting among adolescents may choose to target boys differently than girls. These efforts may include advising parents to set clear rules and expectations about sexting and the appropriate use of mobile devices.

Ophthalmologists' Perspective on Barriers to Cataract Surgery and Surgical Productivity in Ethiopia, Ghana, and Zambia: A Descriptive, Mixed-Methods Survey.

PURPOSE: While progress was made towards the Vision 2020: The Right to Sight goals, Ethiopia, Ghana, and Zambia fell short of the recommended cataract surgical rate (CSR) on a national level. Post-operative cataract surgical outcomes are also lower compared to other regions. This study aimed to describe perceived barriers to cataract surgical uptake, factors related to surgeon surgical productivity, and surgical offerings in each of these countries. METHODS: An online survey was sent to ophthalmologists practicing in Ethiopia, Ghana, and Zambia. Responses were collected between June 25, 2021 and January 30, 2022. RESULTS: Responses were received from 122 ophthalmologists from Ethiopia, Ghana, and Zambia. The estimated participation rate was 47% (122/257). Distance to cataract surgical centres, lack of surgical centres, and lack of surgical equipment were among the top 10 most agreed upon barriers by respondents within each country. Many respondents reported that current financial reimbursement does not incentivise maximum productivity in themselves (56%, 68/122) or their staff (61%, 74/122). Surgeons proposed several ways to improve productivity incentives. Private practice was perceived to have the best reimbursement incentives (77%, 94/122), whereas government hospitals were least agreed upon (4%, 5/122). Discrepancies in timely post-operative refraction and eyeglasses disbursement were reported. CONCLUSIONS: Overcoming the identified barriers, improving surgeon productivity, and addressing identified deficits in cataract care will likely reduce the backlog of cataract blindness while ensuring increasingly improved patient outcomes.

Reduced Violence-Related Burden and Mortality at Higher Altitudes: Examining the Association between High Altitude Living and Homicide Rates in Ecuador.

Esteban Ortiz-Prado, Juan Sebastian Izquierdo-Condoy, María G. Dávila-Rosero, Jorge Vásconez-González, Ana M. Diaz, Carla E. Moyano, Vanessa Arcos-Valle, Ginés Viscor, and Joshua H. West. Reduced Violence-Related Burden and Mortality at Higher Altitudes: Examining the Association between High Altitude Living and Homicide Rates in Ecuador. High Alt Med Biol. 00:000-000, 0000. Background: Homicides are a major public health concern and a leading cause of preventable deaths worldwide. The relationship between altitude and homicides remains unclear, and evidence of the possible effects of living at high altitudes on homicide rates is limited. This research aimed to investigate the mortality rates resulting from various types of aggression that culminated in homicides in Ecuador and to explore potential differences associated with altitude. Methods: An ecological analysis of homicide rates in Ecuador was conducted from 2001 to 2022. Homicide cases and the population at risk were categorized based on their place of residence according to two altitude classifications: a binary classification of low (<2,500 m) and high altitude (>2,500 m), and a detailed classification according to criteria by the International Society for Mountain Medicine, which includes low (<1,500 m), moderate (1,500-2,500 m), high (2,500-3,500 m), and very high altitude (3,500-5,500 m) categories. Both crude and directly age-sex standardized mortality rates were calculated for each altitude category. Results: We analyzed a total of 40,708 deaths attributed to aggressions (ICD-10 codes X85-Y09). The total homicide rate for men was 21.29 per 100,000 (95% confidence interval [CI]: 9.55-32.37), whereas for women, it was 2.46 per 100,000 (95% CI: 1.44-3.27). Average rates across the 22 analyzed years were higher at low altitudes (men: 13.2/100,000 and women: 1.33/100,000) as compared with high altitudes (men: 5.79/100,000 and women: 1.05/100,000). Notably, the male-to-female rate difference was more pronounced at low altitudes (898%) than at high altitudes (451%). Conclusions: Our study revealed a higher prevalence of homicides in certain provinces and significant disparities in mortality rates between men and women. Although we cannot establish a direct relationship between altitude and homicide rates, further research is needed to explore potential confounding factors and a better understanding of the underlying causes for these variations.

Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

Determinants of better health: a cross-sectional assessment of positive deviants among women in West Bengal.

BACKGROUND: Rural women in West Bengal have been found to have low rates of formal education, poor health knowledge, high rates of malnutrition and anemia, and low levels of empowerment. Despite these difficult circumstances, some women have positive health outcomes compared to women with similarly disadvantaged backgrounds. The purpose of this study is to identify factors associated with positive health outcomes among women with primary education or less. METHODS: Multivariable regression models were built for outcomes of positive deviance to better characterize the factors in a woman's life that most impact her ability to deviate from the status quo. RESULTS: Positive deviants in this context are shown to be women who are able to earn an income, who have access to information through media sources, and who, despite little schooling, have marginally higher levels of formal education that lead to improved health outcomes. CONCLUSIONS: Study findings indicate that positive deviant women in disadvantaged circumstances can achieve positive outcomes amidst a host of contextual barriers that would predict poor health outcomes. Focusing on areas such as enhancing access to media sources, facilitating self-help groups for married women, and promoting prolonged education and delayed marriage for girls may improve health knowledge and behavior among married women with low levels of education.

Correlates of health-related social media use among adults.

BACKGROUND: Sixty percent of Internet users report using the Internet to look for health information. Social media sites are emerging as a potential source for online health information. However, little is known about how people use social media for such purposes. OBJECTIVES: The purpose of this study was two-fold: (1) to establish the frequency of various types of online health-seeking behaviors, and (2) to identify correlates of 2 health-related online activities, social networking sites (SNS) for health-related activities and consulting online user-generated content for answers about health care providers, health facilities, or medical treatment. METHODS: The study consisted of a telephone survey of 1745 adults who reported going online to look for health-related information. Four subscales were created to measure use of online resources for (1) using SNS for health-related activities; (2) consulting online rankings and reviews of doctors, hospitals or medical facilities, and drugs or medical treatments; (3) posting a review online of doctors, hospitals or medical facilities, and drugs or medical treatments, and (4) posting a comment or question about health or medical issues on various social media. Univariate and multivariate logistic regression analyses were performed. RESULTS: Respondents consulted online rankings or reviews (41.15%), used SNS for health (31.58%), posted reviews (9.9%1), and posted a comment, question, or information (15.19%). Respondents with a chronic disease were nearly twice as likely to consult online rankings (odds ratio [OR] 2.09, 95% CI 1.66-2.63, P<.001). Lower odds of consulting online reviews were associated with less formal education (OR 0.49, 95% CI 0.37-0.65, P<.001) and being male (OR 0.71, 95% CI 0.57-0.87, P<.001). Respondents with higher incomes were 1.5 times as likely to consult online rankings or reviews (OR 1.49, 95% CI 0.10-2.24, P=.05), than respondents with a regular provider (OR 2.05, 95% CI 1.52-2.78, P<.001), or living in an urban/suburban location (OR 1.61, 95% CI 1.17-2.22, P<.001). Older respondents were less likely to use SNS for health-related activities (OR 0.96, 95% CI 0.95-0.97, P<.001), as were males (OR 0.70, 95% CI 0.56-0.87, P<.001), whereas respondents with a regular provider had nearly twice the likelihood of using SNS for health-related activities (OR 1.89, 95% CI 1.43-2.52, P<.001). CONCLUSIONS: People are using social media for seeking health information. However, individuals are more likely to consume information than they are to contribute to the dialog. The inherent value of "social" in social media is not being captured with online health information seeking. People with a regular health care provider, chronic disease, and those in younger age groups are more likely to consult online rankings and reviews and use SNS for health-related activities.

Health risk behaviors in urban and rural Guatemalan adolescents.

