bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Acetylfentanyl Following Suspected Heroin Overdose When Complicated by the Presence of Toxic Fentanyl and Alprazolam Concentrations
Authors: Fagiola Michael , Hahn Timothy , Avella Joseph
Published: January 2020

A 34-year-old male was reported to be snorting a white powder that was believed to contain heroin. Toxicological analysis revealed free morphine (356 μg/L), fentanyl (34.7 μg/L), alprazolam (64.9 μg/L), and acetylfentanyl (32.9 μg/L) in femoral blood and 6-monoacetylmorphine (6-MAM, <10.0 μg/L) in vitreous fluid. Norfentanyl was only detected in stomach contents (<1.00 μg/total). Heroin, fentanyl, and acetylfentanyl were also detected in solid dose evidence submitted by law enforcement. The fentanyl and alprazolam concentrations might normally be associated with a fatal outcome and are supported with the distribution of fentanyl and alprazolam being consistent with an acute intoxication. In addition, the presence of 6-MAM and a free versus total morphine ratio of 67.9% provide supporting evidence of a rapid death following intranasal (IN) administration. However, the presence of illicit acetylfentanyl complicates toxicologic interpretation due to overlapping recreational and fatal concentrations of this compound reported in the literature as well as a potential for postmortem redistribution (PMR). Reported acetylfentanyl concentrations have also varied when presented with significant fentanyl concentrations and underscore the need to consider a wide range of illicit opioid compounds when investigating drug-related deaths. Based on our comprehensive toxicologic analysis, the results suggest an acute intoxication primarily by IN administration of acetylfentanyl and fentanyl. In addition, we suggest the presence of alprazolam, 6-MAM, and a percentage free morphine is also consistent with rapid death. The cause of death was officially attributed to an acute combined intoxication of acetylfentanyl, fentanyl, alprazolam, and heroin, with the manner of death as accidental.
Forensic Considerations in a Series of 14 Deaths of Patients with a Left Ventricular Assist Device
Authors: Lin Peter T. , Thomas Sarah
Published: January 2020

Introduction: To better understand the forensic implications of death with a left ventricular assist device (LVAD), we reviewed all deaths that were reported to a regional medical examiner jurisdiction involving patients who had an LVAD. Methods: Medical examiner case files between January 2012 and September 2018 were searched for “LVAD” and “left ventricular assist device” to identify deaths that were reported to the medical examiner involving a decedent who had an LVAD at the time of death. Results: During the study period, a total of 14 deaths were reported to the regional medical examiner involving decedents who had an implanted LVAD at the time of death. The average age at death was 64 years, with a range from 40 to 81 years. The underlying cardiac disease leading to LVAD implantation was ischemic heart disease (n = 9), nonischemic dilated cardiomyopathy (n = 4), and chemotherapy-related cardiotoxicity (n = 1). Of these 14 deaths, 2 deaths were due to loss of power to the LVAD, 1 death was due to traumatic subdural hemorrhage occurring in the setting of anticoagulation therapy required by LVAD implantation, and 1 death was due to femur fracture following a fall. Discussion: Medical examiners should be familiar with the potential complications of LVADs, especially those complications that may prompt consideration of non-natural manners of death. Medical examiners should also be aware of the tools and investigative strategies that may assist in the investigation of LVAD-related deaths.
Fat Embolism, Fat Embolism Syndrome and the Autopsy
Authors: Milroy Christopher M. , Parai Jacqueline L.
Published: January 2020

Fat embolism is common following trauma and is a common autopsy finding in these cases. It may also be seen in non-traumatic cases and is seen in children as well as adults. In comparison fat embolism syndrome (FES) only occurs in a small number of trauma and non-trauma cases. Clinical diagnosis is based on characteristic clinical and laboratory findings. Fat embolism exerts its effect by mechanical blockage of vessels and/or by biochemical means including breakdown of fat to free fatty acids causing an inflammatory response. Fat embolism can be identified at autopsy on microscopy of the lungs using fat stains conducted on frozen tissue, including on formalin fixed but not processed tissue. With FES fat emboli can be seen in other organs including the brain, kidney and myocardium. Fat can also be identified with post-fixation staining, typically with osmium tetroxide. Scoring systems have been developed to try and determine the severity of fat embolism in lung tissue. Fat embolism is also common following resuscitation. When no resuscitation has taken place, the presence of fat on lung histology has been used as proof of vitality. Diagnosis of fat embolism syndrome at autopsy requires analysis of the history, clinical and laboratory findings along with autopsy investigations to determine its relevance, but is an important diagnosis to make which is not always identified clinically. This paper reviews the history, clinical and laboratory findings and diagnosis of fat embolism and fat embolism syndrome at autopsy.
Making Spaces for Staff Breaks: A Design Anthropology Approach
Authors: Pink Sarah , Duque Melisa , Sumartojo Shanti , Vaughan Laurene
Published: January 2020

Purpose:

This article proposes and demonstrates a design anthropological approach to hospital design and architecture and engages this approach to advance recent discussions of the question of designing for staff breaks.

