Precision Medicine for Tobacco Dependence: Development and Validation of the Nicotine Metabolite Ratio

Quitting smoking significantly reduces the risk of tobacco-related morbidity and mortality, yet there is a high rate of relapse amongst smokers who try to quit. Phenotypic biomarkers have the potential to improve smoking cessation outcomes by identifying the best available treatment for an individual smoker. In this review, we introduce the nicotine metabolite ratio (NMR) as a reliable and stable phenotypic measure of nicotine metabolism that can guide smoking cessation treatment among smokers who wish to quit. We address how the NMR accounts for sources of variation in nicotine metabolism including genotype and other biological and environmental factors such as estrogen levels, alcohol use, body mass index, or menthol exposure. Then, we highlight clinical trials that validate the NMR as a biomarker to predict therapeutic response to different pharmacotherapies for smoking cessation. Current evidence supports the use of nicotine replacement therapy for slow metabolizers, and non-nicotine treatments such as varenicline for normal metabolizers. Finally, we discuss future research directions to elucidate mechanisms underlying NMR associations with treatment response, and facilitate the implementation of the NMR as biomarker in clinical practice to guide smoking cessation.     

The CSF Diversion via Lumbar Drainage to Treat Dialysis Disequilibrium Syndrome in the Critically Ill Neurological Patient

Neurocritical Care -     

Functional and Patient Reported Outcomes Following Total Glans Resurfacing

BackgroundWhilst there is a trend away from aggressive nonorgan sparing surgical treatments for malignant penile disease, a variety of penile preservation options exist but functional outcomes and patient reported outcomes (PROs) in this area are poorly reported to date.AimThe aim of this study is to report functional outcomes and PROs of total glans resurfacing (TGR) in a consecutive series of patients with lichen sclerosis (LS) or localized penile cancer (PC).MethodsFrom 2004 to 2018 a consecutive series of patients underwent TGR for the management of LS or localized PC in a tertiary referral network. Patient clinical records and operative notes were retrospectively reviewed. Statistical analysis was conducted with Stata 12.OutcomesUrinary and sexual outcomes were recorded utilizing both the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) validated questionnaires while PROs were extrapolated from a 5-item “ad hoc” telephone questionnaire administered at 1 year post procedure.Results37 consecutive patients were enrolled. Histology results demonstrated LS in 16 patients, with the remaining 21 having a diagnosis of PC. The most common reasons for patient presentation were local pain (32.4%), pruritus (37.8%) and bleeding (29.7%). Median follow-up was 22 (IQR 13–77) months. Median age was 62 (IQR 55–68).Neither of the questionnaires assessing urinary and sexual function showed any significant deterioration after surgery. Glans sensitivity was fully maintained in 89.2% of cases. 94.5% of patients reported to be fully satisfied with the aesthetic appearance of the penis and would consider undergoing the same procedure again if necessary. 91.9% of patients would recommend the same procedure to someone else. An overall improvement of the quality of life was reported by 86.4% of patients.Clinical ImplicationsTGR should be considered a treatment of choice for selected cases of benign or malignant penile lesionsStrengths and LimitationsOur study has some limitations, the first being its retrospective nature. Furthermore, despite being one of the largest series to date, follow-up duration is somewhat limited and a control group is lacking.ConclusionTGR represents an excellent surgical option ensuring satisfactory voiding and sexual function, as well as cosmesis for selected cases of penile lesions.M. Preto, M. Falcone, G. Blecher, et al. Functional and Patient Reported Outcomes Following Total Glans Resurfacing. J Sex Med 2021;18:1099–1103.     

Lurasidone: efficacy and safety in the treatment of psychotic and mood disorders

Introduction: Lurasidone ([3aR,4S,7R,7aS]-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1yl-methyl] cyclohexylmethyl]-hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; Latuda®) is a novel benzisothiazole, second-generation antipsychotic drug developed by Dainippon Sumitomo Pharma Corporation in Japan. Similar to other atypical antipsychotics it has a distinctive pharmacodynamic profile,

Areas covered: This review updates reported research findings on the efficacy, safety and tolerability of LRSD for treatment of psychotic and major affective disorders, with meta-analyses. Short-term efficacy of LRSD in schizophrenia is supported by several randomized, controlled trials with daily doses of 40–160 mg, yielding relatively modest symptomatic improvements. Lurasidone has regulatory approval for treatment of undefined duration in schizophrenia. Long-term benefits and effects in schizophrenia, and both short- and long-term use for other psychotic disorders and mania have not been tested. LRSD shows unusual efficacy in acute bipolar depression even without psychotic features. However, trials of adding LRSD to lithium or valproate for bipolar disorder have yielded inconsistent findings.

Expert opinion: Available research findings indicate that LRSD is effective and well-tolerated for short-term treatment of schizophrenia, and for acute bipolar depression. It has low risk of inducing weight-gain, metabolic, or cardiac abnormalities, but its risk of akathisia may exceed that of other modern antipsychotics. Needed is adequate long-term testing in schizophrenia and bipolar disorder and testing for other indications, including against alternative treatments.     

Guinea pig gall bladder contains a single peptide leukotriene receptor which resembles that present in human conducting airway smooth muscle.

The peptide leukotrienes (LTs), LTC4, LTD4 and LTE4, produced concentration-related contraction of isolated strips of guinea pig gall bladder (GPGB) with pD2 values of 8.48 +/- 0.11, 8.26 +/- 0.22 and 7.28 +/- 0.08, respectively. In the presence of propranolol and indomethacin in epithelium-denuded GPGB, pKB values for the LT antagonist ICI198,615 vs. LTC4, LTD4 and LTE4 were, respectively: 8.61 +/- 0.12, 8.89 +/- 0.13 and 8.70 +/- 0.17. Similarly, pKB values for the LT antagonist SKF104,353 were 7.28 +/- 0.19, 7.88 +/- 0.17 and 7.45 +/- 0.17. Previous studies have shown that inhibition of LTC4 metabolism can alter the apparent affinity of the LT, especially LTC4; consequently, metabolism of [3H]LTC4 in chopped GPGB was investigated. [3H]LTC4 was converted rapidly by gamma-glutamyl transpeptidase to [3H]LTD4 with little accumulation of [3H]LTE4. The combination of acivicin (ACI) and reduced glutathione (GSH) provided complete inhibition of gamma-glutamyl transpeptidase. pD2 values for LTC4 in the presence of ACI/GSH were 8.54 +/- 0.16. pKB values for ICI198,615 and SKF104353 in the presence of ACI/GSH were, i.e., 8.42 +/- 0.14 and 7.53 +/- 0.12, respectively, vs. LTC4 and identical to those obtained in the absence of inhibitors. The mechanism(s) underlying LT-induced contraction was evaluated using the calcium channel blockers diltiazem, nifedipine and verapamil. Noncompetitive antagonism was observed against all LTs indicating the involvement of voltage-sensitive calcium channels in the contractile response. Similarly, all LTs increased polyphosphoinositide hydrolysis. These data indicate: 1) GPGB contains a single type of LT receptor similar to that in human airways and 2) LT-induced contraction appears to involve both polyphosphoinositol formation and voltage-dependent Ca++ channels.     

Surgery residents recognized less frequently over time by medical students: A twelve year study of the Arnold P. Gold Humanism and Excellence in Teaching Award

Background

There is a decreasing institutional percentage of surgical resident recipients of The Arnold P. Gold Humanism and Excellence in Teaching Award over time. The hypothesis was that this trend was a national phenomenon.