MR radiomics predicts pathological complete response of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a multicenter study.

BACKGROUND: More than 40% of patients with resectable esophageal squamous cell cancer (ESCC) achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), who have favorable prognosis and may benefit from an organ-preservation strategy. Our study aims to develop and validate a machine learning model based on MR radiomics to accurately predict the pCR of ESCC patients after nCRT. METHODS: In this retrospective multicenter study, eligible patients with ESCC who underwent baseline MR (T2-weighted imaging) and nCRT plus surgery were enrolled between September 2014 and September 2022 at institution 1 (training set) and between December 2017 and August 2021 at institution 2 (testing set). Models were constructed using machine learning algorithms based on clinical factors and MR radiomics to predict pCR after nCRT. The area under the curve (AUC) and cutoff analysis were used to evaluate model performance. RESULTS: A total of 155 patients were enrolled in this study, 82 in the training set and 73 in the testing set. The radiomics model was constructed based on two radiomics features, achieving AUCs of 0.968 (95%CI 0.933-0.992) in the training set and 0.885 (95%CI 0.800-0.958) in the testing set. The cutoff analysis resulted in an accuracy of 82.2% (95%CI 72.6-90.4%), a sensitivity of 75.0% (95%CI 58.3-91.7%), and a specificity of 85.7% (95%CI 75.5-96.0%) in the testing set. CONCLUSION: A machine learning model based on MR radiomics was developed and validated to accurately predict pCR after nCRT in patients with ESCC.

Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer.

Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with BRCA mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.

States of contra-lateral rotator cuff - Based on bilateral shoulder ultrasound results of 401 patients.

BACKGROUND: For patients with rotator cuff tear (RCT), the contra-lateral shoulders have higher risk of RCT than general population. It has been proved by several previous studies. The focus of this study is to obtain the data of contra-lateral rotator cuff tear in Chinese population, and to find the rules of contra-lateral rotator cuff tear through statistical analysis. METHODS: From March 2016 to January 2020, patients who underwent shoulder arthroscopic surgery were included in the study, we conduct bilateral shoulder ultrasound before surgery, patients information collection include gender, age, occupation and whether received contra-lateral rotator cuff surgery within 1-3 years. The above information was statistically analyzed. RESULTS: According to the inclusion and exclusion criteria, 401 patients were included. The incidence of contra-lateral rotator cuff tear was 24.3%, 5.58% of them underwent contra-lateral rotator cuff repair surgery within 3 years. The degree of contra-lateral rotator cuff tear was positively correlated with the degree of the primary side; Patients with full-thickness rotator cuff tear were more likely to have contra-lateral rotator cuff tear than patients with partial rotator cuff tear. For patients with supraspinatus tendon tear, the contra-lateral rotator cuff tear risk increases, For patients with subscapularis muscle tear, the contra-lateral rotator cuff tear risk doesn't increases. Contra-lateral rotator cuff tear is related to age, the risk of contra-lateral rotator cuff tear is higher in elderly patients. CONCLUSIONS: The contra-lateral RCT data obtained in our study was 24.3%, significantly lower than that of previous studies. The reasons may include ethnic variation, lifestyle, and proportion of heavy physical labor. The condition of contra-lateral rotator cuff is closely related to affected side rotator cuff tear.

Forming Analysis and Heat Treatment of TC31 Titanium Alloy Component with High Ribs and Thin Webs.

TC31 is a new type of high-temperature titanium alloy, but few researchers have studied the combination of forming and heat treatment of a component using this material. The component with high ribs and thin webs was studied by numerical simulation and trail production. Based on the establishment of the finite element model, the forming process was analyzed by simulation software, and the maximum forming load of the component was 1920 kN. Ultimately, there were no folding defects of the component during the forming process. The material flow law was revealed by selecting the typical section of the component, and then the forming process was verified and the fully filled component was obtained. After that, the component was subjected to post-processing, and three heat treatment methods were designed to conduct heat treatment experiments on it (heat treatment: solution treatment and aging treatment). By analyzing the influence of three heat treatment methods on mechanical properties, the optimal heat treatment method was obtained, namely a solution treatment at 960 °C for 2.5 h and aging treatment at 610 °C for 7 h. The ultimate tensile strength, yield strength, elongation, and section shrinkage of the component through forging forming and heat treatment are higher than those of original material; meanwhile, it also indicates that the designed heat treatment has a better effect on the high-temperature mechanical properties of this titanium alloy at 650 °C than that at 450 °C. The research on the combination of the forming and heat treatment of this component provides a reference for the engineering application of high-temperature titanium alloys.