Background:

We respond to calls for attention to sensory and experiential dimensions of hospital architecture and design through social science approaches and to research into the sensory environments for staff breaks.

Method:

Design anthropology enables us to surface the experiential and unspoken knowledge and practice of hospital staff, which is inaccessible through conventional consultations, quantitative post-occupancy evaluation surveys, or traditional interviews. We draw on ethnographic research into the everyday experience, improvisatory activity, and imagined futures of staff working in the psychiatric department of a large new architecturally designed hospital in Australia.

Results:

We argue that while the sensory aspects of hospital design conventionally cited—such as light and green areas—are relevant, attention to staff priorities that emerge in practice reveals that well-being is contingent on other qualities and resources.

Conclusions:

This suggests a refocus, away from the idea that environments impact on staff to create well-being, to understanding how staff improvise to create environments of well-being. We outline the implications of this research for an agenda for design for well-being in which architects and designers are often constrained by generic design briefs to argue for a shift in policy that attends more deeply to staff as future users of hospital designs.
Biomimetic gradient scaffold of collagen–hydroxyapatite for osteochondral regeneration
Authors: Parisi Cristian , Salvatore Luca , Veschini Lorenzo , Serra Maria Paola , Hobbs Carl , Madaghiele Marta , Sannino Alessandro , Di Silvio Lucy
Published: January 2020

Osteochondral defects remain a major clinical challenge mainly due to the combined damage to the articular cartilage and the underlying bone, and the interface between the two tissues having very different properties. Current treatment modalities have several limitations and drawbacks, with limited capacity of restoration; however, tissue engineering shows promise in improving the clinical outcomes of osteochondral defects. In this study, a novel gradient scaffold has been fabricated, implementing a gradient structure in the design to mimic the anatomical, biological and physicochemical properties of bone and cartilage as closely as possible. Compared with the commonly studied multi-layer scaffolds, the gradient scaffold has the potential to induce a smooth transition between cartilage and bone and avoid any instability at the interface, mimicking the natural structure of the osteochondral tissue. The scaffold comprises a collagen matrix with a gradient distribution of low-crystalline hydroxyapatite particles. Physicochemical analyses confirmed phase and chemical compositions of the gradient scaffold and the distribution of the mineral phase along the gradient scaffold. Mechanical tests confirmed the gradient of stiffness throughout the scaffold, according to its mineral content. The gradient scaffold exhibited good biological performances both in vitro and in vivo. Biological evaluation of the scaffold, in combination with human bone-marrow–derived mesenchymal stem cells, demonstrated that the gradient of composition and stiffness preferentially increased cell proliferation in different sub-regions of the scaffold, according to their high chondrogenic or osteogenic characteristics. The in vivo biocompatibility of the gradient scaffold was confirmed by its subcutaneous implantation in rats. The gradient scaffold was significantly colonised by host cells and minimal foreign body reaction was observed. The scaffold’s favourable chemical, physical and biological properties demonstrated that it has good potential as an engineered osteochondral analogue for the regeneration of damaged tissue.
Sounding out synthesis: Investigating how educators in a teaching with technology course use sonic composition to remix reflection
Authors: Wargo Jon M
Published: January 2020

This study explores how educators ( n =  23) in a graduate-level “teaching with technology” course used the affordances of digital composing, and sonic composition in particular, to “sound out” reflection. Using the twin-lenses of sociocultural theory and social semiotics, findings suggest that sound operated as a: rhetorical tool for illustrating affect/argument; complementary mode to syncretic meaning; and a diegetic structural feature/locating mechanism. Examining how multimodality became a technology and communicative resource for teachers to remix reflection, this study highlights the frictions and freedoms of using sound to synthesize learning in the online teacher education classroom. As such, this article proposes novel ways to think with sound in e-learning and (re)educates the senses to hear practitioner-inquiry in new ways.
External validation and comparison of the CardShock and IABP-SHOCK II risk scores in real-world cardiogenic shock patients
Authors: Rivas-Lasarte Mercedes , Sans-Roselló Jordi , Collado-Lledó Elena , González-Fernández Víctor , Noriega Francisco J , Hernández-Pérez Francisco J , Fernández-Martínez Juan , Ariza Albert , Lidón Rosa-Maria , Viana-Tejedor Ana , Segovia-Cubero Javier , Harjola Veli-Pekka , Lassus Johan , Thiele Holger , Sionis Alessandro
Published: January 2020

Background

Mortality from cardiogenic shock remains high and early recognition and risk stratification are mandatory for optimal patient allocation and to guide treatment strategy. The CardShock and the Intra-Aortic Balloon Counterpulsation in Acute Myocardial Infarction Complicated by Cardiogenic Shock (IABP-SHOCK II) risk scores have shown good results in predicting short-term mortality in cardiogenic shock. However, to date, they have not been compared in a large cohort of ischaemic and non-ischaemic real-world cardiogenic shock patients.

