tbuckley/cabot-search huggingface dataset:
Distinct genomic instability landscape of lung adenocarcinoma associated with treatment and metastasis.
Authors: Chuanxin Wu, Jing Zhang, Hua Bao, Ao Wang, Zhuang Luo, Yi Shen, Shuyu Wu, Xue Wu, Yang Shao, Jianfeng Huang
Journal: Journal of Clinical Oncology (2020)

9534 Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Genomic instability, defined as genome-wide copy number alterations, is a key pathogenic signature which occurs at the early stage of most cancers and is associated with an increased risk of recurrence or death. We examined the pattern of genomic instability in primary and metastatic LUAD. Methods: We performed deep targeted sequencing (425 genes) of 3395 tissue samples and whole exome sequencing (WES) of 60 tissue samples from LUAD patients. Whole-genome doubling (WGD) and arm level aneuploidy were analyzed to uncover correlation with clinical phenotypes and other genomic alterations including driver mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). Results: Overall, targeted sequencing revealed that WGD occurred in 64.33% LUAD samples, which was comparable with WES results. Compared to primary site, metastasis exhibited higher proportion of WGD (1.14 fold). Specifically, liver metastasis has the highest WGD percentage among metastasis sites (~87.5%; 1.40 fold increase compared to primary). Interestingly, patients who received tyrosine kinase inhibitors (TKI) had higher frequency of WGD than patients without TKI treatment. In addition, TMB was higher in WGD + patients but MSI status was not significantly different between groups. Arm-level aneuploidy was prevalent in this cohort. The most common amplification events were 7p gain (62%), 5p gain (54%), and 8q gain (53%); top deletion events were 19p loss (47%), 15q loss (42%), and 10 q loss (41%). Patients with EGFR or TP53 mutation were more likely to have aneuploidy compared to wildtypes. Subgroup analysis showed distinct patterns of aneuploidy among metastasis sites, suggesting organ-specific alterations. Evolution analysis showed 7p gain was an early event common in primary tumor whereas metastatic tumor had multiple distinct evolutionary trajectories following 7p gain. Several copy number signatures were associated with specific TKI and chemotherapies. For example, TKI-naïve tumors lacked 7p gain but had 19p loss as the most common alteration. Conclusions: The genomic landscape of LUAD was characterized by widespread large-scale copy number alterations including WGD and chromosomal aneuploidy. Metastasis had elevated level of aneuploidy compared to primary tumors which were specific to metastatic site. Copy number signature associated with different treatments may contribute to distinct long-term survival and side effects among patients.
Some issue about diagnosis and treatment of dermatosis which should be concerned by general practitioners
Authors: 张建中
Journal: BMJ (2007)

随着我国医疗卫生改革的发展,全科医生的作用越来越重要,他们担负着各种患者的初级诊疗和筛选工作,全科医生水平的高低,直接影响着患者的健康和疾病的转归.皮肤科是一门专科性很强的临床学科,全科医生如能够掌握皮肤科治疗基本知识和技巧,对提高诊断水平和对患者进行及时合理治疗有重要意义.全科医生在皮肤病诊疗中应当着重注意如下几方面问题:
口服补液盐的演变与进展
Authors: 陈绍潞
Journal: BMJ (2010)

自从世界卫生组织(WHO)推荐使用口服补液盐(ORS)治疗腹泻病脱水电解质紊乱以来,已使腹泻的病死率大大降低,尤其在第三世界广大农村地区,因此ORS被认为是20世纪70年代医学上的一大贡献.ORS的提出是基于1964年后的一些基础研究成果:①证实葡萄糖由小肠上皮细胞吸收有赖于钠离子从肠道的主动吸收,而葡萄糖的吸收又能促进钠离子的吸收;②离体肠管灌注葡萄糖盐水溶液试验证实,含2%左右葡萄糖的盐溶液是促进钠、水吸收的最佳浓度,葡萄糖过低影响钠、水从肠道吸收,过高则可引起渗透性腹泻,反会增加水的丢失;③霍乱等腹泻病虽有大量水及电解质从粪便丢失,但小肠钠-葡萄糖-水吸收系统并未受明显影响。
Assessment of fall risk in elderly hypertensive patients from rural communities
Authors: Deling Zu, Yi Zhuge, Xiaotong Wang
Journal: BMJ (2014)

