Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40 , 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51 , 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.     

Performance of turbo high-pitch dual-source CT for coronary CT angiography: first ex vivo and patient experience

Objectives

To evaluate image quality, maximal heart rate allowing for diagnostic imaging, and radiation dose of turbo high-pitch dual-source coronary computed tomographic angiography (CCTA).

Methods

First, a cardiac motion phantom simulating heart rates (HRs) from 60-90 bpm in 5-bpm steps was examined on a third-generation dual-source 192-slice CT (prospective ECG-triggering, pitch 3.2; rotation time, 250 ms). Subjective image quality regarding the presence of motion artefacts was interpreted by two readers on a four-point scale (1, excellent; 4, non-diagnostic). Objective image quality was assessed by calculating distortion vectors. Thereafter, 20 consecutive patients (median, 50 years) undergoing clinically indicated CCTA were included.

Results

In the phantom study, image quality was rated diagnostic up to the HR75 bpm, with object distortion being 1 mm or less. Distortion increased above 1 mm at HR of 80-90 bpm. Patients had a mean HR of 66 bpm (47-78 bpm). Coronary segments were of diagnostic image quality for all patients with HR up to 73 bpm. Average effective radiation dose in patients was 0.6?±?0.3 mSv.

Conclusions

Our combined phantom and patient study indicates that CCTA with turbo high-pitch third-generation dual-source 192-slice CT can be performed at HR up to 75 bpm while maintaining diagnostic image quality, being associated with an average radiation dose of 0.6 mSv.

Key points

? CCTA is feasible with the turbo high-pitch mode. ? Turbo high-pitch CCTA provides diagnostic image quality up to 73 bpm. ? The radiation dose of high-pitch CCTA is 0.6 mSv on average.     

Combining automated attenuation-based tube voltage selection and iterative reconstruction: a liver phantom study

Objectives

To determine the value of combined automated attenuation-based tube-potential selection and iterative reconstructions (IRs) for optimising computed tomography (CT) imaging of hypodense liver lesions.

Methods

A liver phantom containing hypodense lesions was imaged by CT with and without automated attenuation-based tube-potential selection (80, 100 and 120 kVp). Acquisitions were reconstructed with filtered back projection (FBP) and sinogram-affirmed IR. Image noise and contrast-to-noise ratio (CNR) were measured. Two readers marked lesion localisation and rated confidence, sharpness, noise and image quality on a five-point scale (1 = worst, 5 = best).

Results

Image noise was lower (31–52 %) and CNR higher (43–102 %) on IR than on FBP images at all tube voltages. On 100-kVp and 80-kVp IR images, confidence and sharpness were higher than on 120-kVp FBP images. Scores for image quality score and noise as well as sensitivity for 100-kVp IR were similar or higher than for 120-kVp FBP and lower for 80-kVp IR. Radiation dose was reduced by 26 % at 100 kVp and 56 % at 80 kVp.

Conclusions

Compared with 120-kVp FBP images, the combination of automated attenuation-based tube-potential selection at 100 kVp and IR provides higher image quality and improved sensitivity for detecting hypodense liver lesions in vitro at a dose reduced by 26 %.

Key Points

? Combining automated tube voltage selection/iterative CT reconstruction improves image quality. ? Attenuation values remain stable on IR compared with FBP images. ? Lesion detection was highest on 100-kVp IR images.     

Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion

BACKGROUND: Ischemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage. METHODS: We examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later. RESULTS: An increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery. CONCLUSION: Repertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans.     

Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generating regulatory T cells

BACKGROUND: It was suggested that maintenance of tolerance to organ transplantation may depend on the formation of T regulatory cells. METHODS: Lewis (LW) rats were made tolerant to a Brown Norway kidney by pretransplant donor peripheral blood mononuclear cells (PBMC) infusion. At greater than 90 days after transplantation, lymph node cells (LN) and graft-infiltrating leukocytes (GIL) alloreactivity was tested in mixed lymphocyte reaction (MLR), coculture, and transwell experiments. GIL phenotype was analyzed by FACS. mRNA expression of cytokines and other markers was analyzed on CD4+ T cells from LN. The tolerogenic potential of tolerant cells in vivo was evaluated by adoptive transfer. RESULTS: Tolerant LN cells showed a reduced proliferation against donor stimulators but a normal anti-third-party alloreactivity. In coculture, these cells inhibited antidonor but not antithird-party reactivity of na?ve LN cells. Interleukin (IL)-10 and FasL mRNA expression was up-regulated in tolerant CD4+ T cells, but an anti-IL-10 monoclonal antibody (mAb) only partially reversed their inhibitory effect. Immunoregulatory activity was concentrated in the CD4+ CD25+ T-cell subset. In a transwell system, tolerant T cells inhibited a na?ve MLR to a lesser extent than in a standard coculture. Regulatory cells transferred tolerance after infusion into na?ve LW recipients. CD4+ T cells isolated from tolerized grafts were hyporesponsive to donor stimulators and suppressed a na?ve MLR against donor antigens. CONCLUSIONS: Donor-specific regulatory T cells play a role in tolerance induction by donor PBMC infusion. Regulatory activity is concentrated in the CD4+ CD25+ subset and requires cell-to-cell contact. Regulatory CD4+ T cells accumulate in tolerized kidney grafts where they could exert a protective function against host immune response.     

Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1

The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.     

