bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy
Authors: Yamamoto-Kataoka Sachiko , Shimizu Sayaka , Yamazaki Hajime , Murakami Katsuhiro , Nishizaki Daisuke , Fukuhara Shunichi , Inagaki Nobuya , Yamamoto Yosuke
Published: June 2021

Pancreatectomy is an invasive surgery that is sometimes associated with complications. New-onset diabetes mellitus sometimes develops after partial pancreatectomy and severely affects the patient's quality of life. This study aimed to develop a preoperative prediction model of new-onset diabetes mellitus after partial pancreatectomy, which will help patients and surgeons to achieve more easily better common decisions on regarding whether to perform partial pancreatectomy. This retrospective cohort study analyzed medical records of patients who underwent partial pancreatectomy (total pancreatectomy excluded) from April 1, 2008, to February 28, 2016, which were available in the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The predictors were preoperative age, body mass index, hemoglobin A1c level, blood glucose level, and indication for partial pancreatectomy. The outcome was the development of new-onset diabetes mellitus at 1 to 12 months after partial pancreatectomy. We used a logistic regression model and calculated the scores of each predictor. To determine test performance, we assessed discrimination ability using the receiver operating characteristic curve and calibration with a calibration plot and the Hosmer-Lemeshow test. We also performed internal validation using the bootstrap method. Of 681 patients, 125 (18.4%) had new-onset diabetes mellitus after partial pancreatectomy. The developed prediction model had a possible range of 0 to 46 points. The median score was 13, and the interquartile range was 9 to 22. The C-statistics of the receiver operating characteristic curve on the score to predict the outcome was .70 (95% confidence interval [CI], .65–.75). Regarding the test performance, the Hosmer-Lemeshow test was not significant (P = .17), and calibration was good. In the bootstrapped cohorts, the C-statistics was .69 (95% CI, .62–.76). We developed a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy. This would provide important information for surgeons and patients when deciding whether to perform partial pancreatectomy.
Risk of osteoporosis in patients with erectile dysfunction
Authors: Xu Jiangnan , Wang Chao , Zhang Yuhui , Xu Zekun , Ouyang Jun , Zhang Jianglei
Published: June 2021

Background:

Erectile dysfunction (ED) and osteoporosis are both common health problems and have similar risk factors. Recent studies have found that people with ED have a higher risk of osteoporosis.

We aimed to systematically assess osteoporosis risk in patients with ED.

Methods:

A systematically research was carried out in Medline via PubMed, Cochrane Library, EMBASE, and Web of Science up to June 4, 2020, to identify articles related to ED and osteoporosis. The 2 researchers independently reviewed the literature, extracted the data, and evaluated the quality of the literature. All analyses were done using RevMan5.3 and Stata14.

Results:

A total of 4 studies involving 22,312 participants were included. The meta-analysis results showed that the risk of osteoporosis in the ED group was significantly higher than that in the non-ED group [odds ratio (OR) = 2.66, 95% confidence interval (95% CI) 1.42 to 4.98,P = .002,I2 = 68%]. Interestingly, compared with older participants, the increased risk of osteoporosis in ED patients seemed to be more pronounced in younger participants. Despite the lack of data for meta-analysis, more than half of the literature mentioned this tendency. We found the source of heterogeneity through sensitivity analysis, and there was no significant effect on the results before and after the removal of this literature, indicating that our results were robust. No obvious publication bias was found through Egger method (P = .672).

Conclusion:

People with ED have a higher risk of osteoporosis, especially among younger males. Because the assessment of osteoporosis is economical and noninvasive, ED patients should be evaluated by bone mineral density or men with osteoporosis should be further assessed for erectile function.
Precise medicine of programmed cell death-1/programmed cell death 1 ligand 1 inhibitor immunotherapy combined radiotherapy for inoperable advanced lung cancer
Authors: Liu Gang , Lv Xiaolan , Ding Yanling , Guo Yongbo
Published: June 2021

Background:

Programmed cell death-1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibitors are a group of immune checkpoint inhibitors immunotherapy for cancer treatment. These immune checkpoint inhibitors are becoming first-line treatments for several types of cancer. Radiotherapy for cancer is a traditional treatment and the therapeutic effect is not satisfactory due to the side effect of chemotherapeutic drugs. This study aims to evaluate the efficacy and safety of PD1/PD-L1 inhibitor immunotherapy combined chemotherapy for inoperable advanced lung cancer.

Methods:

We will utilize PubMed, PubMed Central, EMbase, Medline, CNKI, WAN FANG Database, and Web of Science to screen eligible studies published from January 1, 2015 to December 30, 2020. Two reviewers will extract data and evaluate the risk of bias independently. The quality of the included studies will be evaluated using the RevMan 5.3 software for data analysis.

Results:

This review will summarize high-quality evidence of trials to evaluate the precise medicine efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer.

