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Penglu Wei, Kuo Yang, Dehuai Long, Yupei Tan, Wenlong Xing, Xiang Li, Hongli Wu,
Published: 23 November 2021
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.741261

Abstract:
Objective: To compare the efficacy and safety of conventional treatments (CTs) to those that included traditional Chinese medicine injections (TCMIs) in patients with combined coronary heart disease and heart failure (CHD-HF).Methods: Eight electronic literature databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, China National Knowledge Infrastructure Database, Chinese Scientific Journal Database, Wanfang Database, Chinese Biomedical Database) were searched from their inceptions to May 18, 2021, to identify relevant randomised controlled trials (RCTs). The primary outcomes analyzed included the total effectiveness rate and adverse events (ADRs). The secondary outcomes analyzed included the left ventricular ejection fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), and 6-min walk test (6MWT). Cochrane risk-of-bias tool was used to assess quality of the analyzed RCTs. Stata and OpenBUGS software were used to prior to the systematic review and network meta-analysis.Results: Sixty-one eligible trials involved 5,567 patients and one of the following 15 TCMIs: Shuxuetong, Shenmai, Shenfu, Shengmai, Danshenduofenyansuan, Danhong, Dazhuhongjingtian, Xinmailong, Dengzhanxixin, Gualoupi, Shuxuening, Xuesaitong, Yiqi Fumai, Shenqi Fuzheng, Huangqi. Network meta-analysis revealed that Shuxuetong injection + CT group was superior to CT only in improving the total effectiveness rate [odds ratio (OR): 7.8, 95% confidence interval (CI): 1.17–27.41]. Shenmai injection + CT was superior to CT only for LVEF (OR: 8.97, CI: 4.67–13.18), Xinmailong injection + CT was superior to CT only for NT-proBNP (OR: −317.70, CI: −331.10–303.10), Shenqi Fuzheng injection + CT was superior to CT only for BNP (OR: −257.30, CI: −308.40–242.80); and Danhong injection + CT was superior to CT only for 6MWT (OR: 84.40, CI: 62.62−106.20). Different TCMIs had different toxicity spectrums.Conclusion: TCMIs combined with CT are better than CT alone in treating CHD-HF. Different TCMIs improve different outcomes. Additional properly designed RCTs are needed to conduce a more refined comparison of various TCMIs.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021258263].
, Fasih Haider, Sofia De La Fuente Garcia, Davida Fromm, Brian MacWhinney
Published: 21 October 2021
Frontiers in Computer Science, Volume 3; https://doi.org/10.3389/fcomp.2021.780169

Abstract:
Editorial on the Research Topic Alzheimer's Dementia Recognition through Spontaneous Speech The need for inexpensive, safe, accurate and non-invasive biomarkers for Alzheimer’s disease (AD) has motivated much current research (Mandell and Green, 2011). While diagnosis and evaluation of interventions are still primarily done through clinical assessment, “digital biomarkers” have attracted increasing interest. AI-enabled speech and language analysis has emerged as promising such biomarker for the assessment of disease status (de la Fuente Garcia et al., 2020). While a number of studies have investigated speech and language features for the detection of AD and mild cognitive impairment (Fraser et al., 2016), and proposed various signal processing and machine learning methods for this task (Petti et al., 2020), the field still lacks balanced benchmark data against which different approaches can be systematically compared. This Research Topic addresses this issue by exploring the use of speech characteristics for AD recognition using balanced data and shared tasks, such as those provided by the ADReSS Challenges (Luz et al., 2020, Luz et al., 2021). These tasks have brought together groups working on this active area of research, providing the community with benchmarks for comparison of speech and language approaches to cognitive assessment. Reflecting the multidisciplinary character of the topic, the articles in this collection span three journals: Frontiers of Aging Neuroscience, Frontiers of Computer Science and Frontiers in Psychology. Most papers in this Reseach Topic target two main tasks: AD classification, for distinguishing individuals with AD from healthy controls, and cognitive test score regression, to infer the patient’s Mini Mental Status Examination (MMSE) score (Folstein et al., 1975). Of the twenty papers published in this collection, 14 used the ADReSS dataset (Luz et al., 2020), by itself or in combination with other data. The ADReSS dataset is a curated subset of DementiaBank’s Pitt Corpus, matched for age and gender so as to minimise risk of bias in the prediction tasks. The data consist of audio recordings of picture descriptions elicited from participants using the Cookie Theft picture from the Boston Diagnostic Aphasia Examination (Becker et al., 1994; Goodglass et al., 2001), transcribed and annotated using the CHAT coding system (MacWhinney, 2021). The papers covered a variety of approaches and models. Antonsson et al. aimed to distinguish progressive cognitive decline from stable cognitive impairment using semantic analysis of a discourse task. Support Vector Machine (SVM) models performed best (AUC = 0.93) with both semantic verbal fluency scores and disfluency features from the discourse task. Discourse analysis revealed significantly greater use of unrelated speech in the progressive cognitive decline group compared with the stable group and healthy controls (HC). Clarke et al. examined the impact of five different speech tasks (picture description, conversation, overlearned narrative recall, procedural recall, novel narrative retelling) on classification of 50 participants: 25 HC, 13 mild AD, 12 MCI. Linguistic features (n = 286) were automatically extracted from each task and used to train SVMs. Classification accuracy varied across tasks (62–78% for HC vs AD + MCI, 59–90% for HC vs AD, 50–78% for HC vs MCI) as did which features were most important to the classification. Balagopalan et al. used linguistic and acoustic features derived from ADReSS speech and transcripts. They tuned a pretrained BERT model (Devlin et al., 2018) and compared its features to clinically-interpretable language features. The BERT model outperformed other features and achieved accuracy of 83.33% for AD classification. A ridget regressor with 25 pre-engineered features obtained root mean squared error (RMSE) of 4.56 in MMSE prediction. Chlasta and Wołk used VGGish, a pretrained a Tensorflow model for audio feature extraction and a custom raw waveform based convolutional neural (CNN), DemCNN, to model the acoustic characteristics of AD speech on the ADreSS dataset. DemCNN provided better results than VGGish (Hershey et al., 2017) and achieved an accuracy of 62.5% using only the acoustic information. De Looze et al. combined structural MRI, neuropsychological testing and conversational features to explore temporal characteristics of speech in a collaborative referencing task. They investigated associations with cognitive function and volumetry in brain areas known to be affected by MCI and AD. A linear mixed-effect model was built for data of 32 individuals to assess the predictive power of conversational speech features to classify clinical groups. They found that slower speech and slower turn-taking may provide useful markers for early detection of cognitive decline. Guo et al. emphasized the importance of large normative datasets in training accurate and reliable machine learning models for dementia detection. They incorporated a new corpus of Cookie Theft picture descriptions (HC = 839, NC = 115) from the Wisconsin Longitudinal Study (Herd et al., 2014) to train a BERT model and demonstrated improved performance on the detection task compared with results of the model trained on the ADReSS data alone (82.1% vs 79.8, accuracy, and 92.3 vs 88.3% AUC). Haulcy and Glass investigated the use of i-vectors and x-vectors (Snyder et al., 2018), which are acoustic features originally devised for speaker identification, and linguistic features to tackle AD detection and MMSE prediction. The i-vectors and x-vectors were pre-trained on existing datasets unrelated to AD as well as in-domain data. Several classification and regression models were tested, yielding 85.4% accuracy in AD detection with SVM and Random Forests, and 4.56 RMSE with a gradient boosting regressor. Linguistic and acoustic features were modelled separately. The former...
Luchang Cao, Xinmiao Wang, Heping Wang, Jingyuan Wu, Taicheng Lu, Shixin Li,
Evidence-Based Complementary and Alternative Medicine, Volume 2021, pp 1-6; https://doi.org/10.1155/2021/5236454

Abstract:
Introduction. Brucea javanica oil emulsion injection (BJOEI) is an antitumor drug extracted from the traditional Chinese medicinal plant Brucea javanica, which has broad prospects as an adjuvant treatment for gastric cancer (GC); however, its efficacy and safety are still controversial. We plan to conduct a systematic review and meta-analysis to summarise the clinical efficacy and safety of BJOEI in the treatment of GC and provide credible evidence for the clinical application and subsequent studies of BJOEI. Methods and Analysis. This systematic review will include articles identified by electronically searching the following databases: PubMed, EMBASE, CENTRAL, Web of Science, the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Scientific Journals Database (VIP Database) from inception to 31 July 2021. The primary outcomes of this research will be the clinical total effective rate, performance status, and adverse drug reactions (ADRs). The systematic review will be performed using RevMan 5 software. Finally, we will use the Grading of Recommendations Assessment, Development and Evaluation System (GRADE) to assess the quality of evidence. Ethics and Dissemination. Ethical approval is not required for literature-based studies. The results of this systematic review will be published in a peer-reviewed journal. PROSPERO registration number: CRD42021265646.
Manuel Urina-Jassir, Tatiana Pacheco-Paez, Carol Paez-Canro, Miguel Urina-Triana
Published: 1 October 2021
by BMJ
Abstract:
Objectives We aim to describe the frequency and type of adverse drug reactions (ADRs) in patients on statins in published studies from Latin American (LATAM) countries. Design Scoping review. Methods A literature search was conducted in three databases (PubMed, EMBASE and LILACS) in addition to a manual search in relevant journals from LATAM universities or medical societies. A snowballing technique was used to identify further references. Randomised controlled trials (RCTs) and observational studies between 2000 and 2020 were included. Studies were considered eligible if they included adults on statin therapy from LATAM and reported data on ADRs. Data on ADRs were abstracted and presented by study design. Results Out of 8076 articles, a total of 20 studies were included (7 RCTs and 13 observational studies). We identified three head-to-head statin RCTs, two statin-versus-policosanol RCTs and only two placebo-controlled trials. The statin-related ADRs frequency ranged from 0% to 35.1% in RCTs and 0% to 28.4% in observational studies. The most common ADRs were muscle-related events including myalgia and elevated creatine phosphokinase. Other reported ADRs were gastrointestinal symptoms, headache and altered fasting plasma glucose. Conclusions We identified differences in the frequency of ADRs in both observational studies and RCTs from LATAM countries. This could be due to the absence of standard definitions and reporting of ADRs as well as differences among the study’s interventions, population characteristics or design. The variability of ADRs and the absence of definitions are similar to studies from other geographical locations. Further placebo-controlled trials and real-world data registries with universal definitions should follow.
Yogi Ginanjar, Nita Hernita, Wulan Riyadi
Indonesian Community Service and Empowerment Journal (IComSE), Volume 2, pp 165-171; https://doi.org/10.34010/icomse.v2i2.5376

Abstract:
UKM Sehati which is used as a partner in this PKM has problems that are of special concern to find solutions. Partners do not have permanent employees who can maintain product quality, so processed products are often different from the previous taste and texture. Employees do not have extensive knowledge of recording and bookkeeping, so that the resulting financial statements are not in accordance with accounting standards. The production equipment used is still simple, both for processing aleksis (krispi catfish) and shredded catfish. The sealer machine for gluing the packaging is too small, causing the product resistance to be not optimal. The marketing that has been done has not touched the online market. The product does not yet have a halal label and nutritional value information so that the product cannot enter minimarkets and even supermarkets. Mitra's knowledge of catfish farming as a raw material has not been maximized, which causes the catfish mortality rate to reach 15%. Based on the findings regarding the problem, the priority is to find solutions to problems in improving various aspects. Among them are managerial aspects related to finance and human resources in an effort to increase community capacity. Furthermore, the technological aspects in an effort to improve product quality. Changes in marketing aspects towards digitalization and broader marketing aspects by obtaining halal labels and information on nutritional values. The specific goals and targets in this community service are to assist Sehati SMEs in improving product quality and competitiveness through the use of technology and managerial management. The method used in an effort to implement the solution above is by holding partner bookkeeping training every 2 weeks, training on the use of deep frying machines, ADR MPD 140 machines and sealer machines (so that product durability is longer and the production process is more effective and efficient), making management information system, create social media (facebook and instagram), join various e-commerce (shopee, Bukalapak, tokopedia and others), create product information website, participate in culinary exhibitions and bazaars, facilitate the inclusion of halal logos and value information nutrition in packaging, and holding training on catfish farming so that the results are maximized. The output produced is in the form of publications in the form of journals and intellectual property rights.
Kanoot Jaruthamsophon, Paul J. Thomson, Chonlaphat Sukasem, Dean J. Naisbitt, Munir Pirmohamed
Annual Review of Pharmacology and Toxicology, Volume 62; https://doi.org/10.1146/annurev-pharmtox-052120-014115

Abstract:
Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Ibtisam @ Ilyana Ilias, Rusni Hassan, Salina Kassim, Elistina Abu Bakar
UUM Journal of Legal Studies, Volume 12, pp 61-88; https://doi.org/10.32890/uumjls2021.12.2.4