Predictors of Excess Weight Loss in Obese Patients After Gastric Bypass: a 60-Month Follow-up

Background

The objective of this study was to analyze the factors associated with change in body mass index (BMI) and with percentage of excess weight loss (%EWL) in patients undergoing Roux-en-Y gastric bypass (RYGB). The following factors were analyzed: sex, age, surgical access (laparotomy vs. laparoscopy), preoperative BMI, waist circumference (WC), type 2 diabetes mellitus (T2DM), high blood pressure, and dyslipidemia.

Methods

Retrospective cohort study using a convenience sample of 2070 patients of both sexes, aged 18 to 65 years, undergoing RYGB between 2000 and 2013. The outcomes of interest were BMI and %EWL at 0, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after RYGB.

Results

After 36, 48, and 60 months, approximately 50 % of patients had BMI >30 kg/m². As for %EWL, 60-month results were poor for 17 % of patients (%EWL <50 %), good for 40 % of patients (%EWL 50–75 %), very good for 24 % of patients (%EWL from >75–90 %), and excellent for 19 % of patients (%EWL >90 %). The four most significant predictors of BMI change 60 months after RYGB (in descending order of magnitude) were preoperative BMI, preoperative WC, surgical access, and age; and of %EWL, surgical access, preoperative BMI, preoperative WC, and age.

Conclusions

After 60 months of follow-up, the most relevant predictors of weight loss after RYGB were lower preoperative BMI and WC, videolaparoscopy as surgical access, and younger age. Further studies must be carried out to elucidate the impact of these factors on RYGB outcomes.

     

Hemostatic Step-by-Step Procedure to Control Presacral Bleeding During Laparoscopic Total Mesorectal Excision

Background  A new procedure of hemostasis during laparoscopic total mesorectal excision is described. Methods  In our surgical department, from January 2004 to December 2007, 128 patients underwent laparoscopic total mesorectal excision. Among them, 47 patients underwent laparoscopic anterior resection after preoperative radiotherapy, 68 patients underwent laparoscopic anterior resection without preoperative radiotherapy, and 13 patients underwent laparoscopic abdominal perineal amputation. Results  In seven laparoscopic rectal surgery cases, we encountered unstoppable presacral bleeding, not amenable by conventional hemostatic solutions. In these cases we applied a simple staging hemostatic procedure. We first performed local compression: tamponing with a small gauze or absorbable fabric hemostat. If bleeding did not stop, we localized an epiploic or omental scrap and excised it by using bipolar forceps and use it as a plug on the tip of a grasping forceps. This plug is then put on the bleeding source and monopolar coagulation is applied by electrified dissecting forceps through the interposed grasping forceps. If bleeding did not stop, we used a little scrap of bovine pericardium graft and tacked it to the bleeding site using endoscopic helicoidal protack. Conclusions  Our experience suggests that this hemostatic step-by-step procedure is a valid option to control persistent presacral hemorrhages.     

Palliative operation for the treatment of alveolar echinococcosis

Background  The World Health Organization guidelines recommend radical hepatic resection for definite treatment of alveolar echinococcosis (AE), because it can cure the patient. However, parasitic masses are not entirely removable in about 70% of patients. Even so, palliative resections are carried out, although cure cannot be achieved. As conservative treatment has improved, the role of palliative surgical procedures has to be redefined. Methods  Critical appraisal of published reports on palliative resections for AE and estimation of the level of evidence and grade of recommendation. Results  Prospective randomized trials comparing palliative resections, radical resections, and conservative treatment are lacking. Most papers analyzed case series retrospectively. The number of palliative operations is significant. In the past, palliative resections were recommended in order to enhance anthelminthic drug efficacy but advances in conservative and interventional treatment improved the prognosis of AE. Prolonged survival by systematic palliative resections is not evident. However, palliative surgery is an option to treat persistent bacterial infection, fistulas, and obstructing or compressing masses. The indication is based on individual considerations and decisions. Conclusion  Curative surgery for AE is feasible if parasitic tissue is entirely removable. The benefit of palliative resections is uncertain because long-term results of conservative treatment are favorable. Palliative surgery is an option for complications not being manageable otherwise. Study aim Evaluation of the role of palliative operation for AE.     

Major osteoporotic fragility fractures: Risk factor updates and societal impact

Osteoporosis is a silent disease without any evidence of disease until a fracture occurs. Approximately 200 million people in the world are affected by osteoporosis and 8.9 million fractures occur each year worldwide. Fractures of the hip are a major public health burden, by means of both social cost and health condition of the elderly because these fractures are one of the main causes of morbidity, impairment, decreased quality of life and mortality in women and men. The aim of this review is to analyze the most important factors related to the enormous impact of osteoporotic fractures on population. Among the most common risk factors, low body mass index; history of fragility fracture, environmental risk, early menopause, smoking, lack of vitamin D, endocrine disorders(for example insulin-dependent diabetes mellitus), use of glucocorticoids, excessive alcohol intake, immobility and others represented the main clinical risk factors associated with augmented risk of fragility fracture. The increasing trend of osteoporosis is accompanied by an underutilization of the available preventive strategies and only a small number of patients at high fracture risk are recognized and successively referred for therapy. This report provides analytic evidences to assess the best practices in osteoporosis management and indications for the adoption of a correct healthcare strategy to significantly reduce the osteoporosis burden. Early diagnosis is the key to resize the impact of osteoporosis on healthcare system. In this context, attention must be focused on the identification of high fracture risk among osteoporotic patients. It is necessary to increase national awareness campaigns across countries in order to reduce the osteoporotic fractures incidence.