Conclusions:

The findings of the systematic review will provide scientific evidence of the efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer to guide the clinician's drug use.

Ethics and dissemination:

Not applicable.

INPLASY registration number:

INPLASY202140123.
The effect of three-circle post standing (Zhanzhuang) qigong on the physical and psychological well-being of college students
Authors: Lyu Jiaxuan , Wei Yulong , Li Hangyu , Dong Jingjing , Zhang Xinzheng
Published: June 2021

Background:

Qigong has a long-term application by integration of mind, breath and body to prevent and cure diseases. Researches show that qigong practice could adjust anxiety, the mechanism may found on brain and heart functions. Currently there are limitations on qigong's anxiety-release mechanism study between mind and body, and existing studies lack of evidence on electrophysiology research. Our objective to analyse qigong's anxiety-release effect and mechanism.

Methods:

A two-arm randomized clinical trial with 144 qigong naïve anxiety subjects without cerebral or cardiovascular diseases or other severe syndromes will be allocated to either a body and breath regulation group (n = 72) or a body regulation group (n = 72). Participants will conduct three-circle post standing qigong exercise 5 times per week for 8 weeks, while the three-circle post standing qigong combined with abdominal breath regulation (TCPSQ-BR) group will combined with abdominal breath regulation. The primary outcome will be the Self-Rating Anxiety Scale (SAS), and the secondary outcome will be complexity-based measures of heart rate and electroencephalogram (EEG) signals assessed at baseline and 8 weeks. Multiscale entropy analysis will be used as measure of complexity.

Conclusion:

This study will be investigate the effects of qigong's anxiety-release by SAS, and will analyze the coordinates of EEG and heart rate variability (HRV) signals before and after three-circle post standing qigong (TCPSQ) practice, and to analyse their synergies by complex signal process method.

Ethics and trail registration:

The protocol was approved by the institutional review boards of Beijing University of Chinese Medicine (2018BZHYLL0109). This study was registered with the “Chinese Clinical Trail Registry” in the WHO Registry Network (ChiCTR-Bon-17010840).
Sphenoid sinus pseudoaneurysm with carotid cavernous fistula presenting with delayed subarachnoid hemorrhage
Authors: Cho Min Jai , Yi Kyung Sik , Choi Chi-Hoon , Yum Kyu Sun , Cha Sang-Hoon , Kim Yook , Lee Jisun
Published: June 2021

Rationale:

Sphenoid sinus pseudoaneurysm arising from the cavernous segment of the internal carotid artery (ICA) caused by traumatic vessel injury is rare, and rarer is a concomitant carotid-cavernous fistula (CCF). In particular, delayed subarachnoid hemorrhage (SAH) due to pseudoaneurysm rupture has not been reported to-date in literature. Here, we report a case of sphenoid sinus pseudoaneurysm with CCF presenting with delayed SAH.

Patient concerns:

A 73-year-old man presented with traumatic brain injury due to motorcycle accident.

Diagnoses:

Twenty-four days after admission, the patient's neurological status suddenly deteriorated. Brain computed tomography (CT) showed acute SAH along interhemispheric cisterns and suprasellar intracerebral hematoma. Brain CT angiography and digital subtraction angiography revealed giant sphenoid sinus pseudoaneurysm with CCF and the daughter sac of the pseudoaneurysm extended to the intracranial part via fracture in the superior wall of the sphenoid sinus.

Interventions:

As the sphenoid sinus pseudoaneurysm and CCF shared one rupture point, endovascular treatment with intraarterial approach using coil and liquid embolic material by balloon assisted technique was performed simultaneously.

Outcomes:

The origin of the pseudoaneurysmal sac and CCF was sufficiently blocked after injection of liquid embolic material and the lesions completely resolved immediately after endovascular treatment.

Lessons:

Sphenoid sinus pseudoaneurysm and CCF rarely occur following head trauma through a series of processes involving fracture of the lateral wall of the sphenoid sinus and ICA cavernous segment injury. Sphenoid sinus pseudoaneurysm may present as SAH through intracranial rupture with concomitant superior wall fracture of the sphenoid sinus. Therefore, early diagnosis using CT or magnetic resonance angiography and appropriate treatment through understanding the disease mechanism is necessary.
Efficacy of continuous positive airway pressure in neonates with respiratory distress syndrome
Authors: Cao Junyi , Chen Zuowu , You Jinbing , Wang Jiangjiang , Tang Qiongyao
Published: June 2021

Background:

Respiratory distress syndrome (RDS) is a condition caused by a deficiency in pulmonary surfactant. Many interventions, including pulmonary surfactant, non-invasive respiratory support, and other supportive treatments have been used to prevent RDS. However, recent studies have focused on the continuous positive airway pressure as a significant potential agent for preventing RDS. However, its safety and effectiveness are yet to be assessed. To this end, the current study aims to perform to explore the safety and effectiveness of continuous positive airways in treating neonates with RDS.

