SAGES White Paper on the importance of diversity in surgical leadership: creating the fundamentals of leadership development (FLD) curriculum.

BACKGROUND: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has long recognized and championed increasing diversity within the surgical workplace. SAGES initiated the Fundamentals of Leadership Development (FLD) Curriculum to address these needs and to provide surgeon leaders with the necessary tools and skills to promote diversity, equity, and inclusion (DEI) in surgical practice. In 2019, the American College of Surgeons issued a request for anti-racism initiatives which lead to the partnering of the two societies. The primary goal of FLD was to create the first surgeon-focused leadership curriculum dedicated to DEI. The rationale/development of this curriculum and its evaluation/feedback methods are detailed in this White Paper. METHODS: The FLD curriculum was developed by a multidisciplinary task force that included surgeons, education experts, and diversity consultants. The curriculum development followed the Analysis, Design, Development, Implementation and Evaluation (ADDIE) instructional design model and utilized a problem-based learning approach. Competencies were identified, and specific learning objectives and assessments were developed. The implementation of the curriculum was designed to be completed in short intervals (virtual and in-person). Post-course surveys used the Kirkpatrick's model to evaluate the curriculum and provide valuable feedback. RESULTS: The curriculum consisted of interactive online modules, an online discussion forum, and small group interactive sessions focused in three key areas: (1) increasing pipeline of underrepresented individuals in surgical leadership, (2) healthcare equity, and (3) conflict negotiation. By focusing on positive action items and utilizing a problem-solving approach, the curriculum aimed to provide a framework for surgical leaders to make meaningful changes in their institutions and organizations. CONCLUSION: The FLD curriculum is a novel leadership curriculum that provided surgeon leaders with the knowledge and tools to improve diversity in three areas: pipeline improvement, healthcare equity, and conflict negotiation. Future directions include using pilot course feedback to enhance curricular effectiveness and delivery.

Understanding Post-Esophagectomy Complications and Their Management: The Early Complications.

Esophagectomy is a technically complex operation performed for both benign and malignant esophageal disease. Medical and surgical advancements have led to improved outcomes in esophagectomy patients over the past several decades; however, surgeons must remain vigilant as complications happen often and can be severe. Post-esophagectomy complications can be grouped into early and late categories. The aim of this review is to discuss the early complications of esophagectomy along with their risk factors, work-up, and management strategies with special attention given to anastomotic leaks.

Impact of Morbid Obesity on Post-esophagectomy Leak Rate: a NSQIP Analysis.

BACKGROUND: Morbid obesity is becoming more prevalent and is a known risk factor for esophageal cancer. Esophagectomy in this population is technically more challenging than the non-obese, thus increasing the risks of surgery. This study hypothesizes that higher body mass index (BMI) is associated with higher anastomotic leak rates after esophagectomy. METHODS: This study is a retrospective review of patients undergoing esophagectomy in the National Surgical Quality Improvement Program (NSQIP) Targeted Esophagectomy database from 2016 to 2019. Patients were stratified by BMI < 35 versus BMI > 35, with the primary outcome being leak post-esophagectomy. Univariate analyses were performed for demographics and post-operative outcomes, and multivariate analyses were performed specifically for the primary outcome of anastomotic leak (all diagnoses and malignancy/dysplasia subgroup). This study was approved by the Institutional Review Board. RESULTS: Of 4165 patients, 439 (10.5%) had a BMI > 35. Patients with BMI > 35 were often younger (mean age 60 vs 64 years, p < 0.001), White (p < 0.001), female (p < 0.001), non-smoker (p < 0.001), diabetic (p < 0.001), with hypertension (p < 0.001), and ASA ≥ 3 (p < 0.001). There were no differences between BMI groups with regard to indication for esophagectomy (malignancy/dysphasia vs other), conversion to open, mortality, or length of stay. The BMI > 35 cohort reported higher operative times (p < 0.001), open operative approach (p = 0.04), superficial surgical site infection (p < 0.001), return to operating room (p = 0.01), and leak (13.5% vs 10.1%, p = 0.01). BMI > 35 was not an independent predictor of leak for all diagnoses; however, the subgroup analysis of esophagectomy for malignancy/dysplasia demonstrated that BMI > 35 was predictive of leak (OR 1.42, 95% CI 1.05-1.91), as well as operative time and hypertension. CONCLUSION: Patients with a BMI > 35 and who undergo esophagectomy have a higher rate of anastomotic leak. BMI > 35 was also an independent predictor of leak when esophagectomy was performed for malignancy/dysplasia, but not for all diagnoses. The risk of anastomotic leak should be considered in morbidly obese patients undergoing esophagectomy, particularly for malignancy.

