Tag: nevin manimala

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 May;35(5):458-462. doi: 10.3760/cma.j.cn121430-20221104-00966.

ABSTRACT

OBJECTIVE: To explore the predictive value of serum sodium variability within 72 hours, lactic acid (Lac), sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE II) in predicting the 28-day prognosis of sepsis patients.

METHODS: The clinical data of patients with sepsis admitted to the department of intensive care unit (ICU) of the Affiliated Qingdao Municipal Hospital of Qingdao University from December 2020 to December 2021 were retrospectively analyzed, including age, gender, previous medical history, temperature, heart rate, respiratory rate, systolic pressure, diastolic pressure, white blood cell count (WBC), hemoglobin (Hb), platelet count (PLT), C-reactive protein (CRP), pH value, arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂), Lac, prothrombin time (PT), activated partial thromboplastin time (APTT), serum creatinine (SCr), total bilirubin (TBil), albumin (Alb), SOFA, APACHE II score, and 28-day prognosis. Multivariate Logistic regression was used to analyze the risk factors of death in sepsis patients. Receiver operator characteristic curve (ROC curve) was used to analyze the predictive value of serum sodium variability within 72 hours, Lac, SOFA, APACHE II alone and in combination on the prognosis of patients with sepsis.

RESULTS: A total of 135 patients with sepsis were included, 73 survived and 62 died at 28 days, with 28-day mortality of 45.93%. (1) Compared with the survival group, SOFA, APACHE II, Lac and serum sodium variability within 72 hours in the death group were significantly higher [SOFA: 10.00 (8.00, 12.00) vs. 6.00 (5.00, 8.00), APACHE II: 18.00 (16.00, 21.25) vs. 13.00 (11.00, 15.00), Lac (mmol/L): 3.55 (2.90, 4.60) vs. 2.00 (1.30, 2.80), serum sodium variability within 72 hours: 3.4% (2.6%, 4.2%) vs. 1.4% (1.1%, 2.5%)], the differences were statistically significant (all P < 0.01). (2) Multivariate Logistic regression showed that SOFA, APACHE II, Lac, serum sodium variability within 72 hours were independent risk factors of prognosis in patients with sepsis [SOFA: odds ratio (OR) = 1.479, 95% confidence interval (95%CI) was 1.114-1.963, P = 0.007; APACHE II: OR = 1.163, 95%CI was 1.009-1.340, P = 0.037; Lac: OR = 1.387, 95%CI was 1.014-1.896, P = 0.040; serum sodium variability within 72 hours: OR = 1.634, 95%CI was 1.102-2.423, P = 0.015]. (3) ROC curve analysis showed that SOFA, APACHE II, Lac and serum sodium variability within 72 hours had certain predictive value for the prognosis of sepsis patients [SOFA: the area under the ROC curve (AUC) = 0.858, 95%CI was 0.795-0.920, P = 0.000; APACHE II: AUC = 0.845, 95%CI was 0.776-0.913, P = 0.000; Lac: AUC = 0.840, 95%CI was 0.770-0.909, P = 0.000; serum sodium variability within 72 hours: AUC = 0.842, 95%CI was 0.774-0.910, P = 0.000]. The combined predictive value of the four indicators (AUC = 0.917, 95%CI was 0.870-0.965, P = 0.000) was higher than that of any single indicator, and has higher specificity (79.5%) and sensitivity (93.5%), indicating that the combined index has higher predictive value for the prognosis of sepsis patients than any single index.

CONCLUSIONS: SOFA, APACHE II, Lac, serum sodium variability within 72 hours are independent risk factors for 28-day death in patients with sepsis. The combination of SOFA score, APACHE II score, Lac and serum sodium variability within 72 hours has higher predictive value for prognosis than single index.

PMID:37308223 | DOI:10.3760/cma.j.cn121430-20221104-00966

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Apr;35(4):381-386. doi: 10.3760/cma.j.cn121430-20220817-00758.

ABSTRACT

OBJECTIVE: To investigate the effects of gene of phosphate and tension homology (PTEN)-induced putative kinase 1 (PINK1)/Parkin pathway on hippocampal mitophagy and cognitive function in mice with sepsis-associated encephalopathy (SAE) and its possible mechanism.