Methods:

We will conduct comprehensive literature searches on MEDLINE, Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure, and Chinese BioMedical Literature from their inception to April 2021. The search aims to identify all the randomized controlled studies on continuous positive airway pressure in treating neonates with RDS. In addition, we aim to search the gray literature to establish any available potential studies. We will use 2 independent authors to determine study eligibility, extract data using the structured pro-forma table, analyze data, and utilize suitable tools in assessing the risk of bias in the selected studies. Accordingly, we will conduct all statistical analyses using RevMan 5.3 software.

Results:

The current study aims to provide high-quality synthesis of existing evidence concerning the continuous positive airway pressure to treat neonates suffering from RDS.

Conclusion:

Our findings seek to provide evidence to establish whether continuous positive airway pressure can ascertain safety and effectiveness for neonates with RDS.

Ethics and dissemination:

The study will require ethical approval.

OSF registration number:

May 20, 2021.osf.io/7nj8s. (https://osf.io/7nj8s/).
Efficacy and safety of heat-sensitive moxibustion in the treatment of neurogenic bladder after spinal cord injury
Authors: Lin Qianqian , Ren Yafeng , Chen Kewei , Duan Huijie , Chen Meng , Liu Chengmei
Published: June 2021

Background:

Spinal cord injury (SCI) is one of the most disabling and destructive neurological diseases. Neurogenic bladder dysfunction (NBD) is one of the serious complications after SCI, 80% of patients after SCI will have neurogenic bladder symptoms. NBD after SCI may lead to urinary retention, urinary incontinence, and urinary tract infection. In severe cases, it can lead to renal failure or even death. NBD after SCI not only seriously affects the patient's quality of life but also physical and mental health. NBD after SCI is a social and medical problem. In recent years, more and more clinical studies prove that heat-sensitive can improve the clinical symptoms of NBD after SCI. Therefore, this article conducts a systematic evaluation and meta-analysis on the efficacy and safety of heat-sensitive moxibustion in treating NBD after SCI.

Methods:

Search 8 electronic databases including PubMed, Embase, Web of Science, The Cochrane Library, Clinical Trials, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biomedical Literature Database. We will search above electronic databases from the inception to May 2021, without any language restriction. Clinical randomized controlled trials containing heat-sensitive moxibustion for NBD after SCI and eligible interventions(s) and outcome(s) were included, with no limitation of language and publication status. Two researchers will independently conduct literature search, screening, information extraction, quality assessment, and data analysis. Review Manager 5.3 software will be used for statistical analysis.

Results:

The findings will be submitted to a peer-reviewed publication.

Conclusion:

This systematic review and meta-analysis will provide a standard clinical decision-making guideline for heat-sensitive moxibustion treatment of NBD after SCI.

INPLASY registration number:

INPLASY202150071.
Pharmacological and non-pharmacological interventions for osteoporosis
Authors: Tian Jidong , Wu Shuo , Dong Lin , Tang Hao
Published: June 2021

Background:

Osteoporosis is a common bone disease that has a significant social and economic effect. Many meta-analyses of pharmacological and non-pharmacological treatments for osteoporosis have been reported, but the findings may be contradictory, and both the reporting and methodological quality remain unknown. As a result, an overview that includes a network meta-analysis was proposed to address these issues.

Methods:

The Cochrane library, PubMed, Embase, CBM, and CNKI databases will be systematically searched for meta-analyses of osteoporosis interventions from inception to May 2021. In order to evaluate the reporting and methodological quality of each included meta-analysis, Preferred Reporting Items for Systematic Review and Meta-analysis 2020 (PRISMA-2020), and A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) will be used. For the assessment of the relative efficacy and safety of treatments reported in the randomized controlled trials included in the meta-analyses identified by the overview, a Bayesian network meta-analysis will be carried out. The odds ratio and standard mean difference with their 95% credible intervals will be used to present the binary and continuous outcomes, respectively, and the Grading of Recommendations Assessment, Development and Evaluation method will be used to determine the certainty of the evidence through Confidence In Network Meta-Analysis. Data analysis will be performed using WinBUGS, R, and Stata, with a 2-sidedP < .05 considered as statistically significant.

Results:

The findings of this overview, which includes a network meta-analysis, will be submitted to a peer-reviewed journal for publication.

Conclusion:

An overview with network meta-analysis will provide evidence on the efficacy and safety of pharmacological and non-pharmacological interventions for osteoporosis, while also identifying the flaws in previously published meta-analyses. All of these results may be used to improve clinical decision-making and future studies.

INPLASY registration number:

INPLASY202150022.
Clusters of community-dwelling individuals empirically derived from stool diaries correspond with clinically meaningful outcomes
Authors: Jones Michael P. , Walter Susanna , Talley Nicholas J. , Walker Marjorie M. , Holtmann Gerald J. , Shah Ayesha , D’Amato Mauro , Agréus Lars , Andreasson Anna
Published: June 2021

Background

Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability.

Methods

As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis.

Results

The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46–0.74), self-rated health (d = −0.42) and depression (d = −0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001).

Conclusion

A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-analytic system.
Prevention and management of oronasal fistulas
Authors: Othieno Florence , Tatum Sherard A.
Published: June 2021

Purpose of review

The aim of this article is to present the current opinion on the prevention and management of oronasal fistulas in cleft palate patients.

Recent findings

Though cleft palate repair has seen numerous modifications and improvements, oronasal fistulas remain one of the most common complications of palatoplasty. There are various techniques available for preventing and managing this complication.

Oronasal fistulas can be minimized by employing proper principles for palatoplasty. Once a fistula occurs, the repair technique should be appropriate for the fistula type. Oronasal fistula classifications, various repair techniques, tissue adjuncts, and biomaterials used in both the primary palate repair and oronasal fistula repair are discussed in this review.
Human Milk Oligosaccharides Modulate Fecal Microbiota and Are Safe for Use in Children With Overweight: A Randomized Controlled Trial
Authors: Fonvig Cilius Esmann , Amundsen Ingvild Dybdrodt , Vigsnæs Louise Kristine , Sørensen Nikolaj , Frithioff-Bøjsøe Christine , Christiansen Michael , Hedley Paula Louise , Holm Louise Aas , McConnell Bruce , Holm Jens-Christian
Published: June 2021

Objectives:

Human milk oligosaccharides (HMOs) impact the intestinal microbiota by increasing beneficial bacteria in infants and adults, and are safe and well tolerated in these age groups. Effects on intestinal microbiota, safety, and digestive tolerance in children have not been, however, assessed. The aims of this trial were to evaluate if HMOs are able to specifically modulate the intestinal microbiota in children, and to assess safety and digestive tolerance.

Methods:

In this randomized, double-blinded, placebo-controlled trial, 75 children with overweight (including obesity) ages 6 to 12 years were randomized to receive 2′-fucosyllactose (2′FL), a mix of 2′FL and lacto-N-neotetraose (Mix), or a glucose placebo orally administrated once per day for 8 weeks.

Results:

The relative abundance of bifidobacteria increased significantly after 4 (P < 0.001) and 8 (P = 0.025) weeks of intervention in the 2′FL-group and after 4 weeks (P = 0.033) in the Mix-group, whereas no change was observed in the placebo group. Compared with placebo, the 2′FL-group had a significant increase in bifidobacteria abundance after 4 weeks (P < 0.001) and 8 weeks (P = 0.010) and the Mix-group showed a tendency to increased bifidobacteria abundance after 4 (P = 0.071) and 8 weeks (P = 0.071). Bifidobacterium adolescentis drove the bifidogenic effect in the 2 groups. Biochemical markers indicated no safety concerns, and the products did not induce digestive tolerance issues as assessed by Gastrointestinal Symptoms Rating Scale and Bristol Stool Form Scale.

Conclusions:

Both 2′FL and the Mix beneficially modulate intestinal microbiota by increasing bifidobacteria. Furthermore, supplementation with either 2′FL alone or a Mix is safe and well tolerated in children.
Determining the Impact of Best Fit for Newly Licensed Nurses
Authors: Valdes Elise G. , Douglas Laura , Oliveira Jessica , Sadler Felicia
Published: June 2021

Preparing new nursing graduates for independent practice as soon as safely possible is vital for both efficient and effective patient care. The alignment between a nurse’s personality and specialty practice area may impact orientation length, as nurses who are better suited to their job role may adapt more quickly. The current study revealed that nurses hired into a specialty practice area with a higher job fit demonstrates a significant reduction in orientation time.
Histologic Features of Tacrolimus-induced Colonic Injury
Authors: Hissong Erika , Mostyka Maria , Yantiss Rhonda K.
Published: June 2021

Tacrolimus is a common immunosuppressant used in solid organ transplant recipients. Although most patients develop diarrheal symptoms, data regarding patterns of injury in patients taking tacrolimus are limited. We performed this study to characterize tacrolimus-related features of colonic injury. We retrospectively identified colonic samples from 20 patients receiving tacrolimus monotherapy. Records were reviewed for symptoms, endoscopic findings, other medications, and infections. None of the patients had gastrointestinal infections or used other drugs known to cause colonic injury; none had received mycophenolate within 6 months of presentation. Cases were evaluated for the nature and distribution of inflammation and crypt abnormalities, including distortion, destruction, and apoptosis. Eighteen (90%) patients were solid organ transplant recipients. Seventeen (85%) had gastrointestinal symptoms, particularly diarrhea (75%). More than 50% had endoscopic colitis and 15% had ulcers and/or erosions. Most (90%) cases showed regenerative epithelial changes; apoptotic crypt cells were present in 55% and numerous in 10% of cases. Neutrophilic cryptitis was present in 60% of cases; 35% showed crypt destruction. Plasma cell-rich lamina propria inflammation and crypt distortion were observed in 40% and 25% of cases, respectively. There was no correlation between therapy duration and features of chronic injury. We conclude that tacrolimus can cause symptomatic colitis. Histologic abnormalities are often mild, featuring regenerative crypts and scattered apoptotic debris. However, 40% of symptomatic patients have chronic colitis, most likely reflecting drug-induced immune dysregulation. Pathologists should be aware of these associations because colitis often resolves with decreasing drug dosage rather than treatment directed toward inflammatory bowel disease.
Allosteric Inhibition of a Vesicular Glutamate Transporter by an Isoform-Specific Antibody
Authors: Eriksen Jacob , Li Fei , Stroud Robert M. , Edwards Robert H.
Published: June 2021

The role of glutamate in excitatory neurotransmission depends on its transport into synaptic vesicles by the vesicular glutamate transporters (VGLUTs). The three VGLUT isoforms exhibit a complementary distribution in the nervous system and the knockout of each produces severe, pleiotropic neurological effects. However, the available pharmacology lacks sensitivity and specificity, limiting the analysis of both transport mechanism and physiological role. To develop new molecular probes for the VGLUTs, we raised six mouse monoclonal antibodies to VGLUT2. All six bind to a structured region of VGLUT2, five to the luminal face and one to the cytosolic. Two are specific to VGLUT2 whereas the other four bind to both VGLUT1 and 2; none detect VGLUT3. Antibody 8E11 recognizes an epitope spanning the three extracellular loops in the C-domain that explains the recognition of both VGLUT1 and 2 but not VGLUT3. 8E11 also inhibits both glutamate transport and the VGLUT-associated chloride conductance. Since the antibody binds outside the substrate recognition site, it acts allosterically to inhibit function presumably by restricting conformational changes. The isoform specificity also shows that allosteric inhibition provides a mechanism to distinguish between closely related transporters.
State transitions in the statistically stable place cell population are determined by rate of perceptual change
Authors: Tanni Sander , de Cothi William , Barry Caswell
Published: June 2021

The hippocampus plays a central role in mammalian navigation and memory, yet an implementational understanding of the rules that govern the granularity of location encoding and the spatial-statistics of the population as a whole are lacking. We analysed large numbers of CA1 place fields recorded while rats foraged in environments up to 8.75 m2. We found that place cell propensities to form fields were proportional to open-field area, gamma-distributed, and conserved across environments. The properties of place fields varied positionally with a denser distribution of smaller fields near boundaries. Remarkably, field size and density were in a dynamic equilibrium, such that population-level activity statistics remained constant. We showed that the rate of transition through the statistically stable place cell population matched the rate of change in the animals’ visual scenes - demonstrating that the resolution of the spatial-memory system is bounded by perceptual information afforded by the environment.
A CRISPRi/a platform in iPSC-derived microglia uncovers regulators of disease states
Authors: Dräger Nina M. , Sattler Sydney M. , Huang Cindy Tzu-Ling , Teter Olivia M. , Leng Kun , Hashemi Sayed Hadi , Hong Jason , Aviles Giovanni , Clelland Claire D. , Zhan Lihong , Udeochu Joe C. , Kodama Lay , Singleton Andrew B. , Nalls Mike A. , Ichida Justin , Ward Michael E. , Faghri Faraz , Gan Li , Kampmann Martin
Published: June 2021

Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human iPSC-derived microglia. We developed an efficient eight-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the “druggable genome”. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by SPP1 expression was selectively depleted by CSF1R inhibition. Thus, our platform can systematically uncover regulators of microglia states, enabling their functional characterization and therapeutic targeting.
Electrical Potentials of Protoscoleces of the Cestode Echinococcus granulosus from Bovine Origin
Authors: Carabajal Mónica P. A. , Durán Marcos A. , Olivera Santiago , Salom María José Fernández , Cantiello Horacio F.
Published: June 2021

Larval stages of the tenia Echinococcus granulosus are the infective forms of cystic echinococcosis or hydatidosis, a worldwide zoonosis. The protoscolex that develops into the adult form in the definitive host is enveloped by a complex cellular syncytial tegument, where all metabolic interchange takes place. Little information is available as to the electrical activity of the parasite in this developmental stage. To gain insight into the electrical activity of the parasite at the larval stage, here we conducted microelectrode impalements of bovine lung protoscoleces (PSCs) of Echinococcus granulosus in normal saline solution. We observed two distinct intra-parasitic potentials, a transient peak potential and a stable second potential, most likely representing tegumental and intra-parasitic extracellular space electrical potential differences, respectively. These values changed upon the developmental status of the parasite, its anatomical regions, or time course after harvesting. Changes in electrical potential differences of the parasite provide an accessible and useful parameter for the study of transport mechanisms and potential targets for the development of novel antiparasitic therapeutics.

Author summary

Hydatid disease is a parasite-caused zoonosis that causes high morbidity and mortality and has a great impact on public health. The disease has no known cure, and the main lines of treatment include surgery and medical treatments which are not satisfactory, so new drug compounds are urgently needed. Genome sequencing of the parasite has identified different genes encoding ion channels in Echinococcus granulosus, making ion channel inhibitors a promising target for treating hydatidosis. However, no easy technical approaches are available to test the electrical contribution of ion channels to parasite physiology. In the present study, we used the microelectrode impalement technique to determine the electrical properties of the larval stages of the parasite harvested from infected cow lungs. We observed transient electrical potentials not previously reported for the parasite, and changes in these parameters associated with its developmental stage and aging. Our findings indicate that microelectrode impalement of protoscoleces of Echinococcus granulosus may be a strategy of choice to explore and test possible drugs suggested for their therapeutic potential against hydatid disease. Further evaluation of parasites coming from other animals and humans may help address important issues in the treatment and prevention of the hydatid disease.
Prognostic Roles of LncRNA XIST and Its Potential Mechanisms in Human Cancers: A Pan-Cancer Analysis
Authors: Han Wei , Shi Chun-tao , Ma Jun , Shao Qi-xiang , Gao Xiao-jiao , Wang Hao-nan
Published: June 2021

Background

X-inactive specific transcript (XIST), it has been found, is abnormal expression in various neoplasms. This work aims to explore its potential molecular mechanisms and prognostic roles in types of malignancies.

Methods

This research comprehensively investigated XIST transcription across cancers from Oncomine, TIMER 2.0 and GEPIA2. Correlations of XIST expression with prognosis, miRNAs, interacting protens, immune infiltrates, checkpoint markers and mutations of tumor-associated genes were also analyzed by public databases.

Results

Compared to normal tissues, XIST was lower in BRCA, COAD, LUAD, lymphoma and OV in Oncomine; In TIMER 2.0, XIST was decreased in BRCA, KICH, THCA and UCEC, but increased in KIRC and PRAD; In GEPIA2, XIST was down-regulated in CESC, COAD, OV, READ, STAD, UCEC and UCS. Public databases also showed that XIST was a good indicator of prognosis in BRCA, CESC, COAD, STAD, OV and so on, but a bad one in KIRC, KIRP and so on. From starBase, we found 29 proteins interacting with XIST, and identified 4 miRNAs, including miR-103a-3p, miR-107, miR-130b-3p and miR-96-5p, which might be sponged by XIST in cancers. Furthermore, XIST was linked with immune infiltration, especially T cell CD4+, and was related to over 20 immune checkpoint markers. In addition, XIST was associated with several tumor-associated gene mutations in some cancers.

Conclusion

In summary, abnormal expression of XIST influenced prognosis, miRNAs, immune cell infiltration and mutations of tumor-associated genes across cancers, especially BRCA and colorectal cancer. More efforts should be made to detect potential molecular mechanisms of XIST in the carcinogenesis.
Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells
Authors: Okutachi Sunday , Manoharan Ganesh babu , Abankwa Daniel
Published: June 2021

Phenothiazines (PTZ) are well known as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they are used for decades as antipsychotic drugs. In addition, significant anti-cancer properties have been ascribed to them. Several attempts for their repurposing were made, however, their incompletely understood polypharmacology is challenging.

Here we examined the potential of PTZ to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Both proteins are known to modulate the Ras-MAPK pathway activity. Consistently, combinations of a CaM inhibitor and a PP2A activator synergistically inhibited cancer cells with KRAS or BRAF mutations. We identified the covalently reactive PTZ derivative fluphenazine mustard as an inhibitor of Ras driven proliferation and Ras membrane organization. We confirmed its anti-CaM activity in vitro and through a cellular CaM target engagement bioluminescence resonance energy transfer (BRET) assay. Our results suggest that improved PTZ derivatives retaining their synergistic CaM inhibitory and PP2A activating properties, but without neurological side-effects, may be interesting to pursue further as anti-cancer agents.
Specificity and Mechanism of Coronavirus, Rotavirus and Mammalian Two-Histidine-Phosphoesterases That Antagonize Antiviral Innate Immunity
Authors: Asthana Abhishek , Gaughan Christina , Weiss Susan R. , Silverman Robert H.
Published: June 2021

2’,5’-oligoadenylate(2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2’,5’-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses and rotaviruses encode 2-5A degrading enzymes thereby antagonizing RNase L and its antiviral effects. A-kinase anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self double-stranded-RNAs that activate OAS. We show these enzymes, members of the two-histidine-phosphoesterase (2H-PE) superfamily, constitute a sub-family referred here as 2’,5’-PEs. 2’,5’-PEs from mouse coronavirus (CoV) MHV (NS2), MERS-CoV (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3’,5’-oligoribonucleotides, all cleaved 2’,5’-oligoadenylates efficiently, but with variable activity against other 2’,5’-oligonucleotides. The 2’,5’-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2’,5’-p3A3) producing mono- or di- adenylates with 2’,3’-cyclic phosphate termini. Our results suggest that elimination of 2-5A might be the sole function of viral 2’,5’-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L.

