The NIDA Avenir award in genetics or epigenetics of substance use disorders.

NIDA's Avenir Program in the Genetics or Epigenetics of Substance Use Disorders (SUDs) was launched to support early stage investigators who propose innovative, high risk, but potentially high impact research and who show promise of being tomorrow's leaders in this scientific field. Since 2015, NIDA has supported 30 Avenir Investigators with unique expertise and creative ideas. This special issue showcases how some of these ideas have germinated, flourished, and borne fruit. In this perspective article we briefly describe the purpose and implementation of the Avenir award and provide a high altitude overview of the awardees and their scientific projects to date.

The knockout mouse project.

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.

Advancing Biomarkers for Treatment of Smoking and Nicotine Dependence: An Overview.

The special issue on Biomarkers of Nicotine and Tobacco Dependence reviews the science for precision treatment of nicotine dependence and future opportunities for research on biomarkers for inclusion in tobacco product cessation and switching clinical trials to advance translation. This overview summarizes the articles contributed to the special issue by leading researcher in field of addiction.

Is it possible to train surgeons for rural Africa? A report of a successful international program.

BACKGROUND: The critical shortage of surgeons and access to surgical care in Africa is increasingly being recognized as a global health crisis. Across Africa, there is only one surgeon for every 250,000 people and only one for every 2.5 million of those living in rural areas. Surgical diseases are responsible for approximately 11.2% of the total global burden of disease. Even as the importance of treating surgical disease is being recognized, surgeons in sub-Saharan Africa are leaving rural areas and their countries altogether to practice in more desirable locations. METHODS: The Pan-African Academy of Christian Surgeons (PAACS) was formed in 1997 as a strategic response to this profound need for surgical manpower. It is training surgical residents through a 5-year American competency-based model. Trainees are required to be of African origin and a graduate of a recognized medical school. RESULTS: To date, PAACS has established six training programs in four countries. During the 2009-2010 academic year, there were 35 residents in training. A total of 18 general surgeons and one pediatric surgeon have been trained. Two more general surgeons are scheduled to finish training in 2011. Four graduates have gone on to subspecialty training, and the remaining graduates are practicing general surgery in rural and underserved urban centers in Angola, Guinea-Conakry, Ghana, Cameroon, Republic of Congo, Kenya, Ethiopia, and Madagascar. CONCLUSIONS: The PAACS has provided rigorous training for 18 African general surgeons, one of whom has also completed pediatric surgery training. To our knowledge, this is the only international rural-based surgical training program in Africa.

Metabolomics reveals biomarkers of opioid use disorder.

Opioid use disorder (OUD) is diagnosed using the qualitative criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnostic biomarkers for OUD do not currently exist. Our study focused on developing objective biological markers to differentiate chronic opiate users with OUD from chronic opiate users without OUD. Using biospecimens from the Golestan Cohort Study, we compared the metabolomics profiles of high opium users who were diagnosed as OUD positive with high opium users who were diagnosed as OUD negative. High opium use was defined as maximum weekly opium usage greater than or equal to the median usage (2.4 g per week), and OUD was defined as having 2 or more DSM-5 criteria in any 12-month period. Among the 218 high opium users in this study, 80 were diagnosed as OUD negative, while 138 were diagnosed as OUD positive. Seven hundred and twelve peaks differentiated high opium users diagnosed as OUD positive from high opium users diagnosed as OUD negative. Stepwise logistic regression modeling of subject characteristics data together with the 712 differentiating peaks revealed a signature that is 95% predictive of an OUD positive diagnosis, a significant (p < 0.0001) improvement over a 63% accurate prediction based on subject characteristic data for these samples. These results suggest that a metabolic profile can be used to predict an OUD positive diagnosis.

Untargeted Metabolomics: Biochemical Perturbations in Golestan Cohort Study Opium Users Inform Intervention Strategies.