Multi-society consensus conference and guideline on the treatment of gastroesophageal reflux disease (GERD).

BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common diseases in North America and globally. The aim of this guideline is to provide evidence-based recommendations regarding the most utilized and available endoscopic and surgical treatments for GERD. METHODS: Systematic literature reviews were conducted for 4 key questions regarding the surgical and endoscopic treatments for GERD in adults: preoperative evaluation, endoscopic vs surgical or medical treatment, complete vs partial fundoplication, and treatment for obesity (body mass index [BMI] ≥ 35 kg/m2) and concomitant GERD. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Recommendations for future research were also proposed. RESULTS: The consensus provided 13 recommendations. Through the development of these evidence-based recommendations, an algorithm was proposed for aid in the treatment of GERD. Patients with typical symptoms should undergo upper endoscopy, manometry, and pH-testing; additional testing may be required for patients with atypical or extra-esophageal symptoms. Patients with normal or abnormal findings on manometry should consider undergoing partial fundoplication. Magnetic sphincter augmentation or fundoplication are appropriate surgical procedures for adults with GERD. For patients who wish to avoid surgery, the Stretta procedure and transoral incisionless fundoplication (TIF 2.0) were found to have better outcomes than proton pump inhibitors alone. Patients with concomitant obesity were recommended to undergo either gastric bypass or fundoplication, although patients with severe comorbid disease or BMI > 50 should undergo Roux-en-Y gastric bypass for the additional benefits that follow weight loss. CONCLUSION: Using the recommendations an algorithm was developed by this panel, so that physicians may better counsel their patients with GERD. There are certain patient factors that have been excluded from included studies/trials, and so these recommendations should not replace surgeon-patient decision making. Engaging in the identified research areas may improve future care for GERD patients.

Diversity in Scientific Discovery.

Presented here is a brief discussion on the imperative need and thoughtful approaches to embracing diversity, equity and inclusion within scientific enquiry.

Biomarkers for Barrett's esophagus - a contemporary review.

INTRODUCTION: Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate (10%-18%), and incidence has increased dramatically in the past three decades. Barrett's esophagus (BE) is the precursor lesion to EAC and is the replacement of the normally squamous lined esophagus with columnar cells that develop an intestinal phenotype characterized by the presence of goblet cells. Given the known precursor state, EAC is amenable to screening and surveillance strategies (analogous to colon cancer). However, unlike from colon cancer screening, BE poses challenges that make effective screening difficult. Robust and concerted effort is under way to find biomarkers of BE. Areas covered: This review summarizes current known biomarkers for BE. These include dysplasia, genomic markers, and gene expression alterations that occur early in the dysplasia/carcinoma sequence. Expert commentary: Despite the tremendous breadth of work in studying molecular advances, the ideal biomarker for BE has not yet been discerned. This review comments on innovations in the field of BE research that combine state-of-the-art molecular advances with simple technologies.

Feasibility, safety, and short-term efficacy of the laparoscopic Nissen-Hill hybrid repair.

