Biomarkers of Recent Cannabis Use in Blood, Oral Fluid and Breath.

Proving driving under the influence of cannabis (DUIC) is difficult. Establishing a biomarker of recent use to supplement behavioral observations may be a useful alternative strategy. We determined whether cannabinoid concentrations in blood, oral fluid (OF) or breath could identify use within the past 3 h-likely the period of the greatest impairment. In a randomized trial, 191 frequent (≥4/week) and occasional (<4/week) cannabis users smoked one cannabis (placebo [0.02%], or 5.9% or 13.4% Δ9-tetrahydrocannabinol [THC]) cigarette ad libitum. Blood, OF and breath samples were collected prior to and up to 6 h after smoking. Samples were analyzed for 10 cannabinoids in OF, 8 in blood and THC in breath. Frequent users had more residual THC in blood and were more likely to be categorized as 'recently used' prior to smoking; this did not occur in OF. Per se limits ranging from undetectable to 5 ng/mL THC in blood offered limited usefulness as biomarkers of recent use. Cannabinol (CBN, cutoff = 1 ng/mL) in blood offered 100% specificity but only 31.4% sensitivity, resulting in 100% positive predictive value (PPV) and 94.0% negative predictive value (NPV) at 4.3% prevalence; however, CBN may vary by cannabis chemovar. A 10 ng/mL THC cutoff in OF exhibited the overall highest performance to detect its use within 3 h (99.7% specificity, 82.4% sensitivity, 92.5% PPV and 99.2% NPV) but was still detectable in 23.2% of participants ∼4.4 h post-smoking, limiting specificity at later time points. OF THC may be a helpful indicator of recent cannabis intake, but this does not equate to impairment. Behavioral assessment of impairment is still required to determine DUIC. This study only involved cannabis inhalation, and additional research evaluating alternative routes of ingestion (i.e., oral) is needed.

Optimizing biologic sequencing in metastatic colorectal cancer: first line and beyond.

Significant advances in the treatment of metastatic colorectal cancer (mcrc) since the early 2000s have led to improved clinical outcomes, including overall survival (os). When fluorouracil was the sole treatment agent for mcrc, os in phase iii studies was approximately 12 months. Now, in 2019, the median os (mos) in the most recent mcrc clinical trials has been approaching 3 years. The biologic agents that target the vascular endothelial growth factor (vegf), epithelial growth factor receptor (egfr), human epidermal growth factor receptor 2 (her2), PD-1, ctla-4, ntrk, and braf pathways play important roles in the mcrc treatment algorithm, given their significant-sometimes dramatic-activity. Emerging data indicate that the choice of a specific biologic at a particular time (line of treatment) for specific patient populations (based on tumour characteristics) is critical. In the present review, we discuss the available evidence for optimal biologic sequencing in the management of mcrc.

Identifying Spatial Variation Along the HIV Care Continuum: The Role of Distance to Care on Retention and Viral Suppression.

Distance to HIV care may be associated with retention in care (RIC) and viral suppression (VS). RIC (≥ 2 HIV visits or labs ≥ 90 days apart in 12 months), prescribed antiretroviral therapy (ART), VS (< 200 copies/mL at last visit) and distance to care were estimated among 3623 DC Cohort participants receiving HIV care in 13 outpatient clinics in Washington, DC in 2015. Logistic regression models and geospatial statistics were computed. RIC was 73%; 97% were on ART, among whom 77% had VS. ZIP code-level clusters of low RIC and high VS were found in Northwest DC, and low VS in Southeast DC. Those traveling ≥ 5 miles had 30% lower RIC (adjusted odds ratio (aOR) 0.71, 95% CI 0.58, 0.86) and lower VS (OR 0.70, 95% CI 0.52, 0.94). Geospatial clustering of RIC and VS was observed, and distance may be a barrier to optimal HIV care outcomes.

Prognostic significance of baseline fatigue for overall survival: A patient-level meta-analysis of 43 oncology clinical trials with 3915 patients.