Objective: Over 50 million people worldwide are estimated to use opioids, of which ~30 million use opiates (opium and its derivatives). Use of opiates has been associated with a variety of adverse complications such as neurological and behavioral outcomes, addiction, cancers, diabetes, and cardiovascular disease. While it is well known that opiates exert their neurobiological effects through binding with mu, kappa, and delta receptors to exert analgesic and sedative effects, mechanistic links to other health effects are not well understood. Our study focuses on the identification of biochemical perturbations in Golestan Cohort Study (GCS) opium users. Methods: We used untargeted metabolomics to evaluate the metabolic profiles of 218 opium users and 80 non-users participating in the GCS. Urine samples were obtained from adult (age 40-75) opium users living in the Golestan Province of Iran. Untargeted analysis of urine was conducted using a UPLC-Q-Exactive HFx Mass Spectrometry and a 700 MHz NMR Spectrometry. Results: These GCS opium users had a significantly higher intake of tobacco and alcohol and a significantly decreased BMI compared with non-users. Metabolites derived from opium (codeine, morphine, and related glucuronides), nicotine, and curing or combustion of plant material were increased in opium users compared with non-users. Endogenous compounds which differentiated the opium users and non-users largely included vitamins and co-factors, metabolites involved in neurotransmission, Kreb's cycle, purine metabolism, central carbon metabolism, histone modification, and acetylation. Conclusions: Our study reveals biochemical perturbations in GCS opium users that are important to the development of intervention strategies to mitigate against the development of adverse effects of substance abuse.

Defining Substance Use Disorders: The Need for Peripheral Biomarkers.

Addiction is a brain disease, and current diagnostic criteria for substance use disorders (SUDs) are qualitative. Nevertheless, scientific advances are beginning to characterize neurobiological domains. Combining multiple units of measure may provide an opportunity to deconstruct the heterogeneities of a SUD and define endophenotypes by using peripheral biospecimens. There are several recent examples of potential biomarker types that can be examined, together with their categorical applications for SUDs. We propose that, in conjunction with rapidly advancing statistical and mathematical modeling techniques, there is now a unique opportunity for the discovery of composite biomarkers within specific domains of addiction; these may lay the foundation for future biomarker qualification, with important implications for drug development and medical care.

Making connections: the development of mesencephalic dopaminergic neurons.

The disorders of two adjacent sets of mesencephalic dopaminergic (MDNs) are associated with two significant health problems: Parkinson's disease and drug addiction. Because of this, a great deal of research has focused on understanding the growth, development and maintenance of MDNs. Many transcription factors and signaling pathways are known to be required for normal MDNs formation, but a unified model of MDN development is still unclear. The long-term goal is to design therapeutic strategies to: (i) nurture and/or heal endogenous MDNs, (ii) replace the affected tissue with exogenous MDNs from in vitro cultivated stem cells and (iii) restore normal connectivity. Recent developmental biology studies show great promise in understanding how MDNs develop both in vivo and in vitro. This information has great therapeutic value and may provide insight into how environmental and genetic factors increase vulnerability to addiction.

Gene expression profiling: methodological challenges, results, and prospects for addiction research.

This review describes the current methods used to profile gene expression. These methods include microarrays, spotted arrays, serial analysis of gene expression (SAGE), and massive parallel signature sequencing (MPSS). Methodological and statistical problems in interpreting microarray and spotted array experiments are also discussed. Methods and formats such as minimum information about microarray experiments (MIAME) needed to share gene expression data are described. The last part of the review provides an overview of the application of gene-expression profiling technology to substance abuse research and discusses future directions.

Deep imaging technology needed for NIH BRAIN initiative.

This opinion piece discusses potential funding opportunities by the NIH BRAIN initiative to support the development of deep imaging technologies.

Molecular neuroanatomy: a generation of progress.