The fall risk was evaluated with Modified Falls Efficacy Scale (Chinese version) in 426 elderly hypertensive patients (hypertensive group) and 436 elderly people without hypertension (control group) from rural communities in Zhejiang Quzhou areas.The fall risk scores were compared between hypertensive group and control group; and also between patients with history of falls and those without falls. The results showed that the average score was 8.62±2.15 in hypertensive group and 9.35±1.35 in control group (P<0.01). The average score was 6.94±1.85 in hypertensive patients with history of falls (n=112) and 9.22±1.42 in without history of falls (n=314) (P<0.01). Our study suggests that there is a higher fall risk in elderly hypertensive patients than in elderly people without hypertension; and fall risk assessment with Modified Falls Efficacy Scale (Chinese version) can be used for prediction of fall for the elderly people in rural community.


Key words: 
Hypertension; Accidental falls
Screening effects of Montreal Cognitive Assessment for sepsis associated encephalopathy
Authors: Jia-quan Liu, Zi-li Zhang, De-quan Kong, Cheng-bin Yang, Yu-zhen Wu, Ya-ben Yao, Wei-cheng Wu, Man-dong Pan, Ji-yan Lin
Journal: BMJ (2012)

A total of 192 patients with sepsis were tested by Montreal Cognitive Assessment (MoCA) for a preliminary diagnosis of whether or not there was sepsis associated encephalopathy (SAE) according to their test results.SAE was diagnosed or excluded after consultations and comprehensive analysis on the basis of clinical manifestations and auxiliary examination results.The scores of the patients in this group were (25.7 ± 3.3) points.The sensitivity of MoCA for screening SAE was 0.776 and its specificity 0.963.The rate of diagnostic coincidence between MoCA and comprehensive analysis for SAE was 0.880.The diagnostic concordance between two diagnostic methods of SAE was excellent (kappa value =0.753 ± 0.048,P =0.000).The area under the receiver operating characteristic (ROC) curve of MoCA for screening SAE was 0.929 ± 0.019 (P =0.000) ; the optimal cutoff value was 25.5 points; and its sensitivity was 0.779 and specificity 0.962.And negative correlations existed between score of MoCA and age,disease course and co-existing shock or multiple organ dysfunction syndrome (P ＜ 0.05).

Key words: 
Sepsis; Cognition disorder
Patterns of hedgehog inhibitor (HHI) treatment interruptions and re-initiations among patients with basal cell carcinoma (BCC) in real-world clinical practice.
Authors: Jessica J. Jalbert, Chieh-I Chen, Ning Wu, Matthew G. Fury, Emily S Ruiz, Wenzhen Ge
Journal: Journal of Clinical Oncology (2020)