Methods

The Red-Shock is a multicentre cohort of non-selected cardiogenic shock patients. We calculated the CardShock and IABP-SHOCK II risk scores in each patient and assessed discrimination and calibration.

Results

We included 696 patients. The main cause of cardiogenic shock was acute coronary syndrome, occurring in 62% of the patients. Compared with acute coronary syndrome patients, non-acute coronary syndrome patients were younger and had a lower proportion of risk factors but higher rates of renal insufficiency; intra-aortic balloon pump was also less frequently used (31% vs 56%). In contrast, non-acute coronary syndrome patients were more often treated with mechanical circulatory support devices (11% vs 3%, p<0.001 for both). Both risk scores were good predictors of in-hospital mortality in acute coronary syndrome patients and had similar areas under the receiver-operating characteristic curve (area under the curve: 0.742 for the CardShock vs 0.752 for IABP-SHOCK II, p=0.65). Their discrimination performance was only modest when applied to non-acute coronary syndrome patients (0.648 vs 0.619, respectively, p=0.31). Calibration was acceptable for both scores (Hosmer-Lemeshow p=0.22 for the CardShock and 0.68 for IABP-SHOCK II).

Conclusions

In our cohort, both the CardShock and the IABP-SHOCK II risk scores were good predictors of in-hospital mortality in acute coronary syndrome-related cardiogenic shock.
Validation of a Self-Fitting Method for Over-the-Counter Hearing Aids
Authors: Sabin Andrew T. , Van Tasell Dianne J. , Rabinowitz Bill , Dhar Sumitrajit
Published: January 2020

In common practice, hearing aids are fitted by a clinician who measures an audiogram and uses it to generate prescriptive gain and output targets. This report describes an alternative method where users select their own signal processing parameters using an interface consisting of two wheels that optimally map to simultaneous control of gain and compression in each frequency band. The real-world performance of this approach was evaluated via a take-home field trial. Participants with hearing loss were fitted using clinical best practices (audiogram, fit to target, real-ear verification, and subsequent fine tuning). Then, in their everyday lives over the course of a month, participants either selected their own parameters using this new interface (Self group; n = 38) or used the parameters selected by the clinician with limited control (Audiologist Best Practices Group; n = 37). On average, the gain selected by the Self group was within 1.8 dB overall and 5.6 dB per band of that selected by the audiologist. Participants in the Self group reported better sound quality than did those in the Audiologist Best Practices group. In blind sound quality comparisons conducted in the field, participants in the Self group slightly preferred the parameters they selected over those selected by the clinician. Finally, there were no differences between groups in terms of standard clinical measures of hearing aid benefit or speech perception in noise. Overall, the results indicate that it is possible for users to select effective amplification parameters by themselves using a simple interface that maps to key hearing aid signal processing parameters.
Rethinking Pedagogy: An Outcome-Based Approach to Political Science
Authors: V. Shefeeque
Published: January 2020

This article is a discipline-based exploration of the possibilities and prospects of outcome-based education (OBE) in the teaching–learning process of political science at the under graduate level. Developing knowledge-empowered citizenry with critical political consciousness that enables it public policy debates is the key purposes of teaching political science. A serious deficit of the present mode of teacher/curriculum centric teaching–learning process, which fails the cause of imparting such qualities equipping the learner in developing self-critical/self-reflexive knowledge base, is the absence of analytical faculty and criticality. This article seeks to demonstrate the pedagogic advantages and quality assurance plausible in the political science higher education of India through the implementation of OBE.
Protection of Traditional Health Knowledge: International Negotiations, National Priorities and Knowledge Commons
Authors: Javed Ghazala , Priya Ritu , V. K. Deepa
Published: January 2020

Traditional knowledge (TK) is under debate in the contemporary world for its inherent value and need for protection from ‘biopiracy’. International consensus is proving difficult on defining its scope and ambit of protection. Traditional health knowledge (THK) is a promising domain of TK which, due to its immense economic and commercial value, is prone to misappropriation. International provisions exist for protection and definitions of TK and related resources at various fora such as the Convention on Biological Diversity. Proposals to protection of TK under Intellectual Property Right regimes are being addressed by the World Intellectual Property Organisation (WIPO). The text of a proposed treaty is being debated at WIPO’s Intergovernmental Committee on Genetic Resources, Traditional Knowledge and Folklore (IGC-GRTKF). This article spells out the issues being negotiated at the WIPO-IGC-GRTKF. With THK characterised in a tiered manner based on its secret or diffused public availability, consideration of customary law is an imperative. India proposed that the national governments be given status of knowledge holders for THK in the public domain and fiduciary rights in case of closely held/associated THK. The article finds that a comprehensive national policy instrument and sui generis law for the protection of THK have become especially urgent in the light of international debates. It also proposes that, rather than Intellectual property (IP), the framework of a ‘knowledge commons’ for just sharing of TK and its innovations may be a better option.
Gender, Medicine and Globalisation: The Case of Women Ayurveda Physicians of Kerala, India
Authors: Abraham Leena
Published: January 2020

