A ribozyme that uses lanthanides as cofactor.

To explore how an early, RNA-based life form could have functioned, in vitro selection experiments have been used to develop catalytic RNAs (ribozymes) with relevant functions. We previously identified ribozymes that use the prebiotically plausible energy source cyclic trimetaphosphate (cTmp) to convert their 5'-hydroxyl group to a 5'-triphosphate. While these ribozymes were developed in the presence of Mg2+, we tested here whether lanthanides could also serve as catalytic cofactors because lanthanides are ideal catalytic cations for this reaction. After an in vitro selection in the presence of Yb3+, several active sequences were isolated, and the most active RNA was analyzed in more detail. This ribozyme required lanthanides for activity, with highest activity at a 10:1 molar ratio of cTmp : Yb3+. Only the four heaviest lanthanides gave detectable signals, indicating a high sensitivity of ribozyme catalysis to the lanthanide ion radius. Potassium and Magnesium did not facilitate catalysis alone but they increased the lanthanide-mediated kOBS by at least 100-fold, with both K+ and Mg2+ modulating the ribozyme's secondary structure. Together, these findings show that RNA is able to use the unique properties of lanthanides as catalytic cofactor. The results are discussed in the context of early life forms.

Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis.

INTRODUCTION: Circulating tumour DNA (ctDNA) has emerged as a promising biomarker in various cancer types, including locally advanced rectal cancer (LARC), offering potential insights into disease progression, treatment response and recurrence. This review aims to comprehensively evaluate the utility of ctDNA as a prognostic biomarker in LARC. METHODS: PubMed, EMBASE and Web of Science were searched as part of our review. Studies investigating the utility of ctDNA in locally advanced rectal cancer (LARC) were assessed for eligibility. Quality assessment of included studies was performed using the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, ctDNA details and survival data. A meta-analysis was performed on eligible studies to determine pooled recurrence-free survival (RFS). RESULTS: Twenty-two studies involving 1676 participants were included in our analysis. Methodological quality categorised by the Newcastle Ottawa Scale was generally satisfactory across included studies. ctDNA detected at various time intervals was generally associated with poor outcomes across included studies. Meta-analysis demonstrated a pooled hazard ratio of 8.87 (95% CI 4.91-16.03) and 15.15 (95% CI 8.21-27.95), indicating an increased risk of recurrence with ctDNA positivity in the post-neoadjuvant and post-operative periods respectively. CONCLUSION: Our systematic review provides evidence supporting the prognostic utility of ctDNA in patients with LARC, particularly in identifying patients at higher risk of disease recurrence in the post-neoadjuvant and post-operative periods.

Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis.

Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.

Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial.

OBJECTIVE: Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. METHODS: Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. RESULTS: During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; χ2  = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. CONCLUSION: Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania.

Clinical and Serological Predictors of Suicide in Schizophrenia and Major Mood Disorders.

Persons with serious mental illness are at high risk for suicide, but this outcome is difficult to predict. Serological markers may help to identify suicide risk. We prospectively assessed 733 persons with a schizophrenia spectrum disorder, 483 with bipolar disorder, and 76 with major depressive disorder for an average of 8.15 years. The initial evaluation consisted of clinical and demographic data as well as a blood samples from which immunoglobulin G antibodies to herpes viruses and Toxoplasma gondii were measured. Suicide was determined using data from the National Death Index. Cox proportional hazard regression models examined the role of baseline variables on suicide outcomes. Suicide was associated with male sex, divorced/separated status, Caucasian race, and elevated levels of antibodies to Cytomegalovirus (CMV). Increasing levels of CMV antibodies were associated with increasing hazard ratios for suicide. The identification of serological variables associated with suicide might provide more personalized methods for suicide prevention.

Microbiology Alloplastic Total Joint Infections: A 20-Year Retrospective Study.