We have previously identified a single-item measure for baseline overall quality of life (QOL) as a strong prognostic factor for survival, and that fatigue was an important component of patient QOL. To explore whether patient-reported fatigue was supplemental or redundant to the prognostic information of overall QOL, we performed a patient-level pooled analysis of 43 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MCCC) oncology clinical trials assessing the effect of baseline fatigue on overall survival (OS). 3,915 patients participating in 43 trials provided data at baseline for fatigue on a single-item 0-100 point scale. OS was tested for association with clinically deficient fatigue (CDF, score 0-50, n = 1,497) versus not clinically deficient fatigue (nCDF, score 51-100, n = 2,418). We explored whether fatigue contributed to overall survival in the presence of performance status and overall QOL. We used Cox proportional hazards models that adjusted for the effects of overall QOL, performance score, race, disease site, age and gender. Baseline fatigue was a strong predictor of OS for the entire patient cohort (CDF vs. nCDF: 31.5 months vs > 83.9 months, p < 0.0001). The effect sizes of fatigue on survival were more variable across different disease sites than was seen for overall QOL (GI, esophageal, head and neck, prostate, lung, breast and others). After controlling for covariates, including performance status and overall QOL, baseline fatigue remained a strong prognostic factor in multivariate models (CDF vs. nCDF: HR = 1.23, p = 0.02). Baseline fatigue is a strong and independent prognostic factor for OS over and above performance status (PS) and overall QOL in a wide variety of oncology patient populations. Single-item measures of overall QOL and fatigue can help to identify vulnerable subpopulations among cancer patients. We recommend these single-item measures for routine inclusion as a stratification factor or key covariate in the design and analysis of oncology treatment trials.

Improving prediction of malignancy of cytologically indeterminate thyroid nodules.

BACKGROUND: Fine-needle aspiration (FNA) is essential in the investigation of thyroid nodules. The British Thyroid Association guidelines recommend clarification of whether follicular nodules are probable follicular neoplasms that require surgical excision. This study assessed the value of the subclassification of cytologically indeterminate thyroid nodules into either follicular neoplasms or other pathology. METHODS: The cytology reports of all thyroid FNAs performed between November 2005 and December 2007 at a single institution reported as Thy 3 (follicular lesions) were reviewed. They were reclassified as Thy 3A (probable follicular neoplasm) or Thy 3B (probable non-neoplastic lesion), and subsequently correlated with final clinical outcome to determine the predictive value of this subclassification. RESULTS: Forty-nine specimens were categorized as Thy 3A and 55 as Thy 3B. Of excised lesions, 14 (29 per cent) of 48 Thy 3A and 4 (10 per cent) of 42 Thy 3B nodules were malignant. If Thy 3A were to predict malignancy and Thy 3B benign disease, the sensitivity of the classification was 88 per cent, with a specificity of 55 per cent and negative predictive value of 91 per cent. CONCLUSION: Subclassification of Thy 3 nodules into Thy 3A and Thy 3B improves the assessment of risk for thyroid malignancy.

Robotic anterior pelvic exenteration for bladder cancer in the female: outcomes and comparisons to their male counterparts.

BACKGROUND: Recent small case series have now been reported for robotic-assisted laparoscopic radical cystectomy. The majority of these series have reported techniques and outcomes in a predominantly male patient population. The application of such novel techniques to female cystectomy and anterior exenterative procedures has not been well documented and described. In this paper, we report our initial experience with robotic anterior pelvic exenteration in the female with bladder cancer evaluating perioperative and pathologic outcomes of this novel procedure and comparing the outcomes to those observed in their male counterparts. METHODS: Fifty patients underwent a robotic radical cystectomy and extracorporeal diversion for clinically localized bladder cancer: 40 male patients (robotic radical cystoprostatetctomy) and 10 women (robotic anterior pelvic exenteration). Outcome measures evaluated in this series included operative variables, hospital recovery, pathologic outcomes, and complication rate. RESULTS: Mean age of female patients was 68.4 years and of male patients was 62.8. Mean operating room time was 4.6 hours, and mean surgical blood loss was 215 mL. On surgical pathology, 5 patients were <=pT2, 3 patients pT3, and 2 patients N+. In no case was there a positive surgical margin, though in 1 case there was inadvertent entry into the bladder. Mean number of lymph nodes removed was 19 (range, 12-34). Mean time to flatus was 1.9 days, time to bowel movement 2.4 days, and time to discharge 4.9 days. These outcomes were comparable to the male patients, particularly the 20 male patients undergoing robotic radical cystoprostatectomy during the same time period. CONCLUSIONS: In our experience, the robotic anterior exenteration has been readily adapted to the surgical treatment of bladder cancer with similar outcomes to those observed in male patients undergoing a robotic radical cystoprostatectomy. The approach appears to achieve the clinical and oncologic goals of radical cystectomy in both the female and male patient.