Abstract:
This study examines the redress mechanisms accessible to aggrieved consumers dealing with various consumer credit providers in Malaysia. The existing legal and institutional framework characterised by the piecemeal approach has led different groups of consumers to varying levels of access, which can be superior or inferior to one another. The study employs a doctrinal legal research methodology in analysing the two alternative dispute resolution bodies, namely, the Ombudsman for Financial Services, and the Tribunal for Consumer Claims. Primary sources of law, namely, the Consumer Protection Act 1999, the Financial Services Act 2013, the Financial Services (Financial Ombudsman Scheme) Regulation 2014, the Hire-Purchase Act 1967, the Moneylenders Act 1951, and the Pawnbrokers Act 1972, are meticulously analysed along with secondary sources of law that principally comprise journal articles. The study reveals disparities in terms of access to cheap and simple redress mechanisms by various categories of consumers who are aggrieved by the actions of credit providers. The position of bank consumers and those entering into credit sale is accounted for, as there are particular ADR bodies established under relevant legislations to hear their respective disputes. On the contrary, the position of those who wish to lodge claims against moneylenders, pawnbrokers or credit companies offering hire-purchase is problematic. Several recommendations are proposed to resolve this opacity inter alia by referring to the approach adopted by South Africa. This study is significant in ensuring fair access to inexpensive and hassle-free dispute resolutions for all financial consumers, irrespective of the nature of their consumer credit transactions.
Annapurna Kolupoti, Ananya Chakraborty, Shahistha K
Current Drug Safety, Volume 16, pp 1-1; https://doi.org/10.2174/1574886316666210609115148

Abstract:
Introduction: An adverse drug reaction case report refers to a scientific publication that is written by a health care professional who suspects a causal relationship between a drug and an adverse drug reaction (ADR). ADR case reports help to identify potential risks associated with the use of the drug. Most of the case reports do not mention reporting the ADR to regulatory authorities. With this objective, the aim of this study was to analyze the number of Adverse Drug Reaction (ADR) published as case reports (PubMed indexed journals) from January 2018 to June 2019 and observe if they are translated into a regulatory framework like Vigibase and package inserts. Materials And Methods: 321 ADRs were obtained with the keywords “Adverse Drug Reaction.” Out of those, 158 were independently extracted by two investigators, observed and categorized according to classes of the drugs, geographic location, severity, hospitalization, completeness of ADR, and whether they were reported to the regulatory authority (VigiBase) or listed in the package insert. Literature review articles were excluded. Results: Out of the 158 ADRs, antibiotics accounted for 12.65%, CNS drugs and monoclonal antibodies accounted for 11.39%, anticancer drugs for 9.49%, CVS drugs for 4.43%, anti-virals for 3.79%, and the others for 45.56%. According to geographic region, 26 ADRs published were from USA, 4 from Australia, 3 from Italy, 17 from India, 9 from Turkey, 1 from Singapore and the UK, 20 from China, 2 from Denmark and Canada, 10 from Japan, 9 from France, 1 from Austria, 5 from Korea, 3 from South America, and 2 from Switzerland. Depending upon the severity, causality assessment was performed for 45 ADRs only; it was not performed for 113 ADRs. 41.13% of patients (from 65 case reports) were hospitalized. Among the 158 ADRs, 14 ADRs were not found in VigiBase. 32 ADRs were not mentioned in the drug package inserts. When categorized according to the completeness of case reports, weight accounted for 1.89%, lab values and procedure for diagnosis accounted for 96.8%, risk factors for 95.56%, prior exposure for 88.60%, post ADR status for 60.12%, and the start-stop medication, route of administration, first dose, last dose, and the duration of illness accounted for 100%. Conclusion: Depending upon our observation, we have noticed that there is a deficiency in reporting of suspected ADR to the regulatory authorities. Reporting can be included as mandatory criteria for ADR case reports. Also, there is an increased need for various healthcare workers to be aware about reporting ADR.
R. Grassa, N. El Amri, S. Lataoui, O. Jomaa, H. Zeglaoui, K. Baccouche, E. Bouajina
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 923.2-923; https://doi.org/10.1136/annrheumdis-2021-eular.3273

Abstract:
Background: Around 10 million people worldwide contract tuberculosis (TB) every year. According to the World Health Organization (WHO), approximately one-quarter of the world’s population is latently infected with Mycobacterium tuberculosis. Its treatment is extremely long and patients may experience a variety of adverse reactions. Objectives: The aim of this study was to assess the different adverse drug reactions (ADR’s) in patients treated with first-line anti-tubercular drugs. Methods: This retrospective study included 45 cases of TB followed in the Rheumatology department of Farhat Hached hospital in Sousse, Tunisia, over a period of 22 years (1998-2020). Results: The mean age was 52.2 ± 17.72 years [14-95 years]. These were 19 men (42.2%) and 26 women (57.8%).The different locations of tuberculosis were as follows: pulmonary for 5 patients (11.1%), spinal for 26 patients (57.8%), articular for one patient (2.2%), urinary for two (4.4%), and multifocal for 8 patients (17.8%). An anti-tuberculosis treatment (based on quadrytherapy: Rifadine(R), Isoniazide(I), Pyrazinamide (Z) and Ethambutol (E)during 2 months, followed by biotherapy based on (R)and (I) was prescribed for an average duration of 10.85 months [6-24 months]. ADR’s were observed in 53.33% of patients. Abdominal pain and nausea were detected in 5 cases (11.1%). Hepatic cytolyse was noticed in 8 cases (17.8%) under (R). Cholestatic hepatitis occurred in 9 cases (20%) under (R). Asymptomatic Hyperuricemia was detected in 15 cases (33.3%) with (E). Two cases of toxiderma were detected: the first under (E) and the second under (E) + (Z). Ethambutol was responsible for a case of DRESS syndrome and a case of drug-induced hepatitis. One case of hemolytic anemia had occurred under (R). A sensorineural hearing loss was noted under streptomycin in one case. No fatal side effects were observed. These ADR’s were reversible in all cases. Conclusion: The treatment of TB can cause a variety of ADRs’. Early recognition by active surveillance and appropriate management of these ADRs’ might improve adherence and treatment success. References: [1]Prasad, R., Singh, A., & Gupta, N. Adverse drug reactions in tuberculosis and management. Indian Journal of Tuberculosis, 66(4), 520–532 (2019). Disclosure of Interests: None declared
, M.A. Sheela, Lovenesh Kumar, Abhishek Sharma, Aman Jain, K. Nagarajan
Published: 22 April 2021
Materials Today: Proceedings, Volume 47, pp 70-75; https://doi.org/10.1016/j.matpr.2021.03.621

The publisher has not yet granted permission to display this abstract.
, Tino Emanuele Poloni, Lucia Pelloni, , Katia Varani, Fabrizio Vincenzi, Pier Andrea Borea, Stefania Gessi
Published: 22 March 2021
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.652455

