Adherence to guidelines in patients with non-variceal upper gastrointestinal bleeding (UGIB) - results from a retrospective single tertiary center registry.

BACKGROUND: Guidelines for the management of upper gastrointestinal bleeding (UGIB) are regularly published, yet little is known concerning adherence to recommendations in practice. OBJECTIVES: We aimed to assess adherence to European Society of Gastrointestinal Endoscopy (ESGE) recommendations in patients with non-variceal UGIB. MATERIALS AND METHODS: All hospitalized patients with an esophagogastroduodenoscopy (EGD) performed due to suspected non-variceal UGIB at our department were included in a prospective registry. Data between 2018-2020 from this registry were retrospectively analyzed. Adherence to the 2015 ESGE bleeding and propofol sedation guidelines was assessed. Adherence to recommendations concerning preendoscopic (risk) evaluation, preendoscopic PPI, transfusion management, and endoscopic management of peptic ulcers was analyzed. RESULTS: Among 1005 patients (mean age 70.4 years, 42.1% women) the most common bleeding etiologies were gastric or duodenal ulcers (16.8%), esophagitis/GERD (11.1%), and angiodysplasia (9.9%); mortality was 7.6%. Adherence to preendosopic risk evaluation was low, in 0% a Mallampati classification and in 37.5% an ASA scoring was documented. Preendoscopic PPI was started at 58.6%, and adherence to recommended transfusion management was >98%. Peptic ulcers were Forrest-graded in 72.8%. High-risk ulcers were treated appropriately in 77.9% and low-risk ulcers were not treated in 73.6%. Especially Forrest Ib ulcers were undertreated, with an adherence of 59.6%. Only 22/179 (12.3%) patients with peptic ulcers and early endoscopy were consistently managed according to ESGE recommendations. CONCLUSIONS: Adherence to ESGE guidelines in patients with non-variceal UGIB is moderate to low, even at a tertiary university hospital. Strategies must be devised for guidelines to reach patients in everyday practice.

Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

BACKGROUND: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. OBJECTIVES: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. SEARCH METHODS: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. SELECTION CRITERIA: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. DATA COLLECTION AND ANALYSIS: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. MAIN RESULTS: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. AUTHORS' CONCLUSIONS: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

Glycated hemoglobin concentrations of red blood cells minimally increase during storage under standard blood banking conditions.

BACKGROUND: Few and inconsistent data exist describing the effect of storage duration on glycated hemoglobin (HbA1c) concentrations of red blood cells (RBCs), impeding interpretation of HbA1c values in transfused diabetic patients. Hence the aim of this study was to evaluate to what extent HbA1c concentrations of RBCs change during the maximum allowed storage period of 42 days. STUDY DESIGN AND METHODS: Blood was drawn from 16 volunteers, leukofiltered, and stored under standard blood banking conditions. HbA1c concentrations of RBCs were measured on Days 1 and 42 of storage using three different validated devices (ion-exchange high-performance liquid chromatography Method A1 and A2, turbidimetric immunoassay Method B). RESULTS: Mean HbA1c concentrations of RBCs on Day 1 were 5.3 ± 0.3% (Method A1), 5.4 ± 0.4% (Method A2), and 5.1 ± 0.4% (Method B). HbA1c concentrations increased to 5.6 ± 0.3% (A1, p < 0.0001), 5.7 ± 0.3% (A2, p = 0.004), and 5.5 ± 0.4% (B, p < 0.0001) on Day 42, respectively, corresponding to a 1.06-fold increase across all methods. Glucose concentrations in the storage solution of RBCs decreased from 495 ± 27 to 225 ± 55 mg/dL (p < 0.0001), confirming that stored RBCs were metabolically active. CONCLUSION: These results suggest a significant, albeit minor, and most likely clinically insignificant increase in HbA1c concentrations during storage of RBCs for 42 days.

The Twist of the Achilles Tendon - Associations of Torsions in the Lower Extremity.

Achilles tendinopathy and rupture of the Achilles tendon (AT) are frequent pathologies. Even though they may be associated with the twisted morphology of the AT, quantitative data on the extent of the twist of the entire AT are not available. The aim of this study was to investigate the torsion of the AT based on its individual parts and to evaluate a possible correlation with the torsion of the long bones of the lower extremity. Forty embalmed lower extremities were included in this study. The lateral deviation of the AT and its torsional angle as well as the angles of the individual parts in trans-section were measured. Thereafter, the torsions of femur and tibia were evaluated. Measuring the lateral deviation of the fibers resulted in an average torsion of the AT of 34.59° (SD 16.8°). The angles of the different parts of the AT in trans-section resulted in a median AT torsion of 15.73°, showing various patterns of rotations of the individual muscles. A statistically significant correlation between the torsions of the lower extremity and the AT (P =0.0242, r = 0.40) as well as a correlation between the femoral torsion and the AT torsion (P = 0.0127, r = 0.44) were found. This study adds to the morphological understanding of the torsion of the AT and its correlation with the torsions of the long bones of the lower extremity. Especially, the torsion of the femur seems to be connected to the torsion of the tendon. Clin. Anat. 31:1085-1091, 2018. © 2018 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.