Women’s entry into the exclusively male-dominated field of Ayurveda in large numbers and their pursuit of a professional career as physicians, observed since the 1980s in India, are socially and historically significant events. Their overwhelming participation marks a rupture in the unchallenged control of the field by men of certain castes and families of medical lineages for centuries. In Kerala, interestingly, this has occurred when women’s overall workforce participation has remained low. This article attempts to analyse women’s work in Ayurveda in Kerala and its consequences for Ayurvedic transformations in the state that are simultaneously aimed at consolidation of a regional identity and expansion of its global market. It analyses the experiences of women practitioners in the context of the local gender power dynamics and negotiations that define and direct their professional participation. How do these women Ayurveda practitioners negotiate forces of professionalisation as well as gender marginalisation? What are the various personal and societal resources that they mobilise to succeed as Ayurveda practitioners? Do their subjectivities, negotiations and resources alter practices of Ayurveda and infuse it with different sensibilities? Based on interviews of women Ayurveda practitioners from diverse caste, religious and economic backgrounds, the paper argues that women’s experiences vary according to their social locations and all women are not empowered or dis-empowered in a similar fashion by the same gender system. While globalisation has led to increased opportunities for women physicians, their careers and contributions continue to be restricted by the specific gender structures and ideologies that govern women’s lives in the respective local and global sites.
Evolution of the Walch Classification and Its Importance on the B2 Glenoid
Authors: Zimmer Zachary R , Carducci Michael P , Mahendraraj Kuhan A , Jawa Andrew
Published: January 2020

A thorough assessment and understanding of glenoid morphology is critical prior to shoulder arthroplasty for primary glenohumeral osteoarthritis. This is due to the fact that multiple studies have demonstrated the importance of reestablishing the native glenoid anatomy on the long-term survivability of the polyethylene glenoid component. In 1999, Walch et al. created a classification system for primary glenohumeral osteoarthritis based upon glenoid erosion and retroversion, and humeral head posterior subluxation. Since its original publication, the Walch classification has been the most widely used classification system for primary glenohumeral arthritis. However, after its initial publication in 1999, additional modifications have been made to the classification to clarify various definitions as well as further characterize other glenoid morphopathology seen in primary glenohumeral osteoarthritis. This article will discuss the original and modified Walch classification, the key differences between the two and the importance of these differences on the classification of the “B2 glenoid.”
Database on seismic response of instrumented flood control levees
Authors: Zimmaro Paolo , Kwak Dong Youp , Tsai Yi Tyan , Stewart Jonathan P , Brandenberg Scott J , Mikami Atsushi , Kataoka Shojiro
Published: January 2020

We present a database documenting the seismic response of seven instrumented flood control levee segments in Japan. The database includes (1) maps and cross-sections showing levee geometry and instrument layouts; (2) ground motion time series, and (where available) piezometric recordings; (3) reported field performance from post-earthquake reconnaissance (i.e. permanent displacements, other evidence of ground failure); and (4) geotechnical data, including geologic cross-sections, stratigraphy, penetration resistance, and shear wave velocity ( VS) profiles. The data are complete with respect to these attributes for three sites, with geotechnical data and field performance data missing for two and four sites, respectively. The database contains 150 recordings from 25 events and can be accessed through DOI: 10.21222/C2TC95. Ground motions were processed using standard procedures for Next Generation Attenuation projects. We present example data for a segment damaged by the M9.1 2011 Tohoku-oki earthquake, which includes ground motion and pore water pressure measurements.
“My life is under control with these medications”: an interpretative phenomenological analysis of managing chronic pain with opioids
Authors: Ljungvall Hanna , Rhodin Annica , Wagner Sofia , Zetterberg Hedvig , Åsenlöf Pernilla
Published: January 2020

Background

The use of opioids to relieve chronic pain has increased during the last decades, but experiences of chronic opioid therapy (COT) (> 90 days) point at risks and loss of beneficial effects. Still, some patients report benefits from opioid medication, such as being able to stay at work. Guidelines for opioid use in chronic pain do not consider the individual experience of COT, including benefits and risks, making the first person perspective an important scientific component to explore. The aim of this study was to investigate the lived experience of managing chronic pain with opioids in a sample who have severe chronic pain but are able to manage their pain sufficiently to remain at work.