Robot-assisted laparoscopic anterior pelvic exenteration for bladder cancer in the female patient.

INTRODUCTION: Recent small case series have now been reported for robotic-assisted laparoscopic radical cystectomy. Herein, we describe our approach and initial experience with robotic-assisted laparoscopic anterior pelvic exenteration in the female patient with bladder cancer. METHODS: We describe the technique of robotic-assisted laparoscopic anterior pelvic exenteration. The classic da Vinci or the da Vinci S robotic platform is utilized for the procedure. In our experience, 12 women underwent robotic-assisted laparoscopic anterior pelvic exenteration and extracorporeal urinary diversion for clinically localized bladder cancer. RESULTS: Mean age was 67.9 years (range 61-79 years). Nine patients underwent ileal conduit diversion and three patients underwent an orthotopic neobladder. In all cases, the urinary diversion was performed extracorporeally. Mean operating room time was 4.6 h; mean surgical blood loss was 221 mL. On surgical pathology, seven patients were =pT2, three patients were pT3, and two patients were N+. In no case was there positive surgical margins, and in one case there was inadvertent entry into the bladder. Mean number of lymph nodes removed was 19 (range 12-34). Mean time to flatus was 1.9 days and to bowel movement 2.4 days, and time to discharge 4.8 days. Six patients were discharged on postoperative day 4, four patients on postoperative day 5, one on postoperative day 6, and one on postoperative day 8. There were two postoperative complications (17%) in two patients. CONCLUSIONS: Our initial experience with robotic-assisted laparoscopic anterior pelvic exenteration appears to be favorable with acceptable operative, pathologic, and short-term clinical outcomes. Certainly, larger experiences are required to adequately evaluate and validate this procedure as an appropriate surgical and oncologic option.

Current activity guidelines for CABG patients are too restrictive: comparison of the forces exerted on the median sternotomy during a cough vs. lifting activities combined with valsalva maneuver.

BACKGROUND: The current activity guidelines for coronary artery bypass graft surgery (CABG) patients are overly restrictive, hindering recovery. As the sternotomy repair must withstand repeated coughs during convalescence, this provides a benchmark for the force tending to separate the incision that can be tolerated. METHODS: Nine volunteers performed 5 weightlifting activities (lifting 5 lbs [2.3 kg], lifting a 25-lb simulated grandchild [11.4 kg], lifting a 30-lb suitcase [13.6 kg], lifting two 20-lb weights [18.2 kg], and lifting a gallon of milk to a counter [3.7 kg]), plus coughing. Valsalva forces were detected using a mouthpiece configured with an Ashcroft Inc. expiratory pressure gauge (model N10-120CMW). Three measurements were taken for each activity to calculate the mean internal forces while external forces on the sternotomy were calculated using vector algebra. Total force exerted on the sternotomy by the cough was compared to the total force exerted by each of the 5 activities using paired T-tests. RESULTS: The cough exerted a significantly greater force across the median sternotomy (mean 27.5 kg-mass) than any of the five weightlifting activities ( P < 0.05). The greatest difference was observed was for lifting a 5-lb weight (22.5 kg-mass), and the smallest for lifting two 20-lb weights (4.4 kg-mass). CONCLUSION: Lifting even 40 lbs puts less force on the median sternotomy incision than a cough. The strength of the repair is significantly greater than is implied by the recommendation to "not lift more than 5 lbs".

Androgen-independent prostate cancer treated with resection of the solitary metastatic site.

The concept of resection of a solitary metastatic lesion is quite foreign in prostate cancer, as metastases to regional lymph nodes or to other distant sites are most likely suggestive of disseminated disease. The current report demonstrates a very unique case, in whom excision of a solitary pulmonary metastasis has resulted in continued undetectable prostate-specific antigen values over 3 years after resection. Nevertheless, the presence of unusual cases such as this, as well as the work of others, may suggest that surgical excision of solitary or oligometastatic sites could at least be considered for the most highly selected and well-informed patients, whose clinical scenario indicates a potential benefit from such an approach.

Incisional hernia in a 12-mm non-bladed trocar site following laparoscopic nephrectomy.

Non-bladed trocars, radially-dilating systems, and conical blunt devices are considered less traumatic to the abdominal wall because they do not incise the fascia itself. Consequently, several authors have suggested that closure of the abdominal fascia may be unnecessary if such non-bladed laparoscopic trocars are used. We report of a case in whom a port-site hernia was diagnosed at the site of a 12-mm non-bladed trocar 11 days after laparoscopic nephrectomy.

