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Sex, Drugs, and Rodent Reward: An Exploration of the Sex-Specific Roles of Nicotinic Acetylcholine Receptors in Ethanol Reward

Tue, 03/21/2017 - 2:12pm

Alcohol, recently named the most dangerous drug in the world, contributes to nearly 40% of violent crimes and fatal traffic accidents, increases risk of roughly 60 different diseases and injuries, and is responsible for 2.5 million deaths each year worldwide. Despite these staggering figures, treatments remain ineffective and riddled with adverse side effects, making successful use of even the most effective treatments unlikely. Moreover, many of the treatments, and the supporting research, have focused only on male subjects, despite sex differences in various alcohol-related behaviors.

Human alcohol use is frequently accompanied by nicotine use, and vice versa, suggesting a common mechanism of the two drugs. In fact, alcohol may act through the same family of receptors as nicotine, the nicotinic acetylcholine receptors (nAChRs), eliciting similar activation of the reward pathway as nicotine and other drugs of abuse. Studies have shown that nAChRs containing the α4 and/or α6 subunits are involved in nicotine-induced activation of the reward pathway, leading to the hypothesis that these same receptor subtypes may be important for alcohol effects in the brain as well.

Using male and female genetic mouse models and various behavioral assays, we have shown not only that these α4 and/or α6-containing nAChRs are involved in alcohol- related behaviors and activation of the reward pathway, but also show sex differences in this involvement. Uncovering the mechanism of alcohol in the brain, in males as well as in females, is an important step in developing targeted treatments for alcohol abuse.

Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans

Tue, 03/21/2017 - 10:49am

The regulation of cell migration is essential to animal development and physiology. Heparan sulfate proteoglycans shape the interactions of morphogens and guidance cues with their respective receptors to elicit appropriate cellular responses. Heparan sulfate proteoglycans consist of a protein core with attached heparan sulfate glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin (EXT) family. Abnormal HS chain synthesis results in pleiotropic consequences, including abnormal development and tumor formation. In humans, mutations in either of the exostosin genes EXT1 and EXT2 lead to osteosarcomas or multiple exostoses. Complete loss of any of the exostosin glycosyltransferases in mouse, fish, flies and worms leads to drastic morphogenetic defects and embryonic lethality. Here we identify and study previously unavailable viable hypomorphic mutations in the two C. elegans exostosin glycosyltransferases genes, rib-1 and rib-2. These partial loss-of-function mutations lead to a severe reduction of HS levels and result in profound but specific developmental defects, including abnormal cell and axonal migrations. We find that the expression pattern of the HS copolymerase is dynamic during embryonic and larval morphogenesis, and is sustained throughout life in specific cell types, consistent with HSPGs playing both developmental and post-developmental roles. Cell-type specific expression of the HS copolymerase shows that HS elongation is required in both the migrating neuron and neighboring cells to coordinate migration guidance. Our findings provide insights into general principles underlying HSPG function in development.

H2O2-Sensitive Isoforms of Drosophila melanogaster TRPA1 Act in Bitter-Sensing Gustatory Neurons to Promote Avoidance of UV During Egg-Laying

Tue, 03/21/2017 - 10:48am

The evolutionarily conserved TRPA1 channel can sense various stimuli including temperatures and chemical irritants. Recent results have suggested that specific isoforms of Drosophila TRPA1 (dTRPA1) are UV-sensitive and that their UV sensitivity is due to H2O2 sensitivity. However, whether such UV sensitivity served any physiological purposes in animal behavior was unclear. Here, we demonstrate that H2O2-sensitive dTRPA1 isoforms promote avoidance of UV when adult Drosophila females are selecting sites for egg-laying. First, we show that blind/visionless females are still capable of sensing and avoiding UV during egg-laying when intensity of UV is high yet within the range of natural sunlight. Second, we show that such vision-independent UV avoidance is mediated by a group of bitter-sensing neurons on the proboscis that express H2O2-sensitive dTRPA1 isoforms. We show that these bitter-sensing neurons exhibit dTRPA1-dependent UV sensitivity. Importantly, inhibiting activities of these bitter-sensing neurons, reducing their dTRPA1 expression, or reducing their H2O2-sensitivity all significantly reduced blind females' UV avoidance, whereas selectively restoring a H2O2-sensitive isoform of dTRPA1 in these neurons restored UV avoidance. Lastly, we show that specifically expressing the red-shifted channelrhodopsin CsChrimson in these bitter-sensing neurons promotes egg-laying avoidance of red light, an otherwise neutral cue for egg-laying females. Together, these results demonstrate a physiological role of the UV-sensitive dTRPA1 isoforms, reveal that adult Drosophila possess at least two sensory systems for detecting UV, and uncover an unexpected role of bitter-sensing taste neurons in UV sensing.