PURPOSE: Prosthetic joint infection (PJI) is a rare complication of temporomandibular joint replacement (TJR). This study evaluated TJR PJIs at the authors' institution over a 20-year period, including micro-organisms cultured, antibiotic resistance patterns, and intraoperative protocols of TJR. PATIENTS AND METHODS: Patients were identified using Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes and surgical logs from January 1995 through 2015. Inclusion criteria were adults older than 18 years with previous alloplastic TJR and the presence of infection of the prosthesis at explantation. Exclusion criteria were patients younger than 18 years and who received hemiarthroplasty. Primary outcomes included culture data and antibiotic selection for PJI. Secondary outcomes included intraoperative duration and in vivo duration. RESULTS: Eleven patients were identified and 15 joints were explanted. Average length in vivo was 232 months (standard deviation, 478.9 months). Six percent (n = 1) were identified as early PJI (0 to 3 months), 46% (n = 7) were intermediate PJI (3 months to 2 yr), and 33% (n = 5) were late PJI (>2 yr). One patient could not be classified as early, intermediate, or late. Staphylococcus aureus was present in 53% of patients and was the predominant organism isolated. Propionibacterium acnes was isolated in 33% of patients. Penicillin was the antibiotic with the greatest organism resistance (46%). CONCLUSION: In the present study, the most commonly cultured organism was S aureus (53%), a finding consistent with current literature. The prevalence of P acnes colonization was noted in 33% of cases. Although the relevance of P acnes and its contribution to PJI requires further investigation, it is associated with PJI and biofilm formation. Based on this study, consideration could be given to the use of vancomycin and first-generation cephalosporins as perioperative antibiotic coverage.

Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study.

The molecules and pathways of the gut-brain axis represent new targets for developing methods to diagnose and treat psychiatric disorders. Manipulation of the gut microbiome with probiotics may be a therapeutic strategy with the potential to relieve gastrointestinal (GI) comorbidities and improve psychiatric symptoms. Candida albicans and Saccharomyces cerevisiae, commensal yeast species, can be imbalanced in the unhealthy human microbiome, and these fungal exposures were previously found elevated in schizophrenia. In a longitudinal, double-blind, placebo-controlled, pilot investigation of 56 outpatients with schizophrenia, we examined the impact of probiotic treatment on yeast antibody levels, and the relationship between treatment and antibody levels on bowel discomfort and psychiatric symptoms. We found that probiotic treatment significantly reduced C. albicans antibodies over the 14-week study period in males, but not in females. Antibody levels of S. cerevisiae were not altered in either treatment group. The highest levels of bowel discomfort over time occurred in C. albicans-seropositive males receiving the placebo. We observed trends towards improvement in positive psychiatric symptoms in males treated with probiotics who were seronegative for C. albicans. Results from this pilot study hint at an association of C. albicans seropositivity with worse positive psychiatric symptoms, which was confirmed in a larger cohort of 384 males with schizophrenia. In conclusion, the administration of probiotics may help normalize C. albicans antibody levels and C. albicans-associated gut discomfort in many male individuals. Studies with larger sample sizes are warranted to address the role of probiotics in correcting C. albicans-associated psychiatric symptoms.

Individuals hospitalized with acute mania have increased exposure to antimicrobial medications.

OBJECTIVES: We have preciously documented that many individuals with acute mania have immune activation. However, the sources of immune activation have not been identified. We investigated whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents. METHODS: We assessed the recent prescription of systemic antimicrobial medications and the site of presumed bacterial infection in 234 individuals hospitalized for acute mania in either an inpatient unit or a day hospital. We also assessed individuals hospitalized for other psychiatric disorders (n=368) and controls (n=555). We employed logistic regression models to compare the rates of antibiotic prescription in individuals with the different diagnoses, employing demographic variables as covariates. RESULTS: We found that individuals hospitalized with acute mania had a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment (adjusted odds ratio=5.5, 95% confidence interval: 2.2-14.1, P<.0002). Overall, a total of 18 of the 234 (7.7%) individuals hospitalized for acute mania were prescribed antibiotics as opposed to seven of 555 (1.3%) controls. The prescription of antibiotics was associated with being on an inpatient unit as opposed to being in the day hospital, and having increased mania symptom severity but not with other clinical ratings, demographic variables, or psychiatric medications. Hospitalization for other psychiatric disorders was not associated with the recent prescription of antimicrobial medications. The urinary tract was the most common site of infection in women, while the respiratory tract and mucosal surfaces were the most common sites in men. CONCLUSIONS: Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania.