A prospective evaluation of the short-term impact and recovery of health-related quality of life in men undergoing radical prostatectomy.

OBJECTIVE: To prospectively evaluate the acute and short-term effects of radical retropubic prostatectomy (RRP) on health-related quality of life (HRQoL) using a validated generic HRQoL instrument that measures overall health status, as although there is increasing interest in the HRQoL of patients being treated for prostate cancer, most studies have focused on long-term outcomes. PATIENTS AND METHODS: In all, 121 men undergoing RRP for clinically localized prostate cancer were prospectively evaluated for short-term HRQoL using an acute Short Form-12 version-2 Physical and Mental Health Survey Acute Form before and serially each week from 1 to 6 weeks after RRP. The physical (PCS) and mental component score (MCS) were calculated from the questionnaires at each time and the data analysed by random coefficient modelling. Separate models were fitted for MCS and PCS using covariates of race, age, estimated blood loss (EBL), time after RRP, and their interaction terms. RESULTS: The PCS initially declined and improved linearly. and the baseline level was not achieved by 6 weeks, but modelling lines showed an expected return to baseline at 7-8 weeks for all patients. Age had a significant relationship with the PCS; older men (>60 years) scored higher, and their PCS remained significantly higher after RRP than younger men (< or =60 years) until 5 weeks. EBL also had a significant relationship with PCS; men with an EBL of >500 mL had a significantly lower PCS at 1 week and this remained significantly lower than for men with an EBL of < or = 500 mL until approximately 7 weeks. The MCS improved immediately after RRP and remained higher throughout the study than at baseline. Race was the only covariate for which there were significant differences in the MCS. The MCS was significantly lower at baseline for African-Americans than for Caucasian Americans, and remained lower until 6 weeks after RRP. CONCLUSIONS: There were significant changes in HRQoL during in the short-term after RRP. Younger men and those with a higher EBL might have a slower recovery of the PCS after RRP. African-Americans had a slower increase in MCS and might have a different initial emotional or mental health response to RRP than have Caucasians.

Association between mannan-binding lectin and impaired lung function in cystic fibrosis may be age-dependent.

An association between mannan-binding lectin (MBL) status and severity of lung function impairment in cystic fibrosis (CF) has been found in several studies, but not in others. To explore the possible basis for discrepancies in the literature, we related both MBL and L-ficolin concentrations to lung function and examined the results in relation to the age of the patients. For patients under 15 years of age, those with MBL < 200 ng/ml had better lung function than those with MBL > 200 ng/ml [median forced expiratory volume in 1 s (FEV(1)), 99% versus 83%; P = 0.05]. For patients over 15 years of age, those with MBL < 200 ng/ml had poorer lung function than those with MBL > 200 ng/ml (median FEV(1), 44% versus 55%; P = 0.1). Also, for the over 15-year-olds, the proportion of patients with FEV(1) values below the median was greater in the MBL-insufficient subgroup (P < 0.04). In other words, relative deficiency of MBL appears to accelerate the age-related decline in lung function in CF patients. No corresponding relationships could be found between L-ficolin concentration and lung function. These findings and interpretation lend support to the potential value of MBL replacement therapy in a small minority of cystic fibrosis patients.

Large presacral schwannoma after radical prostatectomy.

A 56-year-old man presented with long-standing, mild urinary frequency 6 years after radical prostatectomy. Pathologic assessment showed presence of organ confined prostate cancer (pT2a), Gleason 6 (3+3). Since the time of surgery, PSA level was undetectable and the patient remained without evidence of recurrent disease. However, digital rectal examination revealed the presence of a very large mass palpable on the anterior rectal wall. Therefore, the patient underwent abdominal/pelvic MRI which demonstrated presence of a solid, well-circumscribed pelvic mass extending from the level of the sacrum posteriorly to the anterior abdominal wall. Histologic examination of percutaneous biopsy of the mass was suggestive of schwannoma. The patient underwent laparotomic excision of the mass, which was confirmed to be a schwannoma, with its characteristic slender spill cells and elongate nuclei. No intra-operative complication was reported. The patient has no evidence of recurrence with complete resolution of urinary symptom one year after surgery.

A prospective analysis of the incidence and risk factors associated with junctional ectopic tachycardia following surgery for congenital heart disease.

