Miracle-dz/UniFAR-FTUs huggingface dataset:
Programmed Cell Death Protein‐1 (PD‐1)‐Targeted Immunotherapy for Advanced Hepatocellular Carcinoma in Real World

Background Hepatocellular carcinoma (HCC) is one of the most common malignant solid tumors. Its incidence is increasing worldwide due to the dissemination of hepatitis B infection, HCV infection and nonalcoholic steatohepatitis-related HCC. For patients with advanced HCC, the available treatments are extremely limited and the prognosis is very poor. Therefore, it is urgent to discover new innovative approaches. Programmed cell death protein-1-targeted immunotherapy has shown promising results in multicenter clinical trials. Aim To evaluate the effectiveness and safety of anti-PD-1 agent in patients with advanced primary hepatocellular carcinoma. Methods A retrospective analysis of 55 patients with advanced primary hepatocellular carcinoma who had been administered anti-PD-1 agent. Tumor response was assessed according to the modified Response Evaluation Criteria in Solid Tumors and any adverse events were recorded. Results The median overall survival (OS) was 15 months. The median progression-free survival (PFS) was 10 months. No patient had complete response (CR) and 12 (22%) participants achieved partial response (PR), resulting in an overall response rate (ORR) of 22%. Thirty-seven (67%) patients showed stable disease (SD) and 6 (11%) subjects had progressive disease (PD) at first radiological evaluation. The disease control rate (DCR) was 89%. The total side effect rate was 61.8% and most were relieved after treatment. Conclusion Programmed cell death protein‐1‐targeted immunotherapy is a safe and effective treatment for advanced primary hepatocellular carcinoma.
Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

Biologics are among the most commonly prescribed medications for several chronic inflammatory diseases. Tumor necrosis factor alpha inhibitors, more so than other agents, have been observed to cause drug‐induced liver injury. Additionally, because the approval and popularity of checkpoint inhibitors have grown, similar patterns of liver injury have been documented, with a majority of cases describing immune‐mediated hepatitis. Although the exact mechanism of injury is unknown, various host and medication characteristics play a role in the outcome of the molecular cascade invoked by biologics. Prognosis is usually favorable with cessation of the offending agent, but cases of acute liver failure requiring liver transplantation have also been observed. Therefore, algorithms have been created to assist clinicians in treating drug‐induced autoimmune hepatitis, mostly with corticosteroids. Additionally, case reports have documented successfully rechallenging patients with a different biologic without recurrence of liver injury, but data are limited. Further investigation is warranted regarding the potential for cross‐reactivity and mechanism of injury to develop guidelines to aid clinicians in further management of these patients.
Barriers to Early Diagnosis and Treatment of Familial Hypercholesterolemia: Current Perspectives on Improving Patient Care

Abstract Familial hypercholesterolemia (FH) is a frequent disorder associated with premature atherosclerotic cardiovascular disease. Different clinical diagnosis criteria are available, and cost of genetic testing has been reduced in the last years; however, most cases are not diagnosed worldwide. Patients with FH are at high cardiovascular risk and the risk can be reduced with lifelong lifestyle and pharmacological treatment. Statins and ezetimibe are available as generic drugs in most countries reducing the cost of treatment. However, the use of high-intensity statins combined with ezetimibe and PCSK9 inhibitors, if necessary, is low for different reasons that contribute to a high number of patients not reaching LDL-C targets according to guidelines. On the other hand, cardiovascular risk varies greatly in families with FH; therefore, risk stratification strategies including cardiovascular imaging is another element to consider for improving care and management of FH. There are numerous barriers depending on the awareness, knowledge, perception of risk, management and care of patients living with FH that impact in the diagnosis and treatment of the disorder. In this contemporary review, we analyze different barriers in the diagnosis and care of patients to improve patients’ care and prevention of atherosclerotic cardiovascular disease and describe recent advances and strategies to improve the gaps in the care of FH, including global collaboration and advocacy.
Inhaled Corticosteroids Prescribed for COPD Patients with Mild or Moderate Airflow Limitation: Who Warrants a Trial of Withdrawal?