METHODS: A total of 80 male C57BL/6J mice were randomly divided into Sham group, cecal ligation puncture (CLP) group, PINK1 plasmid transfection pretreatment groups (p-PINK1+Sham group, p-PINK1+CLP group), empty vector plasmid transfection control group (p-vector+CLP group), with 16 mice in each group. The mice in CLP groups were treated with CLP to reproduce SAE models. The mice in the Sham groups were performed laparotomy only. Animals in the p-PINK1+Sham and p-PINK1+CLP groups were transfected with PINK1 plasmid through the lateral ventricle at 24 hours before surgery, while mice in the p-vector+CLP group were transfected with the empty plasmid. Morris water maze experiment was performed 7 days after CLP. The hippocampal tissues were collected, the pathological changes were observed under a light microscope after hematoxylin-eosin (HE) staining, and the mitochondrial autophagy was observed under a transmission electron microscopy after uranyl acetate and lead citrate staining. The expressions of PINK1, Parkin, Beclin1, interleukins (IL-6, IL-1β) and microtubule-associated protein 1 light chain 3 (LC3) were detected by Western blotting.

RESULTS: Compared with the Sham group, CLP group mice in Morris water maze experiment had longer escape latency, shorter target quadrant residence time, and fewer times of crossing the platform at 1-4 days. Under the light microscope, the hippocampal structure of the mouse was injured, the neuronal cells were arranged in disorder, and the nuclei were pyknotic. Under the electron microscope, the mitochondria appeared swollen, round, and wrapped by bilayer or multilayer membrane structures. Compared with the Sham group, CLP group had higher expressions of PINK1, Parkin, Beclin1, LC3II/LC3I ratio, IL-6 and IL-1β in hippocampus, indicating that sepsis induced by CLP could activated inflammatory response and caused PINK1/Parkin-mediated mitophagy. Compared with the CLP group, p-PINK1+CLP group had shorter escape latencies, spent more time in the target quadrant and had more number of crossings in the target quadrant at 1-4 days. Under the light microscope, the hippocampal structures of mice was destroyed, the neurons were arranged disorderly, and the nuclei were pyknotic. Under transmission electron microscope, swollen and rounded mitochondria and mitochondrial structure wrapped by double membrane or multilayer membrane structure were observed. Compared with the CLP group, the levels of PINK1, Parkin, Beclin1 and LC3II/LC3 ratio in the p-PINK1+CLP group were significantly increased [PINK1 protein (PINK1/β-actin): 1.95±0.17 vs. 1.74±0.15, Parkin protein (Parkin/β-actin): 2.06±0.11 vs. 1.78±0.12, Beclin1 protein (Beclin1/β-actin): 2.11±0.12 vs. 1.67±0.10, LC3II/LC3I ratio: 3.63±0.12 vs. 2.27±0.10, all P < 0.05], while the levels of IL-6 and IL-1β were significantly decreased [IL-6 protein (IL-6/β-actin): 1.69±0.09 vs. 2.00±0.11, IL-1β protein (IL-1β/β-actin): 1.11±0.12 vs. 1.65±0.12, both P < 0.05], suggesting that overexpression of PINK1 protein could further activate mitophagy and reduce the inflammatory response caused by sepsis. There was no statistically significant difference in the above pathological changes and related indicators between Sham group and p-PINK1+Sham group, CLP group and p-vector+CLP group.

CONCLUSIONS: PINK1 overexpression can further activate CLP-induced mitophagy by upregulating Parkin, thereby inhibiting inflammation response and alleviate cognitive function impairment in SAE mice.

PMID:37308193 | DOI:10.3760/cma.j.cn121430-20220817-00758

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Apr;35(4):371-375. doi: 10.3760/cma.j.cn121430-20220525-00512.

ABSTRACT

OBJECTIVE: To establish a predictive model for severe swallowing disorder after acute ischemic stroke based on nomogram model, and evaluate its effectiveness.