Efficacy and Safety of Regorafenib Plus Immune Checkpoint Inhibitors with or Without TACE as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

Purpose: We compare the efficacy and safety of regorafenib plus immune checkpoint inhibitors (ICIs) with transarterial chemoembolization (R+ICIs+TACE) versus regorafenib plus ICIs (R+ICIs) as the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). Methods: This retrospective study included patients with advanced HCC who received R+ICIs+TACE or R+ICIs as the second-line treatment from January 2019 to April 2022. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups. The propensity score matching (PSM) was used to reduce the influence of confounding factors on the outcomes. Factors affecting PFS and OS were analyzed using a Cox proportional-hazards regression model. Results: In total, 52 patients were included in this study, of whom 28 patients received R+ICIs+TACE and 24 patients received R+ICIs. After PSM (n=23 in each group), patients who received R+ICIs+TACE had a higher ORR (34.8% vs 4.3%, P=0.009), a longer PFS (5.8 vs 2.6 months, P<0.0001), and a longer OS (15.0 vs 7.5 months, P=0.014) than those who received R+ICIs. Age ≤ 50 years old, Child-Pugh class A6 and B7, and R+ICIs were found as independent prognostic factors for poor PFS. R+ICIs, α-fetoprotein >400 ng/mL, and platelet-to-lymphocyte ratio >133 were noted as independent prognostic factors for poor OS. The difference in the incidence of TRAEs between the two groups was not statistically significant (P> 0.05). Conclusion: Compared to regorafenib plus ICIs, regorafenib plus ICIs with TACE was tolerated and improved survival as the second-line treatment for patients with advanced HCC.

Study on Hot Tensile Deformation Behavior and Hot Stamping Process of GH3625 Superalloy Sheet.

Hot tensile tests of the GH3625 superalloy were carried out under the temperature range of 800-1050 °C and strain rates of 0.001, 0.01, 0.1, 1, and 10 s-1 on a Gleeble-3500 metallurgical processes simulator. The effect of temperature and holding time on grain growth was investigated to determine the proper heating schedule of the GH3625 sheet in hot stamping. The flow behavior of the GH3625 superalloy sheet was analyzed in detail. The work hardening model (WHM) and the modified Arrhenius model, considering the deviation degree R (R-MAM), were constructed to predict the stress of flow curves. The results showed that WHM and R-MAM have good prediction accuracy by evaluating the correlation coefficient (R) and the average absolute relative error (AARE). Additionally, the plasticity of the GH3625 sheet at elevated temperature drops with the increasing temperature and decreasing strain rate. The best deformation condition of the GH3625 sheet in the hot stamping is in the range of 800~850 °C and 0.1~10 s-1. Finally, a hot stamped part of the GH3625 superalloy was produced successfully, which had higher tensile strength and yield strength than the as-received sheet.

Study on the Removal of Oxide Scale Formed on 300 M Steel Special-Shaped Hot Forging Surfaces during Heating at Elevated Temperature by a High-Pressure Water Descaling Process.

Numerical simulations and experiments were utilized to study the removal of oxide scale formed on 300 M steel special-shaped hot forging surfaces during heating at elevated temperature by a high-pressure water descaling process. Specifically, the experimental setup of the special-shaped hot forging was designed and manufactured according to the descaling parameters and simulation results obtained from the hot rolling process. The force states of three typical hot forging surfaces impinged by high-pressure water jets were analyzed. Moreover, the mechanism of the high-pressure water descaling process was proposed based on the research results. The numerical simulations and experimental results revealed that the velocity distribution of the high-pressure water jets is relatively different in various areas of the special-shaped hot forging surfaces. Therefore, the descaling performance is synergistically influenced by the velocity of the high-pressure water jet and the shape of the special-shaped hot forging. Given a certain spray pressure, the value of impact force Fi plays a significant role in the descaling of the typical hot forging. The larger the value of Fi on the typical hot forging surface, the easier it is to remove the oxide scale, and vice versa. Accordingly, the difficulty of removing the oxide scale formed on the 300 M steel special-shaped hot forging surfaces during heating at elevated temperature by a high-pressure water descaling process is in the following order: plane surface < convex surface < concave surface. Additionally, only the inner-layer FeO of the oxide scale remained after the high-pressure water descaling process due to the appearance of FeO-Fe2SiO4 eutectic in the FeO layer.

Application of Tranexamic Acid in Shoulder Arthroscopic Surgery: A Randomised Controlled Trial.