Abstract COPD patients prescribed inhaled corticosteroids (ICS) outside guidelines should be targeted for ICS withdrawal. Within a primary care population of 209,618 we used a combination of digital search algorithm, individual record review, and clinical review to identify COPD patients suitable for a trial of ICS withdrawal. At most, 39% of COPD patients with mild or moderate airflow limitation prescribed ICS were suitable for withdrawal according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Recurrent exacerbations and reversible airway obstruction were the main reasons for patients’ unsuitability for withdrawal. Identifying COPD patients in whom ICS withdrawal should be considered presents a challenge to primary care clinicians.
Unraveling the High Activity of Ylide-Functionalized Phosphines in Palladium-Catalyzed Amination Reactions: A Comparative Study with CyJohnPhos and PtBu3

Comprehensive mechanistic insights into the activity of different catalysts based on different ligands are important for further ligand design and catalyst improvement. Herein, we report a combined computational and experimental study on the mechanism and catalytic activity of the ylide-substituted phosphine Cy3P–C(Me)PCy2 (keYPhos, L1) in C–N coupling reactions including a comparison with the established and often-applied phosphines CyJohnPhos (L2) and P(tBu)3 (L3). Density functional theory (DFT) calculations together with the possible isolation of several intermediates within the catalytic cycle demonstrate that L1 readily forms low-coordinated palladium complexes [such as L1·Pd(dba)], which easily undergo oxidative addition and subsequent amine coordination as well as reductive elimination. Due to the possible opening and closing of the P–C–P angle in L1, the steric bulk can be adjusted to the metal environment so that L1 retains its conformation throughout the whole catalytic cycle, thus leading to fast catalysis at room temperature. Comparative studies of the three ligands with Pd2dba3 as a Pd source show that only L1 efficiently allows for the coupling of aryl chlorides at room temperature. DFT studies suggest that this is mainly due to the reluctance/inability of L2 and L3 to form the catalytically active species under these reaction conditions. In contrast, the YPhos ligand readily forms the prereactive complex and undergoes the first oxidative addition reaction. These observations are confirmed by kinetic studies, which indicate a short induction period for the formation of the catalytically active species of L1, followed by fast catalysis. This behavior of L1 is due to its unique electronic and steric properties, which support low activation barriers and fast catalyst generation.
Protective Effects of Chlorogenic Acid on Cerebral Ischemia/Reperfusion Injury Rats by Regulating Oxidative Stress-Related Nrf2 Pathway

Introduction Cerebral ischemia-reperfusion (CI/R) injury is caused by blood flow recovery after ischemic stroke. Chlorogenic acid (CGA, 5-O-caffeoylquinic acid) is a major polyphenol component of Coffea canephora, Coffea arabica L. and Mate (Ilex paraguariensis A. StHil.). Previous studies have shown that CGA has a significant neuroprotective effect and can improve global CI/R injury. However, the underlying molecular mechanism of CGA in CI/R injury has not been fully revealed. Materials In this study, CI/R rat model was constructed. The rats were randomly divided into nine groups with ten in each group: Control, CGA (500 mg·kg-1), CI/R, CI/R + CGA (20 mg·kg-1), CI/R + CGA (100 mg·kg-1), CI/R + CGA (500 mg·kg-1), ML385 (30 mg·kg-1), CI/R + ML385 (30 mg·kg-1), CI/R + CGA + ML385. Cerebral infarction volume was detected by TTC staining. Brain pathological damage was detected by H&E staining. Apoptosis of cortical cells was detected by TUNEL staining. The expression of related proteins was detected by RT-qPCR and Western blotting. Results Step-down test and Y maze test showed that CGA dose-dependently mitigated CI/R-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins (cleaved caspase 3 and caspase 9). Additionally, CGA reversed CI/R induced inactivation of Nrf2 pathway and promoted Nrf2, NQO-1 and HO-1 expression. Nrf2 pathway inhibitor ML385 destroyed this promotion. Discussion All the data indicated that CGA had a neuroprotective effect on the CI/R rats by regulating oxidative stress-related Nrf2 pathway.
Workshop on Adverse Drug Reaction Reporting, Pharmacovigilance and Its Implementation in Cancer Hospital in Nepal: An Event Report