Adolescence is an important stage of life when health behaviors and attitudes are established. The purpose of this research was to assess health risk behaviors among Guatemalan students in both an urban and rural school. Items were adapted from the Global School-based Student Health Survey and were used to measure and compare the prevalence of risk behaviors between these two demographically and culturally distant school-based samples. In general, the prevalence of adolescent health risk behaviors in both schools was lower than other Latin American countries. Many health risk behaviors were associated with location (urban vs. rural settings) and/or gender. Tobacco use, alcohol use, and sexual activity were higher among urban students. Boys were more likely than girls to use alcohol, use tobacco, and be sexually active. In addition, the prevalence of mental health problems was higher among girls and rural students. These findings imply that measures should be taken to design effective and appropriate health strategies for adolescents attending these schools. Health promotion programs in schools and communities should assist the youth in developing positive health behaviors and cultivating healthy lifestyles in an effort to reduce risk behaviors among adolescent populations. Further research is needed to extend our understanding of risk factors of health behavior in these adolescent populations and to identify effective preventative approaches and strategies that specifically cater to the location and culture of the students.

The Role of Parenting in Alcohol and Tobacco Use Among Latino Adolescents.

Parents can impact adolescent substance use, but it is unclear which substances are most affected. This study compared associations between parenting behaviors and alcohol and tobacco use to see if parenting was equally related to both behaviors. Alcohol and tobacco use data were collected from 252 Latino adolescents living along the San Diego-Tijuana border. Logistic regression was used to test parenting behaviors' impact. Parenting was protective against alcohol use, but not related to tobacco use. Substance using peers affected both alcohol and tobacco use. Alcohol prevention efforts among Latino adolescents should target parenting behaviors.

What difference can fathers make? Early paternal absence compromises Peruvian children's growth.

Considerable evidence suggests that fathers' absence from home has a negative short- and long-term impact on children's health, psychosocial development, cognition and educational experience. We assessed the impact of father presence during infancy and childhood on children's height-for-age z-score (HAZ) at 5 years old. We conducted secondary data analysis from a 15-year cohort study (Young Lives) focusing on one of four Young Lives countries (Peru, n = 1821). When compared with children who saw their fathers on a daily or weekly basis during infancy and childhood, children who did not see their fathers regularly at either period had significantly lower HAZ scores (-0.23, P = 0.0094) after adjusting for maternal age, wealth and other contextual factors. Results also suggest that children who saw their fathers during childhood (but not infancy) had better HAZ scores than children who saw their fathers in infancy and childhood (0.23 z-score, P = 0.0388). Findings from analyses of resilient children (those who did not see their fathers at either round but whose HAZ > -2) show that a child's chances of not being stunted in spite of paternal absence at 1 and 5 years old were considerably greater if he or she lived in an urban area [odds ratio (OR) = 9.3], was from the wealthiest quintile (OR = 8.7) and lived in a food secure environment (OR = 3.8). Interventions designed to reduce malnutrition must be based on a fuller understanding of how paternal absence puts children at risk of growth failure.

The Impact of a Large-Scale Social and Behavior Change Communication Intervention in the Lake Zone Region of Tanzania on Knowledge, Attitudes, and Practices Related to Stunting Prevention.

BACKGROUND: Large-scale social and behavioral change communication (SBCC) approaches can be beneficial to achieve improvements in knowledge, attitudes, and practices (KAP). Addressing Stunting in Tanzania Early (ASTUTE) included a significant SBCC component and targeted precursors to stunting including KAP related to maternal and child health, antenatal care, WASH, childhood development, and male involvement. METHODS: Baseline, midline, and endline surveys were conducted for a total of 14,996 female caregivers and 6726 male heads of household in the Lake Zone region of Tanzania. Regression analyses were used to estimate differences in KAP from baseline to midline and endline. RESULTS: Women's knowledge of handwashing and infant/child feeding practices, and attitudes related to male involvement, consistently improved from baseline to midline and baseline to endline. Women's practices related to antenatal care, breastfeeding, and early child development improved from baseline to midline and baseline to endline. Improvements in KAP among male heads of household were varied across indicators with consistent improvement in practices related to child feeding practices from baseline to midline and baseline to endline. CONCLUSION: Many changes in KAP were observed from baseline to midline and baseline to endline and corresponded with SBCC programming in the region. These results provide support for the value of large SBCC interventions. Public health efforts in settings such as Tanzania may benefit from adopting these approaches.

PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells.

The adrenomedullary chromaffin cell transduces chemical messages into outputs that regulate end organ function throughout the periphery. At least two important neurotransmitters are released by innervating preganglionic neurons to stimulate exocytosis in the chromaffin cell-acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is widely acknowledged as an important secretagogue in this system, the pathway coupling PACAP stimulation to chromaffin cell secretion is poorly understood. The goal of this study is to address this knowledge gap. Here, it is shown that PACAP activates a Gαs-coupled pathway that must signal through phospholipase C ε (PLCε) to drive Ca2+ entry and exocytosis. PACAP stimulation causes a complex pattern of Ca2+ signals in chromaffin cells, leading to a sustained secretory response that is kinetically distinct from the form stimulated by ACh. Exocytosis caused by PACAP is associated with slower release of peptide cargo than exocytosis stimulated by ACh. Importantly, only the secretory response to PACAP, not ACh, is eliminated in cells lacking PLCε expression. The data show that ACh and PACAP, acting through distinct signaling pathways, enable nuanced and variable secretory outputs from chromaffin cells.

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism.

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells. Highlights: RPL22 insufficiency is observed in MDS/AML and is associated with reduced survivalRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesisRpl22-deficiency does not impair global protein synthesis by HSCRpl22 controls leukemia cell survival by non-canonical regulation of lipid oxidation eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through effects on ALOX12 expression, a regulator of fatty acid oxidation.

"Right time, right place" health communication on Twitter: value and accuracy of location information.

BACKGROUND: Twitter provides various types of location data, including exact Global Positioning System (GPS) coordinates, which could be used for infoveillance and infodemiology (ie, the study and monitoring of online health information), health communication, and interventions. Despite its potential, Twitter location information is not well understood or well documented, limiting its public health utility. OBJECTIVE: The objective of this study was to document and describe the various types of location information available in Twitter. The different types of location data that can be ascertained from Twitter users are described. This information is key to informing future research on the availability, usability, and limitations of such location data. METHODS: Location data was gathered directly from Twitter using its application programming interface (API). The maximum tweets allowed by Twitter were gathered (1% of the total tweets) over 2 separate weeks in October and November 2011. The final dataset consisted of 23.8 million tweets from 9.5 million unique users. Frequencies for each of the location options were calculated to determine the prevalence of the various location data options by region of the world, time zone, and state within the United States. Data from the US Census Bureau were also compiled to determine population proportions in each state, and Pearson correlation coefficients were used to compare each state's population with the number of Twitter users who enable the GPS location option. RESULTS: The GPS location data could be ascertained for 2.02% of tweets and 2.70% of unique users. Using a simple text-matching approach, 17.13% of user profiles in the 4 continental US time zones were able to be used to determine the user's city and state. Agreement between GPS data and data from the text-matching approach was high (87.69%). Furthermore, there was a significant correlation between the number of Twitter users per state and the 2010 US Census state populations (r ≥ 0.97, P < .001). CONCLUSIONS: Health researchers exploring ways to use Twitter data for disease surveillance should be aware that the majority of tweets are not currently associated with an identifiable geographic location. Location can be identified for approximately 4 times the number of tweets using a straightforward text-matching process compared to using the GPS location information available in Twitter. Given the strong correlation between both data gathering methods, future research may consider using more qualitative approaches with higher yields, such as text mining, to acquire information about Twitter users' geographical location.