Effects of tolcapone on working memory and brain activity in abstinent smokers: A proof-of-concept study

Background

Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.

Methods

In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24 h of abstinence. Smokers were genotyped prospectively for the COMT val¹⁵⁸met polymorphism for exploratory analysis.

Results

Compared to placebo, tolcapone modestly improved accuracy (p = 0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p = 0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.

Conclusions

Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.     

Ovarian carcinoma: adjuvant treatment with P-32

Twenty-eight patients with ovarian carcinoma received 555 MBq of labeled chromic phosphate (P-32) intraperitoneally. Indications for treatment included a high-grade tumor, extracapsular involvement, positive cytologic findings, or residual tumor. Fifteen patients (group 1) had stage I, II, or III completely resected tumor; 13 patients (group 2) had microscopic or less than 3-mm lesions at second-look laparotomy following combination chemotherapy. A major complication occurred in one patient; two patients had minor complications. Overall, 24 of 28 patients (85.7%) were alive at 11-77 months; 23 (82.1%) had no evidence of tumor. Fifteen of 15 (100%) group 1 patients and eight of 13 (61.5%) group 2 patients did not have tumor relapse after 30 months and 28 1/2 months, respectively. P-32 was found to be an effective adjuvant treatment in a select group of patients with ovarian carcinoma who were at high risk for intraabdominal recurrence.     

Superiority of acridine orange-stained buffy coat smears for diagnosis of partially treated neonatal septicemia

Early diagnosis of neonatal septicemia is a vexing problem because of its non-specific clinical picture. Many of the neonates with septicemia reaching a referral centre have already been exposed to antibiotics and their blood cultures are often sterile. Scarcity of studies evaluating acridine orange-stained buffy coat smears in detecting neonatal septicemia after administration of antibiotics prompted us to undertake this study. The population studied consisted of 34 cases of neonatal septicemia with positive blood cultures and/or positive buffy coat smears (of these 25 had a positive blood culture) and 25 neonates with a clinical course not suggestive of any infection. Venous blood was drawn for culture, preparation of buffy coat smears, blood counts and micro ESR. The culture and smears were repeated after administration of antibiotics for 48–72 h. Acridine orange stain was the most sensitive test and was significantly more sensitive than Gram's stain ( p < 0.005). After the administration of antibiotics, acridine orange was significantly more sensitive than Gram's stain and blood culture (p<0.05).     

Magnetic resonance imaging of the heart: a review of the experience in 172 subjects

Gated magnetic resonance (MR) imaging was used to evaluate central cardiovascular anatomy in 172 subjects, 31 of whom were healthy volunteers. Using the spin-echo technique, images of diagnostic quality were obtained in 93% of cases with TE = 28 msec and in 65% of cases with TE = 56 msec. Transverse multisection sequences encompassing most of the left ventricle required approximately 6-8 minutes. Corroborative studies were available in 134 of 141 patients who had cardiovascular disease; two dimensional echocardiograms and angiography in 133 and 100 patients, respectively. Gated MR demonstrated the wall thinning and complications caused by prior myocardial infarctions and high signal intensity of the myocardium at the site of acute myocardial infarctions. MR accurately demonstrated anatomic abnormalities owing to hypertrophic and congestive cardiomyopathies, congenital abnormalities of the heart and great vessels, rheumatic heart disease, pulmonary hypertension, and cardiac and paracardiac masses. Depiction of cardiovascular anatomy and pathoanatomy was attained without the use of any contrast media. Consequently, gated MR is an effective technique for cardiac diagnosis. The short time required for tomographic examination of the entire heart using the multisection technique renders this a practical cardiac imaging modality.     

High dose vitamin A supplementation in the course of pneumonia in Vietnamese children

We carried out a randomized, placebo-controlled, double-blinded trial to evaluate the effect on morbidity of high dose oral vitamin A, given on hospital admission to 592 children aged 1–59 months with moderate and severe pneumonia. Severely underweight children were not included, but 45% were moderately underweight. The vitamin A and placebo groups were comparable in baseline characteristics. Four patients died. Among all of the surviving children, no differences were found regarding mean time for normalization of fever, respiratory rate and time of hospitalization. Stratification for moderate malnutrition, degree of pneumonia, age and sex revealed moderately malnourished vitamin A-supplemented children to have a shorter time of hospitalization ( p = 0. 04), due to an effect in females aged > 12 months ( p = 0. 02) and females with very severe pneumonia ( p = 0. 048). This study indicates that, in developing countries like Vietnam, supplementation with vitamin A in children with pneumonia could shorten the recovery rate in the ones that are undernourished, especially females > 1 y old.     

Validity evidence for the Fundamentals of Laparoscopic Surgery (FLS) program as an assessment tool: a systematic review

Background

The Fundamentals of Laparoscopic Surgery (FLS) program uses five simulation stations (peg transfer, precision cutting, loop ligation, and suturing with extracorporeal and intracorporeal knot tying) to teach and assess laparoscopic surgery skills. We sought to summarize evidence regarding the validity of scores from the FLS assessment.

Methods

We systematically searched for studies evaluating the FLS as an assessment tool (last search update February 26, 2013). We classified validity evidence using the currently standard validity framework (content, response process, internal structure, relations with other variables, and consequences).

Results

From a pool of 11,628 studies, we identified 23 studies reporting validity evidence for FLS scores. Studies involved residents (n = 19), practicing physicians (n = 17), and medical students (n = 8), in specialties of general (n = 17), gynecologic (n = 4), urologic (n = 1), and veterinary (n = 1) surgery. Evidence was most common in the form of relations with other variables (n = 22, most often expert–novice differences). Only three studies reported internal structure evidence (inter-rater or inter-station reliability), two studies reported content evidence (i.e., derivation of assessment elements), and three studies reported consequences evidence (definition of pass/fail thresholds). Evidence nearly always supported the validity of FLS total scores. However, the loop ligation task lacks discriminatory ability.

Conclusion

Validity evidence confirms expected relations with other variables and acceptable inter-rater reliability, but other validity evidence is sparse. Given the high-stakes use of this assessment (required for board eligibility), we suggest that more validity evidence is required, especially to support its content (selection of tasks and scoring rubric) and the consequences (favorable and unfavorable impact) of assessment.

     

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep~(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.     

Simulation,Mastery Learning and Healthcare

Healthcare organizations, becoming increasingly complex, need to use simulation techniques as a tool to provide consistently safe care. Mastery learning techniques minimize variation in learner outcome, thus improving the consistency and cost-effectiveness of care. Today?s organizations (and their teams of decision makers) exist within varying states of transformation. These transformational times afford opportunities to use mastery learning concepts at an organizational level and to affect necessary change(s). Evolving technologies, including simulation, have provided mechanisms to enhance system performance, reducing reliance on custom-built “problem-solving” solutions for individual system needs. As such, simulation has emerged as an increasingly necessary organizational tool in improving value-driven, consistent processes of care. Both computer-based and non-computer-based algorithms of healthcare simulations offer distinct advantages in improving system performance over traditional methods of quality improvement. Simulation as a process engineering tool, integrated with mastery learning techniques, provides powerful platforms for improving value-based care.