Rehabilitation exercise assessment using inertial sensors: a cross-sectional analytical study.

BACKGROUND: Accurate assessments of adherence and exercise performance are required in order to ensure that patients adhere to and perform their rehabilitation exercises correctly within the home environment. Inertial sensors have previously been advocated as a means of achieving these requirements, by using them as an input to an exercise biofeedback system. This research sought to investigate whether inertial sensors, and in particular a single sensor, can accurately classify exercise performance in patients performing lower limb exercises for rehabilitation purposes. METHODS: Fifty-eight participants (19 male, 39 female, age: 53.9 ± 8.5 years, height: 1.69 ± 0.08 m, weight: 74.3 ± 13.0 kg) performed ten repetitions of seven lower limb exercises (hip abduction, hip flexion, hip extension, knee extension, heel slide, straight leg raise, and inner range quadriceps). Three inertial sensor units, secured to the thigh, shin and foot of the leg being exercised, were used to acquire data during each exercise. Machine learning classification methods were applied to quantify the acquired data. RESULTS: The classification methods achieved relatively high accuracy at distinguishing between correct and incorrect performance of an exercise using three, two, or one sensor while moderate efficacy scores were also achieved by the classifier when attempting to classify the particular error in exercise performance. Results also illustrated that a reduction in the number of inertial sensor units employed has little effect on the overall efficacy results. CONCLUSION: The results revealed that it is possible to classify lower limb exercise performance using inertial sensors with satisfactory levels of accuracy and reducing the number of sensors employed does not reduce the accuracy of the method.

An ambulatory method of identifying anterior cruciate ligament reconstructed gait patterns.

The use of inertial sensors to characterize pathological gait has traditionally been based on the calculation of temporal and spatial gait variables from inertial sensor data. This approach has proved successful in the identification of gait deviations in populations where substantial differences from normal gait patterns exist; such as in Parkinsonian gait. However, it is not currently clear if this approach could identify more subtle gait deviations, such as those associated with musculoskeletal injury. This study investigates whether additional analysis of inertial sensor data, based on quantification of gyroscope features of interest, would provide further discriminant capability in this regard. The tested cohort consisted of a group of anterior cruciate ligament reconstructed (ACL-R) females and a group of non-injured female controls, each performed ten walking trials. Gait performance was measured simultaneously using inertial sensors and an optoelectronic marker based system. The ACL-R group displayed kinematic and kinetic deviations from the control group, but no temporal or spatial deviations. This study demonstrates that quantification of gyroscope features can successfully identify changes associated with ACL-R gait, which was not possible using spatial or temporal variables. This finding may also have a role in other clinical applications where small gait deviations exist.

[Medical escape games: experimenting with a new teaching method]. / Jeu d'évasion médical : expérimentation d'une nouvelle méthode pédagogique.

With escape games gaining in popularity, we decided to adapt the concept of an existing medical escape game to the needs of our family medicine residents, by simulating clinical situations and creating puzzles with medical content. This activity was a fun way to integrate theoretical learning while developing a number of CanMEDS roles. Overall, the residents were very satisfied with the topics chosen and the interactive aspect of the experience. This escape game requires few resources, is adaptable to different environments and can be adjusted according to students' needs.

Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net.