METHODS: A prospective study was conducted. The patients with acute ischemic stroke admitted to Mianyang Central Hospital from October 2018 to October 2021 were enrolled. Patients were divided into severe swallowing disorder group and non-severe swallowing disorder group according to whether severe swallowing disorder occurred within 72 hours after admission. The differences in general information, personal history, past medical history, and clinical characteristics of patients between the two groups were compared. The risk factors of severe swallowing disorder were analyzed by multivariate Logistic regression analysis, and the relevant nomogram model was established. The bootstrap method was used to perform self-sampling internal validation on the model, and consistency index, calibration curve, receiver operator characteristic curve (ROC curve), and decision curve were used to evaluate the predictive performance of the model.

RESULTS: A total of 264 patients with acute ischemic stroke were enrolled, and the incidence of severe swallowing disorder within 72 hours after admission was 19.3% (51/264). Compared with the non-severe swallowing disorder group, the severe swallowing disorder group had a higher proportion of patients aged of ≥ 60 years old, with severe neurological deficits [National Institutes of Health stroke scale (NIHSS) score ≥ 7], severe functional impairments [Barthel index, an activity of daily living functional status assessment index, < 40], brainstem infarction and lesions ≥ 40 mm (78.43% vs. 56.81%, 52.94% vs. 28.64%, 39.22% vs. 12.21%, 31.37% vs. 13.62%, 54.90% vs. 24.41%), and the differences were statistically significant (all P < 0.01). Multivariate Logistic regression analysis showed that age ≥ 60 years old [odds ratio (OR) = 3.542, 95% confidence interval (95%CI) was 1.527-8.215], NIHSS score ≥ 7 (OR = 2.741, 95%CI was 1.337-5.619), Barthel index < 40 (OR = 4.517, 95%CI was 2.013-10.136), brain stem infarction (OR = 2.498, 95%CI was 1.078-5.790) and lesion ≥ 40 mm (OR = 2.283, 95%CI was 1.485-3.508) were independent risk factors for severe swallowing disorder after acute ischemic stroke (all P < 0.05). The results of model validation showed that the consistency index was 0.805, and the trend of the calibration curve was basically consistent with the ideal curve, indicating that the model had good prediction accuracy. ROC curve analysis showed that the area under the ROC curve (AUC) predicted by nomogram model for severe swallowing disorder after acute ischemic stroke was 0.817 (95%CI was 0.788-0.852), indicating that the model had good discrimination. The decision curve showed that within the range of 5% to 90%, the nomogram model had a higher net benefit value for predicting the risk of severe swallowing disorder after acute ischemic stroke, indicating that the model had good clinical predictive performance.

CONCLUSIONS: The independent risk factors of severe swallowing disorder after acute ischemic stroke include age ≥ 60 years old, NIHSS score ≥ 7, Barthel index < 40, brainstem infarction and lesion size ≥ 40 mm. The nomogram model established based on these factors can effectively predict the occurrence of severe swallowing disorder after acute ischemic stroke.

PMID:37308191 | DOI:10.3760/cma.j.cn121430-20220525-00512

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Apr;35(4):358-361. doi: 10.3760/cma.j.cn121430-20220311-00236.

ABSTRACT

OBJECTIVE: To investigate the effect of different fraction of inspired oxygen (FiO₂) baseline levels before endotracheal intubation on the time of expiratory oxygen concentration (EtO₂) reaching the standard in emergency patients with the EtO₂ as the monitoring index.

METHODS: A retrospective observational study was conducted. The clinical data of patients receiving endotracheal intubation in the emergency department of Peking Union Medical College Hospital from January 1 to November 1 in 2021 were enrolled. In order to avoid interference with the final result due to inadequate ventilation caused by non-standard operation or air leakage, the process of the continuous mechanical ventilation after FiO₂ was adjusted to pure oxygen in patients who had been intubated was selected to simulate the process of mask ventilation under pure oxygen before intubation. Combined with the electronic medical record and the ventilator record, the changes of the time required to reach 0.90 of EtO₂ (that was, the time required to reach the standard of EtO₂) and the respiratory cycle required to reach the standard after adjusting FiO₂ to pure oxygen under different baseline levels of FiO₂ were analyzed.