BACKGROUND: A novel antireflux procedure combining laparoscopic Nissen fundoplication and Hill repair components was tested in 50 patients with paraesophageal hernia (PEH) and/or Barrett's esophagus (BE) because these two groups have been found to have a high rate of recurrence with conventional repairs. METHODS: Patients with symptomatic PEH and/or non-dysplastic BE underwent repair. Quality of life (QOL) metrics, manometry, EGD, and pH testing were administered pre- and postoperatively. RESULTS: Fifty patients underwent repair. There was no mortality and four major complications. At 13-month follow-up, there was one (2%) clinical recurrence, and two (4%) asymptomatic fundus herniations. Mean DeMeester scores improved from 57.2 to 7.7 (p < 0.0001). Control of preoperative symptoms was achieved in 90% with 6% resumption of antisecretory medication. All QOL metrics improved significantly. CONCLUSIONS: The hybrid Nissen-Hill repair for patients with PEH and BE appears safe and clinically effective at short-term follow-up. It is hoped that the combined structural components may reduce the rate of recurrence compared to existing repairs.

Liver Transplant Patient Carriers of Polymorphism Cyp3a5*1 Donors May Need More Doses of Tacrolimus From the First Month After Transplantation.

BACKGROUND: The aim of this work was to evaluate the CYP3A5:CYP3A5*1/CYP3A5*3 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients. METHODS: This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n = 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use of a TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele ("minor-allele") was analyzed for correlation with the tacrolimus dose-normalized ratio during the 3 months after transplantation. RESULTS: The following observations were obtained in the population studied: (1) Frequency of the minor allele*1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A5*1/*3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele*1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P < .05). CONCLUSIONS: The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1-polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype.

Rheology and simulation of 2-dimensional clathrin protein network assembly.

Clathrin is a three-legged protein complex that assembles into lattice structures on the cell membrane and transforms into fullerene-like cages during endocytosis. This dynamic structural flexibility makes clathrin an attractive building block for guided assembly. The assembly dynamics and the mechanical properties of clathrin protein lattices are studied using rheological measurements and theoretical modelling in an effort to better understand two dynamic processes: protein adsorption to the interface and assembly into a network. We find that percolation models for protein network formation are insufficient to describe clathrin network formation, but with Monte Carlo simulations we can describe the dynamics of network formation very well. Insights from this work can be used to design new bio-inspired nano-assembly systems.

Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains.

Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, ß-catenin independent pathway and suppress a canonical Wnt/ß-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.

The laparoscopic Nissen-Hill hybrid: pilot study of a combined antireflux procedure.

BACKGROUND: Laparoscopic antireflux surgery is highly effective in patients with uncomplicated gastroesophageal reflux disease (GERD). However, long-term failure rates in paraesophageal hernia (PEH) and Barrett's metaplasia (BE) are higher and warrant a more durable repair. Outcomes for the laparoscopic Nissen fundoplication (LNF) and Hill repair (LHR) are equivalent, but their anatomic components are different and may complement each other (Aye R Ann Thorac Surg, 2012). We designed and tested the feasibility and safety of an operation that combines the essential components of each repair. METHODS: A prospective, phase II pilot study was performed on patients with symptomatic giant PEH hernias and/or GERD with nondysplastic Barrett's metaplasia. Pre- and postoperative esophagogastroduodenoscopy (EGD), upper gastrointestinal study (UGI), 48-hour pH testing, manometry, and three quality-of-life metrics were obtained. RESULTS: Twenty-four patients were enrolled in the study. Three patients did not complete the planned procedure, leaving 21 patients, including 12 with PEH, 7 with BE, and 2 with both. There were no 30-day or in-hospital mortalities. At a median follow-up of 13 (range 6.4-30.2) months, there were no reoperations or clinical recurrences. Two patients required postoperative dilation for dysphagia, with complete resolution. Mean DeMeester scores improved from 54.3 to 7.5 (p < 0.0036). Mean lower esophageal sphincter pressures (LESP) increased from 8.9 to 21.3 mmHg (p < 0.013). Mean short-term and long-term QOLRAD scores improved from 4.09 at baseline to 6.04 and 6.48 (p < 0.0001). Mean short-term and long-term GERD-HQRL scores improved from 22.9 to 7.5 and 6.9 (p < 0.03). Mean long-term Dysphagia Severity Score Index improved from 33.3 to 40.6 (p < 0.064). CONCLUSIONS: The combination of a Nissen plus Hill hybrid reconstruction of the gastroesophageal junction (GEJ) is technically feasible, safe, and not associated with increased side effects. Short-term clinical results in PEH and BE suggest that this may be an effective repair, supporting the value of further study.