Axon degeneration induces glial responses through Draper-TRAF4-JNK signalling

Tue, 03/21/2017 - 10:48am

Draper/Ced-1/MEGF-10 is an engulfment receptor that promotes clearance of cellular debris in C. elegans, Drosophila and mammals. Draper signals through an evolutionarily conserved Src family kinase cascade to drive cytoskeletal rearrangements and target engulfment through Rac1. Glia also alter gene expression patterns in response to axonal injury but pathways mediating these responses are poorly defined. We show Draper is cell autonomously required for glial activation of transcriptional reporters after axonal injury. We identify TNF receptor associated factor 4 (TRAF4) as a novel Draper binding partner that is required for reporter activation and phagocytosis of axonal debris. TRAF4 and misshapen (MSN) act downstream of Draper to activate c-Jun N-terminal kinase (JNK) signalling in glia, resulting in changes in transcriptional reporters that are dependent on Drosophila AP-1 (dAP-1) and STAT92E. Our data argue injury signals received by Draper at the membrane are important regulators of downstream transcriptional responses in reactive glia.

Approaching Document Review in a Systematic Way

Mon, 03/20/2017 - 11:53am

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Counting and Computing with Microsoft Excel

Mon, 03/20/2017 - 11:53am

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

UMCCTS Newsletter, February 2017

Thu, 03/16/2017 - 10:09pm

This is the February 2017 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

UMCCTS Newsletter, January 2017

Thu, 03/16/2017 - 10:09pm

This is the January 2017 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

UMCCTS Newsletter, December 2016

Thu, 03/16/2017 - 9:49pm

This is the December 2016 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

UMCCTS Newsletter, November 2016

Thu, 03/16/2017 - 9:49pm

This is the November 2016 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

UMCCTS Newsletter, October 2016

Thu, 03/16/2017 - 9:49pm

This is the October 2016 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

Heterogeneity of postpartum depression: a latent class analysis

Wed, 03/15/2017 - 10:28pm

BACKGROUND: Maternal depression in the postpartum period confers substantial morbidity and mortality, but the definition of postpartum depression remains controversial. We investigated the heterogeneity of symptoms with the aim of identifying clinical subtypes of postpartum depression.

METHODS: Data were aggregated from the international perinatal psychiatry consortium Postpartum Depression: Action Towards Causes and Treatment, which represents 19 institutions in seven countries. 17,912 unique subject records with phenotypic data were submitted. We applied latent class analyses in a two-tiered approach to assess the validity of empirically defined subtypes of postpartum depression. Tier one assessed heterogeneity in women with complete data on the Edinburgh postnatal depression scale (EPDS) and tier two in those with postpartum depression case status.

FINDINGS: 6556 individuals were assessed in tier one and 4245 in tier two. A final model with three latent classes was optimum for both tiers. The most striking characteristics associated with postpartum depression were severity, timing of onset, comorbid anxiety, and suicidal ideation. Women in class 1 had the least severe symptoms (mean EPDS score 10.5), followed by those in class 2 (mean EPDS score 14.8) and those in class 3 (mean EPDS score 20.1). The most severe symptoms of postpartum depression were significantly associated with poor mood (mean EPDS score 20.1), increased anxiety, onset of symptoms during pregnancy, obstetric complications, and suicidal ideation. In class 2, most women (62%) reported symptom onset within 4 weeks postpartum and had more pregnancy complications than in other two classes (69% vs 67% in class 1 and 29% in class 3).