Abstract Adverse drug reactions are crucial events related to drug usage that ought to be reported and the effects of which can be minimized by careful and vigilant use of drugs. Pharmacovigilance refers to the systematic practice of reporting, assessing and preventing such events. Although such practice is vital in any healthcare system, its actual implementation has been found to be very limited in a country like Nepal. With the aim of disseminating information about such events and the role of healthcare professionals in pharmacovigilance, a one-day workshop was organized with international and national speakers on this subject at Nepal Cancer Hospital and Research Center, Lalitpur, Nepal, which also has a regional pharmacovigilance center . The workshop included lectures and hands-on training and had an audience from diverse fields of healthcare such as pharmacy, medical, surgical and radiation oncology, pathology and nursing staff. The feedback from the participants revealed that practical demonstration and hands-on training with extensive topic coverage were the best feature of the workshop, while less interaction during the lectures was a source of dissatisfaction with a recommendation to conduct more events focused on similar topics in the future.
Relationship Between Pain Reduction and Improvement in Health-Related Quality of Life in Patients with Knee Pain Due to Osteoarthritis Receiving Duloxetine: Exploratory Post Hoc Analysis of a Japanese Phase 3 Randomized Study

Purpose This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT02248480) investigated relationships between changes in pain severity and changes in health-related quality of life (HRQoL) in duloxetine-treated patients with knee osteoarthritis (OA). Patients and Methods Patients with knee OA and Brief Pain Inventory (BPI) average pain score ≥4 received duloxetine 60 mg/day or placebo for 14 weeks. Spearman rank correlation coefficients were calculated for change in pain severity, as assessed by the BPI, and change in HRQoL, as assessed by the items of the (i) 36-item Short-Form Health Survey (SF-36; a generic measure of HRQoL) and (ii) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; an OA-specific measure of HRQoL). Results After 14 weeks of treatment, there was a significantly greater improvement (p<0.001) for duloxetine (n=177) vs placebo (n=176) in BPI average pain severity score and significantly greater improvements (p<0.01) for duloxetine vs placebo for 5 of the 8 SF-36 domains (including the Role-Physical, Bodily Pain, and Physical Functioning domains) and all 24 individual WOMAC items. The correlation between BPI change from baseline and SF-36 item change from baseline was statistically significant (p<0.05) for 2 of the 8 SF-36 items (Bodily Pain, Physical Functioning) in duloxetine-treated patients. The correlation between BPI change from baseline and WOMAC item change from baseline was statistically significant for 22 of the 24 WOMAC items in duloxetine-treated patients. Conclusion This post hoc analysis suggested that the pain reduction observed in duloxetine-treated patients with knee OA was associated with improvements in OA-specific aspects of HRQoL, ie, pain and physical functioning.
Postoperative non‐steroidal anti‐inflammatory drugs and anastomotic leakage after gastrointestinal anastomoses: Systematic review and meta‐analysis

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are commonly used to control postoperative pain; however, their postoperative use has been associated with anastomotic leakage after gastrointestinal surgery. This systematic review and meta‐analysis aimed to determine the correlation between the use of NSAIDs and anastomotic leakage.
The Effect of Visual Working Memory Training Could Transfer Across Stimuli

Background Working memory, as a fundamental cognitive ability, has been shown to improve with learning. However, little is known about the learning effect of visual working memory training and its generalization to other stimuli and tasks. Methods In the present study, we utilized a delayed match-to-sample task to measure the working memory of faces and houses. Subjects were trained ten days on this task and were tested on the same task and a memory span task before and after the training. Results The results showed that training significantly increased the accuracy of visual working memory. More importantly, such a learning effect could partly transfer to a visual working memory task with different stimuli. However, the learning effect may not transfer to a memory span task. Conclusion Our findings demonstrate that training might influence the common processing of different stimuli in a visual working memory task.
Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer

Background ESR1 mutation and its possible relation to endocrine therapy resistance in ER-positive breast cancers have been studied with respect to genetic sequencing data from Western patients but rarely from Chinese patients. This study aimed to investigate the prevalence of ESR1 mutation in Chinese primary and metastatic ER-positive breast cancer. Methods Tumor samples from 297 primary breast cancer (PBC) patients and blood samples from 43 metastatic breast cancer (MBC) patients were obtained to perform whole exon sequencing of the ESR1 gene through next-generation sequencing (NGS). Clinicopathological features of MBC patients were listed and grouped to explore potential factors in ESR1 mutations. Results A total of 15 ESR1 variations, including 11 point mutations, 1 in-frame deletion mutation, 1 synonymous mutation, and 2 amplifications were identified in 13 patients. The ESR1 mutation rate was 1% (3/297) in PBC patients and 18.6% (8/43) in MBC patients. All ESR1 point mutations occurred in the estrogen receptor ligand-binding domain. Six (54.5%) of the 11 point mutations were hotspot mutations. Among all MBC patients, the ESR1 mutation rate in those who had a treatment history using aromatase inhibitors (AI) was significantly higher than those who did not (25.8% versus 0%, P=0.015). Moreover, the ESR1 mutation rate in those who received AI treatment over a period of 12 months was significantly higher than in those whose treatment lasted less than 12 months [36.3% versus 0%, P<0.001]. Conclusion ESR1 mutations were more frequently observed in the circulating cell-free DNA of MBC patients than in PBC patients among the Chinese cohort, and higher among those pretreated with AI, suggesting that such mutations may undergo selection during AI treatment.
The Danish Multidisciplinary Hip Fracture Registry 13-Year Results from a Population-Based Cohort of Hip Fracture Patients

Aim of the Registry The aim of the Danish Multidisciplinary Hip Fracture Registry (DMHFR) is to collect data on processes of treatment, nursing care and rehabilitation as well as outcomes for patients with hip fracture in Denmark, and thereby monitor and improve the quality. Study Population Hip fracture patients at age 65 or older that have undergone surgery with arthroplasty or internal fixation since 2004. Main Variables DMHFR collects quality indicators and descriptive variables. Quality indicators include eight process performance measures within treatment, nursing care and rehabilitation, reflecting recommendations from the national clinical guideline for hip fracture patients, and three outcome measures including survival within 30-days, unplanned acute readmission within 30 days and reoperation within 2 years. Descriptive variables include a number of patient- and surgery-related characteristics. All data are collected prospectively. Results By the end of 2018, the DMHFR included 86,438 hip fracture patients. Since 2006, all hospital departments in Denmark, treating patients with hip fracture, have reported improvement in quality of care and improvement in survival, and reoperation over time as well as high completeness of variables registration. Conclusion The DMHFR is a well-established nationwide clinical registry, which plays a key role for monitoring and improving hip fracture care in Denmark. The registry can further be linked to a range of other nationwide registries in order to answer a number of relevant clinical research questions.
Treatment Mode Preferences in Rheumatoid Arthritis: Moving Toward Shared Decision-Making