Abstract:
According to DSM5, the term neurocognitive disorder (NCD) emphasizes that the cause of mental deficit lies in a pathology affecting neuronal circuits. The early clinical stages of NCD (mild-NCD/MCI) are characterized by functional preservation of everyday activities. Instead, if the disorder has a functional impact it is defined as major-NCD (dementia). On the other hand, the definition of the underlying pathology allows for the etiological classification of NCD (American Psychiatric Association, 2013; Sachdev et al., 2015). Based on the pathological deposition of proteins in brain tissue, NCD due to AD is characterized by a dual proteinopathy in which neurodegeneration is associated with the deposition of amyloid and phosphorylated TAU protein (pTAU). AD is the main age-related degenerative NCD progressively involving memory, complex attention, executive functions, language, and visual-perceptual functions. Personality and behavioural changes are also frequent further complicating the clinical course. On the other hand, due to the late involvement of the movement centers, motor function is usually spared until the most advanced stages of the disease. The AD syndromic evolution reflects the progressive spread of pTAU pathology from the allocortex (entorhinal cortex and hippocampus) to the neocortex (Elahi and Miller, 2017; Hanseeuw et al., 2019). Observing the neuropathology of AD is the starting point for deciphering its pathophysiological mechanisms and, therefore, identifying the biomarkers of the disease and the possible therapeutic targets. The macroscopic pathological feature characterizing advanced AD is diffuse brain atrophy due to widespread neurodegeneration causing synaptic and neuronal loss. Actually, the disease begins decades earlier with amyloid accumulation in the neocortex but amyloid deposition, which is very common even in physiological aging, is not sufficient to cause AD. The fundamental question is: what triggers neurodegeneration? Probably, the excess of amyloid-beta (Aβ) induces neurodegeneration through toxic oligomers. Indeed, soluble Aβ oligomers cause a synaptic reduction with a decrease in long-term potentiation and memory. Moreover, oligomers can reduce blood flow in brain capillaries and induce hyperphosphorylation of the AD-relevant epitopes of TAU protein (Selkoe and Hardy 2016; Nortley et al., 2019). Thus, Aβ load triggers neurodegeneration through oligomers which induce unbalanced activation of neuronal kinases resulting in excessive production of pTAU that, in turn, aggregates in pTAU toxic oligomers and spreads from its initial location in allocortex to neocortex. Together, oligomeric Aβ, synaptic pTAU aggregates and glial inflammatory activation are the main neurotoxic factors involved in the manifestation of a clinically relevant neurocognitive disorder (Perez-Nievas et al., 2013; Jack et al., 2018a). Typically, AD pathology shows extracellular accumulation of Aβ peptides (Aβ or senile plaques), as well as the hyperphosphorylated tau protein aggregates inside the dying neurons named neurofibrillary tangles (NFT) and neuropil threads (NT). Their combination constitutes the neuritic plaque (NP), which is the most typical feature of AD neuropathology. Thus, the neuropathological definition of AD requires a combination of scores for Amyloid, TAU (Braak stages), and NP (CERAD), which constitute the ABC criteria for the grading of AD related pathology (Mirra et al., 1991; Braak et al., 2006; Montine et al., 2012). Senile and neuritic plaques, consisting of protein and cellular debris, activate reactive and inflammatory processes by astrocytes and microglia which produce cytokines (IL-1β, IL-6) and NLRP3 inflammosome activation that, in turn, increase neurotoxic phenomena (Serrano-Pozo et al., 2016; Ising et al., 2019). On the basis of the neuropathological picture, several biomarkers have been developed for the in vivo definition of the pathology. Thus, the ATN system (Amyloid-TAU-Neurodegeneration) has been set up including 1) estimate of the amyloid load: Aβ decrease in cerebrospinal fluid (CSF) and/or Aβ cortical accumulation at amyloid-PET; 2) pTAU valuation: pTAU increase in CSF and/or pTAU cortical accumulation at TAU-PET; 3) extent of neurodegeneration: atrophic pattern at brain MRI and/or hypometabolism at FDG-PET and/or increase of total-TAU in CSF (Jack et al., 2018b; Chételat et al., 2020). These markers can allow for early diagnosis or even can identify those most at risk of developing AD in a preclinical phase (before mild-NCD) in order to implement timely therapeutic interventions (Dubois et al., 2016). Nonetheless, there is now no cure for AD and this approach poses ethical problems, as well as being invasive and expensive; therefore, an intensive search for biomarkers obtainable from peripheral blood is still in progress (Lewczuk et al., 2018; Molinuevo et al., 2018). The early mechanisms leading to Aβ accumulation and initial generation of toxic molecules are elusive and multiple, and belong to the individual trajectory of cerebral aging linked to non-modifiable genetic factors (AD-related polymorphisms, APO-E4 allele, and pathogenic mutations in PSN-1-2 and APP genes, and Williamson et al., 2009; Vermunt et al., 2019), and to modifiable factors related to the individual’s personal history including favorable behaviors (regular physical and mental activity, high education, healthy diet, social engagement) and harmful conditions (midlife obesity, diabetes, hypertension, smoke, excessive alcohol, and hearing loss) (Lourida et al., 2019; Livingston et al., 2020). Early pathogenesis of sporadic AD is quite complex. Just as there are different forms of hepatitis that lead to cirrhosis, there are different pathophysiological paths that lead to AD. However, the sine qua non for the development of AD pathophysiology is the accumulation of amyloid in the cerebral cortex. Indeed, many efforts are being made to reduce the presence of amyloid in the cerebral cortex, especially through the use of costly monoclonal antibodies (e.g., phase3 trials: Aducanumab, Gantenerumab; phase2 trial: Crenezumab). Actually, amyloid reduction is only one aspect of the therapeutic approach and there is increasing attention to non-amyloid targets with 121 agents having clinical trials in course for the treatment of AD (Cummings et al., 2020). Particularly, a new challenge is the development of immunotherapies capable of blocking the toxic pTAU species (Bittar et al., 2020). The multifactorial nature of the AD would require an early, long-lasting, and multi-dimensional therapeutic approach which should be personalized and based on the patient’s clinical and biomarker characteristics (Sperling et al., 2011; Cummings et al., 2018; Hara et al., 2019). The current possible intervention strategies to improve the AD course depend on the stage of pathology and progressively include: prevention measures (healthy and active lifestyle, reduction of detrimental factors), disease modifying treatments (reduction of Aβ load and toxic oligomers, containment of TAU phosphorylation, toxic pTAU species and neuroinflammation, enhancement of neuronal resilience), symptomatic therapies (modulation of synaptic functions and improvement of synaptic efficiency, and Long and Holtzman 2019). Nonetheless, it should be taken into account that many senile cases of AD present mixed pathologies and in the extreme stages of senility it becomes unrealistic to stem neurodegeneration. In this framework, adenosine receptors, especially in the hippocampus, constitute a new and interesting therapeutic target through which it is possible to modulate and improve synaptic activity, obtaining symptomatic and perhaps disease-modifying effects. Adenosine is an ubiquitous autacoid derived by ATP dephosphorylation, that modulates several responses in CNS, by activating four G-protein coupled receptors, A1, A2A, A2B, and A3 present on both neuronal and glial cells (Borea et al., 2018). This nucleoside is generated at both intra– and extracellular level following AMP dephosphorylation by 5′-nucleotidases and its extracellular concentration is regulated both from equilibrative nucleoside transporters as well as through exocytosis by neurons and astrocytes (Borea et al., 2016). Adenosine regulates several physiological functions including sleep, cognitive performances, and memory and its main role is to regulate neuron excitatory synaptic transmission by inhibitory A1 receptors and synaptic plasticity via facilitatory A2A receptors (Cunha, 2008; Cunha, 2016; Cieślak and Wojtczak, 2018). In particular, the A2A subtype, mainly present in striatal area, has been now recognized in other cerebral regions including cortex and hippocampus, where due to its expression at presynaptic level, it affects the release of excitatory neurotransmitters, like glutamate (Cunha et al., 1994; Lopes et al., 2002; Marchi et al., 2002). As for its synaptic expression in spite of episodic evidence (Canas et al., 2018), it is still debatable if there is A2A receptors expression in synapses, although it is well established that A2A receptors are located in hippocampal synapses, with a density about 20–time lower than in the striatum (Lopes et al., 2004; Rebola et al., 2005). Although in healthy human brains the A2A receptor may exert protective functions, by regulating other proteins as BDNF, its signaling is strongly modified in the hippocampus following aging (Rebola et al., 2003; Tebano et al., 2010; Temido-Ferreira et al., 2019; Temido-Ferreira et al., 2020). In this condition, there is a rise of A2A receptor and G proteins-coupling, leading to an increase in glutamate release, mGluR5-dependent NMDA receptor overstimulation, and enhanced calcium influx responsible for synaptic alterations and memory dysfunction (Temido-Ferreira et al., 2020). These findings suggest a role for this receptor subtype in the pathogenesis of different neurocognitive disorders and specifically AD (Costenla et al., 2011; Rebola et al., 2011; Horgusluoglu-Moloch et al., 2017; Temido-Ferreira et al., 2019). Indeed, synaptic dysfunction and damage are key features in early AD (Selkoe, 2002; Coleman et al., 2004). Interestingly, A2A receptor is overexpressed in both frontal cortex and hippocampus of aged and transgenic-AD animals as well as in AD patients (Lopes et al., 1999; Arendash et al., 2006; Albasanz et al., 2008; Espinosa et al., 2013; Li et al., 2015; Orr et al., 2015; Pagnussat et al., 2015; Gonçalves et al., 2019; Temido-Ferreira et al., 2020). APP/PS1 mouse model of AD amyloidosis show an upregulation and activation of A2A adenosine receptors hampering long-term synaptic potentiation (LTP) in hippocampal CA3 pyramidal cells (Viana da Silva et al., 2016). Several literature data report the use of pharmacological and genetic approaches to demonstrate that A2A adenosine receptors block prevents synaptic damage and cognitive impairments in animal models following Aβ exposure, suggesting that A2A receptor antagonists might reduce synaptotoxicity (Dall'Igna et al., 2007; Canas et al., 2009; Orr et al., 2018). Moreover, antagonism of A2A adenosine receptors in animal models of Tau pathology inhibits Tau hyperphosphorylation, hippocampal neuroinflammation, while protects spatial memory and hippocampal long-term depression (Laurent et al., 2016). Accordingly, overexpression of A2A adenosine receptors, in a tauopathy mouse model, increases tau hyperphosphorylation and consequent tau-dependent memory impairments (Carvalho et al., 2019). Adenosine, deriving from an increase of ecto-5′-nucleotidase (CD73) activity in animal model of early AD, induced memory deficits, LTP impairment and synaptic markers reduction in a CD73 or A2A adenosine receptor-dependent way (Gonçalves et al., 2019). Indeed, among the early mechanisms involved in memory deterioration, synaptic dysfunction and selective synaptic degeneration stand out as one of the more robust and reproducible events. In fact, the early works on neuropathological changes associated with dementia established the loss of synaptic markers as a key process (Terry et al., 1991). More recent work showed that the loss of synapses is indeed of the earliest neuropathological changes in the brains of MCI and early AD patients, namely in the hippocampus (Scheff et al., 2007; Scheff et al., 2015). Accordingly, animal studies confirmed that synaptic dysfunction is an early event at the onset of memory perturbations (Canas et al., 2009; Viana da Silva et al., 2016; Silva et al., 2018). This justifies the proposal that AD is a synaptic-based disease (Selkoe, 2002) and that synaptic modulators may be paramount to control early AD (Coleman et al., 2004). Another crucial role for the A2A adenosine receptor is its important ability to modulate glial cell functions, affecting pro-inflammatory cytokines release and neuroinflammation (Illes et al., 2020). Specifically, it plays an essential role in activated microglia, located near amyloid plaques typical of AD (Franco et al., 2020), where its upregulation is responsible for a raise of M1 microglial markers (IL-1β, IL-6, TNF-α) and its antagonism prevents hippocampal LTP impairments, as well as IL-1β production, paventing a regulatory function for it in reducing memory dysfunction (Colella et al., 2018; Franco et al., 2019). Several studies support a role of A2A receptor as drug target in both neurons and microglia to revert memory deficit and neurodegeneration in AD (Santiago et al., 2014; Cunha, 2016). Recently, it has been reported that A2A subtypes interact with NMDA receptors producing A2A-NMDA heteromers, mainly in microglia, characterized by bidirectional cross-antagonism, where A2A receptor inhibition decreases hyperactivation of glutamatergic signalling by blocking NMDA receptor-mediated currents (Rebola et al., 2008; Mouro et al., 2018; Franco et al., 2020; Temido-Ferreira et al., 2020). In addition, it forms important complexes with CB2 cannabinoid receptor subtypes, presenting cross-interaction, thus modifying the pathway of each other. In this heteromer, A2A receptor antagonism provides an increase in CB2 receptor activity suggesting, for the first time, that A2A receptor block rises the neuroprotective action of endocannabinoids important for AD therapy (Franco et al., 2019). Interestingly, these receptorial complexes were enhanced in a transgenic AD mouse model (Franco et al., 2020). Although these heteromers might have a role, recently, A2A receptor-mediated effects in AD-related features have been attributed to monomeric forms (Temido-Ferreira et al., 2020). Clinical data, based on the effect of caffeine consumption in elderly, encourage the use of A2A adenosine antagonists to prevent memory deficits. Indeed, caffeine is the most widely consumed psychostimulant substance, present in coffee, tea, cola, chocolate, and other foods, exerting benefical effects in dementia and AD (Eskelinen et al., 2009; Eskelinen and Kivipelto, 2010; Santos et al., 2010; Gelber et al., 2011; Liu et al., 2016; Sugiyama et al., 2016; Reyes and Cornelis, 2018; Domenici et al., 2019; Dong et al., 2020; Iranpour et al., 2020). Interestingly it has been reported that non-toxic doses/concentrations of caffeine mostly act on A2A receptors in the brain (Yu et al., 2009; Lopes et al., 2019). Accordingly, antagonism of A2A receptors is one of the main effects of caffeine (Jacobson et al., 2020). Specifically, coffee consumption correlated with reduction of cognitive function, with significant effects obtained with three cups of coffee per day (Ritchie et al., 2007; van Gelder et al., 2007). Indeed, a retrospective analysis during 20 years before AD development, revealed a negative correlation between coffee intake and disease diagnosis, with lower quantity of caffeine at day assumed by patients with AD in contrast to higher amounts of caffeine in control subjects (Maia and de Mendonca, 2002). Furthermore, a prospective work evaluating the effect of coffee intake assumed every day on AD development, showed a reduction of AD risk by 31%, following 5 years examination (Lindsay et al., 2002). In addition, lower caffeine levels were observed in plasma of mild cognitive impairments patients developing later dementia, in comparison to those who did not develop the disease. Therefore, high levels of caffeine were related to the lack of dementia development in a window of 2/4 years (Cao et al., 2012). Accordingly, a high daily consumption of 3–5 cups of coffee reduced the risk of dementia and AD of 65–70 and 62–64%, respectively, in comparison to a lower assumption (Eskelinen et al., 2009). More generally, caffeine intake was associated to the absence of dementia and cerebral injuries typical of AD and to an increase of long-term memories consolidation in humans (Gelber et al., 2011; Borota et al., 2014; Favila and Kuhl, 2014). In animal models of AD, administration of caffeine, has been associated to a reduced risk for memory decline and dysfunction, beta-amyloid production and tau hyperphosphorylation (Costa et al., 2008; Arendash et al., 2009; Canas et al., 2009; Cao et al., 2009; Eskelinen and Kivipelto, 2010; Santos et al., 2010; Laurent et al., 2014; Kaster et al., 2015; Kolahdouzan and Hamadeh, 2017). Finally, recent works support the utility of caffeine intake as antioxidant and antiinflammatory agent (Janitschke et al., 2019; Sinyor et al., 2020). However, it has to be remarqued that although caffeine is an abundant bioactive molecule in coffee beverages, these have over 2,000 other chemicals that may have biological effects. In this respect, it is interesting that it is the amounts of a caffeine metabolite, the obrominel, rather than caffeine levels in the CSF that correlate with amyloid/tau markers in demented patients (Travassos et al., 2015). Interestingly, the intake of chocolate, rich in the obromine, is inversely correlated with memory deterioration (Moreira et al., 2016). It is important to remarque that the neuroprotective effects of caffeine, associated to A2A adenosine receptor inhibition, have been observed also in Parkinson’s disease, where much work has been carried out to demonstrate safety of the first A2A adenosine receptor antagonist, istradefylline, recently launched as a new drug for this pathology in Japan (Nouriast) and in the United States (Nourianz) (Borea et al., 2016, Borea et al., 2017; Chen and Cunha, 2020). Istradefylline has been also shown to exert protective effects by reducing memory dysfunction in animal models of AD and for the future it would be crucial to determine whether it could also induce memory improvement in patients with AD (Orr et al., 2018). However, it should be underlined that istradefylline has a narrow therapeutic window in aging and experimental models of AD and PD, leading to the hypothesis that age and other factors may affect safety of A2A receptor antagonists. Finally, this opinion article has presented the main findings supporting the role of A2A adenosine receptor antagonists on AD. Even though further work is necessary to better elucidate the mechanisms involved in the shift of A2A receptor from beneficial target in normal synapses to detrimental one in aging and disease, its capability to modulate synaptotoxicity, glutamate-dependent NMDA signaling and calcium dysfunction, together with its effect on neuroinflammation, suggest a crucial role for its antagonism to prevent AD pathology. SM, SG, PAB, and TEP conceived the work and wrote the manuscript. LP, SP, FV, and KV contributed to writing and editing. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Albasanz, J. L., Perez, S., Barrachina, M., Ferrer, I., and Martín, M. (2008). 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Physiol. Genomics. 37, 199–210. doi:10.1152/physiolgenomics.90353.2008 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: A2A adenosine receptor, Alzheimer’s disease, biomarker, neuroinflammation, therapeutic target Citation: Merighi S, Poloni TE, Pelloni L, Pasquini S, Varani K, Vincenzi F, Borea PA and Gessi S (2021) An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?. Front. Pharmacol. 12:652455. doi: 10.3389/fphar.2021.652455 Received: 14 January 2021; Accepted: 17 February 2021; Published: 22 March 2021. Edited by: Reviewed by: Copyright © 2021 Merighi, Poloni, Pelloni, Pasquini, Varani, Vincenzi, Borea and Gessi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Stefania Merighi, [email protected]; Stefania Gessi, [email protected]
Jie Guo, Jia Zhu, , Juan Wang, Yaodan Jia
Published: 9 March 2021
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.627751

Abstract:
Background: Chinese medicine injection is wildly used in Acute Lung Injury and Acute respiratory distress syndrome (ALI/ARDS) treatment. However, what kinds of CMIs are more effective in the ALI/ARDS treatment is uncertain. Objectives: Compare the efficacy of different CMIs to identify the optimal one for the therapy of ALI/ARDS patients. Data sources: We searched the data up to April 30, 2020 from MEDLINE, EMBASE, The Cochrane Library, Web of Science, the China Science Journal Citation Report (VIP database), WanFang and the China National Knowledge Infrastructure Study selection: Randomized Clinical Trials assessed at least one of the following outcomes: mortality, Oxygenation Index, length of ICU stay, mechanical ventilation duration, APACHEⅡ score, SOFA score and Murray score, for adult patients of ALI/ADRS. Eligible Studies should also use CMIs as complementary therapies in addition to the standard treatment. Data extraction and synthesis: Two reviewers independently assessed the data. Then, we used a Bayesian random-effects network meta-analysis for data synthesis. Results: Twenty-six studies were selected (involved 2073 participants). Seven kinds of CMIs were evaluated. Compared with standard treatment, Xuebijing is associated with lower mortality. Tanreqing and Xuebijing have the best effect on improving the Oxygenation Index. Huangqi, Danshen, Tanreqing and Xuebijing can significantly reduce the APACHE II score (Huangqi works better than Xuebijing). Huangqi and Xuebijing have the best effect on reducing mechanical ventilation duration and Murray score, while Xuebijing has the best effect on shortening the length of ICU stay. Conclusions: As adjuvant drugs, Xuebijing, Tanreqing and Huangqi show certain effects on treating ALI/ARDS in different aspects.
Xinfu Cao, Mingxue Zhou, Hongxu Liu, Xiufen Chen, Xiang Li, Sihan Jia
Published: 22 February 2021
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.613922