e19349 Background: HHIs are oral targeted therapies approved for the treatment of advanced BCC but treatment-related adverse events may result in treatment interruptions or discontinuation. The objective of this study was to describe HHI treatment patterns among patients with BCC in real-world clinical practice. Methods: We conducted an observational cohort study using MarketScan Commercial/Medicare databases (01/01/2013–09/30/2018). We identified new users of HHIs (index date = date of the first dispensation), ≥18 years of age who were continuously enrolled for ≥6 months prior to the index date (i.e. baseline) with ≥1 baseline BCC diagnosis. Treatment interruptions (TI) were defined as a lack of dispensation following the exhaustion of days’ supply and allotted grace period (GP). Re-initiation (RI) was defined as ≥1 HHI dispensation after TI. The Kaplan–Meier method was used to estimate risk and time to TI and, among patients with a TI, incidence of RI. HHIs are generally dispensed in 30-days’ supply and indicated as long as a patient derives a clinical benefit; however, since TIs are commonly employed during HHI therapy, sensitivity analyses were conducted using GPs of 14, 30, 60, 90, and 120 days. Results: We identified 469 patients with a BCC diagnosis initiating HHIs. The mean (SD) age was 67.6 (15.8) years, 64.2% were men, 51.2% were covered by commercial insurance, and 99.2% initiated vismodegib. Using a GP of 14, 30, 60, 90, and 120 days, the risk of TI was 79.2%, 68.8%, 60.0%, 55.4%, and 51.4% at 6 months and 94.8%, 91.3%, 88.2%, 83.2%, and 80.2% at 1 year, respectively. Median HHI treatment duration ranged from 94 days (95% CI: 90–109) using a GP of 14 days to 173 days (95% CI: 156–194) using a GP of 120 days. At 6 months following TI, incidence of RI was 35.8%, 19.8%, 11.3%, 6.9%, and 4.9% using a GP of 14, 30, 60, 90, and 120 days, respectively. The incidence of HHI RI at 1-year following TI ranged from 40.8% using a 14-day GP to 13.4% using a 120-day GP. Conclusions: Median HHI treatment duration was approximately 6 months, even after allowing for a 120-day GP. Median treatment duration was considerably shorter than what has been reported in clinical trials. Our results suggest that long-term HHI therapy may be difficult in a real-world setting.
Association of peripheral white blood cell with type 2 diabetic nephropathy
Authors: Xue-yang Zhang, Xiao-zhen Liu, Ran Bai, Yong-bo Wang, Jian-ling Du, Chang-chen Li
Journal: BMJ (2012)

A total of 473 patients of diabetic nephropathy (DN) with normal serum creatinine were recruited.Blood routine,blood lipids and urine albumin/creatinine ratio (UACR) were measured.They were divided into microalbuminuria group (DN1,n =246 ) and macroalbuminuria group (DN2,n =227 ).The white blood cell (WBC) count,monocyte count and CRP significantly increased with the progression of DN in the DN2 group versus those in the DNI group [ (6.8 ± 1.7 ) × 109/L vs.(6.3 ± 1.5 ) × 109/L,(0.49±0.23) ×109/Lvs.(0.32 ±0.21) ×109/L,(4.1 ±1.1)mg/Lvs.(1.7±0.3) mg/L,all P＜ 0.05].According to multiple linear regression analysis,WBC,monocyte,low density lipoproteincholesterol and lymphocyte were found to be independent influencing factors for the elevation of UACR.

Key words: 
Diabetic nephropathies; Leukocytes
Cost-effectiveness analysis of selective intraoperative laparoscopic cholangiography in county level hospitals
Authors: Feng Wei, Dayu Wang
Journal: BMJ (2017)

Objective
To analyze the cost-effectiveness of selective intraoperative laparoscopic cholangiography (LIOC) in the county level hospitals.


Methods
The medical costs and cost-effectiveness of 60 patients undergoing LIOC (group A) during laparoscopic cholecystectomy (LC) in 2014 and 52 patients undergoing LC (group B) only in 2013 at 3 county level hospitals were analyzed.


Results
The direct medical care costs of group A were less than that of group B significantly [(9 072±1 282)Yuan vs.(10 941±4 064)Yuan, t=-3.38, P=0.001] , there were no significant different in indirect medical care costs between group A and group B[(2 039±1 020)vs.(2 100±1 172)Yuan, t=0.24, P=0.810] . The cure rate was 100% in two groups; however, the cost per patient in group A was less than that in group B [(11 111±2 348)vs.(13 041±5 118)Yuan]. The direct medical care cost of the patients who needed additional treatment in group A was significantly less than that in group B [(10 828±1 101)vs.(16 533±1 733)Yuan, t=-11.45, P=0.000] . There were no significant different in direct operational costs between group A (LIOC+ LC) groups and group B (LC) [(8 378±326)vs.(8 225±363)Yuan, t=1.96, P=0.054].


