bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered Exosomes: A Promising Drug Delivery Strategy for Brain
Diseases
Authors: Jiang Yuan , Wang Fengbo , Wang Ke , Zhong Yongqiang , Wei Xiaofei , Wang Qiongfen , Zhang Hong 
Published: September 2021

:
Exosomes are a heterogeneous group of nano-sized natural membrane vesicles
released from various cells and exist in body fluids. Different from the previous understanding
of the function of exosomes as “garbage bins”, exosomes act as carriers with
many kinds of bioactive molecules (e.g., proteins, lipids, and nucleic acids) to play an important
role in cell-cell communication. Growing evidence in recent years has suggested
that exosomes also play some roles in the pathogenesis, diagnosis, and treatment modalities
of some brain diseases, including ischemic stroke, Alzheimer's disease, Parkinson's
disease, multiple sclerosis, and brain cancers. Exosomes as therapeutic drug carriers for
brain drug delivery have received extensive attention as well as exosomes can overcome
the blood-brain barrier (BBB). However, the low targeting ability and size-dependent cellular
uptake of native exosomes could profoundly affect the delivery performance of exosomes.
Recent studies have indicated that engineered exosomes can increase the drug uptake
efficiency and the subsequent drug efficacy. In the present paper, we will briefly introduce
the engineering methods and applications of engineered exosomes in the treatment
of brain diseases, and then focus on discussing the advantages and challenges of exosome-
based drug delivery platforms to further enrich and boost the development of exosomes
as a promising drug delivery strategy for brain diseases.
Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90)
Authors: Bonanni Davide , Citarella Andrea , Moi Davide , Pinzi Luca , Bergamini Elisa , Rastelli Giulio 
Published: September 2021

:The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases, such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving the therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promotes synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.
Research Progress on the Natural Product Aloperine and Its Derivatives
Authors: Cheng Yu , Rauf Abdur , Pan Xiandao 
Published: September 2021

Abstract:
In this review, an effort towards presenting an all-around account of the recent progress on
the natural product, aloperine, is made, and the antivirus structure-activity relationship of its derivatives
is also summarized comprehensively. In addition, the principal pharmacological effects and corresponding
molecular mechanisms of aloperine are discussed. Some new structural modifications of
aloperine are also given, which might provide brief guidance for further investigations on the natural
product aloperine.
Robust Discovery of Mild Cognitive Impairment Subtypes and Their Risk of Alzheimer's Disease Conversion Using Unsupervised Machine Learning and Gaussian Mixture Modeling
Authors: Nezhadmoghadam Fahimeh , Martinez-Torteya Antonio , Treviño Victor , Martínez Emmanuel , Santos Alejandro , Tamez-Peña Jose , Alzheimer’s Disease Neuroimaging Initiative  
Published: September 2021

Background:
Alzheimer’s Disease (AD) is an irreversible, progressive brain disorder that
slowly destroys memory and thinking skills. The ability to correctly predict the diagnosis of Alzheimer’s
disease in its earliest stages can help physicians make more informed clinical decisions on
therapy plans.

Objective:
This study aimed to determine whether the unsupervised discovering of latent classes of
subjects with Mild Cognitive Impairment (MCI) may be useful in finding different prodromal AD
stages and/or subjects with a low MCI to AD conversion risk.

Methods:
Total 18 features relevant to the MCI to AD conversion process led to the identification of
681 subjects with early MCI. Subjects were divided into training (70%) and validation (30%) sets.
Subjects from the training set were analyzed using consensus clustering, and Gaussian Mixture Models
(GMM) were used to describe the latent classes. The discovered GMM predicted the latent class of the
validation set. Finally, descriptive statistics, rates of conversion, and Odds Ratios (OR) were computed
for each discovered class.