IMPORTANCE

Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here we probed the evolutionary relationships and biochemical activities of two-histidine-phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme, AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, that we refer to as 2’,5’-PEs, specifically degrade 2’,5’-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2’,5’- and not 3’,5’-phosphodiester bonds, producing cleavage products with cyclic 2’,3’-phosphate termini. Our study defines 2’,5’-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but which have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacologic strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.
Epitranscriptomic addition of m6A regulates HIV-1 RNA stability and alternative splicing
Authors: Tsai Kevin , Bogerd Hal P. , Kennedy Edward M. , Emery Ann , Swanstrom Ronald , Cullen Bryan R.
Published: June 2021

Previous work has demonstrated that the epitranscriptomic addition of m6A to viral transcripts can promote the replication and pathogenicity of a wide range of DNA and RNA viruses, including HIV-1, yet the underlying mechanisms responsible for this effect have remained unclear. It is known that m6A function is largely mediated by cellular m6A binding proteins or readers, yet how these regulate viral gene expression in general, and HIV-1 gene expression in particular, has been controversial. Here, we confirm that m6A addition indeed regulates HIV-1 RNA expression and demonstrate that this effect is largely mediated by the nuclear m6A reader YTHDC1 and the cytoplasmic m6A reader YTHDF2. Both YTHDC1 and YTHDF2 bind to multiple distinct and overlapping sites on the HIV-1 RNA genome, with YTHDC1 recruitment serving to regulate the alternative splicing of HIV-1 RNAs. Unexpectedly, while YTHDF2 binding to m6A residues present on cellular mRNAs resulted in their destabilization as previously reported, YTHDF2 binding to m6A sites on HIV-1 transcripts resulted in a marked increase in the stability of these viral RNAs. Thus, YTHDF2 binding can exert diametrically opposite effects on RNA stability, depending on RNA sequence context.
Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA
Authors: Vaisvila Romualdas , Ponnaluri V.K. Chaithanya , Sun Zhiyi , Langhorst Bradley W. , Saleh Lana , Guan Shengxi , Dai Nan , Campbell Matthew A. , Sexton Brittany S. , Marks Katherine , Samaranayake Mala , Samuelson James C. , Church Heidi E. , Tamanaha Esta , Corrêa Ivan R. , Pradhan Sriharsa , Dimalanta Eileen T. , Evans Thomas C. , Williams Louise , Davis Theodore B.
Published: June 2021

Bisulfite sequencing detects 5mC and 5hmC at single-base resolution. However, bisulfite treatment damages DNA, which results in fragmentation, DNA loss, and biased sequencing data. To overcome these problems, enzymatic methyl-seq (EM-seq) was developed. This method detects 5mC and 5hmC using two sets of enzymatic reactions. In the first reaction, TET2 and T4-BGT convert 5mC and 5hmC into products that cannot be deaminated by APOBEC3A. In the second reaction, APOBEC3A deaminates unmodified cytosines by converting them to uracils. Therefore, these three enzymes enable the identification of 5mC and 5hmC. EM-seq libraries were compared with bisulfite-converted DNA, and each library type was ligated to Illumina adaptors before conversion. Libraries were made using NA12878 genomic DNA, cell-free DNA, and FFPE DNA over a range of DNA inputs. The 5mC and 5hmC detected in EM-seq libraries were similar to those of bisulfite libraries. However, libraries made using EM-seq outperformed bisulfite-converted libraries in all specific measures examined (coverage, duplication, sensitivity, etc.). EM-seq libraries displayed even GC distribution, better correlations across DNA inputs, increased numbers of CpGs within genomic features, and accuracy of cytosine methylation calls. EM-seq was effective using as little as 100 pg of DNA, and these libraries maintained the described advantages over bisulfite sequencing. EM-seq library construction, using challenging samples and lower DNA inputs, opens new avenues for research and clinical applications.
Mismatch repair–deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade
Authors: Sena Laura A. , Salles Daniela C. , Engle Elizabeth L. , Zhu Qingfeng , Tukachinsky Hanna , Lotan Tamara L. , Antonarakis Emmanuel S.
Published: June 2021