Abstract:
Background: Shensong Yangxin capsule (SSYX) is a well-known traditional Chinese patent medicine for treating arrhythmia. Recently, a flurry of randomized controlled trials (RCTs) of SSYX combined with amiodarone (SSYX-amiodarone) was reported in the treatment of heart failure (HF) complicated by ventricular arrhythmia (VA) in China. However, these RCTs have not been systematically evaluated. Therefore, this study aimed to evaluate the efficacy and safety of SSYX-amiodarone in the treatment of heart failure complicated by ventricular arrhythmia (HF-VA). Methods: Seven electronic literature databases (the Cochrane Library, PubMed, EMBASE, China Biomedical database web, China National Knowledge Infrastructure Databases, Chinese Scientific Journal database and Wanfang database) were searched from their inceptions to June 1, 2020 to identify RCTs of SSYX-amiodarone in the treatment of HF-VA. The primary outcomes included the total effective rate and adverse events (ADRs). The secondary outcomes included the frequency of ventricular premature complexes, left ventricular ejection fraction, N terminal pro Btype natriuretic peptide (NT-proBNP), and QT dispersion (QTd). The quality of the included RCTs was assessed using the Cochrane risk-of-bias tool. All data was analyzed using RevMan 5.3 software. The registration number of this protocol is PROSPERO CRD42020196689. Results: There are Eighteen trials involving 1,697 patients were included in this study. Meta-analysis showed that SSYX-amiodarone group was superior to the amiodarone group in improving the total effective rate [RR = 1.21; 95%CI (1.16, 1.27); p < 0.01], meanwhile reducing the ADRs [RR = 0.65; 95%CI (0.45, 0.95); p = 0.03], VPCs [MD = 170.96; 95%CI (159.88, 182.04); p < 0.01] and QTd [MD = 8.39; 95%CI (6.91, 9.87); p < 0.01]. No significant difference of enhancing LVEF [MD = 4.32; 95%CI (−0.56, 9.20); p = 0.08] and reducing NT-proBNP [SMD = 0.17; 95%CI (−0.81, 1.14); p = 0.73] was observed between SSYX-amiodarone and amiodarone group. Conclusions: Despite the apparent positive findings reported, the evidence provided by this meta-analysis was still insufficient to support the routine use of SSYX-amiodarone for HF-VA due to the poor methodological quality of included studies. The overall effect should to be verified in further through more well-design clinical studies with reasonable sample and good methodological quality.
Published: 18 January 2021
Philosophy of Management pp 1-14; https://doi.org/10.1007/s40926-020-00156-8

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Published: 1 January 2021
Abstract:
ExtractBibliography: Blackaby/Partasides QC/Redfern/Hunter, Redfern and Hunter on International Arbitration, 6th ed. , Oxford University Press, 2015; Boom/Richards/Leonard, Climate Justice: The international momentum towards climate litigation, Heinrich Böll Stiftung & Climate Justice Programme 2016, https://www. boell. de/en/2016/11/15/climate-justice-international-momentum-towards-climate-litigation; Born, International Commercial Arbitration, 2nd ed. , Kluwer Law International, 2014; Brown, International, Mixed and Private Disputes Arising under the Kyoto Protocol, Journal of International Dispute Settlement, Vol. 1, No. 2 2010, 447–473; Carlarne, Rethinking a Failing Framework: Adaptation and Institutional Rebirth for the Global Climate Change Regime, 25 Geo. Int’l Envtl. L. Rev. 1 2013; Ellis, Has International Law Outgrown Trail Smelter? , in: Bratspies/Miller (eds. ) , Transboundary Harm in International Law: Lessons from the Trail Smelter Arbitration, Cambridge University Press, 2006, pp. 56–65; European Commission, A future multilateral investment court, Memo/16/4350 2016, https://ec. europa. eu/commission/presscorner/detail/en/MEMO_16_4350; Garimella, Environmental Dispute Resolution, ADR Methods and the PCA Arbitration Rules, in: ILI Law Review, Summer...
Xinye Jin, Lingen Shi, Congyue Wang, Tao Qiu, Yi Yin, Mingwang Shen, Gengfeng Fu, Peng Zhihang
Published: 1 January 2021
SSRN Electronic Journal; https://doi.org/10.2139/ssrn.3950264

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Charles L. Bennett, Shamia Hoque, Nancy Olivieri, Matthew A. Taylor, David Aboulafia, Courtney Lubaczewski, Andrew C. Bennett, Jay Vemula, Benjamin Schooley, Bartlett J. Witherspoon, et al.
Published: 23 December 2020
EClinicalMedicine, Volume 31; https://doi.org/10.1016/j.eclinm.2020.100693

Abstract:
Background Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. Methods We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. Findings Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p Interpretation Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. Funding This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13–043–01) https://www.cancer.org/ (SH; BS).
Published: 12 December 2020
Reactions Weekly, Volume 1834, pp 200-200; https://doi.org/10.1007/s40278-020-87392-y

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Hongdou Chen, Fangfang Zheng, , Xu Wang, Qingqing Yang, Lu Ye, Yao Lu, Shule Yu, Wei Li
Evidence-Based Complementary and Alternative Medicine, Volume 2020, pp 1-8; https://doi.org/10.1155/2020/3869698

Abstract:
Objective. To carry out the meta-analysis on the clinical safety of glycyrrhizic acid and the influencing factors between 18α-glycyrrhizinate (18α-GL) and 18β-glycyrrhizinate (18β-GL). Methods. Magnesium isoglycyrrhizinate injection was used as the representative preparation of 18α-GL, and compound glycyrrhizin injection was used as the representative preparation of 18β-GL. The clinical control trial of magnesium isoglycyrrhizinate injection and compound glycyrrhizin injection was searched in a computer, which was published from January 2006 to December 2019 on the databases such as PubMed, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (CSTJ), and Wanfang Medical Network (Wanfang Data). The data associated with adverse drug reactions (ADRs) were extracted. RevMan5.3 was used for statistical analysis. Results. Finally, 24 studies were included, and 2757 patients were involved, of which the experimental group was mainly treated with magnesium isoglycyrrhizinate, while the control group was mainly treated with compound glycyrrhizin. The results showed that the occurrence of ADRs was significantly lower in the experimental group than that in the control group, and the difference between two groups was statistically significant (RR = 0.26, 95% CI = (0.18, 0.38), P < 0.00001 ). There was no heterogeneity among the studies (I2 = 0%, P = 1.00 ). Conclusion. Compared with 18β-GL, 18α-GL had a lower incidence of adverse reactions and better clinical safety.
Nora Abdul Hak, Ahmad Mukhlis Mansor, Roslina Che Soh
Journal of Islam in Asia (E-ISSN 2289-8077), Volume 17, pp 150-169; https://doi.org/10.31436/jia.v17i3.990

Abstract:
Mediation or sulh at the Malaysian Shariah Court deals with a variety of issues relating to Islamic family law including the child custody issues. Disputes that exist between the parties can be resolved through litigation (court) and non-litigation (outside the court). Sulh is one of the non-litigation methods in settling disputes in peace and harmony. The Government initiative by introducing sulh since 2001 helps in reducing the backlog of cases, speeds up settlement of dispute and it has become a very constructive method of resolving disputes amicably. This article aims to discuss and analyse the principles of sulh in Islamic Law, its foundations and its implementation in Malaysia particularly in child custody disputes. The article also will look at how sulh interacts with the new implementation of the Special Court of Hadanah established in the Shariah Court of Federal Territories (MSWP). The methodology adopted, is library-based research to collect information, data and theories involved, from selected materials including journal articles, textbooks, statutes, as well as interview method. The data were analysed using the content analysis method. The study concludes that the practice of sulh in the child custody disputes is not only in line with the Islamic Law but also plays a vital role in protecting the children’s rights as outlined by the intent of the Divine Guidance (Maqasid Shariah). Keywords: Sulh, mediation, Shariah court, child custody dispute, ADR. Abstrak Mediasi atau Sulh yang dilaksanakan di Mahkamah Syariah melibatkan pelbagai isu kekeluargaan termasuklan kes penjagaan kanak-kanak. Pertikaian yang terjadi diantara pihak-pihak dapat diselesaikan melalui dua kaedah iaitu perbicaraan (di dalam mahkamah) dan penyelesaian tanpa perbicaraan (luar mahkamah). Sulh adalah salah satu kaedah penyelesaian pertikaian secara damai dan harmoni yang dilakukan tanpa perbicaraan. Inisiatif Kerajaan memperkenalkan Sulh mulai tahun 2001 telah membantu mengurangkan lambakan kes di mahkamah, menyelesaikan kes dalam tempoh yang singkat dan ianya menjadi kaedah yang sangat konstruktif dalam menyelesaikan pertikaian secara damai tanpa sengketa. Tujuan kertas kerja ini disediakan adalah untuk membincangkan serta menganalisa kewujudan Sulh di dalam Undang-Undang Islam, melihat kepada asas serta pelaksanaan Sulh di Malaysia terutama dalam kes melibatkan pertikaian penjagaan kanak-kanak. Artikel ini juga meneliti bagaimana pelaksanaan Sulh membantu ke arah pelaksanaan Mahkamah Khas Hadhanah yang baharu ditubuhkan di Mahkamah Syariah Wilayah Persekutuan (MSWP). Metodologi yang dilaksanakan di dalam kertas kerja ini melibatkan kajian perpustakaan bagi mengumpulkan maklumat, data dan teori yang terlibat daripada bahan-bahan terpilih termasuklah jurnal artikel, buku teks, statut serta kaedah temubual. Data yang diperolehi kemudiannya dianalisa menggunakan kaedah analisa kandungan. Kajian ini menyimpulkan bahawa amalan Sulh melibatkan pertikaian penjagaan kanak-kanak bukan sahaja selari dengan Undang-Undang Islam, namun Sulh juga berperanan penting dalam melindungi hak kanak-kanak seperti yang digariskan oleh Maqasid Syariah. Kata Kunci: Sulh, mediasi, mahkamaah Syariah, pertikaian penjagaan kanak-kanak, ADR.
Published: 24 October 2020
Reactions Weekly, Volume 1827, pp 10-10; https://doi.org/10.1007/s40278-020-84767-2

Abstract:
CONSORT = Consolidated Standards of Reporting Trials The total harm reporting score could range from 0 (i.e. worst possible score) to 19 (best possible score). Based on the total harm reporting score, the researchers classified the quality of reporting of the AE as "high" (i.e. score of 15−19), moderate (score of 10−14), "low" (score of 5−9), and "very low" (score 0−4). Kow CS, et al. Quality of adverse event reporting in clinical trials of remdesivir in patients with COVID-19. European Journal of Clinical Pharmacology : 1-3, 4 Oct 2020 Download references Reprints and Permissions Quality of ADR reporting evaluated for remdesivir trials of COVID-19. Reactions Weekly 1827, 10 (2020). https://doi.org/10.1007/s40278-020-84767-2 Download citation Published: 24 October 2020 Issue Date: October 2020 DOI: https://doi.org/10.1007/s40278-020-84767-2
Published: 29 September 2020
Pharmaceutical Medicine, Volume 34, pp 347-355; https://doi.org/10.1007/s40290-020-00353-w

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Ni Kadek Sri Jayanti, Politeknik Negeri Bali, I Ketut Budarma, I Wayan Jendra
Journal of Applied Sciences in Travel and Hospitality, Volume 3, pp 107-115; https://doi.org/10.31940/jasth.v3i2.1915

Abstract:
This study aims to analyze the relationship and influence of the Chinese market Average Daily Rate (ADR) on the overall ADR at Conrad Bali Hotel. Data collection used in this study through observation, interview, and documentation. The analysis techniques used are descriptive statistics, correlation analysis, simple linear regression, and the coefficient of determination test (R2). The results of this study indicated that the Chinese market ADR (X) variable has a positive correlation with very strong category, overall ADR with a correlation value of 0.819. The coefficient regression is 1.085 and the coefficient determination shows that the influence of Chinese market ADR (X) on overall ADR (Y) is 66%. Thus, Chinese market can be an option to filling the occupancy when low seasons and a good target market when special occasion but should be followed by a necessary way to optimize its strength.
Augustine Augustine Ele,
American International Journal of Business and Management Studies, Volume 2, pp 28-40; https://doi.org/10.46545/aijbms.v2i2.223

Abstract:
This research work focused on the effect of alternative dispute resolution dimensions on employees’ performance in Nigeria work organizations using a theoretical perspective. The information was sourced from text books, journal articles and internet materials. The study revealed that alternative dispute resolution dimensions or mechanisms such as mediation, arbitration, facilitation, conciliation, negotiation, collaboration, compromise, mini-trial, expert determination, good governance and communication has a positive and significant effect on employees’ performance in Nigeria work organizations. It also found that alternative dispute resolution has a significant influence on employees ‘performance in the workplace. And there is also a substantial correlation between alternative dispute resolution and employees’ performance in Nigeria work organizations. The study recommended that management as well as administrators should adopt ADR mechanisms/dimensions in resolving disputes or conflicts among parties in Nigeria work organizations in order to reduce cost, save time or avoid delay and being fast in reaching a consensus agreement as well as compromise.
Published: 22 August 2020
Reactions Weekly, Volume 1818, pp 8-8; https://doi.org/10.1007/s40278-020-82288-3

