Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.     

Current Therapeutic Approaches to DCIS

Treatment for ductal carcinoma in-situ (DCIS) has historically been extrapolated from studies of invasive breast cancer. Accepted local therapy approaches range from small local excisions, with or without radiation, to bilateral mastectomies. Systemic treatment with endocrine therapy is often recommended for hormone positive patients. With improvements in imaging, pathologic review, and treatment techniques in the modern era, combined with new information regarding tumor biology, the management of DCIS is rapidly evolving. A multidisciplinary approach to treatment is now more important than ever, with a shift towards de-escalating therapy to reduce treatment related toxicity. This review focuses on nuances of clinical management of DCIS in the modern era, highlighting key differences between DCIS as compared to invasive breast cancer. The American Cancer Society (ACS) currently recommends beginning screening with annual mammograms for women age 45, with the option to start at age 40. As treatment of DCIS has not been shown to impact survival, the USPSTF has more conservative screening recommendations of biennial mammograms from age 50–74. Unlike invasive breast cancer, DCIS is almost exclusively diagnosed by mammographic detection, and lymph node evaluation is not recommended. Pathologic review of biopsy specimens should follow the guidelines of the College of American Pathologists. Surgical management options include breast conservation, mastectomy, or possibly nipple sparing mastectomy, with upfront sentinel lymph node evaluation in the case of mastectomy. Radiation therapy is generally recommended as a component of breast conserving therapy for patients with DCIS, though in some low risk patients, there is trial data to suggest that adjuvant radiation may be omitted. Techniques for minimizing radiation toxicity should always be emphasized. Endocrine therapy is offered to women with hormone positive DCIS who have undergone lumpectomy for risk reduction, and has the benefit of decreasing incidence of events in both the ipsilateral and contralateral breast. More recent studies have explored use of targeted treatments such as trastuzumab in DCIS for HER2 overexpression. Future directions include tailoring therapy based on patient characteristics and tumor biology. With so many different options for treatment, it is also critical to engage in a discussion with the patient to arrive at a treatment decision that balances patient preferences for disease control versus treatment toxicity, financial toxicity, cosmesis, and quality of life.     

Door-to-Balloon Time for Primary Percutaneous Coronary Intervention: How Does Northern West Virginia Compare?

Background

The National Registry of Myocardial Infarction reported that only 4% of patients transferred for primary percutaneous coronary intervention (PCI) achieved the recommendation of a door-to-balloon time of < 90 min.

Objectives

To see if the American College of Cardiologists/American Heart Association (ACC/AHA) guideline of < 90 min door-to-balloon time for primary PCI is being met in a rural area of West Virginia, and compare to the national average.

Methods

A chart review of all cases of emergent primary PCI for ST-segment elevation myocardial infarction (STEMI) performed in the northern panhandle of West Virginia.

Results

The northern panhandle of West Virginia has seven hospitals, of which only one has the capability to perform primary PCI. Two hundred two patients underwent emergent PCI for STEMI from January 1, 2009–September 11, 2010. For each patient, the initial presenting time, arrival time to the PCI hospital, and start of PCI time were recorded. Eight patients were eliminated from the study for not having an initial presenting time. Of the remaining 194 patients, 89 were transferred for primary PCI. Forty-nine patients met the ACC/AHA recommendation of < 90 min door-to-balloon time. The average door-to-balloon time for patients transferred for primary PCI was 104.9 min (Standard Deviation [STD]. 58.2219, 95% confidence interval 92.85–117.04).

Conclusion

Fifty-five percent of patients transferred for primary PCI in the northern panhandle of West Virginia met the recommended guidelines. This is an improvement on the national average of 4%.     

A descriptive model for a multidisciplinary unit for colorectal and pelvic malformations

Introduction

Patients with anorectal malformations (ARM), Hirschsprung disease (HD), and colonic motility disorders often require care from specialists across a variety of fields, including colorectal surgery, urology, gynecology, and GI motility. We sought to describe the process of creating a collaborative process for the care of these complex patients.

Alcohol binge drinking decreases brain glucose metabolism and functional connectivity in adolescent rats

Alcohol misuse represents a serious health concern, especially during adolescence, with approximately 18% of high school students engaging in binge drinking. Despite widespread misuse of alcohol, its effects on how the brain functions is not fully understood. This study utilized a binge drinking model in adolescent rats to examine effects on brain function as measured by brain glucose metabolism (BGluM). Following an injection of [¹⁸ FDG] fluro-2-deoxy-D-glucose, rats had voluntary access to either water or various concentrations of ethanol to obtain the following targeted doses: water (no ethanol), low dose ethanol (0.29?±?0.03 g/kg), moderate dose ethanol (0.98?±?0.05), and high dose ethanol (2.19?±?0.23 g/kg). Rats were subsequently scanned using positron emission tomography. All three doses of ethanol were found to decrease BGluM in the restrosplenial cortex, visual cortex, jaw region of the somatosensory cortex, and cerebellum. For both the LD and MD ethanol dose, decreased BGluM was seen in the superior colliculi. The MD ethanol dose also decreased BGluM in the subiculum, frontal association area, as well as the primary motor cortex. Lastly, the HD ethanol dose decreased BGluM in the hippocampus, thalamus, raphe nucleus, inferior colliculus, and the primary motor cortex. Similar decreases in the hippocampus were also seen in the LD group. Taken together, these results highlight the negative consequences of acute binge drinking on BGluM in many regions of the brain involved in sensory, motor, and cognitive processes. Future studies are needed to assess the long-term effects of alcohol binge drinking on brain function as well as its cessation.

