bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcutaneous ultrasound-mediated gene delivery into canine livers achieves therapeutic levels of factor VIII expression
Authors: Manson Megan A. , Zhang Feng , Novokhodko Alexander , Chen Chun-Yu , Parker Maura , Loeb Keith R. , Kajimoto Masaki , Campbell Carley , Storb Rainer F. , Miao Carol H. 
Published: April 2022

Abstract
A safe, effective, and inclusive gene therapy will significantly benefit a large population of patients with hemophilia. We used a minimally invasive transcutaneous ultrasound-mediated gene delivery (UMGD) strategy combined with microbubbles (MBs) to enhance gene transfer into 4 canine livers. A mixture of high-expressing, liver-specific human factor VIII (hFVIII) plasmid and MBs was injected into the hepatic vein via balloon catheter under fluoroscopy guidance with simultaneous transcutaneous UMGD treatment targeting a specific liver lobe. Therapeutic levels of hFVIII expression were achieved in all 4 dogs, and hFVIII levels were maintained at a detectable level in 3 dogs throughout the 60-day experimental period. Plasmid copy numbers correlated with hFVIII antigen levels, and plasmid-derived messenger RNA (mRNA) was detected in treated livers. Liver transaminase levels and histology analysis indicated minimal liver damage and a rapid recovery after treatment. These results indicate that liver-targeted transcutaneous UMGD is promising as a clinically feasible therapy for hemophilia A and other diseases.
BreakAlign: a Perl program to align chimaeric (split) genomic NGS reads and allow visual confirmation of novel retroviral integrations
Authors: Marchi Emanuele , Jones Mathew , Klenerman Paul , Frater John , Magiorkinis Gkikas , Belshaw Robert 
Published: April 2022

Abstract
Background
Retroviruses replicate by integrating a DNA copy into a host chromosome. Detecting novel retroviral integrations (ones not in the reference genome sequence of the host) from genomic NGS data is bioinformatically challenging and frequently produces many false positives. One common method of confirmation is visual inspection of an alignment of the chimaeric (split) reads that span a putative novel retroviral integration site. We perceived the need for a program that would facilitate this by producing a multiple alignment containing both the viral and host regions that flank an integration.

Results
BreakAlign is a Perl program that uses blastn to produce such a multiple alignment. In addition to the NGS dataset and a reference viral sequence, the program requires either (a) the ~ 500nt host genome sequence that spans the putative integration or (b) coordinates of this putative integration in an installed copy of the reference human genome (multiple integrations can be processed automatically). BreakAlign is freely available from https://github.com/marchiem/breakalign and is accompanied by example files allowing a test run.

Conclusion
BreakAlign will confirm and facilitate characterisation of both (a) germline integrations of endogenous retroviruses and (b) somatic integrations of exogenous retroviruses such as HIV and HTLV. Although developed for use with genomic short-read NGS (second generation) data and retroviruses, it should also be useful for long-read (third generation) data and any mobile element with at least one conserved flanking region.
Answering medical questions in Chinese using automatically mined knowledge and deep neural networks: an end-to-end solution
Authors: Zhang Li , Yang Xiaoran , Li Shijian , Liao Tianyi , Pan Gang 
Published: April 2022