INTERPRETATION: PPD seems to have several distinct phenotypes. Further assessment of PPD heterogeneity to identify more precise phenotypes will be important for future biological and genetic investigations.

FUNDING: Sources of funding are listed at the end of the article.

HIV Stigma, Testing Attitudes and Health Care Access Among African-Born Men Living in the United States

Wed, 03/15/2017 - 10:28pm

The purpose of this study was to describe HIV-testing attitudes, HIV related stigma and health care access in African-born men taking part in the African Health Cup (AHC), a soccer tournament held annually to improve HIV awareness and testing. Venue sampling was used to collect survey and qualitative interview data related to HIV-testing attitudes, stigma and experiences associated with the AHC. The sample included 135 survey respondents and 27 interview participants. AHC participants were successfully accessing health care services. Although the AHC was viewed positively, HIV testing rates remain low due to stigma and privacy concerns. This population continues to have misconceptions about HIV transmission and to use condoms inconsistently. The AHC is a successful intervention to engage African-born men in HIV awareness and education. More work is needed to enhance these AHC aspects and address stigma and privacy concerns related to using onsite health screenings. Continuing to develop novel strategies to educate African-born immigrants about HIV is urgently needed.

A Pilot Study of Deaf Trauma Survivors' Experiences: Early Traumas Unique to Being Deaf in a Hearing World

Wed, 03/15/2017 - 10:28pm

Conducting semi-structured American Sign Language interviews with 17 Deaf trauma survivors, this pilot study explored Deaf individuals' trauma experiences and whether these experiences generally align with trauma in the hearing population. Most commonly reported traumas were physical assault, sudden unexpected deaths, and "other" very stressful events. Although some "other" events overlap with traumas in the general population, many are unique to Deaf people (e.g., corporal punishment at oral/aural school if caught using sign language, utter lack of communication with hearing parents). These findings suggest that Deaf individuals may experience developmental traumas distinct to being raised in a hearing world. Such traumas are not captured by available trauma assessments, nor are they considered in evidence-based trauma treatments.

A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo

Wed, 03/15/2017 - 10:28pm

We conducted a small, randomized, double-blind, placebo-controlled, phase II clinical trial to test simvastatin as a treatment for vitiligo.

Digital Pills to Measure Opioid Ingestion Patterns in Emergency Department Patients With Acute Fracture Pain: A Pilot Study

Wed, 03/15/2017 - 10:28pm

BACKGROUND: Nonadherence to prescribed regimens for opioid analgesic agents contributes to increasing opioid abuse and overdose death. Opioids are frequently prescribed on an as-needed basis, placing the responsibility to determine opioid dose and frequency with the patient. There is wide variability in physician prescribing patterns because of the lack of data describing how patients actually use as-needed opioid analgesics. Digital pill systems have a radiofrequency emitter that directly measures medication ingestion events, and they provide an opportunity to discover the dose, timing, and duration of opioid therapy.

OBJECTIVE: The purpose of this study was to determine the feasibility of a novel digital pill system to measure as-needed opioid ingestion patterns in patients discharged from the emergency department (ED) after an acute bony fracture.

METHODS: We used a digital pill with individuals who presented to a teaching hospital ED with an acute extremity fracture. The digital pill consisted of a digital radiofrequency emitter within a standard gelatin capsule that encapsulated an oxycodone tablet. When ingested, the gastric chloride ion gradient activated the digital pill, transmitting a radiofrequency signal that was received by a hip-worn receiver, which then transmitted the ingestion data to a cloud-based server. After a brief, hands-on training session in the ED, study participants were discharged home and used the digital pill system to ingest oxycodone prescribed as needed for pain for one week. We conducted pill counts to verify digital pill data and open-ended interviews with participants at their follow-up appointment with orthopedics or at one week after enrollment in the study to determine the knowledge, attitudes, beliefs, and practices regarding digital pills. We analyzed open-ended interviews using applied thematic analysis.