     

Using Machine Learning to Compare Provaccine and Antivaccine Discourse Among the Public on Social Media: Algorithm Development Study

BackgroundDespite numerous counteracting efforts, antivaccine content linked to delays and refusals to vaccinate has grown persistently on social media, while only a few provaccine campaigns have succeeded in engaging with or persuading the public to accept immunization. Many prior studies have associated the diversity of topics discussed by antivaccine advocates with the public’s higher engagement with such content. Nonetheless, a comprehensive comparison of discursive topics in pro- and antivaccine content in the engagement-persuasion spectrum remains unexplored.ObjectiveWe aimed to compare discursive topics chosen by pro- and antivaccine advocates in their attempts to influence the public to accept or reject immunization in the engagement-persuasion spectrum. Our overall objective was pursued through three specific aims as follows: (1) we classified vaccine-related tweets into provaccine, antivaccine, and neutral categories; (2) we extracted and visualized discursive topics from these tweets to explain disparities in engagement between pro- and antivaccine content; and (3) we identified how those topics frame vaccines using Entman’s four framing dimensions.MethodsWe adopted a multimethod approach to analyze discursive topics in the vaccine debate on public social media sites. Our approach combined (1) large-scale balanced data collection from a public social media site (ie, 39,962 tweets from Twitter); (2) the development of a supervised classification algorithm for categorizing tweets into provaccine, antivaccine, and neutral groups; (3) the application of an unsupervised clustering algorithm for identifying prominent topics discussed on both sides; and (4) a multistep qualitative content analysis for identifying the prominent discursive topics and how vaccines are framed in these topics. In so doing, we alleviated methodological challenges that have hindered previous analyses of pro- and antivaccine discursive topics.ResultsOur results indicated that antivaccine topics have greater intertopic distinctiveness (ie, the degree to which discursive topics are distinct from one another) than their provaccine counterparts (t₁₂₂=2.30, P=.02). In addition, while antivaccine advocates use all four message frames known to make narratives persuasive and influential, provaccine advocates have neglected having a clear problem statement.ConclusionsBased on our results, we attribute higher engagement among antivaccine advocates to the distinctiveness of the topics they discuss, and we ascribe the influence of the vaccine debate on uptake rates to the comprehensiveness of the message frames. These results show the urgency of developing clear problem statements for provaccine content to counteract the negative impact of antivaccine content on uptake rates.     

Slowed Processing Speed Disrupts Patient Expectancy in Late Life Depression

ObjectiveSlowed processing speed and executive dysfunction are associated with poor outcomes in Late Life Depression (LLD), though it is unclear why. We investigated whether these variables interfere with the development of positive treatment expectancies in an antidepressant trial.MethodsDepressed older subjects were randomized to Open (intended to increase patient expectancy) or Placebo-controlled (termed ‘Hidden,’ intended to decrease expectancy) administration of antidepressant medication for 8 weeks. Analysis of covariance analyzed the between-group difference on expectancy (Credibility and Expectancy Scale [CES]) and depression (Hamilton Rating Scale for Depression [HRSD], Clinical Global Impressions [CGI] Severity). Moderator analyses examined whether these Open versus Hidden differences varied based on higher versus lower processing speed and executive function.ResultsAmong the 108 participants, a significant between-group difference was observed on expectancy (effect size [ES, Cohen's d] = 0.51 on CES Item 2; ES = 0.64 on Item 4), indicating the manipulation was effective. Processing speed as measured by the Stroop Color-Word Test (number color-words named in congruent condition) was a significant moderator of the Open versus Hidden effect on expectancy. Depressive symptom improvement was greater on average for Open versus Hidden participants who received active drug (CGI-severity ES = 1.25, HRSD ES = 0.41), but no neurocognitive moderators of the between-group difference reached statistical significance.ConclusionsSlowed processing speed impairs the development of expectancies in antidepressant trials for LLD, which may help explain lower antidepressant response among older adults. Future studies may address whether interventions to optimize treatment expectancies are capable of improving treatment outcomes.     

Metabolic Crosstalk: Molecular Links Between Glycogen and Lipid Metabolism in Obesity

Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, PTG deletion also blocked hepatic steatosis in HFD-fed mice and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis.