Effects of Negative Affect,Urge to Smoke,and Working Memory Performance (n-back) on Nicotine Dependence

Background: Three key domains including negative emotionality, incentive salience, and executive function form the core functional elements of addictive behaviors. Variables related to these broader domains have been studied extensively in relation to one another; however, no studies to date, have examined models including variables from all three domains, in relation to nicotine dependence. Method: Smokers (N = 117), 65.8% female, 78% white, mean age of 44.4 (SD = 10.8), enrolled in a smoking cessation program completed measures of negative affect (a component of negative emotionality), urge to smoke (incentive salience), and working memory (WM; a core executive function), during a baseline assessment period prior to initiating treatment. Results: Negative affect was associated with greater urge to smoke, and this elevated urge to smoke was associated with higher levels of nicotine dependence. Further, a significant moderated mediation indicated that WM moderated the relationship between increased urge to smoke and nicotine dependence. For those with low to average WM, urge to smoke was significantly related to nicotine dependence; however, for those with higher WM (+1 SD), urge to smoke stemming from negative affect was not associated with nicotine dependence. Conclusions: To our knowledge, this is the first reported relationship between negative affect, urge to smoke, WM, and nicotine dependence. Although preliminary, results indicate that WM may moderate the relationship between urge to smoke associated with negative affect and nicotine dependence. Treatments targeting WM may be particularly useful for individuals with average to low WM who experience urge to smoke related to negative affect.     

Detection of Memory B Activity Against a Therapeutic Protein in Treatment-Naïve Subjects

Bridging immunoassays commonly used to detect and characterize immunogenicity during biologic development do not provide direct information on the presence or development of a memory anti-drug antibody (ADA) response. In this study, a B cell ELISPOT assay method was used to evaluate pre-existing ADA for anti-TNFR1 domain antibody, GSK1995057, an experimental biologic in treatment naive subjects. This assay utilized a 7-day activation of PBMCs by a combination of GSK1995057 (antigen) and polyclonal stimulator followed by GSK1995057-specific ELISPOT for the enumeration of memory B cells that have differentiated into antibody secreting cells (ASC) in vitro. We demonstrated that GSK1995057-specific ASC were detectable in treatment-naïve subjects with pre-existing ADA; the frequency of drug-specific ASC was low and ranged from 1 to 10 spot forming units (SFU) per million cells. Interestingly, the frequency of drug-specific ASC correlated with the ADA level measured using an in vitro ADA assay. We further confirmed that the ASC originated from CD27⁺ memory B cells, not from CD27^?-naïve B cells. Our data demonstrated the utility of the B cell ELISPOT method in therapeutic protein immunogenicity evaluation, providing a novel way to confirm and characterize the cell population producing pre-existing ADA. This novel application of a B cell ELISPOT assay informs and characterizes immune memory activity regarding incidence and magnitude associated with a pre-existing ADA response.     

The antivascular action of physiotherapy ultrasound on a murine tumor: role of a microbubble contrast agent

This study investigated whether a microbubble-containing ultrasound contrast agent had a role in the antivascular action of physiotherapy ultrasound on tumor neovasculature. Ultrasound images (B-mode and contrast-enhanced power Doppler [0.02 mL Definity]) were made of 22 murine melanomas (K1735²²). The tumor was insonated (I_SATA = 1.7 W cm^–2, 1 MHz, continuous output) for 3 min and the power Doppler observations of the pre- and postinsonation tumor vascularities were analyzed. Significant reductions (p = 0.005 for analyses of color-weighted fractional area) in vascularity occurred when a contrast-enhanced power Doppler study occurred before insonation. Vascularity was unchanged in tumors without a pretherapy Doppler study. Histologic studies revealed tissue structural changes that correlated with the ultrasound findings. The underlying etiology of the interaction between the physiotherapy ultrasound beam, the microbubble-containing contrast agent and the tumor neovasculature is unknown. It was concluded that contrast agents play an important role in the antivascular effects induced by physiotherapy ultrasound. (E-mail: sehgalc@uphs.upenn.edu)     

Integration of nurse practitioners into a family health network

A randomized controlled study called Anticipatory and Preventative Team Care (APTCare) explored a new role for nurse practitioners (NPs) within a multidisciplinary team. The aim of the study was to evaluate whether integrating NPs and a pharmacist was an effective approach for the management of patients living with multiple chronic illnesses. Over an 18-month period, three part-time NPs and a pharmacist became part of a rural Family Health Network (FHN). They established relationships with study patients and collaborated to provide optimum care. Each NP had 40 patients, all of whom received care in the home. Study results showed that an initial home visit was invaluable for establishing a care plan, developing a relationship with the patient and assessing the home environment. Ongoing monitoring at home, however, was found to be an inefficient use of the NP role. By the end of the study, all clinicians agreed that the NP role had been successfully integrated into the multidisciplinary team.     

Bootstrapped DEPICT for error estimation in PET functional imaging

Basis pursuit denoising is a new approach for data-driven estimation of parametric images from dynamic positron emission tomography (PET) data. At present, this kinetic modeling technique does not allow for the estimation of the errors on the parameters. These estimates are useful when performing subsequent statistical analysis, such as, inference across a group of subjects or when applying partial volume correction algorithms. The difficulty with calculating the error estimates is a consequence of using an overcomplete dictionary of kinetic basis functions. In this paper, a bootstrap approach for the estimation of parameter errors from dynamic PET data is presented. This paper shows that the bootstrap can be used successfully to compute parameter errors on a region of interest or parametric image basis. Validation studies evaluate the methods performance on simulated and measured PET data ([(11)C]Diprenorphine-opiate receptor and [(11)C]Raclopride-dopamine D(2) receptor). The method is presented in the context of PET neuroreceptor binding studies, however, it has general applicability to a wide range of PET/SPET radiotracers in neurology, oncology and cardiology.     

Associations of perceived information adequacy and knowledge with pursuit of live donor kidney transplants and living donor inquiries among African American transplant candidates

We studied associations between perceived adequacy of live donor kidney transplant (LDKT) information or knowledge with pursuit of LDKT or receipt of live donor inquiries among 300 African American kidney transplant candidates. Participants reported via questionnaire how informed or knowledgeable they felt regarding LDKT. Participants also reported their pursuit of LDKT, categorized as “low” (no discussion with family or friends about LDKT and no identified donor), “intermediate” (discussed LDKT with family but no identified donor) or “high” (discussed LDKT with family and identified a potential donor). We reviewed participants' electronic health records to identify potential donors' transplant center inquiries on participants' behalves. A minority of participants reported they felt “very” or “extremely” well informed about LDKT (39%) or had “a great deal” of LDKT knowledge (38%). Participants perceiving themselves as “very” or “extremely” (vs “not” or “slightly”) well informed about LDKT had statistically significantly greater odds of intermediate or high (vs low) pursuit of LDKT (odds ratio [95% confidence interval] 2.71 [1.02-7.17]). Perceived LDKT knowledge was not associated with pursuit of LDKT. Neither perceived information adequacy nor knowledge was associated with living donor inquiries. Efforts to better understand the role of education in the pursuit of LDKT among African American transplant candidates are needed.     

Anxiety Sensitivity Prospectively Predicts Increased Acute Posttraumatic Stress and Related Symptoms After Sexual Assault

Anxiety sensitivity is a potential risk factor for posttraumatic stress symptoms (PTSS) and has been hypothesized to contribute to PTSS development. However, few prospective studies have evaluated whether anxiety sensitivity predicts PTSS. In a subsample of 48 women sexual assault survivors enrolled as part of a larger prospective observational study, elevated anxiety sensitivity measured via a brief assessment 1 week after experiencing a sexual assault was concurrently associated with PTSS at 1 week and prospectively predicted PTSS 6 weeks after the event, with small-to-medium effect sizes, η²_p = .10, even after covarying for trauma history. Heightened anxiety sensitivity at 1-week postevent also interacted with time to predict anxiety and depression both before and after sexual assault, with medium-to-large effect sizes, η_p² = .21– .24. This is consistent with research linking anxiety sensitivity to PTSS, but this was the first prospective study of which we are aware to demonstrate that anxiety sensitivity in the acute posttrauma period predicts PTSS among women who have recently experienced sexual assault. Future research should use the full Anxiety Sensitivity Index to replicate findings in a larger sample and explore whether targeting anxiety sensitivity could mitigate the development of PTSS in this vulnerable population.     

Diagnosis and management of acute cholecystitis: a single-centre audit of guideline adherence and patient outcomes

BackgroundThe Tokyo Guidelines were published in 2007 and updated in 2013 and 2018, with recommendations for the diagnosis and management of acute cholecystitis. We assessed guideline adherence at our academic centre and its impact on patient outcomes.MethodsThis is a retrospective chart review of patients with acute calculous cholecystitis who underwent cholecystectomy at our institution between November 2013 and March 2015. Severity of cholecystitis was graded retrospectively if it had not been documented preoperatively. Compliance with the Tokyo Guidelines’ recommendations on antibiotic use and time to operation was recorded. Cholecystitis severity groups were compared statistically, and logistic regression was used to determine predictors of complications.ResultsOne hundred and fifty patients were included in the study. Of these, 104 patients were graded as having mild cholecystitis, 45 as having moderate cholecystitis, and 1 as having severe cholecystitis. Severity was not documented preoperatively for any patient. Compliance with antibiotic recommendations was poor (18.0%) and did not differ by cholecystitis severity (p = 0.90). Compliance with the recommendation on time to operation was 86.0%, with no between-group differences (p = 0.63); it improved when an acute care surgery team was involved (91.0% v. 76.0%, p = 0.025). On multivariable analysis, comorbidities (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.19–1.85, p < 0.001) and conversion to laparotomy (OR 13.45, 95% CI 2.16–125.49, p = 0.01) predicted postoperative complications, while severity of cholecystitis, antibiotic compliance and time to operation had no effect.ConclusionIn this study, compliance with the Tokyo Guidelines was acceptable only for time to operation. Although the poor compliance with recommendations relating to documentation of severity grading and antibiotic use did not have a negative affect on patient outcomes, these recommendations are important because they facilitate appropriate antibiotic use and patient risk stratification.     

Unexpectedly high affinity of a novel histamine H3 receptor antagonist,GSK239512, in vivo in human brain,determined using PET

BACKGROUND AND PURPOSE

This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H₃ receptor antagonist, GSK239512, and the brain occupancy of H₃ receptors (RO) in healthy human volunteers.

EXPERIMENTAL APPROACH

PET scans were obtained after i.v. administration of the H₃-specific radioligand [¹¹C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.

KEY RESULTS

Following administration of GSK239512, there was a reduction in the brain uptake of [¹¹C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL⁻¹. This corresponds to a free concentration of 4.50 × 10⁻¹²M (pK = 11.3).

CONCLUSIONS AND IMPLICATIONS

The affinity of GSK239512 for brain H₃ receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.