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Published: 18 July 2020
Reactions Weekly, Volume 1813, pp 173-173; https://doi.org/10.1007/s40278-020-80930-0

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Yoseph A Mekori, Mencarelli A, Gunawan M, Yong Ksm, Bist P, Tan Wws, Tan Sy, Liu M, Fan Y, Chan Jky, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 107; https://doi.org/10.3410/f.737191281.793576467

Abstract:
Recently a G-protein-coupled receptor, MAS Related GPR Family Member X2 (MRGPRX2), was identified as a specific receptor on human mast cells responsible for IgE independent adverse drug reactions (ADR). Although a murine homologue, Mrgprb2, has been identified for this receptor, its affinity for many ADR-causing drugs is poor making it difficult to undertake in vivo studies to examine mechanisms of ADR and to develop therapeutic strategies. Here, we have created humanized mice capable of generating MRGPRX2-expressing human MCs allowing for the study of MRGPRX2 MCs-mediated ADR in vitro as well as in vivo. Humanized mice were generated by hydrodynamic-injection of plasmids expressing human GM-CSF and IL-3 into NOD-scid IL2R-γ-/- strain of mice that had been transplanted with human hematopoietic stem cells. These GM/IL-3 humice expressed high numbers of tissue human MCs but the MRGPRX2 receptor expressed in MCs were limited to few body sites including the skin. Importantly, large numbers of MRGPRX2-expressing human MCs could be cultured from the bone marrow of GM/IL-3 humice revealing these mice to be an important source of human MCs for in vitro studies of MRGPRX2-related MCs activities. When GM/IL-3 humice were exposed to known ADR causing contrast agents (meglumine and gadobutrol), the humice were found to experience anaphylaxis analogous to the clinical situation. Thus, GM/IL-3 humice represent a valuable model for investigating in vivo interactions of ADR-causing drugs and human MCs and their sequelae, and these mice are also a source of human MRGPRX2-expressing MCs for in vitro studies.© 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology.
Published: 11 July 2020
Reactions Weekly, Volume 1812, pp 5-5; https://doi.org/10.1007/s40278-020-80484-5

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Britain International of Humanities and Social Sciences (BIoHS) Journal, Volume 2, pp 403-411; https://doi.org/10.33258/biohs.v2i2.238

Abstract:
This study tries to discuss the investigation process of civil servants candidate fraud in the jurisdiction of Police Station Binjai, and how are the efforts made by the police in preventing civil servants candidate fraud. The research uses the type of empirical legal research that is a legal research method that functions to see the law in the real sense and examine how the law works in the community. Because in this study examines people in living relationships in the community, empirical legal research methods can be said as sociological legal research. Research conducted based on the study of literature namely books, laws, journals, opinions of legal experts and academics of a scientific nature relating to the problem in writing this thesis. The results obtained are civil servants candidate fraud in the jurisdiction of Police Station Binjai in accordance with procedures, which are carried out by Pro Justitia and Non Pro Justitia with the understanding that there are up to court trials and some only up to the police because between the victims and the suspect made peace and the victim withdrew his complaint so that the police and investigators stopped their investigation on the basis of a North Sumatera Police Chief Telegram letter. Police. : STR / 315 / V / 2011, May 27, 2011 concerning the handling of alternative Dispute Resolution (ADR) cases and also in accordance with the Restotative Justice Principle.
Published: 23 May 2020
Reactions Weekly, Volume 1805, pp 10-10; https://doi.org/10.1007/s40278-020-78720-y

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Ashley Caitlin Godwin, Shamia Hoque, Jayanth Vemula, Henry C Ausdenmoore, Michael Zhu, Charles L. Bennett
Journal of Clinical Oncology, Volume 38, pp 2074-2074; https://doi.org/10.1200/jco.2020.38.15_suppl.2074

Abstract:
2074 Background: Some clinicians have reported initial series of severe or fatal adverse drug reactions (ADRs) that affected large hematology-oncology patient numbers and for which pharmaceutical manufacturers subsequently paid large settlements or fines for allegedly failing to inform physicians about such ADRs. Based on their large human costs ( > 1,000 serious illnesses or deaths) and large financial costs ( > $100 million in settlements or fines), we have termed these ADRs as titanic ADRs. At a Senate hearing on one titanic, Vioxx, (a COX-2 inhibitor that was evaluated for colorectal cancer prevention), the clinician reporter was termed a “whistleblower” by a senator although this individual had not filed a formal whistleblower lawsuit. We identified physicians who would fit this characterization of whistleblowers and had published titanic hematology-oncology ADR reports in high impact journals. Methods: Hematology-oncology titanic ADRs were identified by collaborators with two NIH-funded drug safety networks (RADAR and SONAR (1998-2019)). Exclusion criteria included having also filed a whistleblower lawsuit. Qualitative research analyses evaluated content of statements made by whistleblowers to national reporters or at congressional hearings. Results: 18 physicians who reported titanic hematology/oncology-associated ADRs in peer-reviewed literature and discussed their findings in national news media outlets are included. Titanic ADRs included death, nephrogenic systemic fibrosis, coronary artery disease, and venous thromboembolism related to COX-2 inhibitors, heparin, gadolinium dye, thalidomide, lenalidomide, epoetin, and darbepoetin. Related financial settlements ranged from $100 million to $4.85 billion. Whistleblowers were from the United States, Denmark, and Germany. Primary motivations were public health and medical awareness. Whistleblowers reported having gone through lawsuits and having had executives request that the whistleblowers’ university terminate employment. One whistleblower was quoted saying “I believe that the lawsuit is an attempt to silence me.” Conclusions: Clinician whistleblowers of titanic hematology-oncology ADRs experienced reputational, financial, and personal threats. Motivations for reporting titanic ADRs were mainly public health and medical awareness focused. This differs from our previous study on clinicians publishing on non-titanic ADRs, where the primary motivation was scientific curiosity.
Published: 23 April 2020
Drug Safety, Volume 43, pp 619-622; https://doi.org/10.1007/s40264-020-00937-0

Abstract:
Herbal medicines, or herbal medicinal products, cover manufactured products containing herbal ingredients, and simple preparations of herbal substances. Most, if not all, traditional medical systems, including traditional Chinese medicine (China), Ayurvedic medicine (Indian subcontinent), Aboriginal medicine (Australia), te rongoā Māori (New Zealand), and many others, include the use of herbal ingredients (i.e. substances originating from plants); many traditional (indigenous) medicines also include ingredients from other sources (e.g. animals, insects, minerals). Herbal and traditional medicines (H&TMs) are a popular, sometimes the only, healthcare choice among people worldwide. In Western countries, out-of-pocket expenditure on herbal medicines and other ‘natural health’ products (NHPs), and on consultations with H&TM practitioners, is substantial [1,2,3,4,5,6,7,8]. Market data indicate large sales volumes: for the year 2018, in the USA alone, estimated retail sales of “herbal supplements” totaled more than $US8.84 billion, an increase of almost 10% over the previous year [9]. Many consumers of these types of products use them concurrently with conventional prescription medicines [10], which can lead to serious drug interactions. In many low- to middle-income countries, a substantial proportion of the population relies on H&TMs and traditional healers as their main, or only, source of primary healthcare [11]. The need to improve pharmacovigilance for H&TMs and other NHPs is recognized internationally, not least because the use of these types of products is highly prevalent and because safety concerns associated with their use continue to emerge. For example, in recent years, signals (i.e. a causal relationship has not necessarily been established) of hepatotoxicity associated with black cohosh (Actaea racemosa L.) root extracts [12], green tea (Camellia sinensis (L.) Kuntze) leaf extracts [13], and a supercritical carbon-dioxide extract of Artemisia annua L. in grapeseed oil [14] have emerged in different countries. Detection of signals of safety concerns associated with H&TMs continues to rely almost solely on analysis and assessment of spontaneous reports of suspected adverse drug reactions (ADRs) associated with the use of these types of products submitted by health professionals and the general public. The limitations of spontaneous reporting, and the unique and additional challenges in pharmacovigilance for H&TMs, are well-documented, but progress toward resolving them has been slow. Key international organizations have supported the development of pharmacovigilance practices for H&TMs. For example, the World Health Organization (WHO) published guidelines on safety monitoring and pharmacovigilance for herbal medicines [15]. Also, the Uppsala Monitoring Centre (UMC) launched a traditional medicines programme to stimulate reporting for these products and developed the herbal anatomical therapeutic chemical (ATC) classification system [16], which has a structure consistent with that of the regular ATC system and provides a unique framework for the nomenclature and therapeutic classification of herbal substances and combinations of herbal ingredients. The International Society of Pharmacovigilance (ISoP) has also focused attention on this topic. Pharmacovigilance for H&TMs has featured at ISoP annual conferences for many years, including in plenary and parallel sessions. Further, ISoP working groups have been mindful of the need to include a herbal- medicines perspective in their work. For example, the International Society for Pharmacoepidemiology (ISPE) initiated a venture, supported by ISoP, that was tasked with preparing guidelines for the submission of reports of suspected ADRs to journals. This venture included an ISoP member with herbal medicines expertise, and the resulting guidelines—approved by both ISoP and ISPE—included reference to some of the additional items of information required for comprehensive literature reports of ADRs associated with herbal medicines [17]. Against this background, in 2016, the new ISoP Executive Committee encouraged the creation and development of a new special interest group (SIG) in ISoP dedicated to exploring issues relating to the safety and pharmacovigilance of H&TMs. The H&TMs SIG was formally launched at the 17th annual meeting of ISoP, held in Liverpool, UK, in October 2017. The conference also featured a plenary session on pharmacovigilance for H&TMs, which included a keynote lecture “Pharmacovigilance for herbal and traditional medicines: towards solutions and innovations” by Professor Phil Routledge, then Clinical Director of the All Wales Therapeutics & Toxicology Centre, Wales, and Chair of the Committee on Herbal Medicinal Products, Medicines and Healthcare products Regulatory Agency (MHRA), UK. Membership of the H&TMs SIG is diverse in several ways. As reported at the 20th annual meeting of ISoP, held in Bogota, Colombia, in October 2019, the H&TMs SIG included 22 members from 14 countries by the end of 2019. Members of the H&TMs SIG have specific interests in H&TMs in the broadest sense, including marketed commercial herbal medicinal products as well as all types of traditional herbal and indigenous medicines and other natural products used in healthcare. Members are employed in a range of pharmacovigilance settings, including national pharmacovigilance centers, medicines’ regulatory agencies, academic institutions, and the herbal and pharmaceutical industries. Collectively, members bring a range of skills, expertise and experience across H&TMs and pharmacovigilance; thus, the H&TMs SIG is well-placed to advance the topic at a global level and in ways that are impactful, not least for users of H&TMs. Current members of ISoP with an interest in H&TMs are invited to join the SIG. The group is keen to attract members from different continents and hopes to achieve...
, Peter Bossew
Published: 23 March 2020
Abstract:
<p><strong>Using Safecast data for estimating ambient dose rate in cities around the world</strong></p><p>Petr KU&#268;A<sup>1 </sup>and Peter Bossew<sup>2</sup></p><p><sup>1</sup> National Radiation Protection Institute (SURO), Praha, Czech Republic&#160;</p><p><sup>2</sup> German Federal Office for Radiation Protection, Berlin</p><p>&#160;</p><p>Safecast [1] is a citizen science project, aimed to environmental monitoring. Its main activity is measuring ambient dose rate (ADR) all over the world. Motivated by the Fukushima NPP accident in March 2011, the project started soon after, and since, numerous citizens have contributed, carrying monitors with them.</p><p>In this presentation, the Safecast project is introduced together with its standard instrument for ADR measurement, called bGeigie Nano. We discuss matters of quality assurance connected to data generation mainly by citizens who are generally no trained metrologists, and consequently, interpretation problems of Safecast data.</p><p>The freely accessible data, currently (January 2020) over 120 million observations, were used to calculate mean ADR in various cities around the world where sufficient data is available. The resulting geographical pattern mainly reflects the variability of dose rate from terrestrial radiation, which is controlled by the one of geochemistry, namely the concentrations of uranium, thorium and potassium. Further influence comes from cosmic radiation, natural radionuclides in the air (a small contribution) and in a few cases, from anthropogenic radiation caused by nuclear fallout.</p><p>In some cities at high altitude, such as Cusco (Peru), Nairobi (Kenia) or Denver (USA), secondary cosmic radiation clearly contributes strongly to ADR. In low to medium altitude, cosmic dose rate varies relatively little, so that it contributes little to the geographical pattern. Apart from the regional geological background, ADR is generated by building materials typical for an urban environment. Mean terrestrial ADR in cities around the world ranges between several 10 nSv/h and several 100 nSv/h. Anthropogenic radiation contributes little, except close to areas affected by the Chernobyl and Fukushima accidents. However, one can argue that also radiation from building materials, although originating from natural radionuclides, is anthropogenic, as buildings are anthropogenic objects and the choice of building materials is an anthropogenic one.</p><p>We show maps displaying mean ADR for a number of cities. Geology and in some cases, altitude above sea level are clearly reflected in these maps. Besides, we address statistical issues related to spatial dispersion of ADR and of data clustering as resulting from varying and heterogeneous sampling density. Finally, we discuss merits of the Safecast project as well as inevitable limitations.</p><p>[1] www.safecast.org ; Brown, A., Franken, P., Bonner, S., Dolezal, N., Moross, J. (2016): Safecast: successful citizen-science for radiation measurement and communication after Fukushima. Journal of Radiological Protection, 36 (2), S82 &#8211; S101; doi:10.1088/0952-4746/36/2/s82</p>
Stefanus Bernard,
Frontiers in Health Informatics, Volume 9; https://doi.org/10.30699/fhi.v9i1.209