Results:
Through consensus clustering, we discovered three different clusters among MCI subjects.
The three clusters were associated with low-risk (OR = 0.12, 95%CI = 0.04 to 0.3|), medium-risk (OR
= 1.33, 95%CI = 0.75 to 2.37), and high-risk (OR = 3.02, 95%CI = 1.64 to 5.57) of converting from
MCI to AD, with the high-risk and low-risk groups highly contrasting. Hence, prodromal AD subjects
were present in only two clusters.

Conclusion:
We successfully discovered three different latent classes among MCI subjects with varied
risks of MCI-to-AD conversion through consensus clustering. Two of the discovered classes may represent
two different prodromal presentations of Alzheimer´s disease.
The Effect of Melissa officinalis on Premenstrual Syndrome and Primary
Dysmenorrhea in Women of Reproductive Age: A Systematic Review and
Meta-Analysis
Authors: Mirghafourvand Mojgan , Maghalian Mahsa , Ghassab-Abdollahi Nafiseh 
Published: September 2021

Background:
Premenstrual syndrome (PMS) and dysmenorrhea are prevalent disabling
conditions and affecting the quality of life of women of reproductive age. Melissa officinalis exhibits
multiple pharmacological properties, including anti-inflammatory, antispasmodic, analgesic,
and antidepressant activities.

Objective:
The aim of this study was to systematically review the effect of Melissa officinalis on
PMS and primary dysmenorrhea.

Methods:
A systematic search in English (Embase ،PubMed, ProQuest, Scopus, Clininaltrial.gov,
Cochrane Library), and Persian (SID, Magiran, Iran Doc) databases to find articles was carried out
in May 2020. All types of clinical trials were included. Two authors independently selected the articles
and quality assessments and extracted the data. Standardized Mean Difference (SMD) was described
as a measure of effect size due to the application of multiple tools to measure the severity
of PMS. The quality of evidence was assessed using the GRADE approach.

Results:
A total of 978 articles were obtained from databases. Ultimately, 7 articles were included
in the study. Based on the results of these 7 studies, the consumption of Melissa officinalis
improved the symptoms of PMS and primary dysmenorrhea after treatment, as compared to the
control group. Also, from the meta-analysis results, the consumption of Melissa officinalis in the intervention
group as compared to the control group, significantly reduced the mean severity of PMS's
symptoms following treatment) SMD: -0.93; 95% CI: -.19 to -0.67; P=0. 88; I2=0%).

Conclusion:
Due to the limited number of articles included in the meta-analysis, conducting well-
designed clinical trials with large sample size to ascertain the effect of Melissa officinalis on PMS
and primary dysmenorrhea are recommended.
Choice of Restorative Materials for Direct Posterior Restorations among Undergraduate Saudi College Students
Authors: Iqbal Azhar , Khattak Osama , Fayyaz Alam , Issrani Rakhi , Alrasheed Osama Sulaiman , Almandel Mosleh Naeim , Alruwaili Abdullah Qanas 
Published: September 2021

Background:
The most common restorative materials used in dentistry are amalgam and composite. Amalgam is a controversial material owing to its mercury toxicity. With recent advances in the properties of composite materials, there has been a shift towards its use.

Objectives:
The aim of this study was to understand the perceptions of undergraduate dental students in a northern Saudi Arabian dental school about the choice of restorative materials for restoring posterior teeth.

Methodology:
The study included undergraduate students studying in 4th and 5th year dental program in College of Dentistry, Jouf University. A four-item questionnaire with 18 close-ended questions was developed by the investigators, which were hand delivered to all the students. Data analysis is presented through tables and descriptive methods.

Results:
A total of 98 (out of 131) undergraduate students participated in this study. Overall, the students reported a significantly strong influence of the type of restorative materials in relation to the cavity size and margin of the restorations along with the esthetics factor(p<0.05). There was slight influence on the student’s choice because of the instructor's influence, whereas the students felt they were knowledgeable and had appropriate training to use either amalgam or composite. The study also found that patient’s preference had a strong influence on choosing composite material. The students were mostly not influenced while choosing the material as far as the safety of it was concerned. However, the patient’s influence was slight when it came to the choice of the material. A significant difference was noted among the students when it came to pregnancy-related safety concerns where the choice of material was not influenced by either amalgam or composite (p=.002).