Methods

We used a qualitative research design: interpretative phenomenological analysis. Ten individuals with chronic pain and opioid therapy were purposively sampled in Swedish tertiary care.

Results

Three super-ordinate themes emerged from the analyses: Without opioids, the pain becomes the boss; Opioids as a salvation and a curse, and Acknowledgement of the pain and acceptance of opioid therapy enables transition to a novel self. The participants used opioids to regain control over their pain, thus reclaiming their wanted life and self, and sense of control over one’s life-world. Using opioids to manage pain was not unproblematic and some of the participants had experienced a downward spiral of escalating pain and uncontrollable opioid use, and stigmatisation.

Conclusions

All participants emphasised the importance of control, regarding both pain and opioid use. To accomplish this, trust between participants and health care providers was essential for satisfactory treatment. Regardless of the potential sociocultural benefits of staying at work, participants had experiences of balancing positive and negative effects of opioid therapy, similar to what previous qualitative research has found.

Measurable improvement of function and quality of life, may justify the long-term use of opioids in some cases. However, monitoring of adverse events should be mandatory. This requires close cooperation and a trusting relationship between the patients and their health care provider.
Potential benefits of oral administration of AMORPHOPHALLUS KONJAC glycosylceramides on skin health – a randomized clinical study
Authors: Heggar Venkataramana Sudeep , Puttaswamy Naveen , Kodimule Shyamprasad
Published: January 2020

Background

Ceramides play a fundamental role in maintaining the skin health as a function of improved barrier permeability. Reduced ceramide content results in skin dryness and wrinkledness. Intake of dietary ceramides potentially compensates the skin ceramide content. In the present study we have assessed the skin health benefits of oral supplementation of a hydroalcoholic extract fromAmorphophallus konjactubers standardized to 5% glycosylceramides, in a placebo-controlled clinical trial.

Methods

Fifty-one healthy human volunteers (aged 18–60 years) were supplemented with 100 mg/day of either a placebo orA. konjacextract capsules (5 mg glycosylceramides) for 6-weeks. The skin parameters were evaluated through dermatological diagnosis. Subject perceived efficacy of the product was further evaluated by a self-assessment questionnaire.

Results

Oral intake ofA. konjacextract significantly decreased the skin dryness, hyperpigmentation, redness, itching and oilyness (p < 0.05). The improvement in skin health following intake ofA. konjacextract was observed to be time-dependent from the start. Further,A. konjacextract was well-tolerated throughout the study, as no adverse events or toxic changes were recorded.

Conclusion

The study demonstrates the skincare properties of orally ingested glycosyl ceramides from konjac tubers.

Trial registration

CTRI/2018/12/016661 dated 13/12/2018 retrospectively registered,http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=19851&EncHid=&userName=SkinCera
Genomic profiles and transcriptomic microenvironments in 2 patients with synchronous lung adenocarcinoma and lung squamous cell carcinoma: a case report
Authors: Wu Licheng , Kang Poming , Tao Shaolin , Zhao Zhikun , Chen Longyun , Xiao Yajie , Tan Qunyou
Published: January 2020

Background

Multifocal lung cancers (MLCs) are common in patients newly diagnosed with lung cancer, and histological results of most synchronous MLCs are similar. Few cases with different histology findings have been reported, and no genomic or transcriptomic profiling of this kind of cases were done before. Here, we analyzed genomic and transcriptomic profiles of all lung tumors from 2 patients with synchronous adenocarcinoma and squamous cell carcinoma in the same lung lobe.

Case presentation

Two patients were diagnosed as synchronous adenocarcinoma and squamous cell carcinoma and underwent surgical resection. All 4 tumors showed distinct genomic profiles, therefore were independent primary tumors. Several cancer-associated pathways, such as RTK-RAS pathway and Notch pathway, exhibited different mutated genes in different tumors from the same patient. Several known cancer genes with different mutations, including TP53 and KEAP1, were also detected. Mutation signature analysis demonstrated that the tumor initiation might be related to the transcription coupled nucleotide excision repair process. Two tumors for these 2 patients had loss of heterogeneity (LOH) in HLA genes, showing tumor escaping mechanism. Furthermore, tumor microenvironments showed different patterns in 2 tumors from the same patient. The tumor with more neoantigens and no HLA LOH showed more infiltrating CD8+ T cells and more clonal TCRs, indicating a more active microenvironment.

Conclusions

The lung squamous cell carcinoma and lung adenocarcinoma form the same patient are from independent origins. The genetic profiles and transcriptomic microenvironments are quite different for these 2 tumors. With the same genetic background, the 2 tumors in one patient exhibited different tumor escape mechanisms and immune responses, including HLA LOH and T cell infiltrating and expansion.
Mechanisms underpinning the association between physical activity and mental health in adolescence: a 6-year study
Authors: Doré Isabelle , Sylvester Benjamin , Sabiston Catherine , Sylvestre Marie-Pierre , O’Loughlin Jennifer , Brunet Jennifer , Bélanger Mathieu
Published: January 2020

Background

Physical activity (PA) can promote mental health, but the mechanisms underpinning this association are not well-established. This study examined if perceptions of three basic psychological needs (autonomy, competence, relatedness) and moderate-to-vigorous physical activity (MVPA) mediate the association between number of years participating in PA and mental health in adolescence.

Methods

Participants included 937 children (55% female) age 10–11 at inception of the longitudinal MATCH study, who provided data every 4 months over 6 years. Mediation analyses were used to assess the natural direct effect of number of years of PA participation (cycles 1–15) during late childhood and adolescence on later mental health (cycle 16), measured with the Mental Health Continuum-Short Form (MHC-SF), and the natural indirect effect through each of self-perceived autonomy, competence and relatedness, and self-report MVPA (cycle 15).

Results

In single mediator models, indirect effects of autonomy, competence, relatedness and self-report MVPA were statistically significant. In joint mediation models (each of three models including one basic psychological need and MVPA), autonomy, competence and relatedness mediated 71, 27, and 51% of the association respectively; MVPA mediated 27–31% of the association. In the mediation model including all four mediators, relatedness mediated the largest proportion of the association, followed by autonomy and MVPA.

Conclusion

Results support developing strategies to encourage adolescents to engage and remain involved in PA. This could foster perceptions of autonomy, competence, and relatedness as well as MVPA, which in turn may enhance mental health.
Design and synthesis of HLA-A*02-restricted Hantaan virus multiple-antigenic peptide for CD8+ T cells
Authors: Ma Yan , Tang Kang , Zhang Yusi , Zhang Chunmei , Zhang Yun , Jin Boquan , Ma Ying
Published: January 2020

Background

Hantaan virus (HTNV) can cause hemorrhagic fever with renal syndrome (HFRS) in humans with severe morbidity and high mortality. Although inactivated HFRS vaccines are given annually for prevention in populations, China still has the highest number of HFRS cases and deaths worldwide. Consequently, vaccination for HFRS requires the development of novel, more effective vaccines. Epitope peptide vaccines have been developed rapidly in recent years and are considered a novel approach for the prevention of infection. Specifically, the multiple antigenic peptide (MAP) design with preferable immunogenicity can arouse a satisfactory immune response for vaccination. However, there are few reports on the design and evaluation of MAP for HTNV.

Methods

Three HLA-A*02-restricted 9-mer cytotoxic T lymphocyte (CTL) epitopes on HTNV glycoprotein and one HLA-A*02-restricted 9-mer CTL epitope on the HTNV nucleocapsid, which have been proven to be immunoprotective in our previous study, were selected for the design of HTNV MAP. A four-branched HTNV MAP was evaluated by the IFN-γ-secreting enzyme-linked immunospot assay and proliferation induction capacity of CD8+ T cells and compared with the single HTNV CTL epitope in 17 HLA-A*02+ patients with HFRS. The Mann–Whitney U test was used for comparison of parameters between different subject groups.

Results

The macromolecular HTNV MAP was designed with a polylysine core and four radially branched single CTL epitope chains. Importantly, HTNV MAP could stimulate CD8+ T cell secretion of IFN-γ in HLA-A*02+ patients with HFRS. The frequency of IFN-γ-secreting CD8+ T cells in the MAP stimulation group was significantly higher than that in the single HTNV CTL epitope stimulation groups (P < 0.005). Meanwhile, the activity of IFN-γ-secreting CD8+ T cells in the HTNV MAP group was also higher than that of the single CTL epitope groups (P < 0.05). Moreover, there was a much stronger ability of HTNV MAP to stimulate CD8+ T cell proliferation compared with that of a single HTNV CTL epitope.

Conclusions

The designed HTNV MAP could induce CTL responses ex vivo and may be considered a candidate for the design and development of novel HTNV peptide vaccines.
Tetramethylpyrazine reverses high-glucose induced hypoxic effects by negatively regulating HIF-1α induced BNIP3 expression to ameliorate H9c2 cardiomyoblast apoptosis
Authors: Liu Shih-Ping , Shibu Marthandam Asokan , Tsai Fuu-Jen , Hsu Yuan-Man , Tsai Chang-Hai , Chung Jing-Gung , Yang Jai-Sing , Tang Chih-Hsin , Wang Shulin , Li Qiaowen , Huang Chih-Yang
Published: January 2020

Background

Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.

Methods

The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.

Results

The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.