AbstractBackgroundMedical information has rapidly increased on the internet and has become one of the main targets of search engine use. However, medical information on the internet is subject to the problems of quality and accessibility, so ordinary users are unable to obtain answers to their medical questions conveniently. As a solution, researchers build medical question answering (QA) systems. However, research on medical QA in the Chinese language lags behind work on English-based systems. This lag is mainly due to the difficulty of constructing a high-quality knowledge base and the underutilization of medical corpora in the Chinese language.ResultsThis study developed an end-to-end solution to implement a medical QA system for the Chinese language with low cost and time. First, we created a high-quality medical knowledge graph from hospital data (electronic health/medical records) in a nearly automatic manner that trained a supervised model based on data labeled using bootstrapping techniques. Then, we designed a QA system based on a memory-based neural network and attention mechanism. Finally, we trained the system to generate answers from the knowledge base and a QA corpus on the internet.ConclusionsBootstrapping and deep neural network techniques can construct a knowledge graph from electronic health/medical records with satisfactory precision and coverage. Our proposed context bridge mechanisms perform training with a variety of language features. Our QA system can achieve state-of-the-art quality in answering medical questions with constrained topics. As we evaluated, complex Chinese language processing techniques, such as segmentation and parsing, were not necessary for practice and complex architectures were not necessary to build the QA system. Lastly, we created an application using our method for internet QA usage.
Discovery of moiety preference by Shapley value in protein kinase family using random forest models
Authors: Huang Yu-Wei , Hsu Yen-Chao , Chuang Yi-Hsuan , Chen Yun-Ti , Lin Xiang-Yu , Fan You-Wei , Pathak Nikhil , Yang Jinn-Moon 
Published: April 2022

Abstract
Background
Human protein kinases play important roles in cancers, are highly co-regulated by kinase families rather than a single kinase, and complementarily regulate signaling pathways. Even though there are > 100,000 protein kinase inhibitors, only 67 kinase drugs are currently approved by the Food and Drug Administration (FDA).

Results
In this study, we used “merged moiety-based interpretable features (MMIFs),” which merged four moiety-based compound features, including Checkmol fingerprint, PubChem fingerprint, rings in drugs, and in-house moieties as the input features for building random forest (RF) models. By using > 200,000 bioactivity test data, we classified inhibitors as kinase family inhibitors or non-inhibitors in the machine learning. The results showed that our RF models achieved good accuracy (> 0.8) for the 10 kinase families. In addition, we found kinase common and specific moieties across families using the Shapley Additive exPlanations (SHAP) approach. We also verified our results using protein kinase complex structures containing important interactions of the hinges, DFGs, or P-loops in the ATP pocket of active sites.

Conclusions
In summary, we not only constructed highly accurate prediction models for predicting inhibitors of kinase families but also discovered common and specific inhibitor moieties between different kinase families, providing new opportunities for designing protein kinase inhibitors.
Thorough statistical analyses of breast cancer co-methylation patterns
Authors: Sun Shuying , Dammann Jael , Lai Pierce , Tian Christine 
Published: April 2022

Abstract
Background
Breast cancer is one of the most commonly diagnosed cancers. It is associated with DNA methylation, an epigenetic event with a methyl group added to a cytosine paired with a guanine, i.e., a CG site. The methylation levels of different genes in a genome are correlated in certain ways that affect gene functions. This correlation pattern is known as co-methylation. It is still not clear how different genes co-methylate in the whole genome of breast cancer samples. Previous studies are conducted using relatively small datasets (Illumina 27K data). In this study, we analyze much larger datasets (Illumina 450K data).

Results
Our key findings are summarized below. First, normal samples have more highly correlated, or co-methylated, CG pairs than tumor samples. Both tumor and normal samples have more than 93% positive co-methylation, but normal samples have significantly more negatively correlated CG sites than tumor samples (6.6% vs. 2.8%). Second, both tumor and normal samples have about 94% of co-methylated CG pairs on different chromosomes, but normal samples have 470 million more CG pairs. Highly co-methylated pairs on the same chromosome tend to be close to each other. Third, a small proportion of CG sites’ co-methylation patterns change dramatically from normal to tumor. The percentage of differentially methylated (DM) sites among them is larger than the overall DM rate. Fourth, certain CG sites are highly correlated with many CG sites. The top 100 of such super-connector CG sites in tumor and normal samples have no overlaps. Fifth, both highly changing sites and super-connector sites’ locations are significantly different from the genome-wide CG sites’ locations. Sixth, chromosome X co-methylation patterns are very different from other chromosomes. Finally, the network analyses of genes associated with several sets of co-methylated CG sites identified above show that tumor and normal samples have different patterns.