Conclusion:
The undergraduate dental students at College of Dentistry, Jouf University are comfortable in using both amalgam and composite as a posterior restorative material. They are knowledgeable about both the materials and are adequately trained to use either one.
Initial Validation of a 33-Item Recovery-Stress Questionnaire for Italian Athletes
Authors: di Fronso Selenia , Robazza Claudio , Montesano Cristina , Bertollo Maurizio 
Published: September 2021

Background:
The Recovery-Stress Questionnaire for Athletes (RESTQ-Sport-36) is a self-report measure intended to monitor the recovery-stress balance in athletes. A validated Italian version of this instrument was not available so far.

Objective:
The aim of this study was to provide an initial validation in Italian language of the RESTQ-Sport-36.

Methods:
A sample of Italian athletes (N = 339; women = 148; men = 191) from various sports completed the RESTQ-Sport-36 and the Italian Mood Scale (ITAMS). We examined the factorial validity and the internal consistency of the RESTQ-Sport-36 and its concurrent validity with the ITAMS.

Results:
A confirmatory factor analysis supported a 12-factor structure after the removal of 3 items. Reliability analysis showed a satisfactory internal consistency of the 33-item Recovery-Stress Questionnaire for Athletes (RESTQ-Sport-33). Pearson correlation coefficients revealed that the RESTQ-Sport-33 and ITAMS share some common variance but measure different constructs.

Conclusion:
Our results provided support to the factorial validity and reliability of the RESTQ-Sport-33. This instrument can be used to reliably monitor recovery-stress balance of Italian athletes throughout the season.
Working with Transgender Adolescents: Essential Guidelines and
Applications
Authors: Chou Kevin , Johnson Brandon 
Published: September 2021

Background:
There has been a rise in the numbers of adolescents
identifying as transgender and seeking medical treatment for gender dysphoria.
While gender clinics are developing across the country, not all transgender
adolescents have access to these centers. There is, therefore, an increased need for
other clinicians to be aware of interventions and guidelines to help transgender
youth and their families.

Objective:
The aim of this article is to provide an overview of current literature and
guidelines for treating transgender adolescents with gender dysphoria.

Methods:
Using keywords “gender”, “gender dysphoria”, “transgender”, “trans*”,
“adolescent trans*”, the authors searched PubMed to gather current literature on treating
transgender adolescents. Additionally, sources from primary transgender resources online
were obtained, including current endocrine and psychological guidelines.

Results:
This article discusses important gender concepts that are relevant to treating
all transgender individuals. It describes models of engagement with transgender
adolescents seeking treatment, including assenting and consenting to medical
intervention. Finally, we discuss the assessment of transgender adolescents’ needs
and present an overview of the various guidelines outlining both non-medical and
medical interventions targeted to treat gender dysphoria in this population.

Conclusions:
Knowledge of treating adolescents with gender dysphoria is imperative
as gender dysphoria presents more commonly in practice. Multidisciplinary
collaboration is required to provide comprehensive treatment to this population.
Guidelines from professional organizations such as the World Professional
Association for Transgender Health and the Endocrine Society provide instructions
for clinical practice while the evidence base in this field continues to expand.
Studi Perbandingan Metode Standardized Precipitation Index (SPI) dan Rainfall Anomaly Index (RAI) untuk Mengestimasi Kekeringan pada DAS Welang
Authors: Muarifah Aulia Rahmawati , Harisuseno Donny , Suhartanto Ery 
Published: September 2021