Engineered clathrin nanoreactors provide tunable control over gold nanoparticle synthesis and clustering.

The use of biomolecules to direct nanomaterial synthesis has been an area of growing interest due to the complexity of structures that can be achieved in naturally occurring systems. We previously reported the functionalization of self-assembled clathrin protein cages to enable synthesis of nanoparticles from a range of inorganic materials. Here, we investigate the ability of this engineered biomolecule complex to act as a tunable nanoreactor for the formation of different arrangements of gold nanoparticles in three dimensions. We find that self-assembled clathrin cages functionalized with engineered bi-functional peptides induce formation of gold nanoparticles to generate solutions of either dispersed or clustered gold nanoparticles on demand. The 3D arrangement of nanoparticles is dependent on the concentration of the engineered peptide, which fulfills multiple roles in the synthesis process including stabilization of the nanoparticle surface and localization of the nanoparticles within the self-assembled clathrin cage. We propose and evaluate a mechanism that allows us to predict the peptide concentration at which the nanoreactor behavior switches. This work provides insight into peptide-based surfactants and the potential for incorporating them into strategies for tuning biological mineralization processes in mild solution conditions to generate complex structures.

Template engineering through epitope recognition: a modular, biomimetic strategy for inorganic nanomaterial synthesis.

Natural systems often utilize a single protein to perform multiple functions. Control over functional specificity is achieved through interactions with other proteins at well-defined epitope binding sites to form a variety of functional coassemblies. Inspired by the biological use of epitope recognition to perform diverse yet specific functions, we present a Template Engineering Through Epitope Recognition (TEThER) strategy that takes advantage of noncovalent, molecular recognition to achieve functional versatility from a single protein template. Engineered TEThER peptides span the biologic-inorganic interface and serve as molecular bridges between epitope binding sites on protein templates and selected inorganic materials in a localized, specific, and versatile manner. TEThER peptides are bifunctional sequences designed to noncovalently bind to the protein scaffold and to serve as nucleation sites for inorganic materials. Specifically, we functionalized identical clathrin protein cages through coassembly with designer TEThER peptides to achieve three diverse functions: the bioenabled synthesis of anatase titanium dioxide, cobalt oxide, and gold nanoparticles in aqueous solvents at room temperature and ambient pressure. Compared with previous demonstrations of site-specific inorganic biotemplating, the TEThER strategy relies solely on defined, noncovalent interactions without requiring any genetic or chemical modifications to the biomacromolecular template. Therefore, this general strategy represents a mix-and-match, biomimetic approach that can be broadly applied to other protein templates to achieve versatile and site-specific heteroassemblies of nanoscale biologic-inorganic complexes.

A descriptive analysis of gastric cancer specimen processing techniques.

BACKGROUND: Adherence to guidelines for adequate gastric cancer specimen assessment is poor in North America. Inadequate staging and poor prognosis were noted in some series when these guidelines are not met. Recent advances have been made in standardizing cancer pathology reports in Canada; however, the uptake of these reporting systems is unknown for gastric cancer. A survey of pathologists in Ontario was performed to outline the processing techniques and practices for assessing gastric cancer specimens. METHODS: A survey was designed through a collaboration of surgical oncologists, general surgeons, pathologists, and research staff. Pathologists were identified using the College of Physicians and Surgeons of Ontario and MD Select databases. Participants were surveyed online or by mail-out. RESULTS: The response rate was 40.2% (147/366). Vascular invasion, perineural invasion, and signet ring cells were all reported as being examined for by the majority of pathologists. Fat clearing solution and keratin immunohistochemical techniques were not reported as being consistently utilized. Less than 70% of pathologists indicated using a form of synoptic report. CONCLUSION: Variations in practice and technique were observed. This may or may not reflect differences in quality of care or simply preferences for achieving equivalent results in the absence of standardized procedures. Education, evidence-based procedural guidelines and further research are required to provide infrastructure and support for pathologists and surgeons involved in the care of gastric cancer patients.

Multiple sclerosis and cognitive decline: is ApoE-4 a surrogate marker?