RESULTS: 113 EtO₂ assay records were collected from 42 patients. Among them, 2 patients had only one EtO₂ record due to the FiO₂ baseline level of 0.80, while the rest had two or more records of EtO₂ reaching time and respiratory cycle corresponding to different FiO₂ baseline level. Among the 42 patients, most of them were male (59.5%), elderly [median age was 62 (40, 70) years old] patients with respiratory diseases (40.5%). There were significant differences in lung function among different patients, but the majority of patients with normal function [oxygenation index (PaO₂/FiO₂) > 300 mmHg (1 mmHg ≈ 0.133 kPa), 38.0%]. In the setting of ventilator parameters, combined with the slightly lower arterial partial pressure of carbon dioxide of patients [33 (28, 37) mmHg], mild hyperventilation phenomenon was considered to be widespread. With the increased in FiO₂ baseline level, the time of EtO₂ reaching standard and the number of respiratory cycles showed a gradually decreasing trend. When the FiO₂ baseline level was 0.35, the time of EtO₂ reaching the standard was the longest [79 (52, 87) s], and the corresponding median respiratory cycle was 22 (16, 26) cycles. When the FiO₂ baseline level was increased from 0.35 to 0.80, the median time of EtO₂ reaching the standard was shortened from 79 (52, 78) s to 30 (21, 44) s, and the median respiratory cycle was also reduced from 22 (16, 26) cycles to 10 (8, 13) cycles, with statistically significant differences (both P < 0.05).

CONCLUSIONS: The higher the FiO₂ baseline level of the mask ventilation in front of the endotracheal intubation in emergency patients, the shorter the time for EtO₂ reaching the standard, and the shorter the mask ventilation time.

PMID:37308188 | DOI:10.3760/cma.j.cn121430-20220311-00236

Pediatr Emerg Care. 2023 Jun 12. doi: 10.1097/PEC.0000000000002988. Online ahead of print.

ABSTRACT

OBJECTIVES: Performing pediatric otoscopy can be difficult secondary to patient compliance, which potentiates misdiagnosis and inaccurate treatment of acute otitis media. This study used a convenience sample to assess the feasibility of using a video otoscope for the examination of tympanic membranes in children presenting to a pediatric emergency department.

METHODS: We obtained otoscopic videos using the JEDMED Horus + HD Video Otoscope. Participants were randomized to video or standard otoscopy, and a physician completed their bilateral ear examinations. In the video group, physicians reviewed otoscope videos with the patient’s caregiver. The caregiver and physician completed separate surveys using a 5-point Likert Scale regarding perceptions of the otoscopic examination. A second physician reviewed each otoscopic video.

RESULTS: We enrolled 213 participants in 2 groups (standard otoscopy, n = 94; video otoscopy, n = 119). We used Wilcoxon rank sum, Fisher exact test, and descriptive statistics to compare results across groups. For physicians, there were no statistically significant differences between groups with ease of device use, quality of otoscopic view, or diagnosis. There was moderate agreement between physician video otoscopic view satisfaction and slight agreement between physician video otologic diagnosis. Estimates of length of time to complete the ear examinations were longer more often for the video otoscope compared with standard for both caregivers (OR, 2.00; 95% confidence interval, 1.10-3.70; P = 0.02) and physicians (OR, 3.08; 95% confidence interval, 1.67-5.78; P < 0.01). There were no statistically significant differences between video and standard otoscopy with regard to caregiver perception of comfort, cooperation, satisfaction, or diagnosis understanding.

CONCLUSIONS: Caregivers perceive that video otoscopy and standard otoscopy are comparable in comfort, cooperation, examination satisfaction, and diagnosis understanding. Physicians made a wider range of more subtle diagnoses with the video otoscope. However, examination length of time may limit the JEDMED Horus + HD Video Otoscope’s feasibility in a busy pediatric emergency department.

PMID:37308169 | DOI:10.1097/PEC.0000000000002988

Pediatr Emerg Care. 2023 Jun 12. doi: 10.1097/PEC.0000000000002972. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Trauma is the leading cause of death in children. Several trauma severity scores exist: the shock index (SI), age-adjusted SI (SIPA), reverse SI (rSI), and rSI multiplied by Glasgow Coma Score (rSIG). However, it is unknown which is the best predictor of clinical outcomes in children. Our goal was to determine the association between trauma severity scores and mortality in pediatric trauma.