Objective To explore the optimal administration route of tranexamic acid (TXA) in shoulder arthroscopic surgery. Methods Patients undergoing arthroscopic rotator cuff repair were randomly divided into four groups: control group (without TXA treatment), intravenous group (TXA was intravenously administered 10 minutes before surgery), irrigation group (TXA was added to the irrigation fluid during subacromial decompression and acromioplasty), and intravenous plus irrigation group (TXA was applied both intravenously and via intra-articular irrigation). The primary outcome was visual clarity assessed with visual analog scale (VAS) score, and the secondary outcomes included irrigation fluid consumption and time to subacromial decompression and acromioplasty procedure. Results There were 134 patients enrolled in the study, including 33 in the control group, 35 in the intravenous group, 32 in the irrigation group, and 34 in the intravenous plus irrigation group. The median and interquartile range of VAS scores for the intravenous, irrigation, and intravenous plus irrigation groups were 2.70 (2.50, 2.86) (Z = -3.677, P = 0.002), 2.67 (2.50, 2.77) (Z = -3.058, P < 0.001), and 2.91 (2.75, 3.00) (Z = -6.634, P < 0.001), respectively, significantly higher than that of the control group [2.44 (2.37, 2.53)]. Moreover, the control group consumed more irrigation fluid than the intravenous group, irrigation group, and intravenous plus irrigation group (all P < 0.05). The intravenous plus irrigation group consumed less irrigation fluid than either the intravenous group or the irrigation group (both P < 0.001). There was no difference in subacromial decompression and acromioplasty operative time among the four groups. Conclusion TXA applied both topically and systematically can improve intraoperative visual clarity, and the combined application is more effective.

Remote B-Ring Oxidation of Sclareol with an Engineered P450 Facilitates Divergent Access to Complex Terpenoids.

Though chiral pool synthesis is widely accepted as a powerful strategy in complex molecule synthesis, the effectiveness of the approach is intimately linked to the range of available chiral building blocks and the functional groups they possess. To date, there is still a pressing need for new remote functionalization methods that would allow the installation of useful chemical handles on these building blocks to enable a broader spectrum of synthetic manipulations. Herein, we report the engineering of a P450BM3 variant for the regioselective C-H oxidation of sclareol at C6. The synthetic utility of the resulting product was demonstrated in a formal synthesis of ansellone B, the first total synthesis of the 2,3-seco-labdane excolide B, and a model study toward (+)-pallavicinin.

DCE-MRI of esophageal carcinoma using star-VIBE compared with conventional 3D-VIBE.

To investigate the value of the star-VIBE sequence in dynamic contrast-enhanced magnetic resonance imaging of esophageal carcinoma under free breathing conditions. From February 2019 to June 2020, 60 patients with esophageal carcinoma were prospectively enrolled to undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the K-space golden-angle radial stack-of-star acquisition scheme (star-VIBE) sequence (Group A) or conventional 3D volumetric-interpolated breath-hold examination (3D-VIBE) sequence (Group B), completely randomized grouping. The image quality of DCE-MRI was subjectively evaluated at five levels and objectively evaluated according to the image signal-to-noise ratio (SNR) and contrast-noise ratio (CNR). The DCE-MRI parameters of volume transfer constant (Ktrans), rate constant (Kep) and vascular extracellular volume fraction (Ve) were calculated using the standard Tofts double-compartment model in the post-perfusion treatment software TISSUE 4D (Siemens). Each group included 30 randomly selected cases. There was a significant difference in subjective classification between the groups (35.90 vs 25.10, p = 0.009). The study showed that both the SNR and CNR of group A were significantly higher than those of group B (p = 0.004 and < 0.001, respectively). There was no significant difference in Ktrans, Kep or Ve between the groups (all p > 0.05). The star-VIBE sequence can be applied in DCE-MRI examination of esophageal carcinoma, which can provide higher image quality than the conventional 3D-VIBE sequence in the free breathing state.

Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis.

A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss-DAF-12 ligand and elucidated the hormone's biosynthetic pathway. Genetic loss of function of the ligand's rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits Ss-DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.

Application of virtual touch tissue imaging quantification in diagnosis of supraspinatus tendon injury.