This study was designed to evaluate the incidence and risk factors associated with the occurrence of junctional ectopic tachycardia (JET) in patients after congenital heart surgery. We prospectively analyzed cardiac rhythm status in 336 consecutive patients undergoing surgery for congenital heart disease at our institution during a 1-year period. The incidence of JET was 8% (27/336). Repairs with the highest incidence of JET were arterial switch operation (3/13, 23%), atrioventricular (AV) canal repair (4/19, 21%), and Norwood repair (2/10, 20%). Compared to patients with no arrhythmias, patients with JET were more likely to be younger (2.75 +/- 2.44 vs 5.38 +/- 7.25 years, p < 0.01), have had longer cardiopulmonary bypass times (126 +/- 50 vs 85 +/- 73, p < 0.01), and have a higher inotrope score (6.26 +/- 7.55 vs 2.41 +/- 8.11, p < 0.01). By multivariate analysis, ischemic time was the only factor associated with JET [odds ratio, 1.01 (confidence interval, 1.005-1.02); p = 0.0014). The presence of JET did not correlate with electrolyte abnormalities. JET is not necessarily related to surgery near the His bundle or hypomagnesemia. Longer ischemic time is the best predictor of JET. Patients undergoing arterial switch operation, AV canal repair, and Norwood repair are at highest risk of postoperative JET and should be considered for prophylactic therapy.

Incisional hernia in a 12-mm nonbladed trocar site following laparoscopic nephrectomy.

Non-bladed trocars and radially dilating systems are considered less traumatic to the abdominal wall because they do not incise the fascia itself. Since the fascia is not cut, it has believed that the fascia closes by itself. Consequently, several authors have suggested that closure of the abdominal fascia may be unnecessary when such non-bladed laparoscopic trocars are used. We report of a case in which a port site hernia was diagnosed at the site of a 12 mm non-bladed trocar 11 days after laparoscopic nephrectomy. Although it may be true that in many cases port site closure is unnecessary and does not result in bowel herniation, this case along with a prior report serve as important reminders that port site hernias are possible even in the use of non-bladed or radial dilating systems, and that there exists a number of potential variables that may predispose to herniation and consequently the ability to predict such events in individual patients remains uncertain. As such, we recommend closing 10 mm or larger port sites irrespective of trocar design.

Erectile dysfunction and treatment of carcinoma of the prostate.

Prostate cancer is the leading malignancy in men in the United States and causes more than 60,000 deaths annually. Treatment of prostate cancer, whether it be with surgery, radiation therapy, cryotherapy, or medical treatment, is associated with significant life-altering morbidity. Incontinence and erectile dysfunction (ED) too often are sequelae of these treatment alternatives. ED can be a significant complication and can alter the life of the patient with prostate cancer and his partner. Newer modifications of the radical prostatectomy with nerve-sparing techniques are the cornerstone of erection preservation. Time following radical prostatectomy has been shown to increase erectile function such that more patients have functional erections at 3 years than 1 year after surgery. With the advent of phosphodiesterase-5 (PDE-5) inhibitors, many men can have improved functional erections and return to active coitus. Prevention of ED also is an important management technique. Evidence is gathering that prophylaxis with regular vasoactive injection or daily PDE-5 agents may be an integral part of preservation of corpus cavernosum smooth muscle function. Combination medical therapy and surgical penile prosthesis implantation also are options for patients who do not respond to oral PDE-5 inhibitors.

Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster.

The hypothesis that overexpression of glutamate-cysteine ligase (GCL), which catalyzes the rate-limiting reaction in de novo glutathione biosynthesis, could extend life span was tested in the fruit fly, Drosophila melanogaster. The GAL4-UAS binary transgenic system was used to generate flies overexpressing either the catalytic (GCLc) or modulatory (GCLm) subunit of this enzyme, in a global or neuronally targeted pattern. The GCL protein content of the central nervous system was elevated dramatically in the presence of either global or neuronal drivers. GCL activity was increased in the whole body or in heads, respectively, of GCLc transgenic flies containing global or neuronal drivers. The glutathione content of fly homogenates was increased by overexpression of GCLc or GCLm, particularly in flies overexpressing either subunit globally, or in the heads of GCLc flies possessing neuronal drivers. Neuronal overexpression of GCLc in a long-lived background extended mean and maximum life spans up to 50%, without affecting the rate of oxygen consumption by the flies. In contrast, global overexpression of GCLm extended the mean life span only up to 24%. These results demonstrate that enhancement of the glutathione biosynthetic capability, particularly in neuronal tissues, can extend the life span of flies, and thus support the oxidative stress hypothesis of aging.