OBJECTIVE: Here we report our preclinical, proof-of-concept testing to assess the ability of a novel device to correct mitral regurgitation. The Milwaukee Heart device aims to enable any cardiac surgeon to perform high-quality mitral valve repair using a standard annuloplasty ring with a crosshatch of microporous, monofilament suture. METHODS: Hemodynamic, echocardiographic, and videographic data were collected at baseline, following induction of mitral regurgitation, and after repair using porcine hearts in an ex vivo biosimulator model. A commercially available cardiac prosthesis assessment platform was then used to assess the hydrodynamic characteristics of the study device. RESULTS: Porcine biosimulator pressure and flow metrics exhibited successful correction of mitral regurgitation following device implantation with similar values to baseline. Hydrodynamic results yielded pressure gradients and an effective orifice area comparable to currently approved prostheses. CONCLUSIONS: The study device effectively reduced mitral valve regurgitation and improved hemodynamics in our preclinical model with similar biophysical metrics to currently approved devices. Future in vivo trials are needed to evaluate the efficacy, biocompatibility, and freedom from the most likely adverse events, such as device thrombosis, embolic events, and hemolysis.

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

BACKGROUND AND OBJECTIVE: Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients. This work aimed to characterize the population pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine) and its pharmacokinetic/pharmacodynamic relationship in pediatric patients with OAB or NDO following administration of fesoterodine. METHODS: 5-HMT plasma concentrations from 142 participants of age ≥ 6 years were analyzed, and a nonlinear mixed-effects model was developed. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity (MCC) were conducted using the final models. RESULTS: A one-compartment model with first-order absorption and a lag time, which included the effects of body weight, sex, cytochrome (CYP) 2D6 metabolizer status and fesoterodine formulation on pharmacokinetic parameters, best described the 5-HMT pharmacokinetics. An Emax model described the exposure-response relationship adequately. The median maximum concentration at steady state for pediatric patients weighing 25-35 kg and receiving 8 mg once daily (QD) was estimated to be 2.45 times greater than that in adults receiving 8 mg QD. Furthermore, simulation results showed dosing with fesoterodine 4 mg QD to pediatric patients weighing 25-35 kg and 8 mg QD to pediatric patients weighing >35 kg would achieve adequate exposure to demonstrate a clinically meaningful change from baseline (CFB) MCC. CONCLUSIONS: Population models were developed for 5-HMT and MCC in pediatric patients. Weight-based simulations indicated that 4 mg QD for pediatric patients weighing 25-35 kg and 8 mg QD for those weighing > 35 kg provided similar exposures to those in adults following 8 mg QD and a clinically meaningful CFB MCC. CLINICAL TRIAL NUMBERS: NCT00857896, NCT01557244.

Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients in the US. Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed for 5-HMT based on data from two pediatric clinical trials that included 142 patients of age ≥ 6 years with OAB or NDO. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity were conducted using the final models to examine the impact of covariates on 5-HMT exposure and the exposure­response profile. The results of these simulations indicate that 4 mg QD for pediatric patients weighing 25­35 kg and 8 mg QD for those weighing > 35 kg provide similar exposures to those in adults following 8 mg QD.

Population PK/PD modeling of low-density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti-PCSK9 monoclonal antibody.

We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low-density lipoprotein cholesterol [LDL-C] measurements, 3499 participants). A two-compartment disposition model with parallel linear and Michaelis-Menten elimination and an indirect response model was used to characterize the population PK and LDL-C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti-drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL-C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL-C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL-C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody-based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.

Peptide conjugates with polyaromatic hydrocarbons can benefit the activity of catalytic RNAs.

Early stages of life likely employed catalytic RNAs (ribozymes) in many functions that are today filled by proteins. However, the earliest life forms must have emerged from heterogenous chemical mixtures, which included amino acids, short peptides, and many other compounds. Here we explored whether the presence of short peptides can help the emergence of catalytic RNAs. To do this, we conducted an in vitro selection for catalytic RNAs from randomized sequence in the presence of ten different peptides with a prebiotically plausible length of eight amino acids. This in vitro selection generated dozens of ribozymes, one of them with ∼900-fold higher activity in the presence of one specific peptide. Unexpectedly, the beneficial peptide had retained its N-terminal Fmoc protection group, and this group was required to benefit ribozyme activity. The same, or higher benefit resulted from peptide conjugates with prebiotically plausible polyaromatic hydrocarbons (PAHs) such as fluorene and naphthalene. This shows that PAH-peptide conjugates can act as potent cofactors to enhance ribozyme activity. The results are discussed in the context of the origin of life.