OBJECTIVE: To explore the value of virtual touch imaging and quantification (VTIQ) shear wave elastography (SWE) in diagnosis of supraspinatus tendon tear. METHODS: Eighty patients with unilateral supraspinatus tendon tear underwent shoulder arthroscopy were prospective studied. Tendinopathy, partial-thickness tear or full-thickness tear of supraspinatus tendon were diagnosed according 2D ultrasound examination. Sensitivity, specificity and accuracy of ultrasonic diagnosis of supraspinatus tendon tear were calculated by arthroscopy as the gold standard. VTIQ was applied to measure the shear-wave velocity (SWV) of both normal and affected supraspinatus tendon. The differences of SWV in three types of supraspinatus tendon tear and receiver operating characteristic (ROC) curves were analyzed. RESULTS: Among 80 patients, there were 20 tendinopathy, 31 partial tears and 29 full-thickness tears diagnosed by shoulder arthroscopy. Sensitivity, specificity and accuracy of 2D ultrasound in diagnosis of tendinopathy, partial tear and full-thickness tear groups were 78%, 90%and 83%; 71%, 86%and 73%; 86%, 88%and 88%, respectively. SWV of 80 supraspinatus tendon tears was 4.59±1.00 m/s, which was lower than that of normal supraspinatus tendon (4.59±1.00 m/s vs. 6.68±1.05 m/s, P < 0.01). SWV of supraspinatus tendon in tendinopathy, partial tear and full-thickness tear groups respectively were 5.66±0.97, 4.66±1.00, and 3.78±0.55 m/s, all lower than that of the contralateral normal supraspinatus tendon (all P < 0.05). In addition, the analysis of variance and pairwise comparison showed that SWV of supraspinatus tendon among three different degree of injury was statistically significant (all P < 0.001). The cutoff thresholds of SWV was 4.83 m/s to identify tendinopathy tear from partial tear and was 4.08 m/s to identify full-thickness tear from partial-thickness tear. CONCLUSION: VTIQ SWE with SWV might identify degree of supraspinatus tendon tear and improve the value of ultrasonography, which should be further evaluated in large multicenter studies.

The clinical value of color Doppler ultrasonography in measuring the hemodynamics of liver cirrhosis patients' portal and splenic veins.

OBJECTIVE: To investigate the clinical value of color Doppler ultrasonography (CDUS) in measuring the hemodynamics of liver cirrhosis (LC) patients' portal and splenic veins. METHODS: The clinical data of 81 LC patients admitted to our hospital were collected retrospectively and classified into Group A, and the clinical data from 51 healthy volunteers were classified into Group B. All the patients were examined with CDUS, and the ultrasonography images were analyzed. The hemodynamic indices of the portal and splenic veins were compared, and the differences in the hemodynamic indices of the LC patients with varying degrees of esophageal varices and hepatic injuries were analyzed. RESULTS: Group A exhibited higher Qpv, Dpv, Qsv, and Dsv and lower Vpv and Vsv than Group B (P < 0.05). The Qpv and Dpv of the patients with Grade B LC were higher than they were in the patients with Grade A LC and lower than they were in the patients with Grade C LC (P < 0.05). The Vpv of the patients with Grade B LC was higher than it was in the patients with Grade C LC and lower than it was in the patients with Grade A LC (P < 0.05). The Qsv and Dsv of the patients with Grade B LC were higher than they were in the patients with Grade A LC and lower than they were in the patients with Grade C LC (P < 0.05). The Vsv of the patients with Grade B LC was higher than it was in the patients with Grade C LC and lower than it was in the patients with Grade A LC (P < 0.05). The patients with mild, moderate, and severe esophageal varices showed lower Vpv and Vsv and higher Qpv, Dpv, Qsv, and Dsv than the patients without esophageal varices (P < 0.05). CONCLUSION: CDUS has certain clinical values in measuring the hemodynamics of LC patients' portal and splenic veins and can be used to predict the degrees of hepatic injuries and esophageal varices.

Ultrasonographic Diagnosis of Lipomatosis of Nerve: A Review of Ultrasonographic Finding for 8 Cases.

OBJECTIVE: Lipomatosis of nerve (LN) is a rare tumor-like condition with epineural and perineural infiltration by adipose and fibrous tissue. The purpose was to analyze the ultrasonographic findings of LN involving upper limb peripheral nerves. METHODS: This was a retrospective analysis of a series of 8 patients with LN involving upper-limb peripheral nerves between 2013 and 2019. All patients underwent preoperative ultrasonography for the upper-extremity nerves and were diagnosed as LN by surgery. The clinical manifestations, ultrasonography characteristics, and accuracy were analyzed. RESULTS: In this series, LN was involved in 10 peripheral nerves from 8 patients. The median nerve was the most commonly affected nerve (60%). Four cases presented macrodactyly combined with masses from distal forearm and extending to wrist and palm areas. Among 8 patients, 5 cases were diagnosed with LN by preoperative ultrasonography, an accuracy of 62.5%. Axial ultrasonic imaging showed the punctate hypoechoic fascicles was embedded in hyperechoic adipose tissue in the "lotus root-like" appearance; longitudinal ultrasonic imaging showed the strip hypoechoic fascicles alternates with hyperechoic adipose tissue in the "cable-like" appearance. Meanwhile, ultrasonic imaging showed the thickened of adipose tissue around the affected nerve and the enlargement of flexor tendons in some patients. CONCLUSIONS: Ultrasonography has the potential to be a useful tool for the noninvasive examination of LN. The possibility of LN should be considered in patients with a mass in wrist and palm, macrodactyly, or syndactyly. Our finding may benefit the preoperative differential diagnosis with common nerve tumors.