There are 20 villages in 5 sub districts in Pasuruan Regency and 19 villages in 9 sub districts in Malang Regency that are classified as drought prone areas. It is necessary to analyze the drought index as an effort to monitor drought as a preparation Â for drought adaptation and mitigation in the future. Drought analyzed used meteorological drought index Standardized Precipitation Index (SPI) and Rainfall Anomaly Index (RAI). The results of the drought analysis are SPI produced the minimum value drought index was -4.09 at 3-month period time scale. RAI was produced minimum index value -3.93 at 1-month period time scale. After analyzing the hydrological drought index using the Standardized Streamflow Index (SSI), the results of the correlation are weak. Therefore, a qualitative comparison option was chosen by comparing the discharge pattern and monthly rainfall data where the RAI method was chosen as a more suitable method for use in Welang watershed. Spatial interpolation was performed by Inverse Distance Weighted (IDW) in years with the most extreme dry events, which are in 2007 and 2015. The result showed that there are 42 villages have the potential to be affected by meteorological drought and the dry months are August, September and October.Terdapat 20 desa di 5 kecamatan di Kabupaten Pasuruan serta 19 desa di 9 kecamatan di Kabupaten Malang yang termasuk daerah rawan kekeringan. Maka dari itu perlu dilakukan analisis indeks kekeringan sebagai usaha untuk pemantauan kekeringan pada suatu daerah sebagai langkah untuk adaptasi maupun mitigasi akan bencana kekeringan yang melanda kedepannya di DAS Welang. Analisis kekeringan menggunakan indeks kekeringan meteorologi metode Standardized Precipitation Index (SPI) dan Rainfall Anomaly Index (RAI) yang diharapkan dapat dijadikan sebagai referensi oleh pihak terkait mengenai skala prioritas dalam penanganan bencana pada wilayah terdampak kekeringan terparah. Hasil analisis kekeringan Metode SPI menghasilkan indeks kekeringan paling minimum pada stasiun hujan Purwodadi sebesar -4,09 pada periode 3 bulanan. Sedangkan metode RAI menghasilkan nilai indeks minimum sebesar -3,93 pada periode 1 bulanan. Setelah dilakukan analisis hubungan kesesuaian dengan indeks kekeringan hidrologi menggunakan metode Standardized Streamflow Index (SSI), didapatkan hasil korelasi yang bersifat lemah. Maka dari itu dipilih opsi perbandingan kualitatif dengan membandingkan pola debit dan data curah hujan bulanan dan metode RAI yang lebih sesuai. Hasil penggambaran peta sebaran kekeringan menggunakan metode IDW pada tahun dengan jumlah kejadian kering terparah yaitu tahun 2007 dan 2015, didapatkan sebanyak 42 desa berpotensi terdampak kekeringan dengan bulan kering yaitu bulan Agustus, September, dan Oktober.
Trends and Patterns in the Public Awareness of Palliative Care, Euthanasia, and End-of-Life Decisions in 3 Central European Countries Using Big Data Analysis From Google: Retrospective Analysis
Authors: Huemer Matthias , Jahn-Kuch Daniela , Hofmann Guenter , Andritsch Elisabeth , Farkas Clemens , Schaupp Walter , Masel Eva Katharina , Jost Philipp J , Pichler Martin 
Published: September 2021

Background
End-of-life decisions, specifically the provision of euthanasia and assisted suicide services, challenge traditional medical and ethical principles. Austria and Germany have decided to liberalize their laws restricting assisted suicide, thus reigniting the debate about a meaningful framework in which the practice should be embedded. Evidence of the relevance of assisted suicide and euthanasia for the general population in Germany and Austria is limited.

Objective
The aim of this study is to examine whether the public awareness documented by search activities in the most frequently used search engine, Google, on the topics of palliative care, euthanasia, and advance health care directives changed with the implementation of palliative care services and new governmental regulations concerning end-of-life decisions.

Methods
We searched for policies, laws, and regulations promulgated or amended in Austria, Germany, and Switzerland between 2004 and 2020 and extracted data on the search volume for each search term topic from Google Trends as a surrogate of public awareness and interest. Annual averages were analyzed using the Joinpoint Regression Program.