Parenchymal brain metastases from prostate cancer are unusual and are associated with poor prognosis. Given the rarity of this entity, little is known about its molecular and histologic characteristics. Here we describe a patient with metastatic castration-resistant, mismatch repair–deficient (dMMR) prostate cancer with parenchymal brain metastases. Analysis of a brain metastasis revealed MLH1 loss consistent with dMMR, yet few tumor-infiltrating lymphocytes (TILs). He was treated with immune checkpoint blockade (ICB) and exhibited an extra–central nervous system (CNS) systemic response but CNS progression. Subsequent assessment of a brain metastasis following ICB treatment surprisingly showed increased TIL density and depletion of macrophages, suggestive of an enhanced antitumor immune response. Post-treatment tumoral DNA sequencing did not reveal acquired mutations that might confer resistance to ICB. This is the first description of ICB therapy for a patient with prostate cancer with parenchymal brain metastases, with pre- and post-treatment immunogenomic analyses.
UAV icing: the influence of airspeed and chord length on performance degradation
Authors: Hann Richard , Johansen Tor Arne
Published: June 2021

Purpose

The main purpose of this paper is to investigate the effects of icing on unmanned aerial vehicles (UAVs) at low Reynolds numbers and to highlight the differences to icing on manned aircraft at high Reynolds numbers. This paper follows existing research on low Reynolds number effects on ice accretion. This study extends the focus to how variations of airspeed and chord length affect the ice accretions, and aerodynamic performance degradation is investigated.

Design/methodology/approach

A parametric study with independent variations of airspeed and chord lengths was conducted on a typical UAV airfoil (RG-15) using icing computational fluid dynamic methods. FENSAP-ICE was used to simulate ice shapes and aerodynamic performance penalties. Validation was performed with two experimental ice shapes obtained from a low-speed icing wind tunnel. Three meteorological conditions were chosen to represent the icing typologies of rime, glaze and mixed ice. A parameter study with different chord lengths and airspeeds was then conducted for rime, glaze and mixed icing conditions.

Findings

The simulation results showed that the effect of airspeed variation depended on the ice accretion regime. For rime, it led to a minor increase in ice accretion. For mixed and glaze, the impact on ice geometry and penalties was substantially larger. The variation of chord length had a substantial impact on relative ice thicknesses, ice area, ice limits and performance degradation, independent from the icing regime.

Research limitations/implications

The implications of this manuscript are relevant for highlighting the differences between icing on manned and unmanned aircraft. Unmanned aircraft are typically smaller and fly slower than manned aircraft. Although previous research has documented the influence of this on the ice accretions, this paper investigates the effect on aerodynamic performance degradation. The findings in this work show that UAVs are more sensitive to icing conditions compared to larger and faster manned aircraft. By consequence, icing conditions are more severe for UAVs.

Practical implications

Atmospheric in-flight icing is a severe risk for fixed-wing UAVs and significantly limits their operational envelope. As UAVs are typically smaller and operate at lower airspeeds compared to manned aircraft, it is important to understand how the differences in airspeed and size affect ice accretion and aerodynamic performance penalties.

Originality/value

Earlier work has described the effect of Reynolds number variations on the ice accretion characteristics for UAVs. This work is expanding on those findings by investigating the effect of airspeed and chord length on ice accretion shapes separately. In addition, this study also investigates how these parameters affect aerodynamic performance penalties (lift, drag and stall).
Awareness and perception of medical genetic services among Malaysian parents of autism spectrum disorders children: the lessons to be learned
Authors: Amini Farahnaz , Yee Kok Wah , Soh Siew Chin , Alhadeethi Abdulateef , Amini Roya , Ng Edmond Siah Chye
Published: June 2021

Purpose

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with uncertain etiology. Evidence shows that genetic testing can explain about 20% of cases. This study aims to assess the level of awareness and perception of medical genetic services among Malaysian parents with ASD children.

Design/methodology/approach

A cross-sectional survey using an interviewer-administered questionnaire was done among 111 parents of children with ASD from August 2017 to September 2019 in two clinics in Malaysia.

Findings

A majority of children with ASD (80.20%) were male and diagnosed at the age of 3–4 years old (47.80%). When the autistic child was born, most mothers and fathers were aged 26–30 (40.50%) and 31–35 years old (42.30%), respectively. Another child with ASD in nuclear and extended families was reported for 11.70% and 13.50%, respectively. Only 24.30% have seen a professional genetic consultant, and 19.8% have done genetic testing for affected children. The mean score of awareness of genetic services for ASD was 2.48 ± 3.30. Having medical insurance and another child with ASD in the nuclear family was significantly associated with a higher level of awareness (p = 0.01 and p < 0.001, respectively). Most of the participants have a positive perception of these services.

Originality/value

Regardless of demographic factors, participants have poor awareness of genetic services for ASD, likely because the primary physician did not recommend it upon diagnosis. Increasing health-care providers’ knowledge about the current potential of genetic testing for ASD and educational campaigns for the public are critical components of using available genetic tests to improve ASD management.