RESULTS: We recruited 10 study participants and recorded 96 ingestion events (87.3%, 96/110 accuracy). Study participants reported being able to operate all aspects of the digital pill system after their training. Two participants stopped using the digital pill, reporting they were in too much pain to focus on the novel technology. The digital pill system detected multiple simultaneous ingestion events by the digital pill system. Participants ingested a mean 8 (SD 5) digital pills during the study period and four participants continued on opioids at the end of the study period. After interacting with the digital pill system in the real world, participants found the system highly acceptable (80%, 8/10) and reported a willingness to continue to use a digital pill to improve medication adherence monitoring (90%, 9/10).

CONCLUSIONS: The digital pill is a feasible method to measure real-time opioid ingestion patterns in individuals with acute pain and to develop real-time interventions if opioid abuse is detected. Deploying digital pills is possible through the ED with a short instructional course. Patients who used the digital pill accepted the technology.

Attempted and Successful Vacuum-Assisted Vaginal Delivery by Prepregnancy Body Mass Index

Wed, 03/15/2017 - 10:28pm

OBJECTIVE: To examine rates of attempted and successful vacuum-assisted vaginal delivery by prepregnancy body mass index (BMI).

METHODS: We conducted a retrospective cohort study of 2,084 women with singleton gestations needing operative delivery assistance and vacuum-eligible (fully dilated, +2 station or greater, 34 weeks of gestation or greater) using 2006-2014 inpatient records. Prepregnancy BMI was categorized as underweight (less than 18.5), normal weight (18.5 to less than 25), overweight (25 to less than 30), or obese (30 or greater). Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of attempted and successful vacuum-assisted vaginal delivery by prepregnancy BMI adjusted for age, race, marital status, parity, diabetes, labor induction-augmentation, episiotomy, gestational age, and neonatal birth weight.

RESULTS: Thirty-nine percent of women requiring delivery assistance and eligible for a vacuum were overweight or obese, 79% had vacuum attempts, and 95.3% of attempted vacuum-assisted vaginal deliveries were successful. Compared with women who were normal weight prepregnancy (82.8%), women who were overweight or obese were less likely to have vacuum attempted (75.8%, OR 0.71, 95% CI 0.53-0.96 and 71.2%, OR 0.53, 95% CI 0.39-0.74, respectively). Among women with attempted vacuum-assisted vaginal delivery, successful delivery did not differ by prepregnancy BMI (92.6%, OR 0.54, 95% CI 0.21-1.37 for underweight; 94.5%, OR 1.07, 95% CI 0.57-2.00 for overweight; 96.3%, OR 1.09, 95% CI 0.51-2.33 for obese compared with 95.6% among normal-weight women).

CONCLUSION: Among women in need of operative delivery assistance, prepregnancy obesity was associated with lower likelihood of attempted vacuum-assisted vaginal delivery but, if attempted, success rates were similar to rates among normal-weight women. With significant morbidity of second-stage cesarean delivery in obese women, research should examine whether vacuum-assisted vaginal delivery may be appropriate for additional obese patients.

Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta-analysis

Wed, 03/15/2017 - 10:27pm

Essentials: Despite trial data, guidelines have not endorsed direct oral Xa inhibitors above other options. We provide profiles of venous thromboembolism and hemorrhage risk for 12 options. Direct oral Xa inhibitors had a favorable profile compared with low-molecular-weight heparin. Other options did not have favorable profiles compared with low-molecular-weight heparin.

SUMMARY: Background There are numerous trials and several meta-analyses comparing venous thromboembolism (VTE) prophylaxis options after total hip and knee replacement (THR and TKR). None have included simultaneous comparison of new with older options.

Objective: To measure simultaneously the relative risk of VTE and hemorrhage for 12 prophylaxis options.

Methods: We abstracted VTE and hemorrhage information from randomized controlled trials published between January 1990 and June 2016 comparing 12 prophylaxis options. We then constructed networks to compute the relative risk for each option, relative to once-daily dosing with low-molecular-weight heparin (LMWH) Low.