Conclusions
Our findings will provide researchers with a new understanding of co-methylation patterns in breast cancer. Our ability to thoroughly analyze co-methylation of large datasets will allow researchers to study relationships and associations between different genes in breast cancer.
Genome-wide investigations reveal the population structure and selection signatures of Nigerian cattle adaptation in the sub-Saharan tropics
Authors: Mauki David H. , Tijjani Abdulfatai , Ma Cheng , Ng’ang’a Said I. , Mark Akanbi I. , Sanke Oscar J. , Abdussamad Abdussamad M. , Olaogun Sunday C. , Ibrahim Jebi , Dawuda Philip M. , Mangbon Godwin F. , Kazwala Rudovick R. , Gwakisa Paul S. , Yin Ting-Ting , Li Yan , Peng Min-Sheng , Adeola Adeniyi C. , Zhang Ya-Ping 
Published: April 2022

AbstractBackgroundCattle are considered to be the most desirable livestock by small scale farmers. In Africa, although comprehensive genomic studies have been carried out on cattle, the genetic variations in indigenous cattle from Nigeria have not been fully explored. In this study, genome-wide analysis based on genotyping-by-sequencing (GBS) of 193 Nigerian cattle was used to reveal new insights on the history of West African cattle and their adaptation to the tropical African environment, particularly in sub-Saharan region. ResultsThe GBS data were evaluated against whole-genome sequencing (WGS) data and high rate of variant concordance between the two platforms was evident with high correlated genetic distance matrices genotyped by both methods suggestive of the reliability of GBS applicability in population genetics. The genetic structure of Nigerian cattle was observed to be homogenous and unique from other African cattle populations. Selection analysis for the genomic regions harboring imprints of adaptation revealed genes associated with immune responses, growth and reproduction, efficiency of feeds utilization, and heat tolerance. Our findings depict potential convergent adaptation between African cattle, dogs and humans with adaptive genesSPRY2andITGB1BP1possibly involved in common physiological activities.ConclusionThe study presents unique genetic patterns of Nigerian cattle which provide new insights on the history of cattle in West Africa based on their population structure and the possibility of parallel adaptation between African cattle, dogs and humans in Africa which require further investigations.
Accuracy of the COPD diagnostic questionnaire as a screening tool in primary care
Authors: Pagano Lisa , McKeough Zoe , Wootton Sally , Zwar Nicholas , Dennis Sarah 
Published: April 2022

Abstract
Background
The COPD Diagnostic Questionnaire (CDQ) was developed to identify people who would benefit from spirometry testing to confirm Chronic Obstructive Pulmonary Disease (COPD). The aim of this study was to determine the usefulness of a cut-off score of 16.5 on the CDQ in identifying those at increased risk of obstruction, in a mixed population of people ‘at risk’ of COPD and those with an ‘existing’ COPD diagnosis.

Methods
People ‘at risk’ of COPD (aged > 40 years, current/ex-smoker) and those with ‘existing’ COPD were identified from four general practices and invited to participate. Participants completed the CDQ and those with a CDQ score ≥ 16.5 were categorised as having intermediate to increased likelihood of airflow obstruction. Pre and post-bronchodilator spirometry determined the presence of airway obstruction (FEV1/FVC ratio < 0.7). Sensitivity, specificity and accuracy of the CDQ was determined compared to spirometry as the gold standard.

Results
One hundred forty-one participants attended an initial assessment (‘at risk’ = 111 (79%), ‘existing’ COPD = 30 (21%)). A cut-off score of 16.5 corresponded to a sensitivity of 81%, specificity of 36% and accuracy of 50%, in the entire mixed population. The area under the ROC curve was 0.59 ± 0.50 indicating low diagnostic accuracy of the CDQ. Similar results were found in the ‘existing’ COPD group alone.

Conclusion
Whilst a cut-off score of 16.5 on the CDQ may result in a large number of false positives, clinicians may still wish to use the CDQ to refine who receives spirometry due to its high sensitivity.