Abstract:
Introduction- Colorectal cancer (CRC) is a development of abnormal cells either in colon or rectum. CRC considered being the 3rd leading cause of death in 2018 only behind lung and breast cancer. It first arises during pre-cancerous stages called as polyps. The detection and removal of polyp is important to increase the survival rate of patient. Various method of polyp detection are available. However, only colonoscopy remains the gold standard in detection and removal of polyps. Several studies showed how Artificial Intelligence (AI) used in colonoscopy area particularly in detecting polyps, assessing physicians and predicting patient with high risk of CRC. The aim of this study is to describe the involvement of AI in colonoscopy and its impact in reducing the Materials and methods– Search for journal articles conducted between May and June 2016 from various resources including PubMed and Google Scholar. 6 research journals were reviewed and all the advantages and limitations were discussed throughout this study. Results– Various study showed that AI able to improve medical diagnostic of CRC in several ways, including in the improvement of adenoma detection rate (ADR) in terms of medical diagnostic, finding physicians associated with high Adenoma Detection Rate (ADR) and predicting patients with high risk of CRC. In addition, the use of AI in colonoscopy also associated with limitations including require large amount of datasets and advance computational resources in order to generate accurate output. Conclusion– The utilization of AI in colonoscopy shows how it able to improve the diagnosis accuracy and survival rate of patients associated with CRC despite several limitations that were identified during the study. However in the future, instead of allowing it to fully automatically conducting diagnosis, it still needs to be accompanied by physicians conducting the operation as there is no hundred percent perfect algorithms.
, Susana Herranz, Rosa Jordana, Maria Queralt Gorgas, Sara Ortonobes, Daniel Sevilla, Elisabet De Jaime, Olatz Ibarra, Candelaria Martín
Published: 10 January 2020
by BMJ
Abstract:
Introduction Multimorbidity is a major challenge for current healthcare systems and professionals. From the different approaches that have been proposed to analyse this issue, the hypothesis of the existence of association patterns of different chronic conditions is gaining visibility. In addition, multimorbidity can be associated to polypharmacy, which can lead to a higher risk of potentially inappropriate prescribing (PIP) and consequently to adverse drug reactions (ADRs). The general objective of this novel study is to identify the association between PIP, multimorbidity patterns, polypharmacy and the presence of ADRs in older patients admitted for exacerbation of chronic diseases. Methods and analysis The MoPIM (morbidity, potentially inappropriate medication) study is a multicentre prospective cohort study of an estimated sample of 800 older (≥65 years) patients admitted to five general hospitals in Spain due to an exacerbation of a chronic disease. Patients referred to home hospitalisation, admitted due to an acute process or with a fatal outcome expected at the time of admission are excluded. Sociodemographic data, chronic morbidities and geriatric syndromes, number of chronic prescribed medications, PIP at admission to hospital and on discharge, according to the newest screening tool of older screening tool of older person's potentially inappropriate prescriptions/screening tool to alert doctors to right treatment criteria, and ADRs during hospitalisation are being collected. Multimorbidity patterns will be identified using cluster analyses techniques, and the frequency of polypharmacy, PIP and ADRs will be calculated. Finally, the possible relationship between those indicators will be identified through bivariate and multivariate analyses. Ethics and dissemination The project has been approved by the clinical research ethics committees of each centre: Comité Ético de investigación Clínica del Parc Taulí, Comitè Ètic d'Investigació Clínica Osona per a la Recerca i Educació Sanitàries (FORES), Comité de Ètica de la Investigación con Medicamentos (CEIm)-Parc de Salut MAR, Comité Ético de Investigación Clínica de Euskadi, Comité de Ética de Investigación del Hospital Universitario de Canarias. The results will be actively and mainly disseminated through publication in peer-reviewed journals and communications in scientific conferences. Trial registration number NCT02830425.
Charles L. Bennett, Shamia Hoque, David Aboulafia, Courtney Lubaczewski, Andrew C. Bennett, Jay Vemula, Benjamin Schooley, Matthew A. Taylor, Bartlett J. Witherspoon, Ashley Godwin, et al.
Published: 1 January 2020
SSRN Electronic Journal; https://doi.org/10.2139/ssrn.3669128

The publisher has not yet granted permission to display this abstract.
, Krisha Danekhu, Bhuvan Kc, , Mohamed Izham Mohamed Ibrahim
Therapeutic Advances in Drug Safety, Volume 11; https://doi.org/10.1177/2042098620922480

Abstract:
Background: Bibliometric analyses have been used previously to study the measures of quality and impact of research performed in several health-related areas such as adverse drug reactions (ADRs) and pharmacovigilance (PV), etc. This method can assess the research performance of publications quantitatively and statistically. There is no evidence of bibilometric studies analyzing ADRs and PV from Nepal. Therefore, the present study aimed to assess scientific output on ADRs and PV-related research activities in Nepal using a bibliometric analysis of publications from 2004 January to December 2018, that is, 15 years. Methods: A systematic search was conducted in PubMed, Web of Science, Google Scholar, Scopus and Nepal Journal Online (NepJOL) databases. ‘Adverse Drug Reactions‘ or ‘ADRs‘ or ‘ADR‘ or ‘Adverse drug reaction‘ or ‘AE‘ or ‘Adverse Event‘ or ‘Drug-Induced Reaction‘ or ‘Pharmacovigilance‘ or ‘PV‘ and ‘Nepal‘. The search covered 15 years (January 2004 to December 2018) of study on ADRs and PV in Nepal. Only articles retrieved from databases were included, whereas published/unpublished drug bulletins, pharmacy newsletters and thesis were excluded. The articles thus retrieved were recorded, and thereafter analyzed. Word count code was used for the analysis of keywords used in the retrieved articles. Results: A total of 124 articles were retrieved, with the highest rate of publications in 2006 and 2007, with 16 papers each. Among the articles, 10 (8.1%) were published in Kathmandu University Medical Journal (KUMJ). Single papers were published in 38 different journals. Brief reports (1.6%), case reports (31.2%), case series (0.8%), education forums (0.8%), letters to the editor (5.6%), original research articles (41.9%), review articles (9.7%), short communications and short reports (8.1%) on ADRs and PV were recorded. Out of 124 papers, 52 (41.9%) were original research publications. The majority (74.1%) of research was done in the category of ADR incidence, types, prevention, and management, followed by policy and suggestions for strengthening national and regional pharmacovigilance centers of Nepal (14.5%). Conclusions: During the study years, there was an increase in scientific publications on drug safety. A total of 124 published articles were found during bibliometric analysis of ADRs and PV research activities in Nepal.
Manjur Hossain Patoari, Amir Husin Mohd Nor, Muhammad Nizam Bin Awang, Abdul Hamid Chowdhury, Jaforullah Talukder
Beijing Law Review, Volume 11, pp 415-428; https://doi.org/10.4236/blr.2020.112026

Abstract:
Alternative Dispute Resolution (ADR) is an innovative movement in the civil justice system of Bangladesh including land conflict. Traditional judicial process of Bangladesh especially land litigation is time consuming, expensive and very much complex. People involved in the land conflict, are fear to go to the court to settle their dispute due to unreasonable delay, expenses and unbearable sufferings and most of them prefer ADR as a way of resolving their dispute. Bangladesh has emphasized Alternative Dispute Resolution (ADR) as a means to resolve civil conflict as it saves time, money and energy of conflicting parties, reduces backlog of cases and work volume of court officials and also saves valuable time of the court. Recently ADR has become a popular means of settlement of land conflict among the people of Bangladesh as it is confidential, informal and relieves the parties from sufferings. The main objective of this study is to identify the legal and administrative challenges of ADR as a means of settlement of land conflict in Bangladesh and also to suggest an avenue for the complete success of ADR as an effective means to resolve land conflict in the rural areas of Bangladesh. This study is qualitative in nature which is conducted on the basis of secondary data. Data are collected from various journals, books, reports, newspaper writing and decision of apex court of Bangladesh. The core implication of this research is that it will open a new avenue for the policy maker of the country and the conflicting parties would be able to resolve their land dispute through a peaceful means.
Published: 18 December 2019
Laryngo-Rhino-Otologie, Volume 52, pp 15-16; https://doi.org/10.1055/a-1058-8854