Results
Important policy changes yielded significant changes in search trends for the investigated topics. The enactment of laws regulating advance health care directives coincided with a significant drop in the volume of searches for the topic of euthanasia in all 3 countries (Austria: −24.48%, P=.02; Germany: −14.95%, P<.001; Switzerland: −11.75%, P=.049). Interest in palliative care increased with the availability of care services and the implementation of laws and policies to promote palliative care (Austria: 22.69%, P=.01; Germany: 14.39, P<.001; Switzerland: 17.59%, P<.001). The search trends for advance health care directives showed mixed results. While interest remained steady in Austria within the study period, it increased by 3.66% (P<.001) in Switzerland and decreased by 2.85% (P<.001) in Germany.

Conclusions
Our results demonstrate that legal measures securing patients’ autonomy at the end of life may lower the search activities for topics related to euthanasia and assisted suicide. Palliative care may be a meaningful way to raise awareness of the different options for end-of-life care and to guide patients in their decision-making process regarding the same.
Predictability of Mortality in Patients With Myocardial Injury After Noncardiac Surgery Based on Perioperative Factors via Machine Learning: Retrospective Study
Authors: Shin Seo Jeong , Park Jungchan , Lee Seung-Hwa , Yang Kwangmo , Park Rae Woong 
Published: September 2021

Background
Myocardial injury after noncardiac surgery (MINS) is associated with increased postoperative mortality, but the relevant perioperative factors that contribute to the mortality of patients with MINS have not been fully evaluated.

Objective
To establish a comprehensive body of knowledge relating to patients with MINS, we researched the best performing predictive model based on machine learning algorithms.

Methods
Using clinical data from 7629 patients with MINS from the clinical data warehouse, we evaluated 8 machine learning algorithms for accuracy, precision, recall, F1 score, area under the receiver operating characteristic (AUROC) curve, and area under the precision-recall curve to investigate the best model for predicting mortality. Feature importance and Shapley Additive Explanations values were analyzed to explain the role of each clinical factor in patients with MINS.

Results
Extreme gradient boosting outperformed the other models. The model showed an AUROC of 0.923 (95% CI 0.916-0.930). The AUROC of the model did not decrease in the test data set (0.894, 95% CI 0.86-0.922; P=.06). Antiplatelet drugs prescription, elevated C-reactive protein level, and beta blocker prescription were associated with reduced 30-day mortality.

Conclusions
Predicting the mortality of patients with MINS was shown to be feasible using machine learning. By analyzing the impact of predictors, markers that should be cautiously monitored by clinicians may be identified.
Medical Students’ Perceptions of a Blockchain-Based Decentralized Work History and Credentials Portfolio: Qualitative Feasibility Study
Authors: Hasselgren Anton , Kralevska Katina , Gligoroski Danilo , Faxvaag Arild 
Published: September 2021

Background
Increased digitization of health care might challenge some of the trust functions that are established in a traditional health care system. We have, with the concept of VerifyMed, developed a decentralized service for work history and competence verification, as a means to increase trust in the virtual interaction between a patient and a caregiver, mitigate administrative burden, and provide patient-reported outcomes seamlessly for health professionals.

Objective
This research aimed to validate the use case of a decentralized credentials service for health care professionals in Norway. We also aimed to evaluate the proof-of-concept of VerifyMed, a blockchain-based credential service for health care professionals.

Methods
A qualitative approach was applied with data collection through 9 semistructured interviews and 2 focus groups (one with 4 participants and the other with 5 participants). The System Usability Scale (SUS) was used as a part of the interviews. Data were analyzed through the principles of systematic text condensation. The recruitment of participants ended when it was concluded that the data had reached saturation.

Results
The following 5 themes were identified from the interviews and focus groups: (1) the need for aggregated storage of work- and study-related verification, (2) trust in a virtual health care environment, (3) the potential use of patient feedback, (4) trust in blockchain technology, and (5) improvements of the VerifyMed concept. The SUS questionnaire gave a score of 69.7.

Conclusions
This study has validated the need for a decentralized system where health care professionals can control their credentials and, potentially, their reputation. Future work should update the VerifyMed system according to this input. We concluded that a decentralized system for the storage of work-related verifiable credentials could increase trust in a virtualized health care system.