Conclusion

The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
Improving quality of care and clinical outcomes for rectal cancer through clinical audits in a multicentre cancer care organisation
Authors: Torras M. G. , Canals E. , Muñoz-Montplet C. , Vidal A. , Jurado D. , Eraso A. , Villà S. , Caro M. , Molero J. , Macià M. , Puigdemont M. , González-Muñoz E. , López A. , Guedea F. , Borras J. M.
Published: January 2020

Introduction

Colorectal cancer treatment requires a complex, multidisciplinary approach. Because of the potential variability, monitoring through clinical audits is advisable. This study assesses the effects of a quality improvement action plan in patients with locally advanced rectal cancer and treated with radiotherapy.

Methods

Comparative, multicentre study in two cohorts of 120 patients each, selected randomly from patients diagnosed with rectal cancer who had initiated radiotherapy with a curative intent. Based on the results from a baseline clinical audit in 2013, a quality improvement action plan was designed and implemented; a second audit in 2017 evaluated its impact.

Results

Standardised information was present on 77.5% of the magnetic resonance imaging (MRI) staging reports. Treatment strategies were similar in all three study centres. Of the patients whose treatment was interrupted, just 9.7% received a compensation dose. There was an increase in MRI re-staging from 32.5 to 61.5%, and a significant decrease in unreported circumferential resection margins following neoadjuvant therapy (ypCRM), from 34.5 to 5.6% (p <  0.001).

Conclusions

The comparison between two clinical audits showed improvements in neoadjuvant radiotherapy in rectal cancer patients. Some indicators reveal areas in need of additional efforts, for example to reduce the overall treatment time.
Involvement of supralemniscal nucleus (B9) 5-HT neuronal system in nociceptive processing: a fiber photometry study
Authors: Moriya Shunpei , Yamashita Akira , Masukawa Daiki , Kambe Yuki , Sakaguchi Junichi , Setoyama Honami , Yamanaka Akihiro , Kuwaki Tomoyuki
Published: January 2020

Nociception is important perception that has harmful influence on daily life of humans. As to main pain management system, some descending pathways are called descending antinociceptive systems (DAS). As main pathways of DAS, it is well known that dorsal raphe (B6/B7) - rostral ventromedial medulla (B3) - spinal dorsal horn includes serotonergic system. However, possible role of supralemniscal (B9) serotonin (5-HT) cell group in pain management is still open question. In this study, we measured activities of B9 5-HT neuronal cell bodies and B9 5-HT neuron-derived axons located in the locus coeruleus (LC) and ventral tegmental area (VTA), which are also main players of pain management, using fiber photometry system. We introduced the G-CaMP6 in B9 5-HT neurons using transgenic mice carrying a tetracycline-controlled transactivator transgene (tTA) under the control of a tryptophan hydroxylase-2 (TPH2) promoter and site-specific injection of adeno associated virus (AAV-TetO(3G)-G-CaMP6). After confirmation of specific expression of G-CaMP6 in the target population, G-CaMP6 fluorescence intensity in B9 group and LC/VTA groups was measured in awake mice exposed to acute tail pinch and heat stimuli. G-CaMP6 fluorescence intensity rapidly increased by both stimuli in all groups, but not significantly reacted by nonnociceptive control stimuli. The present results clearly indicate that acute nociceptive stimuli cause a rapid increase in the activities of B9-LC/B9-VTA 5-HTergic pathways, suggesting that B9 5-HT neurons play important roles in nociceptive processing.
Myeloid-derived suppressor cells—new and exciting players in lung cancer
Authors: Yang Zhenzhen , Guo Jiacheng , Weng Lanling , Tang Wenxue , Jin Shuiling , Ma Wang
Published: January 2020

Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.
Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps
Authors: Abbruzzese Claudia , Matteoni Silvia , Persico Michele , Villani Veronica , Paggi Marco G.
Published: January 2020

Background

Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue.

Main body

The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities.

Short conclusions

On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.
Correlation between detergent activity and anti-herpes simplex virus-2 activity of commercially available vaginal gels
Authors: Szöllősi Andrea , Raffai Tímea , Bogdanov Anita , Endrész Valéria , Párducz László , Somogyvári Ferenc , Janovák László , Burián Katalin , Virok Dezső P.
Published: January 2020

Objective

Herpes simplex virus-2 (HSV-2) infections are almost exclusively sexually transmitted. The presence of vaginal gels during sexual activity may have a significant positive or negative impact on viral transmission. Therefore we investigated three off-the-shelf vaginal lubricants and one pH restoring gel to evaluate their impact on HSV-2 replication.