DESIGN AND METHODS: A multicenter retrospective study was performed using the 2015 US National Trauma Data Bank, including patients 1 to 18 years old and excluding patients with unknown emergency department dispositions. The scores were calculated using initial emergency department parameters. Descriptive analysis was carried out. Variables were stratified by outcome (hospital mortality). Then, for each trauma score, a multivariate logistic regression was conducted to determine its association with mortality.

RESULTS: A total of 67,098 patients with a mean age of 11 ±5 years were included. Majority of the patients were male (66%) and had an injury severity score <15 (87%). Eighty-four percent of patients were admitted: 15% to the intensive care unit and 17% directly to the operating room. The mortality at hospital discharge was 3%.There was a statistically significant association between SI, rSI, rSIG, and mortality (P < 0.05). The highest adjusted odds ratio for mortality corresponded to rSIG, followed by rSI then SI (8.51, 1.9, and 1.3, respectively).

CONCLUSION: Several trauma scores may help predict mortality in children with trauma, the best being rSIG. Introduction of these scores in algorithms for pediatric trauma evaluations can impact clinical decision-making.

PMID:37308163 | DOI:10.1097/PEC.0000000000002972

Int J Sports Physiol Perform. 2023 Jun 12:1-7. doi: 10.1123/ijspp.2022-0460. Online ahead of print.

ABSTRACT

PURPOSE: This study aimed to examine the effect of a 6-day basketball tournament on the physical demands, perceptual-physiological responses, well-being, and game statistics of elite under-18 (years of age) players.

METHODS: Physical demands (player load [PL], steps, impacts, and jumps, all normalized by playing time), perceptual-physiological responses (heart rate and rating of perceived exertion), well-being (Hooper index), and game statistics of 12 basketball players were monitored during 6 consecutive games. Linear mixed models and Cohen d effect sizes were used to assess differences among games.

RESULTS: Significant changes were found for PL per minute, steps per minute, impacts per minute, peak heart rate, and Hooper index over the tournament. Pairwise comparisons showed that PL per minute was higher in game #1 than in games #4 (P = .011, large), #5 (P < .001, very large), and #6 (P < .001, very large). PL per minute recorded during game #5 was also lower than in games #2 (P = .041, large) and #3 (P = .035, large). The number of steps per minute was higher in game #1 than in all other games (all P < .05, large to very large). Impacts per minute were significantly higher in game #3 than in games #1 (P = .035, large) and #2 (P = .004, large). The only physiological variable that varied significantly was peak heart rate (higher in game #3 than in game #6; P = .025, large). The Hooper index gradually increased throughout the tournament, indicating poorer player well-being as the tournament advanced. Game statistics did not significantly change among games.

CONCLUSIONS: The average intensities of each game and the players’ well-being gradually decreased throughout the tournament. Conversely, physiological responses were mostly unaffected, and game statistics were unaffected.

PMID:37308139 | DOI:10.1123/ijspp.2022-0460

Semin Thromb Hemost. 2023 Jun 12. doi: 10.1055/s-0043-1769510. Online ahead of print.

ABSTRACT

The release of extracellular traps by neutrophils (NETs) represents a novel active mechanism of cell death that has been recently implicated in the pathogenesis of thrombotic disorders. The aim of this study was to investigate the generation of NETs in different groups of patients with acute thrombotic events (ATEs) and to establish whether NETs markers can predict the risk of new cardiovascular events. We performed a case-control study of patients with ATE, including acute coronary syndrome (n = 60), cerebrovascular accident (n = 50), and venous thromboembolism (n = 55). Control subjects (n = 70) were identified among patients admitted for acute chest pain and in which a diagnosis of ATE was excluded. Serum levels of NET markers and neutrophil activation, such as myeloperoxidase (MPO)-DNA complexes, neutrophil gelatinase-associated lipocalin, polymorphonuclear neutrophil elastase, lactoferrin, and MPO, were measured in each patient. We found that circulating levels of MPO-DNA complexes were significantly increased in patients with ATE (p < 0.001) compared with controls and that this association remained significant even after fully adjustment for traditional risk factors (p = 0.001). A receiver operating characteristics analysis of circulating MPO-DNA complexes in discriminating between controls and patients with ATE showed a significant area under the curve of 0.76 (95% confidence interval: 0.69-0.82). After a median follow-up of 40.7 (± 13.8) months, 24 out of the 165 patients with ATE presented a new cardiovascular event and 18 patients died. None of the markers under investigation influenced survival or the incidence of new cardiovascular events. In conclusion, we found that increase of markers of NETosis can be observed in acute thrombotic conditions, occurring both on the arterial and venous site. Nevertheless, the level of neutrophil markers measured during the ATE is not predictive of future risk of mortality and cardiovascular events.