BACKGROUND - The role of the apolipoprotein E (ApoE) polymorphism has been well demonstrated in neurodegenerative disorders such as Alzheimer. However, its role in multiple sclerosis (MS) remains unclear. AIMS - The aims of our study were as follows: (i) to assess whether ApoE-4 might be a surrogate marker of cognitive decline in MS; (ii) to confirm the presence of cognitive impairment in mildly disabled patients treated with interferon-beta; and (iii) to analyse the correlation between cognitive disturbances and clinical variables. MATERIAL AND METHODS - Fifty relapsing-remitting MS patients underwent a battery of neuropsychological tests and were genotyped for ApoE. Their scores were compared with those of 35 controls. RESULTS - No association was found between ApoE-4 and cognitive impairment. Significant differences in most domains were observed between MS and the control group. Cognitive decline was not related to disability progression. CONCLUSION - No association between cognitive impairment and ApoE-4 or clinical markers was detected in our MS patients.

High speed water sterilization using one-dimensional nanostructures.

The removal of bacteria and other organisms from water is an extremely important process, not only for drinking and sanitation but also industrially as biofouling is a commonplace and serious problem. We here present a textile based multiscale device for the high speed electrical sterilization of water using silver nanowires, carbon nanotubes, and cotton. This approach, which combines several materials spanning three very different length scales with simple dying based fabrication, makes a gravity fed device operating at 100000 L/(h m(2)) which can inactivate >98% of bacteria with only several seconds of total incubation time. This excellent performance is enabled by the use of an electrical mechanism rather than size exclusion, while the very high surface area of the device coupled with large electric field concentrations near the silver nanowire tips allows for effective bacterial inactivation.

Improving the quality of processing gastric cancer specimens: the pathologist's perspective.

BACKGROUND AND OBJECTIVES: Research into surgeon and pathologist knowledge of guidelines for lymph node (LN) assessment in gastric cancer demonstrated a knowledge deficit. To understand factors affecting optimal assessment we surveyed pathologists to identify external barriers. METHODS: Pathologists were identified using two Ontario physician databases and surveyed online or by mail, with a 40% response rate. RESULTS: The majority (56%) of pathologists stated assessing an additional five LNs would not be a burden. Most (80%) pathologists disagreed with pay for performance for achieving quality standards. Qualitative analysis determined the majority of pathologists believed achieving quality standards was inherent to their profession and should not require incentives. Poor surgical specimen was identified as a barrier and underscores the importance of aiming quality improvement initiatives at the multidisciplinary team. CONCLUSION: In addition to education, tailoring an intervention to address all barriers, including laboratory constraints may be an effective means of improving gastric cancer care.

Quality indicators for gastric cancer surgery: a survey of practicing pathologists in Ontario.

BACKGROUND: Adequate lymph node (LN) assessment and R0 resection are critical to the staging and management of gastric cancer. The American Joint Committee on Cancer/International Union Against Cancer recommend at least 15 LN be assessed, and the literature suggests a gross disease-free margin of 5-6 cm be achieved. Results of an Ontario general surgeons' survey indicated these standards were not widely known. Because disease management is highly collaborative, we surveyed pathologists to assess their knowledge of LN assessment and margins for processing gastric cancer specimens. METHODS: Pathologists were identified by the College of Physicians and Surgeons of Ontario and MD Select databases. Participants were surveyed online or by mail. RESULTS: Pathologists indicated a goal of assessing <5 LN (2%), 5-10 LN (27%), 10-15 LN (40%), 15-20 LN (20%), or >20 LN (11%). Most self-reported an actual assessment of 5-10 LN (49%), with 88% reporting a number below current standards. Additionally, 54% of responding pathologists identified >1 cm as an adequate gross margin, and 89% of pathologists indicated a response below current standards. Ninety-four percent of pathologists agreed that more education on gastric cancer is valuable. CONCLUSIONS: To improve the quality of gastric cancer management, our findings suggest the need for clear, consistent guidelines for adequate gross margin resection length. Furthermore, there is a critical need for education aimed at closing the knowledge gap among practicing pathologists and surgeons regarding current recommended guidelines for LN assessment and adequate margin length.