All radial scars/complex sclerosing lesions seen on breast screening mammograms should be excised.

AIM: To determine the incidence of pre-malignant and malignant conditions in radial scars identified from screening mammograms in women taking part in the UK NHS breast cancer screening programme. METHODS: All women in our screening population from 1988 to 2002 with a radiological diagnosis of radial scar or complex sclerosing lesion confirmed on subsequent histopathology were included in this study. Patients were investigated with fine needle aspiration cytology then localisation biopsy (n=46) or straight to localisation biopsy (n=78). Patients where divided into two groups, one with pure RS/CSL with no associated epithelial features and the second with associated ADH, DCIS or invasive cancer. RESULTS: One hundred and twenty-four lesions were confirmed histologically as radial scar or complex sclerosing lesions. The median age was 58 years. Of the 124 patients, 82 were pure RS/CSL. Forty-two had associated epithelial lesions, 22 patients had ADH and 20 patients had either in situ or invasive carcinoma. Where FNA was performed (n=46), mammograms had shown three lesions suspicious of cancer, which were not proven histologically. Mammograms picked up five malignancies out of the nine RS/CSL with associated cancers. Of these, FNA confirmed malignancy in only two patients. Where FNA was not done (n=78), mammogram had read five pure RS/CSL as cancers. It picked up only four cancers in RS lesions with DCIS/Ca out of 11. CONCLUSION: All screen-detected stellate lesions should be excised due to their association with pre-malignant and malignant conditions.

Exposure measures applied to the bioequivalence of two sustained release formulations of bupropion.

OBJECTIVE: To examine the effect of the exposure measures C(max) (peak exposure), AUC(E) (early exposure) and AUC (total exposure) on the bioequivalence of two sustained release formulations of bupropion (i) in the fasted state and (ii), after a high fat meal. The ratio C(max)/AUC (sensitive to rate of absorption) was also evaluated. METHODS: A two-formulation, two-sequence, four-period replicate design study was performed in 29 healthy men and women after an overnight fast. Similarly, a two-period study was performed in 20 healthy men and women after ingestion of a high fat breakfast. Plasma concentrations of bupropion were measured by HPLC/MS/MS and the data were analyzed (SAS PROC MIXED) by the Schuirmann-Sattersthwaite procedure (four-period study) and by the two one-sided test procedure (SAS PROC GLM) (two-period study). Standard bioequivalence limits of 80 - 125% were applied to all measures including AUC(E) and C(max)/AUC. RESULTS: In the fasting study, the mean plasma concentration vs. time curves from (including over the first 24 hours) following the two administrations of each formulation were similar although there was a significant difference in median t(max) between formulations. This may have contributed to a low estimate of geometric mean ratio (GMR) for AUC(E) (69%) which was judged to have failed bioequivalence. There was also rather low GMRs for Cmax (88%) and C(max)/AUC (89%) but these measure passed because the within-subject variabilities (WSV) were relatively low (19.6% and 11.2%, respectively). Total exposure (AUC(last)) met standard bioequivalence limits of 80 - 125% easily. The raw data from the two-period fed also showed differences in the shapes of the plasma concentration vs. time curves around C(max) although there was no difference in median t(max). The WSV at median t(max) was high (34%) as was the GMR (117%) for AUCE which failed, as did C(max) (GMR 112%). The WSV was very high at early time points before settling into a "plateau" at about 11%. DISCUSSION: There was no "spike" in the plasma concentration vs. time profiles up to median t(max) or beyond and therefore there was no evidence of dose dumping of the test formulation in either fasted or fed states. No bioequivalence limits have been set for AUC(E) but the application of standard BE limits of 80 to 125% meant that the fed study was clearly underpowered given the high WSV at early time points. CONCLUSIONS: More research is needed on the interesting concept of early exposure. The WSV is often high at median t(max) which means that standard bioequivalence limits of 80 - 125% may be inappropriate. Despite the lack of dose dumping, application of AUC(E) to the fasting study, would have resulted in failure to declare bioequivalence since the GMR for this measure was only 69.5%. Application of a 90% confidence interval to AUC(E) to the fed study would have required powering to cope with the fact that this measure was highly variable.