Conclusions
Selective LIOC is a cost-effective procedure and should be recommended in county level hospitals in which magnetic resonance cholangiopancreatography is not available.


Key words: 
Cholecystectomy, laparoscopic; Cholangiography; Fees, medical; Cost-and cost analysis
A comparison of CD34+ mobilization effects of standard dose pegfilgrastim (Peg) versus low-dose peg combined with plinabulin (Plin).
Authors: Douglas W. Blayney, Lan Huang, Ramon W. Mohanlal
Journal: Journal of Clinical Oncology (2020)

e20000 Background: Plin is a novel, small molecule immune-enhancing agent with in vitro anticancer activity currently in Phase (Ph) 3 clinical trials for NSCLC treatment and Chemotherapy (Chemo)-Induced Neutropenia (CIN). Single agent (SA) Plin is equally effective as Peg for the prevention of CIN, however does not cause bone pain and is given on the same day of Chemo by 30 min IV infusion, 30 min after Chemo (Blayney ASH 2018). SA Plin also mobilizes CD34+ cells to clinically relevant levels (Blayney ASH 2019). Plin has been administered to &gt; 600 patients (pts) and has a favorable safety/tolerability profile. In clinical practice, Peg dose is often reduced to 3 mg in patients (pts) experiencing side effects with standard dose (6 mg) Peg, such as bone pain, myalgia and leucocytosis (Kim ASCO 2010; Goodman Oncology Times 2008; Lacovelli JHOP 2012; Lower Cancer Chemother Pharmacol 2018). We evaluated CD34+ cell counts and adverse events (AE) with low dose Peg combined with Plin vs full dose Peg. Methods: In a subset of Breast Cancer pts in the CIN Ph 2 trial BPI-2358-106 (NCT0329457) receiving TAC (taxotere (75), doxorubicin (50 ) and cyclophosphamide (500) mg/m2, pts also received either Peg 6mg (n = 7) or low dose peg ( n = 9, of which 7pts received 3mg and 2 pts 1.5 mg Peg) combined with Plin (20 mg/m2). CD34+ counts were obtained by central laboratory FACS analysis (Covance) at screening (SC), Day (D) 6,8 and 21 cycle 1 (see table below) and AE frequency was collected. Results: Clinical trial information: NCT0329457 . Frequency of bone pain, myalgia and leukocytosis was numerically lower with low dose Peg/Plin vs 6mg Peg. Conclusions: Under highly myelosuppressive TAC Chemo conditions, CD34+ counts increased significantly (p &lt; 0.03) vs predose SC in cycle 1 in the low dose Peg/Plin goup. CD34+ counts were not different for full dose Peg vs low dose Peg/Plin in cycle 1. Adverse Events were fewer with the low dose Peg/Plin. The Peg/Plin combination is worthy of test in hematopoietic stem cell mobilization regimens. [Table: see text]
Pathogen distribution and therapeutic efficacy of atypical neonatal pneumonia
Authors: Wei-dong Li, Yu-jing Wang
Journal: BMJ (2012)

The pathogens were tested in 682 cases of neonatal pneumonia,atypical pathogens were found in 167 cases (24.49％).Among the 167 cases,chlamydia trachomatis was detected in 124(74.25％),ureaplasma urealyticum in 55 (32.93％),chlamydia pneumoniae in 47 (28.14％) and mycoplasma pneumoniae in 35 (20.56％).The Chlamydia trachomatis-positive rate in mothers of 167 cases was 80.84％,ureaplasma urealyticum was 53.29％,chlamydia pneumoniae was 50.90％,Mycoplasma pneumoniae was 53.29％.The patients were treated with azithromycin and other antibiotics,151 cases were cured and 11 were effective with an overall efficacy rate of 97.01％.The liver and kidney function were tested before and after treatment; and there were no significant changes after treatment.The results show that azithromycin is safe and effective for treatment of neonatal infectious pneumonia from atypical pathogens.