Spatial repellents: from discovery and development to evidence-based validation.

International public health workers are challenged by a burden of arthropod-borne disease that remains elevated despite best efforts in control programmes. With this challenge comes the opportunity to develop novel vector control paradigms to guide product development and programme implementation. The role of vector behaviour modification in disease control was first highlighted several decades ago but has received limited attention within the public health community. This paper presents current evidence highlighting the value of sub-lethal agents, specifically spatial repellents, and their use in global health, and identifies the primary challenges towards establishing a clearly defined and recommended role for spatial repellent products in disease control.

Study protocol: the Registrar Clinical Encounters in Training (ReCEnT) study.

BACKGROUND: Patient encounters are the core learning activity of Australian general practice (family practice) training. Exposure to patient demographics and presentations may vary from one general practice registrar (vocational trainee) to another. This can affect comprehensiveness of training. Currently, there is no mechanism to systematically capture the content of GP registrar consultations. The aim of the Registrar Clinical Encounters in Training (ReCEnT) study is to document longitudinally the nature and associations of consultation-based clinical and educational experiences of general practice registrars. METHODS/DESIGN: This is an ongoing prospective multi-site cohort study of general practice registrars' consultations, entailing paper-based recording of consultation data. The study setting is general practices affiliated with three geographically-based Australian general practice regional training providers. Registrars record details of 60 consecutive consultations. Data collected includes registrar demographics, details of the consultation, patient demographics, reasons for encounter and problems managed. Problems managed are coded with the International Classification of Primary Care (second edition) classification system. Additionally, registrars record educational factors related to the encounter. The study will follow the clinical exposure of each registrar six-monthly over the 18 months to two years (full-time equivalent) of their general practice training program. CONCLUSIONS: The study will provide data on a range of factors (patient, registrar and consultation factors). This data will be used to inform a range of educational decisions as well as being used to answer educational research questions. We plan to use ReCEnT as a formative assessment tool for registrars and help identify and address educational needs. The study will facilitate program evaluation by the participating training providers and thus improve articulation of educational programs with practice experience. From the research point of view it will address an evidence gap - the in-practice clinical and educational experience of general practice trainees, determinants of these experiences, and the determinants of registrars' patterns of practice (for example, prescribing practice) over the course of their training.

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism.

BACKGROUND: Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. METHODS: The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans. RESULTS: In Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human. CONCLUSIONS: Urinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively. TRIAL REGISTRATION: For clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements. Clinical study reference A6141115: http://clinicaltrials.gov, http://NIHclinicaltrails.gov; NCTID: NCT00990223.

Procedural skills in general practice vocational training - what should be taught?

BACKGROUND: A list of procedural skills is an important component of a curriculum for general practice vocational training. This study aimed to establish an up-to-date list of core procedural skills that doctors undergoing general practice vocational training should be taught. METHOD: A Delphi process was used to rank the importance of 185 general practice procedures. In 2009, 31 general practitioners took part in a two round Delphi process. A 4-point Likert scale was used to rate the importance of each procedure in vocational training. RESULTS: Mean rating scores for all the procedural items listed were determined, and a core list of 112 procedures was agreed on the basis of the relative importance of procedures determined by the Delphi participants. DISCUSSION: The ranked list of clinical procedures provides a resource to form the basis of a procedures training curriculum which can be adapted to different general practice training contexts.

Population pharmacokinetics and exposure-response analyses of varenicline in adolescent smokers.

Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC24 ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC24 (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.