The Effectiveness of Ultrasonography in the Diagnosis of Spontaneous Hourglasslike Constriction of Peripheral Nerve in the Upper Extremity.

OBJECTIVE: To investigate the ultrasonographic characteristics in hourglasslike constriction of peripheral nerve in the upper extremity and to evaluate the value of ultrasonography in the diagnosis. METHODS: Nineteen patients with hourglasslike constriction of peripheral nerve in the upper extremity underwent ultrasonography and the results were compared with surgery. The ultrasonographic characteristics, the accurate rate, and the relation between the ultrasonography and surgery were analyzed. RESULTS: There were 22 affected nerves involved in 19 patients, including 17 radial neuropathies, 4 median neuropathies, and 1 musculocutaneous neuropathy. The accuracy rate of ultrasonography in diagnosing hourglasslike constriction of upper limb nerve was 87.93%. Ultrasonography showed that the constriction sites were completely consistent with the operation. The ultrasonography characteristics of hourglasslike constriction of upper limb nerves were hourglasslike nerve incompleteness or complete constriction, and the nerves at both ends were thickened, and no compression structure was seen around. All lesions with complete constriction diagnosed by ultrasonography were treated with resection of the lesion with or without graft. In addition, 71.43% with incomplete constriction were treated with neurolysis, and 28.57% with resection of the lesion with direct repair. CONCLUSIONS: Ultrasonography could be used as a routine noninvasive examination for hourglasslike constriction of upper limb nerves. Ultrasonography suggests that resection of the lesion rather than neurolysis should be considered in the treatment of complete constriction. For patients with clinical symptoms, ultrasonography showed local nerve enlargement but no constriction; clinicians should be prompted to explore carefully during operation to avoid missing nerve hourglasslike constriction.

The accuracy assessment of ultrasound for the diagnosis of ischiofemoral space - A Validation Study.

OBJECTIVE: To investigate and evaluate the accuracy of ultrasound (US) imaging for measurement of ischiofemoral space (IFS) compared with magnetic resonance imaging (MRI). METHODS: Twenty-five hips of 16 patients with hip pain and ipsilateral quadratus femoris muscle (QFM) edema were recruited to the IFI group, and 19 hips of 19 patients without hip pain and QFM edema were recruited as the control group. IFS of both groups was measured by US and MRI. The correlations and differences between US and MRI measurements were then assessed. Last, the receiver operating characteristic (ROC) data analysis was performed. RESULTS: The US results revealed a decreased IFS in IFI hips compared with controls (P < 0.001), suggesting that US were valuable in identifying IFI. IFS measured by US and MRI showed positive correlations in both the IFI group (r = 0.409, P = 0.042) and control group (r = 0.575, P = 0.01). There were no statistically significant differences between IFS measured by US and MRI in the control group (P = 0.657), while IFS measurements in the IFI group performed with US were significantly greater than those with MRI (P < 0.001). ROC curve analysis revealed that the cutoff value of IFS measured with US was 2.14 cm, with a sensitivity of 92.0% and specificity of 68.4%, while measured by MRI was 1.87 cm, with a sensitivity of 96.0% and specificity of 84.2%. CONCLUSIONS: IFS measurements obtained with US are very similar to those obtained with MRI. Therefore, US provides a low-cost and easy-to-operate alternative imaging modality to measure IFS.

Antioxidant and xanthine oxidase inhibitory activities of total polyphenols from onion.

Onions (Allium cepa L.) comprise a valuable vegetable crop in many countries. Modern scientific research has shown that onions possess many biological activities, including antibacterial, anticancer, hypoglycemic, hypolipidemic, antiplatelet aggregation, and antioxidant activities. The goal of this study was to investigate the impact of total onion polyphenols on antioxidant and xanthine oxidase (XO) inhibitory activities. Total onion polyphenols showed significant antioxidant activity in DPPH, FRAP, and OH-assays (IC50 [µg/mL]), 43.24, 560.61, and 12.97, respectively). In a X/XO system, antioxidant properties of these polyphenols significantly inhibited XO activity (IC50 [µg/mL], 17.36). These results indicated that total onion polyphenols showed promising antioxidant and anti-gout properties and might be used as potential, natural drugs against oxidative diseases after successful studies in vivo as well as clinical trials.