Purpose Current knowledge of the reasons for patients’ preference for rheumatoid arthritis (RA) treatment modes is limited. This study was designed to identify preferences for four treatment modes, and to obtain in-depth information on the reasons for these preferences. Patients and Methods In this multi-national, cross-sectional, qualitative study, in-depth interviews were conducted with adult patients with RA in the United States, France, Germany, Italy, Spain, Switzerland, the United Kingdom, and Brazil. Patients’ strength of preference was evaluated using a 100-point allocation task (0–100; 100=strongest) across four treatment modes: oral, self-injection, clinic-injection, and infusion. Qualitative descriptive analysis methods were used to identify, characterize, and summarize patterns found in the interview data relating to reasons for these preferences. Results 100 patients were interviewed (female, 75.0%; mean age, 53.9 years; mean 11.6 years since diagnosis). Among the four treatment modes, oral administration was allocated the highest mean (standard deviation) preference points (47.3 [33.1]) and was ranked first choice by the greatest percentage of patients (57.0%), followed by self-injection (29.7 [27.7]; 29.0%), infusion (15.4 [24.6]; 16.0%), and clinic-injection (7.5 [14.1]; 2.0%). Overall, 56.0% of patients had a “strong” first-choice preference (ie, point allocation ≥70); most of these patients chose oral (62.5%) vs self-injection (23.2%), infusion (10.7%), or clinic-injection (3.6%). Speed and/or ease of administration were the most commonly reported reasons for patients choosing oral (52.6%) or self-injection (55.2%). The most common reasons for patients not choosing oral or self-injection were not wanting to take another pill (37.2%) and avoiding pain due to needles (46.5%), respectively. Conclusion These data report factors important to patients regarding preferences for RA treatment modes. Patients may benefit from discussions with their healthcare professionals and/or patient support groups, regarding RA treatment modes, to facilitate shared decision-making.
Nonsuicidal Self-Injury: Diagnostic Challenges And Current Perspectives

Abstract Nonsuicidal self-injury (NSSI) involves deliberate and intentional injury to body tissue that occurs in the absence of suicidal intent. Typical examples here might include self-cutting, burning, or self-hitting. Behavior of this kind is fundamentally unsettling as well as perplexing. It is also the case that self-harming behavior of any kind runs counter to a fundamental survival instinct. In the past, behaviors such as these were viewed as self-mutilation and considered to be a form of attenuated suicide. Much has changed over time, culminating in the entry of NSSI Disorder into DSM-5 as a condition in need of further study. In this review we describe the evolution of the NSSI construct and consider current issues in its diagnosis and assessment.
Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice

Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting and used rodents to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as hepatic steatosis, inflammation, lipotoxicity, and fibrosis. The absorption, tissue distribution, and excretion of icosabutate was investigated in rats along with its effects in mouse models of insulin resistance (ob/ob) and metabolic inflammation/NASH (high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice) and efficacy was compared with synthetic peroxisome proliferator‐activated receptor α (PPAR‐α) (fenofibrate) and/or PPAR‐γ/(α) (pioglitazone and rosiglitazone) agonists. Icosabutate was absorbed almost entirely through the portal vein, resulting in rapid hepatic accumulation. Icosabutate demonstrated potent insulin‐sensitizing effects in ob/ob mice, and unlike fenofibrate or pioglitazone, it significantly reduced plasma alanine aminotransferase. In high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice, icosabutate, but not rosiglitazone, reduced microvesicular steatosis and hepatocellular hypertrophy. Although both rosiglitazone and icosabutate reduced hepatic inflammation, only icosabutate elicited antifibrotic effects in association with decreased hepatic concentrations of multiple lipotoxic lipid species and an oxidative stress marker. Hepatic gene‐expression analysis confirmed the changes in lipid metabolism, inflammatory and fibrogenic response, and energy metabolism, and revealed the involved upstream regulators. In conclusion, icosabutate selectively targets the liver through the portal vein and demonstrates broad beneficial effects following insulin sensitivity, hepatic microvesicular steatosis, inflammation, lipotoxicity, oxidative stress, and fibrosis. Icosabutate therefore offers a promising approach to the treatment of both dysregulated glucose/lipid metabolism and inflammatory disorders of the liver, including NASH.
Measuring cognitive change in Alzheimer's disease clinical drug trials.

: In the following paper the cognitive measures used in clinical trials of drugs for Alzheimer's disease are reviewed. The potential benefits of employing innovative tests that map cognitive domains poorly indexed by traditional measures such as the ADAS-cog are considered. Finally, issues pertaining to the cognitive breadth of any proposed new instrument are discussed, as well as the clinical relevance of cognitive change.