Results

HeLa cells were infected with untreated virions and virions incubated with the particular gels. The accumulation of viral genomes was monitored by quantitative PCR (qPCR) method at 24 h post infection. Two of the tested gels had no significant effect on HSV-2 replication at the maximum applied concentration, while two had a strong inhibitory effect (~ 98% reduction of replication). The replication inhibitory effect was observed at various multiplicity of infection (MOI 0.4–6.4) and the two inhibitory gels were also capable of inhibiting the HSV-2 induced cytopathic effect on HeLa cells. The surface tension decreasing activity—an indication of detergent activity—was strongly correlated with the anti-HSV-2 activity of the gels (R2: 0.88). Our results indicate that off-the-shelf vaginal gels have a markedly different anti-HSV-2 activity that may influence HSV-2 transmission.
Bradycardia and syncope as sole manifestations of a cranial lesion: a case report
Authors: Pchejetski Dmitri , Kenbaz Mojiba , Alshaker Heba , Jesudason Kiruparajan
Published: January 2020

Background

Bradycardia and syncope are known sequelae of brain lesions. However, in the absence of neurological signs and symptoms, bradycardia and syncope are often investigated purely from the cardiovascular perspective and central nervous system-related causes may be easily overlooked during differential diagnosis.

Case presentation

Here we report a case of a 69-year-old Caucasian man who presented to the emergency department after a fall. He had 1-year history of syncope and bradycardia with frequent ectopic beats shown on his electrocardiogram. He had no neurological symptoms. He was previously investigated as an out-patient and a diagnosis of idiopathic bradycardia with ventricular ectopic beats was made. On admission, cardiovascular investigations could not reveal the cause of his bradycardia. Computed tomography and magnetic resonance imaging scans of his head showed a localized mass in left basal ganglia consistent with infiltrating glioma.

Conclusion

To the best of our knowledge this is the first case report demonstrating central nervous system-related bradycardia and syncope without other neurological symptoms. This case will serve as a useful reminder to general practitioners, accident and emergency doctors, and cardiologists.
Simulation and multi-objective optimization to improve the final shape and process efficiency of a laser-based material accumulation process
Authors: Bänsch Eberhard , Luttmann Andreas , Montalvo-Urquizo Jonathan , Schmidt Alfred , Villarreal-Marroquín Maria G.
Published: January 2020

Common goals of modern production processes are precision and efficiency. Typically, they are conflicting and cannot be optimized at the same time. Multi-objective optimization methods are able to compute a set of good parameters, from which a decision maker can make a choice for practical situations. For complex processes, the use of physical experiments and/or extensive process simulations can be too costly or even unfeasible, so the use of surrogate models based on few simulations is a good alternative.

In this work, we present an integrated framework to find optimal process parameters for a laser-based material accumulation process (thermal upsetting) using a combination of meta-heuristic optimization models and finite element simulations. In order to effectively simulate the coupled system of heat equation with solid-liquid phase transitions and melt flow with capillary free surface in three space dimensions for a wide range of process parameters, we introduce a new coupled numerical 3d finite element method. We use a multi-objective optimization method based on surrogate models. Thus, with only few direct simulations necessary, we are able to select Pareto sets of process parameters which can be used to optimize three or six different performance measures.
Dissecting the factors shaping fish skin microbiomes in a heterogeneous inland water system
Authors: Krotman Yaron , Yergaliyev Timur M. , Alexander Shani Rivka , Avrahami Yosef , Szitenberg Amir
Published: January 2020

Background

Fish skin microbiomes are rarely studied in inland water systems, in spite of their importance for fish health and ecology. This is mainly because fish species distribution often covaries with other biotic and abiotic factors, complicating the study design. We tackled this issue in the northern part of the Jordan River system, in which a few fish species geographically overlap, across steep gradients of water temperature and salinity.

Results

Using 16S rRNA metabarcoding, we studied the water properties that shape the skin bacterial communities, and their interaction with fish taxonomy. To better characterise the indigenous skin community, we excluded bacteria that were equally abundant in the skin samples and in the water samples, from our analysis of the skin samples. With this in mind, we found alpha diversity of the skin communities to be stable across sites, but higher in benthic loaches, compared to other fish. Beta diversity was found to be different among sites and to weakly covary with the dissolved oxygen, when treated skin communities were considered. In contrast, water temperature and conductivity were strong factors explaining beta diversity in the untreated skin communities. Beta diversity differences between co-occurring fish species emerged only for the treated skin communities. Metagenomics predictions highlighted the microbiome functional implications of excluding the water community contamination from the fish skin communities. Finally, we found that human-induced eutrophication promotes dysbiosis of the fish skin community, with signatures relating to fish health.

Conclusions

Consideration of the background water microbiome when studying fish skin microbiomes, across varying fish species and water properties, exposes patterns otherwise undetected and highlight among-fish-species differences. We suggest that sporadic nutrient pollution events, otherwise undetected, drive fish skin communities to dysbiosis. This finding is in line with a recent study, showing that biofilms capture sporadic pollution events, undetectable by interspersed water monitoring.