Low 25-hydroxyvitamin D concentrations in obese women: their clinical significance and relationship with anthropometric and body composition variables.

UNLABELLED: Obesity is associated with low concentrations of 25-hydroxyvitamin D [25(OH) D]. However, conflicting results have been found regarding the relationship of 25(OH) D with anthropometric and adiposity parameters. The aim of our study was to analyze the association between 25(OH) D and body fat (BF) in a homogeneous cohort of non-obese, obese, and morbidly obese Caucasian women. The study was performed in L'Hospitalet de Llobregat, a city adjacent to Barcelona with a latitude of 41 degrees, 22 minutes, and 5 seconds north. MATERIALS AND METHODS: Plasma concentrations of 25(OH) D were determined and body composition was evaluated by bioelectrical impedance in a group of 43 women with morbid obesity, 28 non-morbidly obese, and 50 non-obese women matched for age. RESULTS: Morbidly obese women showed lower 25(OH) D concentrations compared to non-morbidly and non-obese women (37.9+/-16 vs 40.2+/-13 vs 56.7+/-21 nmol/l, p=0.001). Fifty-one percent of morbidly obese women had vitamin D deficiency [25(OH) D<38 nmol/l] compared to 22% of non-obese patients, (p=0.004). In the bivariate correlation analysis 25(OH) D was inversely associated with weight (r=-0.41, p=0.001), body mass index (BMI) (r=-0.432, p=0.001), waist to hip ratio (WHR)(r=-0.40, p=0.001), BF (r=-0.53, p=0001), fat mass (r=-0.44, p=0.0001), fat-free mass (r=-0.35, p=0.001). In the multivariate general linear model analysis, 25(OH) D was associated with season of examination (p=0.001) and was negatively associated with BF (beta=-0.75, p=0.001), after adjusting for age, BMI, and WHR. CONCLUSIONS: 25(OH) D concentrations are associated with body composition variables especially by BF, independently of seasonal variability. Therefore, body adiposity should be considered when assessing vitamin D requirements in obese patients.

Profile, mean residence time of ACTH and cortisol responses after low and standard ACTH tests in healthy volunteers.

OBJECTIVE: No consensus exists until now about the suitable dose of tetracosactin in the ACTH stimulation test for detecting adrenal insufficiency. Our aim was to characterize both the ACTH(1-24) and the cortisol profiles after standard high-dose test (250 microg) (HDT) and low-dose test (1 microg) (LDT) in healthy subjects in order to provide a deeper knowledge about the relationship between stimulus and response. DESIGN AND PATIENTS: ACTH tests were performed in 10 healthy volunteers (five men, five women) with at least 1 week of difference. MEASUREMENTS: Plasma ACTH(1-24) and ACTH(1-39) and serum cortisol were measured before tetracosactin i.v. injection and at 5, 15, 30, 45, 60, 75 and 90 min after stimulus. Area under the curve (AUC) of ACTH(1-24) and cortisol, as well as mean residence time (MRT) for ACTH(1-24) were calculated in both tests. RESULTS: Elimination of ACTH(1-24) was faster in HDT than in LDT (MRTs of 0.14 vs 0.37, respectively, P = 0.008), but plasma concentrations were higher up to 60 min cortisol production in HDT reaching a higher maximum concentration (Cmax: 1144 vs 960 nmol/l) but delayed in time (75 vs 52.5 min). No significant relationship was observed between AUC or Cmax of ACTH(1-24) and AUC, Cmax and increment of cortisol in any of the tests. However, a negative correlation of basal cortisol values was observed with relative cortisol increment (HDT: r = 0.77 P = 0.009; LDT: r = 0.94 P < 0.0001), but not so with Cmax (HDT: r = 0.22 P = 0.55; LDT: r = 0.57 P = 0.09). CONCLUSIONS: The elimination rate of ACTH in healthy volunteers was significantly lower in LDT than in HDT, but cortisol production rate appears to be identical in both tests, so that a maximum adrenal stimulation seems to exist. The use of LDT may be more adequate, although data from patients need studying.