Trial registration
ANZCTR, ACTRN12619001127190. Registered 12 August 2019 – Retrospectively registered, http://www.ANZCTR.org.au/ACTRN12619001127190.aspx
Nuclear morphometry and chromatin texture changes in hepatocellular carcinoma samples may predict outcomes of liver transplanted patients
Authors: dos Santos Jordan Boeira , Starosta Rodrigo Tzovenos , Pilar Emily Ferreira Salles , Kunz Jefferson Daniel , Tomedi Joelson , Cerski Carlos Thadeu Schmidt , Ruppenthal Rúbia Denise 
Published: April 2022

Abstract
Background
Nuclear changes are typical in the carcinogenesis of hepatocellular carcinoma (HCC). Morphometry and chromatin texture analysis are quantitative methods for their quantification. In this study, we analyzed nuclear morphometry and chromatin texture parameters in samples of hepatocellular carcinoma from liver transplant patients and their associations with clinicopathologic variables.

Methods
Samples of HCC and adjacent tissue from 34 individuals were collected in tissue microarray blocks. Stained slides were microphotographed using an optical microscope and nuclear parameters analyzed in ImageJ (FracLac plug-in). ROC curve analysis was used to find accurate cut-offs for differentiation of neoplastic and non-neoplastic cells. The inter-rater agreement was also evaluated.

Results
Nuclear morphometric and textural differences were observed between the samples of HCC and adjacent tissue of liver transplant patients. Lower mean gray value (p = 0.034) and Feret diameter (p = 0.024) were associated with higher Model for End-Stage Liver Disease (MELD) scores. Nuclei with larger area (p = 0.014) and larger Feret diameter (p = 0.035) were associated with lower survival. Lower aspect ratio was associated with HCC recurrence after the transplant (p = 0.048). The cut-off of 1.13 μm (p =  < 0.001) for aspect ratio and cut-off of 21.15 μm (p = 0.038) for perimeter were established for the differentiation of neoplastic and non-neoplastic cells. The morphometric analysis was reproducible to area, circularity, Feret diameter, mean gray value and aspect ratio between observers (p =  < 0.001).

Conclusions
Nuclear morphometric differences between the HCC and the adjacent tissue samples were associated with prognostic variables (MELD scores, recurrence and survival) and may predict liver transplant patients’ outcomes.
Social trust and stress symptoms among older adults during the COVID-19 pandemic: evidence from Asia
Authors: Jiang Nan , Wu Alfred M. , Cheng Edmund W. 
Published: April 2022

AbstractObjectivesTo investigate whether social trust is associated with more stress symptoms among middle-aged and older adults in six East and Southeast Asia regions during the COVID-19 pandemic.MethodsThis multi-region study used cross-sectional survey data collected in May 2020. Participants were a probability-based internet sample of adults aged 55 or older.ResultsGovernment trust was negatively associated with stress in Singapore and South Korea. Higher levels of health care trust were significantly associated with less stress in Singapore and Taiwan. Trust in neighbors was associated with a higher likelihood of stress in Hong Kong and a lower likelihood in Singapore. Social trust was not associated with stress in Japan or Thailand.DiscussionFindings suggest the level of social trust in relation to stress substantially varied by region. Interventions to strengthen trust during COVID-19 and other major health crises need to be tailored to fit regions’ unique circumstances.
Awareness of HIV functional cure and willingness in participating in related clinical trials: comparison between antiretroviral naïve and experienced men who have sex with men living with HIV
Authors: Kwan Tsz Ho , Chan Chin Pok , Wong Ngai Sze , Lee Shui Shan 
Published: April 2022

Abstract
Background
Human immunodeficiency virus (HIV) functional cure is a novel biomedical strategy characterized by sustained viral suppression without the need for life-long medications. The attitude of people living with HIV (PLHIV) towards functional cure and clinical trials are understudied. We aimed to examine the awareness and levels of anticipation for HIV functional cure among men who have sex with men (MSM) living with HIV, and their willingness to join trials as differentiated by their antiretroviral treatment status.