Key words: 
Infant,newborn; Pneumonia; Atypical pathogens
Multiband mucosectomy in treatment of early cancer and precancerous lesions of esophagogastric junction
Authors: Bin Deng, Dacheng Wu, Mei Wang, Yaosheng Chen, Yuanzhi Wang, Jian Wu
Journal: BMJ (2014)

Eighteen patients with early cancer and precancerous lesions of esophagogastric junction underwent multiband mucosectomy (MBM) in Yangzhou First People's Hospital from January 2013 to February 2014. The clinicopathological data of patients were analyzed retrospectively and the short-term efficacy and safety of MBM were evaluated. Operations were successful in all 18 cases.The mean operative time was 35.8 min. Intraoperative bleeding occurred in 3 cases and successfully managed by endoscopic hemostasis.Small perforation occurred in 1 patient and was closed by metal clips.Pathological examination showed mucosal cancer in 5 cases, high-grade intraepithelial neoplasia in 8 cases and low-grade intraepithelial neoplasia in 5 cases. No relapse of cancer was found during follow-up.Results indicate that MBM is an effective and safe method in treatment of early cancer and precancerous lesions in the esophagogastric junction.


Key words: 
Esophageal neoplasma; Treatment
Career identity and satisfaction of family doctors in Pudong New Area of Shanghai municipality
Authors: Zhiqun Shu, Limei Jing, Xiaoming Sun
Journal: BMJ (2015)

Objective
To survey the career identity and satisfaction of family doctors in Pudong New Area of Shanghai municipality.


Methods
Two hundred and thirty four family doctors were selected with random sampling method from 6 community health centers in Pudong New Area of Shanghai. The survey on career identity and satisfaction was conducted using a self-designed questionnaire.


Results
The results showed that 37.2% of participants were very satisfied (8.1%, 19/234) or satisfied (29.1%, 68/234) with their current career situation. The three lowest satisfaction factors were salary(14.1%, 33/234), benefit and social insurance (27.3%, 64/234), professional reputation and social status(20.9%, 49/234). Meanwhile, the three highest factors were quality of their leadership (79.5%, 186/234), interpersonal relationship(74.4%, 174/234)and the institutional management(63.3%, 148/234). The survey also showed that 44.5% and 30.6% of participants expected their monthly pay as 8 001-10 000 and 5 000-8 000 RMB; 39.1% thought the current performance evaluation mechanism as effective, while 25.7% thought the opposite.


Conclusion
The social status and salary level of family doctors need to be improved; there is also an urgent need to improve the performance evaluation mechanism and other supporting measures.


Key words: 
Job satisfaction; Questionnaires; General practitioners
Clinical analysis of 314 children with chest pain
Authors: Si-rui Yang
Journal: BMJ (2008)

Objective To understand the cause of chest pain (precordium indisposition) in children and explore the thread of thought in its analysis.Methods Clinical data of 314 children with chest pain who visited the cardiovascular department for children of our hospital were collected and analyzed to study its causes.Results The cause could be attributed to organic cardiac diseases in 43 of 314 children (13.7%) with chest pain,to non-organic cardiac diseases in 108 (34.4%),to psychiatric-psychological factors in 60 (19.1%) and to unknown cause in 41 (13.1%).Average age of children with organic cardiac diseases was younger than that of children with other causes (P<0.05).Symptoms accompanied simultaneously in children with organic cardiac diseases were much more frequent significantly than those in them with non-organic cardiac chest pain and unknown causes (P<0.05).Conclusions Chest pain in children could be caused by a few causes,which was non-specific symptom for organic cardiac diseases,so, more should be taken into account in analyzing the cause of chest pain in children.