The neuroscience research landscape has changed dramatically over the past decade. Specifically, an impressive array of new tools and technologies have been generated, including but not limited to: brain gene expression atlases, genetically encoded proteins to monitor and manipulate neuronal activity, and new methods for imaging and mapping circuits. However, despite these technological advances, several significant challenges must be overcome to enable a better understanding of brain function and to develop cell type-targeted therapeutics to treat brain disorders. This review provides an overview of some of the tools and technologies currently being used to advance the field of molecular neuroanatomy, and also discusses emerging technologies that may enable neuroscientists to address these crucial scientific challenges over the coming decade.

An alternative method of management of pediatric airway foreign bodies in the absence of rigid bronchoscopy.

OBJECTIVE: Pediatric airway foreign body aspiration is a life-threatening clinical entity. The standard of care for managing this situation is endoscopic retrieval using rigid bronchoscopy. However in resource-limited settings rigid bronchoscopy may not be available. This retrospective case series describes the successful application of one treatment modality for pediatric airway foreign body. METHODS: A retrospective review was performed for seven pediatric patients who were treated at Soddo Christian Hospital with a diagnosis of airway foreign body aspiration. All patients were treated in the operating room using general anesthesia, a combination of inhaled halothane and intravenous ketamine. Paralytics were not used in any patient and spontaneous breathing was maintained. Flexible fiberoptic bronchoscopy was initially performed on each patient to confirm the presence of a foreign body and identify the anatomic position with the airway. Using a standard technique, a tracheotomy was performed. If the foreign body was still noted to be distal to the tracheotomy, postural percussion was performed to dislodge the foreign body into the trachea. Once the foreign body was identified at the tracheotomy, it was removed. RESULTS: All seven patients presented in respiratory distress and were emergently managed in the operating room. The average age was 2.8 years (6 months-8 years of age). The foreign bodies were successfully removed in all patients. There were no mortalities and all patients were successfully discharged from the hospital. CONCLUSIONS: Pediatric airway foreign body aspiration is a life-threatening clinical entity in any setting, but it presents unique challenges in resource-limited settings where rigid bronchoscopy is not available. This report presents one such treatment modality and utilizes a combination of flexible fiberoptic bronchoscopy and tracheotomy to treat such patients.

Definitive surgical treatment of enterocutaneous fistula: outcomes of a 23-year experience.

OBJECTIVE: To analyze postoperative outcomes, morbidity, and mortality following enterocutaneous fistula (ECF) takedown. DESIGN, SETTING, AND PATIENTS: Retrospective review of the complete medical records of patients who presented to a single tertiary care referral center from December 24, 1987, to June 18, 2010, and subsequently underwent definitive surgical treatment for ECF originating from the stomach, small bowel, colon, or rectum. MAIN OUTCOME MEASURES: Postoperative fistula recurrence and mortality. RESULTS: A total of 153 patients received operative intervention for ECF. Most ECFs were referred to us from outside institutions (75.2%), high output (52.3%), originating from the small bowel (88.2%), and iatrogenic in cause (66.7%). Successful ECF closure was ultimately achieved in 128 patients (83.7%). Six patients (3.9%) died within 30 days of surgery, and overall 1-year mortality was 15.0%. Postoperative complications occurred in 134 patients, for an overall morbidity rate of 87.6%. Significant risk factors for fistula recurrence were numerous, but postoperative ventilation for longer than 48 hours, organ space surgical site infection, and blood transfusion within 72 hours of surgery carried the most considerable impact (relative risks, 4.87, 4.07, and 3.91, respectively; P < .05). Risk of 1-year mortality was also associated with multiple risk factors, the most substantial of which were postoperative pulmonary and infectious complications. Closure of abdominal fascia was protective against both recurrent ECF and mortality (relative risks, 0.47 and 0.38, respectively; P < .05). CONCLUSIONS: Understanding risk factors both associated with and protective against ECF recurrence and postoperative morbidity and mortality is imperative for appropriate ECF management. Closure of abdominal fascia is of utmost importance, and preventing postoperative complications must be prioritized to optimize patient outcomes.