PMID:37308098 | DOI:10.1055/s-0043-1769510

J Oral Maxillofac Surg. 2023 May 27:S0278-2391(23)00470-6. doi: 10.1016/j.joms.2023.05.009. Online ahead of print.

ABSTRACT

BACKGROUND: An edema assessment following dental surgeries is essential to improving the dental surgeon’s technique and, consequentially, patient comfort.

PURPOSE: Two-dimensional (2D) methods are limited in analyzing 3-dimensional (3D) surfaces. Currently, 3D methods are used to investigate postoperative swelling. However, there are no studies that directly compare 2D and 3D methods. The goal of this study is to directly compare 2D and 3D methods used in the assessment of postoperative edema.

STUDY DESIGN AND SAMPLE: The investigators implemented a prospective, cross-sectional study with each subject serving as its own control. The sample was composed of dental student volunteers without facial deformities.

PREDICTOR VARIABLE: The predictor variable is the method used to measure edema. After simulating edema, manual (2D) and digital (3D) techniques were used to measure edema. The manual method used direct facial perimeter measurements. The two digital methods were photogrammetry using a smartphone (iPhone 11, Apple Inc, Cupertino, California), and facial scanning with a smartphone application (Bellus3D FaceApp, Bellus3D Inc, Campbell, California) [3D measurements] MAIN OUTCOME VARIABLE: The coefficient of variation (CV) (CV = standard deviation /mean) was used to assess homogeneity of edema measurements.

ANALYSIS: The Shapiro-Wilk and equal variance tests were applied to assess data homogeneity. Next, one-way analysis of variance was performed, followed by a correlation analysis. Finally, the data were submitted to Tukey’s test. The statistical significance threshold was set at 5% (P < .05).

RESULTS: The sample was composed of 20 subjects aged 18-38 years. The CV showed higher values using the manual (2D) method (47%; 4.88% ± 2.99), compared with the photogrammetry method (18%; 8.55 mm ± 1.52) and the smartphone application (21%; 8.97 mm ± 1.93). A statistically significant difference was observed between the manual method values and those of the other two groups (P < .001). There was no difference between the facial scanning and photogrammetry groups (3D methods) (P = .778) CONCLUSION AND RELEVANCE: Both digital measuring methods (3D) demonstrated greater homogeneity in analyzing facial distortions caused by the same swelling simulation. Therefore, it can be affirmed that digital methods may be more reliable that manual methods for assessing facial edema.

PMID:37308089 | DOI:10.1016/j.joms.2023.05.009

Contemp Clin Trials. 2023 Jun 10:107265. doi: 10.1016/j.cct.2023.107265. Online ahead of print.

ABSTRACT

We propose a simple and powerful data-dependent contrast test with ordinal-constraint contrast coefficients of the dose response determined from observed responses. The contrast coefficients are easily calculated using a pool-adjacent-violators algorithm and making assumptions for the contrast coefficients. Once the dose response is determined for p < 0.05 in the data-dependent contrast test, the best dose-response model is selected from multiple dose-response models. Using the best model, a recommended dose is identified. We demonstrate the data-dependent contrast test for sample data. In addition, we calculate the ordinal-constraint contrast coefficients and test statistic for an actual study, and we obtain a recommended dose. Finally, we perform a simulation study with 11 scenarios to evaluate the performance of the data-dependent contrast test by comparing multiple comparison procedures with modeling techniques. We confirm the dose response for both the sample data and the actual study. In the simulation study, the data-dependent contrast test is more powerful than the conventional method on the simulation datasets generated using non-dose-response models. In addition, the type-1 error rate of the data-dependent contrast test remains at a significant level when there is no difference between the treatment groups. We conclude that the data-dependent contrast test can be applied unproblematically in a dose-finding clinical trial.

PMID:37308075 | DOI:10.1016/j.cct.2023.107265