Abstract:
The adenoma detection rate (ADR) is defined as the percentage of patients undergoing colonoscopy who have one or more adenomas detected [1] [2]. ADR has been the hallmark of high quality colonoscopy since a landmark study from Poland published in the New England Journal of Medicine in 2010 established the relationship between an individual endoscopist’s ADR and their patient’s risk of colorectal cancer (CRC) after colonoscopy (so-called interval cancer) [1]. The association of endoscopist’s ADR with CRC was confirmed by a large US cohort in 2014, and extended by establishing its importance also for CRC mortality [2]. “…it may be premature to establish a benchmark for serrated polyp detection (SDR) and advanced adenoma detection (AADR) rates … until the magnitude and pattern of the association of SDR and AADR with interval cancer risk, and their relationship to ADR, are established.” Today, colonoscopy ADR is the most established quality indicator in gastrointestinal endoscopy. It is recognized as the key performance indicator in multiple guidelines, and its measurement and benchmarking is strongly recommended throughout the World [3] [4]. However, although there is no doubt that high ADR is strongly associated with desirable outcomes after colonoscopy, it is important to recognize that it is not a perfect or universal quality indicator. 1. ADR has been developed in colonoscopies that are performed for detection of colorectal adenomas (screening or surveillance). It may be difficult to apply to clinical colonoscopies with a patient population where polyp detection is not the primary focus of the intervention, such as in inflammatory bowel disease [3]. 2. ADR is dependent on the prevalence of adenomas in the population. This prevalence is different in different countries and regions, and is dependent on patient age and sex [1] [2]. 3. ADR may be prone to gaming by the endoscopist [5]. Endoscopists may be inclined to focus on finding one small adenoma in as many patients as possible, and have less interest in finding more than one because the number of adenomas is not incentivized when using ADR as a quality indicator. 4. ADR is dependent not only on endoscopist performance but also on the quality of the histopathology service. 5. Polyps other than adenomas may be independently related to interval CRC risk, such as serrated polyps or advanced adenomas [3]. 6. Complete removal of detected adenomas may be more important than detection of adenomas and may differ between endoscopists with similar ADRs [6]. Because of these shortcomings, there is continued interest in exploring alternative quality indicators for colonoscopy performance related to the protection against CRC. In this issue of Endoscopy, Klair et al. report on a multicenter cohort study at five medical centers in the United States to investigate whether detection rates for serrated polyps (SDR) or advanced adenomas (AADR), respectively, may be alternatives to ADR [7]. In accordance with current guidance, the authors restricted the serrated polyps that were used to calculate the SDR to serrated polyp ≥ 1 cm located anywhere in the colon or hyperplastic polyp ≥ 5 mm located proximally to the sigmoid colon (so-called clinically significant serrated polyps) [7]. The findings of a moderate association between ADR and SDR or AADR illustrated by a Spearman’s R value of 0.67 and 0.56, respectively is in line with previous studies, which have also found positive but not strong associations of ADR with SDR and AADR, respectively [8] [9] [10] [11]. The strengths of the new study are the consecutive sampling and the rigorous manual chart review, the inclusion of patients with a first colonoscopy, and the restriction to screening indication. Of note, almost all colonoscopists in the Klair et al. study had high ADRs (≥ 25 %), and colonoscopies with suboptimal bowel preparation and incomplete colonoscopies were excluded. Thus, the findings relate to performance measures in high quality colonoscopy services only. If SDR and AADR were strongly correlated to ADR, it would mean that they measure the same thing. We then would have the luxury to choose what detection rate to use for quality assurance. Our choice would depend on the pros and cons of each of them as outlined above; for example, the risk of gaming or the yield that determines sample sizes required for quality monitoring (rare outcomes such as AADR require larger sample sizes compared with more frequent outcomes such as ADR). If they are not correlated strongly but still predict interval cancer risk, it means that they measure different things that are related to the same outcome – interval cancer. In that case, we may consider to measure both (i. e. introduce an additional key performance indicator to ADR). To reliably answer these questions, we need to take a step back and reliably establish the association of SDR or AADR with the real outcome of interest – interval CRC after colonoscopy. To my knowledge, there are no studies to date that have presented data for that most interesting outcome. Without such studies, it is difficult to establish a quantification of the association of SDR and AADR with interval CRC. Such a quantification, however, is an absolute prerequisite for key quality indicators in medicine. Benchmarking is not advisable without it, and can only be derived through rigorous studies with hard end points (CRC incidence and mortality), as has been done so nicely for ADR [1] [2]. Consequently, it may be premature to establish a benchmark for SDR and AADR, as Klair et al. and others have tried [7] [11], until the magnitude and pattern of the association of SDR and AADR with interval cancer risk, and their relationship to ADR, are established. There may be good reasons to move from ADR to SDR or AADR as the key quality indicator in colonoscopy. However, my recommendation would be not to establish SDR...
Rahmad Sugiarto
Published: 12 December 2019
Abstract:
Artikel ini telah diuji dan dipertanggungjawabkan dalam seminar ujian tutup oleh penulis. Urgensi informasi terkait bagaimana perlindungan hukum terhadap pengguna e-Toll Card dalam penggunaannya di jalan tol dan informasi bagaimana upaya penyelesaian sengketa antara pihak konsumen dan pihak penerbit e-Toll Card dibutuhkan sebagai referensi para penstudi dan pengemban ilmu hukum.DAFTAR PUSTAKAAl-Quran Abdul Halim Barkatullah, 2010, Hak-Hak Konsumen, Bandung : Nusa MediaAhmadi Miru dan Sutarman Yodo, 2011, Hukum Perlindungan Konsumen, Jakarta: PT Rajagrafindo PersadaAz. Nasution, 2001, Hukum Perlindungan Konsumen Suatu Pengantar, Jakarta: Diadit MediaBramantyo Djohanputro, 2008, Manajemen risiko korporat, Jakarta: PPMCelina Tri Siwi Kristiyanti, 2011, Hukum Perlindungan Konsumen, Jakarta: Sinar GrafikaC. Tantri D. dan Sulastri, 1995, Gerakan Organisasi Konsumen, Seri Panduan Konsumen, Jakarta: Yayasan Lembaga Konsumen Indonesia-The Asia FoundationErman Rajagukguk, dkk, 2000, Hukum Perlindungan Konsumen, Bandung: CV Mandar MajuFrans Hendra Winarta, 2012, Hukum Penyelesaian Sengketa. Jakarta: Sinar Grafika.Gatot Supramono, 2013, Perjanjian Utang Piutang, Jakarta: Kencana Prenada Media GroupJimmy Joses Sembiring, 2011, Cara Menyelesaian Sengketa Di Luar Pengadilan, . jakarta: Visi MediaMariam Darus Badrulzaman, 1994, Aneka Hukum Bisnis, Bandung: Alumni N.H.T. Siahaan, 2005, Hukum Konsumen: Perlindungan Konsumen Dan Tanggungjawab Produk, Jakarta: Panta ReiNurnaningsih Amriani, 2012, Mediasi Alternatif Penyelesaian Sengketa Perdata di Pengadilan, Jakarta: Rajawali Pers Philipus M. Hadjon, 2007, Perlindungan Hukum Bagi Rakyat Indonesia, Surabaya: Percetakan M2 Print, Edisi KhususR. Serfianto, dkk, 2012, Untung Dengan Kartu Kredit, Kartu ATM-Debit, & Uang Elektronik, Jakarta: Visi MediaSatjipto Raharjo, 2000, Ilmu Hukum, Bandung: PT. Citra Aditya BaktiSatijipto Rahardjo, 2014, Ilmu Hukum, Bandung: PT Citra Aditya Bakti Shidarta, 2000, Hukum Perlindungan Konsumen, Jakarta: GrasindoSoerjono Soekanto, 1986, Pengantar Penelitian Hukum, Jakarta: Penerbit Universitas Indonesia (UI Press)Soerjono Soekanto & Sri Mamudji, 2003, Penelitian Hukum Normatif: Suatu Tinjauan singkat, Jakarta: Rajawali Pers Sudaryatmo, 1999, Hukum dan Advokasi Konsumen, Bandung: PT. Citra Aditya Bakti Takdir Rahmadi, 2010, Mediasi Penyelesaian Sengketa Melalui Pendekatan Mufakat, Jakarta: PT. Raja GrafindoTakdir Rahmadi, 2011, Mediasi Penyelesaian Sengketa Melalui Pendekatan Mufakat, Jakarta: Rajawali Pers Zainuddin Ali, 2015, Metode Penelitian Hukum, Jakarta: Sinar GrafikaZulham, 2013, Hukum Perlindungan Konsumen, Jakarta: Kencana prenada media groupAssaad, A. Istiqlal. (2017). Hakikat Sanksi Dalam Perspektif Hukum Pidana Indonesia Dan Hukum Pidana Islam (Studi Tentang Pidana Mati). Makassar: Al Ishlah Jurnal Ilmiah Hukum, Vol. 19 No. 01Aswari, A. (2017). Sibernetika, Teknologi Siber Dan Kebutuhan Hukum. Palu: Jurnal Ilmiah FH Universitas Muhammadiyah Palu, Vol. 3. No. 2Aswari, A., Pasamai, S., Qomar, N., & Abbas, I. (2017). Legal Security On Cellphone Trading Through Electronic Media In Indonesia. Jurnal Dinamika Hukum, 17(2), 181-187.Azis, D. E. P., & Nurhaedah, N. (2018). Juridical Review The Implementation of Oral Agreement is associated with the Law of Treaties and Law Number 8 Year 1999 concerning Consumer Protection. Substantive Justice International Journal of Law, 1(1), 56-64.Buana, A. P., Aswari, A., Said, M. F., & Arifin, M. Y. R. (2018). Responsibility Parking Service Business to The Protection Of Consumer Of The Parking Services in Makassar. Substantive Justice International Journal of Law, 1(1), 23-32.Haikal Ramadhan, Aminah, Suradi, (2016), Perlindungan Hukum Terhadap Pengguna Uang Elektronik Dalam Melakukan Transaksi Ditinjau Dari Peraturan Bank Indonesia Nomor 16/8/Pbi/2014 Tentang Uang Elektronik (E-Money),Semarang: Diponegoro Law Review, vol.5 No. 2 Kapindha, Ros Angesti anas. Dwi M., S., Febrina, W. Rizky. (2014). Efektivitas Dan Efisiensi Alternative Dispute Resolution (ADR) Sebagai Salah Satu Penyelesaian Sengketa Bisnis Di Indonesia. Surakarta: Jurnal Hukum, Universitas Sebelas Maret Surakarta.Nurhaedah, N. (2015). Analisis Hukum Terhadap Asuransi Kendaraan Bermotor Bagi Pemilik Kendaraan Sebagai Tertanggung. PLENO JURE, 4(5), 28-41.Maria Margaretha Christi Ningrum Blegur Laumuri, 2016: Perlindungan Hukum Bagi Pemegang Uang Elektronik (Electronic Money) Pada Bank Dalam Melakukan Transaksi Pembayaran Non Tunai, Denpasar: Universitas Udayana
Montree Tungjai, Nuttakan Tubthaing,
Bangladesh Journal of Medical Science, Volume 18, pp 830-834; https://doi.org/10.3329/bjms.v18i4.42915

Abstract:
Background: Low-energy/low-dose ionizing radiation is increasingly being used in medical diagnosis, yet the effects of low-energy/low-dose medical diagnostic X-rays on biological systems remains a mystery. Thus, the aim of this present study is to determine the characteristics of lysosomes of cancerous and normal cells in response to low-energy/low-dose medical diagnostic X-rays. Methods and materials: Three cell lines composed of peripheral blood mononuclear cells (PBMCs), adriamycin-sensitive erythroleukemia cells (K562), and adriamycin-resistant erythroleukemia cells (K562/adr), were all exposed to low-energy/low-dose medical diagnostic X-rays that operated at 50, 70, and 100 kV, and 100 mAs for obtaining radiation doses at 0.03, 0.07, and 0.10 mGy, respectively. Accumulation of acridine orange in the lysosomes of each cell line was determined using flow cytometry completed at 4 and 6 hours-post irradiation. Results: The data showed an increase in fluorescence intensity of acridine orange in three irradiated cells line at 4 hours post-irradiation, but this intensity did not change at 6 hours post-irradiation when compared to that of corresponding non-irradiated cells. Conclusion: This finding suggests that changes in lysosomes might be a response to low-energy/low-dose medical diagnostic X-rays. Bangladesh Journal of Medical Science Vol.18(4) 2019 p.830-834
Comment
, Cynthia W. Ko
American Journal of Gastroenterology, Volume 114, pp 1199-1201; https://doi.org/10.14309/ajg.0000000000000307

Abstract:
The adenoma detection rate (ADR) is our current best colonoscopy quality indicator, but it is not without limitations. In this issue of the Journal, novel ADR benchmarks are proposed based on historical local colonoscopy results. These minimally acceptable, standard of care, and aspirational benchmarks may encourage continuous quality improvement through the explicit determination of notably higher but proven achievable ADR targets, although validation in clinical practice is needed. Ultimately, we must transition from ADR measurement to the implementation of robust quality improvement processes that assure the best outcomes for our patients.
Azadeh Nikfarjam, , , Erik Jones, Brian Loew, , ,
JMIR Public Health and Surveillance, Volume 5; https://doi.org/10.2196/11264

Abstract:
Adverse drug reactions (ADRs) occur in nearly all patients on chemotherapy, causing morbidity and therapy disruptions. Detection of such ADRs is limited in clinical trials, which are underpowered to detect rare events. Early recognition of ADRs in the postmarketing phase could substantially reduce morbidity and decrease societal costs. Internet community health forums provide a mechanism for individuals to discuss real-time health concerns and can enable computational detection of ADRs. The goal of this study is to identify cutaneous ADR signals in social health networks and compare the frequency and timing of these ADRs to clinical reports in the literature. We present a natural language processing-based, ADR signal-generation pipeline based on patient posts on Internet social health networks. We identified user posts from the Inspire health forums related to two chemotherapy classes: erlotinib, an epidermal growth factor receptor inhibitor, and nivolumab and pembrolizumab, immune checkpoint inhibitors. We extracted mentions of ADRs from unstructured content of patient posts. We then performed population-level association analyses and time-to-detection analyses. Our system detected cutaneous ADRs from patient reports with high precision (0.90) and at frequencies comparable to those documented in the literature but an average of 7 months ahead of their literature reporting. Known ADRs were associated with higher proportional reporting ratios compared to negative controls, demonstrating the robustness of our analyses. Our named entity recognition system achieved a 0.738 microaveraged F-measure in detecting ADR entities, not limited to cutaneous ADRs, in health forum posts. Additionally, we discovered the novel ADR of hypohidrosis reported by 23 patients in erlotinib-related posts; this ADR was absent from 15 years of literature on this medication and we recently reported the finding in a clinical oncology journal. Several hundred million patients report health concerns in social health networks, yet this information is markedly underutilized for pharmacosurveillance. We demonstrated the ability of a natural language processing-based signal-generation pipeline to accurately detect patient reports of ADRs months in advance of literature reporting and the robustness of statistical analyses to validate system detections. Our findings suggest the important contributions that social health network data can play in contributing to more comprehensive and timely pharmacovigilance.
, , Cédric Bousquet, Marie-Christine Jaulent,
Frontiers in Pharmacology, Volume 10; https://doi.org/10.3389/fphar.2019.00415

Abstract:
Drug Safety (DS) is a domain with significant public health and social impact. Knowledge Engineering (KE) is the Computer Science discipline elaborating on methods and tools for developing “knowledge-intensive” systems, depending on a conceptual “knowledge” schema and some kind of “reasoning” process. The present systematic and mapping review aims to investigate KE-based approaches employed for DS and highlight the introduced added value as well as trends and possible gaps in the domain. Journal articles published between 2006 and 2017 were retrieved from PubMed/MEDLINE and Web of Science® (873 in total) and filtered based on a comprehensive set of inclusion/exclusion criteria. The 80 finally selected articles were reviewed on full-text, while the mapping process relied on a set of concrete criteria (concerning specific KE and DS core activities, special DS topics, employed data sources, reference ontologies/terminologies, and computational methods, etc.). The analysis results are publicly available as online interactive analytics graphs. The review clearly depicted increased use of KE approaches for DS. The collected data illustrate the use of KE for various DS aspects, such as Adverse Drug Event (ADE) information collection, detection, and assessment. Moreover, the quantified analysis of using KE for the respective DS core activities highlighted room for intensifying research on KE for ADE monitoring, prevention and reporting. Finally, the assessed use of the various data sources for DS special topics demonstrated extensive use of dominant data sources for DS surveillance, i.e., Spontaneous Reporting Systems, but also increasing interest in the use of emerging data sources, e.g., observational healthcare databases, biochemical/genetic databases, and social media. Various exemplar applications were identified with promising results, e.g., improvement in Adverse Drug Reaction (ADR) prediction, detection of drug interactions, and novel ADE profiles related with specific mechanisms of action, etc. Nevertheless, since the reviewed studies mostly concerned proof-of-concept implementations, more intense research is required to increase the maturity level that is necessary for KE approaches to reach routine DS practice. In conclusion, we argue that efficiently addressing DS data analytics and management challenges requires the introduction of high-throughput KE-based methods for effective knowledge discovery and management, resulting ultimately, in the establishment of a continuous learning DS system.
Jiarui Wu, Mengwei Ni, Jialian Zhu, Kaihuan Wang, Dan Zhang, Shuyu Liu
The Journal of Alternative and Complementary Medicine, Volume 25, pp 542-551; https://doi.org/10.1089/acm.2018.0096