Methods
MSM living with HIV with and those without treatment history were recruited from Hong Kong’s HIV specialist clinics. Self-administered questionnaires covering behavioral profile, perceived impact of HIV cure, attitude towards HIV functional cure and related clinical trials were collected. Clinical data were separately transcribed. Determinants of perceptions and attitudes were identified by logistic regression models.

Results
Of 356 MSM living with HIV recruited, less than half (42%) were aware of HIV functional cure, but they had a high level of anticipation for it. Treatment-experienced participants were more likely to be aware of HIV functional cure. Awareness was associated with continued engagement in sexual activities after HIV diagnosis and sexually transmitted infection (STI) diagnosis. Higher anticipation was observed among older MSM living with HIV but it was negatively associated with one’s awareness. Over 90% were willing to join functional cure trials, especially those who had previously been diagnosed with STI and had engaged in chemsex in the past year. Advice from healthcare professional was an important factor considered by those willing to join clinical trials. Younger, better educated MSM, and those with lower CD4 counts were more concerned about potential risk of AIDS and potential complications upon trial participation.

Conclusions
MSM living with HIV, especially those sexually active, showed positive attitude towards functional cure and willingness to join related clinical trials despite low awareness. To enhance preparedness for HIV functional cure trials, community education, updated information and appropriate medical advice would be needed. Safety is a major concern for potential enrollees in HIV functional cure trials.
Does current ovarian endometrioma increase the time for DOR patients to reach live birth in IVF?
Authors: Deng Yu , Ou Zhanhui , Yin Minna , Chen Zhiheng , Chen Shiling , Sun Ling 
Published: April 2022

AbstractBackgroundThe contents of ovarian endometrioma (OMA) such as inflammatory mediators, reactive oxygen species, and iron may disrupt normal folliculogenesis and result in subsequent oocyte apoptosis. Therefore, women with OMA have a potential risk of diminished ovarian reserve (DOR). The purpose of this study is to compare the in vitro fertilization (IVF) outcomes and efficiency between DOR patients with and without current OMA.MethodsThis retrospective case-control study included a total of 493 women with DOR (serum anti-Müllerian hormone level < 1.1 ng/mL). Ninety patients with OMA (Group A) underwent 191 IVF cycles and 403 patients without ovarian OMA (Group B) underwent 888 IVF cycles in our center between January 2014 and December 2018. Basal characteristics and IVF outcomes were compared between Group A and Group B. Time to achieve live birth were compared between patients with live birth in two groups (Group A1, 31 patients; Group B1, 132 patients).ResultsClinical and demographic characteristics of patients were similar respectively between groups (A vs. B, A1 vs. B1). There were no statistically significant differences in implantation rate, live birth rate per OPU and per ET cycle and the cumulative live birth rate per patient and per patient with good-quality embryos between Group A and Group B (P > 0.05). Total time to achieve live birth has no statistically significant difference between Group A1 and Group B1 (P > 0.05).ConclusionFor DOR women, presence of endometrioma did not affect the IVF outcomes. Even the time to get live birth was not prolonged by current OMA.
Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol
Authors: Thivat Emilie , Rouanet Jacques , Auzeloux Philippe , Sas Nicolas , Jouberton Elodie , Levesque Sophie , Billoux Tommy , Mansard Sandrine , Molnar Ioana , Chanchou Marion , Fois Giovanna , Maigne Lydia , Chezal Jean-Michel , Miot-Noirault Elisabeth , D’Incan Michel , Durando Xavier , Cachin Florent 
Published: April 2022

Abstract
Background
Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT).
[131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma.

Methods
The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part.

Discussion
This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ.

Trial registration
Clinicaltrials.gov: NCT03784625. Registered on December 24, 2018.
Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.