Results Main: Relative to LMWH Low, direct oral Xa inhibitors had the lowest risk of total deep vein thrombosis (DVT)-asymptomatic and symptomatic- (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.35-0.57), translating to 53-139 fewer DVTs per 1000 patients. Vitamin K antagonists (VKAs) titrated to International Normalized Ratio [INR] 2-3 predicted 56% more DVT events (OR, 1.56; 95% CI, 1.14-2.14). Aspirin performed similarly (OR, 0.80; 95% CI, 0.34-1.86), although small numbers prohibit firm conclusions. Direct oral Xa inhibitors did not lead to significantly more bleeding (OR, 1.21; 95% CI, 0.79-1.90). Secondary: Relative to LMWH Low, direct oral Xa inhibitors prevented 4-fold more symptomatic DVTs (OR, 0.25; 95% CI, 0.13-0.47).

Conclusion: Relative to LMWH Low, direct oral Xa inhibitors had a more favorable profile of VTE and hemorrhage risk, whereas VKAs had a less favorable profile. The profile of other agents was not more or less favorable. Clinicians should consider these profiles when selecting prophylaxis options.

Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year

Wed, 03/15/2017 - 10:27pm

BACKGROUND: Due to its potent effects on social behavior, including maternal behavior, oxytocin has been identified as a potential mediator of postpartum depression and anxiety. The objective of this study was to examine the relationship between peripartum synthetic oxytocin administration and the development of depressive and anxiety disorders within the first year postpartum. We hypothesized that women exposed to peripartum synthetic oxytocin would have a reduced risk of postpartum depressive and anxiety disorders compared with those without any exposure.

METHODS: Population-based data available through the Massachusetts Integrated Clinical Academic Research Database (MiCARD) were used to retrospectively (2005-2014) examine this relationship and calculate the relative risk of peripartum synthetic oxytocin for the development of postpartum depressive and anxiety disorders in exposed (n = 9,684) compared to unexposed (n = 37,048) deliveries.

RESULTS: Among deliveries to women with a history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 36% (relative risk (RR): 1.36; 95% confidence interval (95% CI): 1.20-1.55). In deliveries to women with no history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 32% compared to those not exposed (RR: 1.32; 95% CI: 1.23-1.42).

CONCLUSIONS: Contrary to our hypothesis, results indicate that women with peripartum exposure to synthetic oxytocin had a higher relative risk of receiving a documented depressive or anxiety disorder diagnosis or antidepressant/anxiolytic prescription within the first year postpartum than women without synthetic oxytocin exposure.

Meta-Analysis of Odds Ratios: Current Good Practices

Wed, 03/15/2017 - 10:27pm

BACKGROUND: Many systematic reviews of randomized clinical trials lead to meta-analyses of odds ratios (ORs). The customary methods of estimating an overall OR involve weighted averages of the individual trials' estimates of the logarithm of the OR. That approach, however, has several shortcomings, arising from assumptions and approximations, that render the results unreliable. Although the problems have been documented in the literature for many years, the conventional methods persist in software and applications. A well-developed alternative approach avoids the approximations by working directly with the numbers of subjects and events in the arms of the individual trials.

OBJECTIVE: We aim to raise awareness of methods that avoid the conventional approximations, can be applied with widely available software, and produce more-reliable results.

METHODS: We summarize the fixed-effect and random-effects approaches to meta-analysis; describe conventional, approximate methods and alternative methods; apply the methods in a meta-analysis of 19 randomized trials of endoscopic sclerotherapy in patients with cirrhosis and esophagogastric varices; and compare the results. We demonstrate the use of SAS, Stata, and R software for the analysis.

RESULTS: In the example, point estimates and confidence intervals for the overall log-odds-ratio differ between the conventional and alternative methods, in ways that can affect inferences. Programming is straightforward in the 3 software packages; an appendix, Suppemental Digital Content 1 (http://links.lww.com/MLR/B335) gives the details.

CONCLUSIONS: The modest additional programming required should not be an obstacle to adoption of the alternative methods. Because their results are unreliable, use of the conventional methods for meta-analysis of ORs should be discontinued.