Abstract:
Objectives: This meta-analysis aimed to assess the clinical effectiveness and safety of Javanica oil emulsion injection (JOEI) combined with the radiotherapy (RT) for treating esophageal cancer (EC). Design: A literature search was conducted for collecting the randomized controlled trials (RCTs) on EC treated by JOEI in the Cochrane Library, PubMed, Embase, the Chinese Biomedical Literature Database (SinoMed), the China National Knowledge Infrastructure Database, the China Science and Technology Journal Database (VIP), and the Wanfang Database from inception to February 4, 2017. The quality of the RCTs was evaluated by the Cochrane risk of bias assessment tool, and objective remission rate, performance status, adverse drug reactions (ADRs), 1-year survival rate, and 2-year survival rate were analyzed by Review Manager 5.3 and Stata 13.0 software. Results: A total of 11 RCTs with 909 participants were involved in this meta-analysis. The results showed that in comparison with RT alone, the JOEI combined with RT was associated with the better effects on improving objective remission rate (relative risk [RR] = 1.33, 95% confidence interval [CI 1.17–1.52], Z = 4.44, p< 0.00001), performance status (RR = 1.52, 95% CI [1.25–1.85], Z = 4.24, p< 0.00001), 1-year survival rate (RR = 1.37, 95% CI [1.17–1.60], Z = 3.86, p< 0.0001), and 2-year survival rate (RR = 1.36, 95% CI [1.09–1.70], Z = 2.68, p = 0.007). The differences between the two groups in objective remission rate, performance status, 1-year survival rate, and 2-year survival rate were statistically significant. Besides, the JOEI combined with RT could reduce the incidence of ADRs. Specifically, the statistically significant difference was detected between these two groups about leukopenia (RR = 0.39, 95% CI [0.25–0.61], Z = 4.19, p< 0.0001), radiation esophagitis (RR = 0.68, 95% CI [0.50–0.93], Z = 2.42, p = 0.02), thrombocytopenia (RR = 0.92, 95% CI [0.12–0.66], Z = 2.95, p = 0.003), and hemoglobin reduction (RR = 0.53, 95% CI [0.35–0.79], Z = 3.14, p = 0.002); however, there was no statistically significant difference for the outcome of nausea and vomiting (RR = 0.61, 95% CI [0.36–1.03], Z = 1.85, p = 0.06) between two groups. Conclusion: This meta-analysis indicated that the combination of JOEI and RT was associated with the more beneficial treatment for patients with EC compared with only receiving RT. However, more well-designed and multicenter RCTs should be carried out to confirm this finding because of the limitations of enrolled 11 RCTs.
Jincheng Yang, Jun Yang
American Journal of Therapeutics, Volume 26; https://doi.org/10.1097/mjt.0000000000000900

Abstract:
Hyperglycemic ADR Distribution of Doxorubicin From VigiBase Jincheng Yang;Jun Yang; American Journal of Therapeutics
, Mostafa E. Rateb, Susana Rodriguez-Couto, Maria De Lourdes Teixeira De Moraes Polizeli, Wen-Jun Li
Published: 26 April 2019
Frontiers in Microbiology, Volume 10; https://doi.org/10.3389/fmicb.2019.00914

Abstract:
Editorial on the Research topicMicrobial Secondary Metabolites: Recent Developments and Technological Challenges Microbial secondary metabolites, like antibiotics, pigments, growth hormones, antitumor agents, and others, are not essential for the growth and development of microorganism, but they have shown a great potential for human and animal health (Ruiz et al., 2010). Among the microorganisms producing the above-mentioned compounds, bacteria, including actinobacteria, and fungi produce a diverse array of bioactive small molecules with significant potential to be used in medicine (O‘Brien and Wright, 2011). These bioactive compounds are mainly produced by the activation of cryptic gene clusters which are not active under normal conditions and, thus, the expression of these clusters would be helpful in the exploitation of the chemical diversity of microorganisms (Pettit, 2011; Xu et al., 2019). Although several reports on microbial secondary metabolites have been published in recent years (Passari et al., 2017; Zothanpuia et al., 2018; Overy et al., 2019), our understanding to enhance the production of bioactive secondary metabolites is still limited. The research topic “Microbial Secondary Metabolites: Recent Developments and Technological Challenges” comprises 25 articles covering important aspects on biodiversity, exploitation and utilization of microbial resources (terrestrial, marine, and endophytic) for the production of secondary metabolites together with their biological functions. The current knowledge and potential of marine fungi for producing anticancer compounds has been reviewed (Deshmukh et al.) and the ability of the sea-derived Streptomyces helimycini for the production of actinomycins is presented (Zhu et al.). In a very interesting study, Wakefield et al. proved that the co-cultivation of fungi and bacteria led to the production of new secondary metabolites. There is a growing interest in looking for unique sources for the exploration of novel microbial populations having prospective to produce bioactive natural products. Thereby, the bacterial and fungal population obtained from Aquilaria malaccensis tree and soil enhanced the production of agarospirol within 3 months of artificial infection (Chhipa and Kaushik). The present research topic includes four important research papers dealing with the production of bioactive secondary metabolites. Thus, a study by Alenezi et al. emphasized that the biological activity of Aneurinibacillus migulans isolates was directly correlated with the production of a new gramicidin. Narsing Rao et al. has focused on the importance of pigments originated from fungi and bacteria and their wide applications in health and industry. The article by Li et al. presented the production of somalimycin, a new antimycin-type depsipeptide, from a mutant of the deep-sea-derived Streptomyces somaliensis. Similarly, Thøgersen et al. demonstrated the production of the potentially antibacterial compounds violacein and indolmycin by a maeA mutant of the sea bacterium Pseudoalteromonas luteoviolacea. A cluster of three articles gives emphasis to the biosynthetic gene clusters involved in microorganisms for the production of secondary metabolites. Hence, Derntl et al. demonstrated the role of genes, namely sor1, sor3, and sor4 of the orbicillinoid gene cluster and disclosed the function of sor4 which was not known. Another article by Rojas-Aedo et al. explained the role of the adr gene cluster involved in the biosynthesis of the potent antitumor compoundandrastin A in Penicillium roqueforti. In this article, the authors also have demonstrated that all the 10 genes of adr gene cluster were essential for the production of andrastin A. Lastly, Nah et al. reviewed the potential of the phylum Actinomycetes for natural production (NP) through biosynthetic gene clusters (BGC) heterologous expression systems as well as recent strategies specialized for the large-sized NP BGCs in Streptomyces heterologous hosts. Other important candidates for the production of secondary metabolites are the endophytic microorganisms which were addressed by Mefteh et al. Thus, they presented that plants under biotic stress offered new and unique endophytes with diverse bioactivities as compared to healthy plants. Sharma et al. reported that the application of dietary components like grape skin and turmeric extracts enhanced the production of cryptic and bioactive metabolites, with anti-oxidant and antibacterial potential, by the endophytic fungus Colletotrichum gloeosporioides. Also, the endophytic fungi Chaetomium globosum isolated from Egyptian medicinal plants, proved to have anti-rheumatoid activity (Abdel-Azeem et al.). In summary, the articles gathered in the research topic “Microbial Secondary Metabolites: recent development and Technological Challenges” explore the role of microorganisms from different sources showing biological activities. This will further enhance the present knowledge on the potential of microbial secondary metabolites in health and industry. One challenge which needs to be answered is the development of methods to understand the detailed mechanisms of cryptic genes and their relation to the production of bioactive compounds. Researchers also need to give more emphasis on the co-cultivation of different microorganisms having positive synergistic effect to produce novel bioactive molecules. We believe that this special issue gives some in-depth information about one of the important matters of the microbial world. Finally, our great thanks to all contributions, in total 165 authors, for the cohesive information in the form of reviews and research articles which have been compiled in this ebook. We strongly believe that the information compiled and presented in this ebook will be useful for the readers and will be the basis for the future investigation on “microbial secondary metabolites.” All authors mentioned have made significant contributions in the production of the editorial and have approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank all of the contributing authors and also the Frontiers team, for their constant efforts and support throughout in managing the research topic. BPS is thankful to the Department of Biotechnology, Ministry of Science and Technology for financial support in the form of DBT Unit of Excellence programme for NE (102/IFD/SAN/4290-4291/2016-2017). O‘Brien, J., and Wright, G. D. (2011) An ecological perspective of microbial secondary metabolism. Curr. Opin. Biotechnol. 22, 552–558. doi: 10.1016/j.copbio.2011.03.010 PubMed Abstract | CrossRef Full Text | Google Scholar Overy, D. P., Rämä, T., Oosterhuis, R., Walker, A. K., and Pang, K. L. (2019). The neglected marine fungi, sensu stricto, and their isolation for natural products' discovery. Mar. Drugs 17:E42. doi: 10.3390/md17010042 PubMed Abstract | CrossRef Full Text | Google Scholar Passari, A. K., Mishra, V. K., Singh, G., Singh, P., Kumar, B., Gupta, V. K., et al. (2017). Insights into the functionality of endophytic actinobacteria with a focus on their biosynthetic potential and secondary metabolites production. Sci. Rep. 7:11809. doi: 10.1038/s41598-017-12235-4. PubMed Abstract | CrossRef Full Text | Google Scholar Pettit, R. K. (2011). Small-molecule elicitation of microbial secondary metabolites. Microb. Biotechnol. 4, 471–478. doi: 10.1111/j.1751-7915.2010.00196.x PubMed Abstract | CrossRef Full Text | Google Scholar Ruiz, B., Chávez, A., Forero, A., García-Huante, Y., Romero, A., Sánchez, M., et al. (2010) Production of microbial secondary metabolites: regulation by the carbon source. Crit. Rev. Microbiol. 36, 146–167. doi: 10.3109/10408410903489576. PubMed Abstract | CrossRef Full Text | Google Scholar Xu, F., Wu, Y., Zhang, C., Davis, K. M., Moon, K., Bushin, L. B., et al. (2019) A genetics-free method for high-throughput discovery of cryptic microbial metabolites. Nat. Chem. Biol. 15, 161–168. doi: 10.1038/s41589-018-0193-2. PubMed Abstract | CrossRef Full Text | Google Scholar Zothanpuia, Passari, A K, Leo, V. V., Kumar, B., Chnadra, P., Nayak, C., et al. (2018). Bioprospection of actinobacteria derived from freshwater sediments for their potential to produce antimicrobial compounds. BMC Microb. Cell Fact. 17:68. doi: 10.1186/s12934-018-0912-0 CrossRef Full Text Keywords: microbial, secondary, metabolite, change, challenges Citation: Singh BP, Rateb ME, Rodriguez-Couto S, Polizeli MdLTdM and Li W-J (2019) Editorial: Microbial Secondary Metabolites: Recent Developments and Technological Challenges. Front. Microbiol. 10:914. doi: 10.3389/fmicb.2019.00914 Received: 15 February 2019; Accepted: 10 April 2019; Published: 26 April 2019. Edited by: Reviewed by: Copyright © 2019 Singh, Rateb, Rodriguez-Couto, Polizeli and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Bhim Pratap Singh, [email protected]
, Aswin Anapathoor Nagarajan
Indian Journal of Medical and Paediatric Oncology, Volume 40, pp 305-306; https://doi.org/10.4103/ijmpo.ijmpo_56_18

Abstract:
Chronic myelogenous leukemia (CML) also known as chronic granulocytic leukemia, is characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. The standard treatment for chronic phase (CP) CML is a tyrosine kinase inhibitor such as imatinib, nilotinib, or dasatinib.[1] The documented adverse effects of imatinib mesylate are nausea, vomiting, edema, tumor necrosis, muscle cramps, hematologic side effects, cardiovascular side effects, hepatic side effects, nephrotoxicity, and dermatologic side effects such as skin rash, pruritus, and petechiae. This case study is a rare adverse effect seen with imatinib mesylate, which has not been reported so far. A 45-year-old postmenopausal female came to the outpatient department with the complaints of upper abdominal pain and weight loss of 2 months duration. On examination, she had splenomegaly (4 cm size from the costal margin). Complete blood examination showed increased leukocyte count including mature myeloid cells and myeloid precursors [Figure 1]. fluorescent in situ hybridization revealed the presence of philadelphia chromosome [t(9;22)]. She was diagnosed with a case of CML-CP and was started on imatinib mesylate 400 mg once daily orally. After 5 months of treatment with imatinib mesylate, the patient symptomatically improved. Blood examination showed white blood cell count <10,000 cells/mm 3 and a differential count showed no blast cells. Cytogenetics revealed Ph+0. Hence, the patient was deemed as complete clinical and pathological response. Nevertheless, the patient developed painful swelling of the digits of the upper limb which was diagnosed with dactylitis [Figure 2]. The patient was treated with oral and topical corticosteroids, and imatinib mesylate was withheld until the reaction subsided. Dactylitis has not been reported as an adverse effect of imatinib mesylate in the literature. This is one of the rarest adverse effects of imatinib mesylate. Based on Naranjo causality assessment scale, the adverse drug reaction (ADR) is categorized as possible.[2] The occurrence of ADRs causing loss of working days to the patient, which in turn is a loss to the community and the nation, is preventable. This case report also emphasizes that physicians should be aware of the occurrence of dactylitis with imatinib mesylate therapy. Since rational prescribing is a part of doctor ethics, awareness of such rare ADRs will enable the physicians to safely administer drugs to the patient community. In addition, the patients should be informed of such rare ADRs, to prevent further events. Reporting of ADRs should be encouraged among health professionals. The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Publication Date:03 June 2021 (online) © 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd.A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
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