Factors Affecting the Learning Curve in the Endoscopic Ultrasound-Guided Sampling of Solid Pancreatic Lesions: A Prospective Study.

Background/Aims: Endosonography is associated with a long learning curve. We aimed to assess variables that may influence the diagnostic outcomes in endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/B) of solid pancreatic tumors regarding the level of endoscopists' experience. Methods: Consecutive patients undergoing EUS-guided puncture of solid pancreatic tumors (eight endosonographers, including six trainees) were prospectively enrolled. An experienced endosonographer was defined as having performed at least 250 EUS examinations, including 75 FNA/Bs. The final diagnosis was determined by cytopathology, histopathology, or clinical follow-up. Results: In total, 283 EUS-FNA/Bs of solid pancreatic tumors (75.6% malignant) in 239 patients (median age 69 years, 57.6% males) were enrolled. Trainees performed 149/283 (52.7%) of the interventions. Accuracy and sensitivity for detecting malignancy were significantly higher in the expert group than in the trainee group (85.8% vs 73.2%, p=0.01 and 82.5% vs 68.4%, p=0.02). Solid lesions evaluated by an expert using FNB needles showed the best odds for a correct diagnosis (odds ratio, 3.07; 95% confidence interval, 1.15 to 8.23; p=0.02). More experienced endoscopists achieved better accuracy in sampling via the transduodenal approach (86.7% vs 68.5%, p<0.001), in the sampling of malignant lesions (82.5 vs 68.4, p=0.02), and in the sampling of lesions located in the pancreatic head (86.1 vs 69.1, p=0.02). In cases involving these factors, we observed a moderate improvement in the diagnostic accuracy after 40 attempts. Conclusions: Transduodenal approach, pancreatic head lesions, and malignancy were recognized as the most important clinical factors affecting the learning curve in EUS-FNA/B of solid pancreatic lesions.

Kidney biopsy in patients with glomerulonephritis: is the earlier the better?

BACKGROUND: Interventional diagnostic procedures are established for several diseases in medicine. Despite the KDOQI guideline recommendation for histological diagnosis of kidney disease to enable risk stratification, its optimal time point has not been evaluated. We have therefore analyzed whether histological diagnosis of glomerulonephritis (GN) at an early stage of chronic kidney disease (CKD) is associated with different outcome compared to diagnosis at a more advanced stage. METHODS: A cohort of 424 consecutive patients with histological diagnosis of GN were included in a retrospective data analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy and after consecutive immunosuppressive therapy. Censored events were death, initiation of dialysis or kidney transplantation, or progression of disease, defined as deterioration of CKD stage ≥ 1 from kidney biopsy to last available kidney function measurement. RESULTS: Occurrence of death, dialysis/transplantation or progression of disease were associated with GFR and CKD stage at the time of kidney biopsy (p < 0.001 for all). Patients with CKD stage 1 and 2 at kidney biopsy had fewer endpoints compared to patients with a GFR of <60 ml/min (p < 0.001). CONCLUSION: Kidney function at the time point of histological GN diagnosis is associated with clinical outcome, likely due to early initiation of specific drug treatment. This suggests that selection of therapy yields greatest benefit before renal function is impaired in GN.

Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models.

The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 µg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator.

A brief, high-dose remifentanil infusion partially reverses neuropathic pain in a subgroup of post herpetic neuralgia patients.

Mechanism-based therapy for chronic pain is desperately needed. Recent basic science research demonstrated that remifentanil can reverse long-term potentiation at C-fiber synapses in the dorsal horn of rats. In this exploratory, single group study, patients with chronic post-herpetic pain were treated with a single, one-hour, high-dose remifentanil infusion. The mean overall change of pain intensity seven days after treatment was -18 (-7.5; -28.5, 95%CI, p<0.001) points on the numeric rating scale (0-100) (-33 (±11) points amongst responders only). Eleven of 20 patients responded to treatment (≥30% reduction in pain), the mean relative reduction in pain from baseline amongst responders was 61.0%. These promising preliminary results suggest that a mechanism-based reversal of chronic pain may be impending.

Rovsing sign revisited-effects of an erroneous translation on medical teaching and research.

OBJECTIVE: To investigate whether Rovsing sign in the diagnosis of appendicitis is described and applied inaccurately in the current literature, scientific papers, and books; quantify the problem; and investigate the cause of this error. BACKGROUND: The method of eliciting Rovsing sign is not described uniformly throughout the literature. METHODS: PubMed, MEDLINE, and Embase searches were conducted, and 1178 individual studies were searched for the use of Rovsing sign. A total of 57 studies were included in this study; of these, 14 described the way that the sign was executed. Additionally, 3 current English (text)books on surgery, 3 German (text)books on surgery, and 3 German books on anatomy were analyzed. The descriptions in studies and books were compared with the original publication by Niels Thorkild Rovsing in 1907. RESULTS: No included study that described the method of eliciting Rovsing sign provided a correct description. None of the 3 English (text)books on surgery described the sign accurately, but all 6 German (text)books provided a correct description. CONCLUSION: Rovsing sign is used erroneously in clinical practice and medical research and is most likely already taught incorrectly to most medical students. All statistical data available on this sign must be questioned and reinvestigated in future well-designed studies to assess the actual value of Rovsing sign in the diagnosis of appendicitis.