Key words: 
Cardiovascular diseases; Child; Diagnosis
未婚姑娘发烧之谜
Authors: 曾昭耆
Journal: BMJ (2006)

20多年前9月初的一天,近中午门诊快下班时,一个20岁的姑娘在她父亲的陪伴下来找我看病.据其父说,孩子暑假和同学们到北戴河玩,受凉感冒,发烧已近半个月,曾用过一些口服抗生素,但未见效。
Designing, Conducting, and Reporting Clinical Decision Support Studies: Recommendations and Call to Action
Authors: Kensaku Kawamoto, Clement J. McDonald
Journal: Annals of Internal Medicine (2020)

By enabling more efficient and effective medical decision making, computer-based clinical decision support (CDS) could unlock widespread benefits from the significant investment in electronic health record (EHR) systems in the United States. Evidence from high-quality CDS studies is needed to enable and support this vision of CDS-facilitated care optimization, but limited guidance is available in the literature for designing and reporting CDS studies. To address this research gap, this article provides recommendations for designing, conducting, and reporting CDS studies to: 1) ensure that EHR data to inform the CDS are available; 2) choose decision rules that are consistent with local care processes; 3) target the right users and workflows; 4) make the CDS easy to access and use; 5) minimize the burden placed on users; 6) incorporate CDS success factors identified in the literature, in particular the automatic provision of CDS as a part of clinician workflow; 7) ensure that the CDS rules are adequately tested; 8) select meaningful evaluation measures; 9) use as rigorous a study design as is feasible; 10) think about how to deploy the CDS beyond the original host organization; 11) report the study in context; 12) help the audience understand why the intervention succeeded or failed; and 13) consider the financial implications. If adopted, these recommendations should help advance the vision of more efficient, effective care facilitated by useful and widely available CDS.
Effects of three surgical modalities on ovarian reserve by assessing the serum level of anti-Mullerian hormone for uterine fibroids
Authors: Hua Yuan, Shaojie Zhao, Hua Gong, Xi Liang
Journal: BMJ (2015)

To compare the effects of laparoscopic total or subtotal hysterectomy and myomectomy on ovarian reserve by measuring the serum level of anti-Mullerian hormone (AMH). A total of 96 patients with uterine fibroids underwent total laparoscopic hysterectomy (TLH group, n=32), laparoscopic subtotal hysterectomy (LSH group, n=31) and laparoscopic myomectomy (LM group, n=33). Changes in ovarian reserve were examined by measuring the level of AMH pre-operation and at 1 and 4 months post-operation. No significant differences existed in AMH in LM group[(1.42±0.65), (1.31±0.53) & (1.33±0.61) μg/L, P>0.05]. The levels of AMH in both groups were significantly lower than those at pre-operation[(1.17±0.11), (1.01±0.10), (0.48±0.54) & (1.18±0.93), (0.45±0.39), (0.14±0.0) μg/L, P<0.001]. The mean percentage decrease in AMH was lower in TLH group than that in LSH group at 4-month follow-up[(-37.4±37.6)% vs. (-27.0±23.0)%, P=0.017]. The results showed that LM had no effect on ovarian reserve. Both LSH and TLH had adverse effects on ovarian reserve and TLH was more marked.


Key words: 
Hysterectomy, laparoscopic; Ovarian function
Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial
Authors: Nancy U. Lin, Virginia Borges, Carey Anders, Rashmi K. Murthy, Elisavet Paplomata, Erika Hamilton, Sara Hurvitz, Sherene Loi, Alicia Okines, Vandana Abramson, Philippe L. Bedard, Mafalda Oliveira, Volkmar Mueller, Amelia Zelnak, Michael P. DiGiovanna, Thomas Bachelot, A. Jo Chien, Ruth O’Regan, Andrew Wardley, Alison Conlin, David Cameron, Lisa Carey, Giuseppe Curigliano, Karen Gelmon, Sibylle Loibl, JoAl Mayor, Suzanne McGoldrick, Xuebei An, Eric P. Winer
Journal: Journal of Clinical Oncology (2020)

In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs.Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease.There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03).In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.