bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation
Authors: Lindell Robert B. , Zhang Donglan , Bush Jenny , Wallace Douglas C. , Rabinowitz Joshua D. , Lu Wenyun , Wherry E. John , Weiss Scott L. , Henrickson Sarah E.
Published: June 2022

Background:

Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use.

Objective:

To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis.

Methods:

Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type.

Results:

Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+ T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106 cells vs. 8.4 pmol/s/106 cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen.

Conclusion:

Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.
Whole Blood Selective Aortic Arch Perfusion for Exsanguination Cardiac Arrest: Assessing Myocardial Tolerance to the Duration of Cardiac Arrest
Authors: Madurska Marta J. , Abdou Hossam , Elansary Noha N. , Edwards Joseph , Patel Neerav , Stonko David P. , Richmond Michael J. , Scalea Thomas M. , Rasmussen Todd E. , Morrison Jonathan J.
Published: June 2022

Introduction:

Selective aortic arch perfusion (SAAP) is an endovascular technique that consists of aortic occlusion with perfusion of the coronary and cerebral circulation. It been shown to facilitate return of spontaneous circulation (ROSC) after exanguination cardiac arrest (ECA), but it is not known how long arrest may last before the myocardium can no longer be durably recovered. The aim of this study is to assess the myocardial tolerance to exsanguination cardiac arrest before successful ROSC with SAAP.

Methods:

Male adult swine (n = 24) were anesthetized, instrumented, and hemorrhaged to arrest. Animals were randomized into three groups: 5, 10, and 15 min of cardiac arrest before resuscitation with SAAP. Following ROSC, animals were observed for 60 min in a critical care environment. Primary outcomes were ROSC, and survival at 1-h post-ROSC.

Results:

Shorter cardiac arrest time was associated with higher ROSC rate and better 1-h survival. ROSC was obtained for 100% (8/8) of the 5-min ECA group, 75% (6/8) of the 10-min group, 43% (3/7) of the 15-min group (P = 0.04). One-hour post-ROSC survival was 75%, 50%, and 14% in 5-, 10-, and 15-min groups, respectively (P = 0.02). One-hour survivors in the 5-min group required less norepinephrine (1.31 mg ± 0.83 mg) compared with 10-SAAP (0.76 mg ± 0.24 mg), P = 0.008.

Conclusion:

Whole blood SAAP can accomplish ROSC at high rates even after 10 min of unsupported cardiac arrest secondary to hemorrhage, with some viability beyond to 15 min. This is promising as a tool for ECA, but requires additional optimization and clinical trials.

Animal Use Protocol, IACUC: 0919015.
Protective Effect of Cardiomyocyte-Specific Prolyl-4-Hydroxylase 2 Inhibition on Ischemic Injury in a Mouse MI Model
Authors: Pradeep Seetur R , Lim Sue Ting , Thirunavukkarasu Mahesh , Joshi Mandip , Cernuda Bryan , Palesty J Alexander , Maulik Nilanjana
Published: June 2022

BACKGROUND:

Our earlier studies showed that inhibiting prolyl-4-hydroxylase enzymes (PHD-1 and PHD-3) improves angiogenesis, heart function, and limb perfusion in mouse models via stabilizing hypoxia-inducible transcription factor-alpha (HIF-1α). The present study explored the effects of the prolyl-4-hydroxylase enzyme, PHD-2, on ischemic heart failure using cardiac-specific PHD-2 gene knockout (KO) mice (PHD2−/−).

STUDY DESIGN:

Adult wild-type (WT) and PHD2−/− mice, 8–12 weeks old, were subjected to myocardial infarction (MI) by irreversibly ligating the left anterior descending (LAD) coronary artery. All sham group mice underwent surgery without LAD ligation. Animals were divided into 4 groups: (1) wild-type sham (WTS); (2) wild-type myocardial infarction (WTMI); (3) PHD2KO sham (PHD2−/−S); (4) PHD2KO myocardial infarction (PHD2−/−MI). Left ventricular tissue samples collected at various time points after surgery were used for microRNA expression profiling, Western blotting, and immunohistochemical analysis.

RESULTS:

Volcano plot analysis revealed 19 differentially-expressed miRNAs in the PHD2−/−MI group compared with the WTMI group. Target analysis using Ingenuity Pathway Analysis showed several differentially regulated miRNAs targeting key signaling pathways such as Akt, VEGF, Ang-1, PTEN, apoptosis, and hypoxia pathways. Western blot analysis showed increased HIF-1α, VEGF, phospho-AKT, β-catenin expression and reduced Bax expression for the PHD2−/−MI group compared with the WTMI group. Echocardiographic analysis showed preserved heart functions, and picrosirius red staining revealed decreased fibrosis in PHD2−/−MI compared with the WTMI group.

CONCLUSIONS:

PHD2 inhibition showed preserved heart function, enhanced angiogenic factor expression, and decreased apoptotic markers after MI. Overall, cardiac PHD2 gene inhibition is a promising candidate for managing cardiovascular diseases.
A resilience sensing system for the biosphere
Authors: Lenton Timothy M. , Buxton Joshua E. , Armstrong McKay David I. , Abrams Jesse F. , Boulton Chris A. , Lees Kirsten , Powell Thomas W. R. , Boers Niklas , Cunliffe Andrew M. , Dakos Vasilis
Published: June 2022

We are in a climate and ecological emergency, where climate change and direct anthropogenic interference with the biosphere are risking abrupt and/or irreversible changes that threaten our life-support systems. Efforts are underway to increase the resilience of some ecosystems that are under threat, yet collective awareness and action are modest at best. Here, we highlight the potential for a biosphere resilience sensing system to make it easier to see where things are going wrong, and to see whether deliberate efforts to make things better are working. We focus on global resilience sensing of the terrestrial biosphere at high spatial and temporal resolution through satellite remote sensing, utilizing the generic mathematical behaviour of complex systems—loss of resilience corresponds to slower recovery from perturbations, gain of resilience equates to faster recovery. We consider what subset of biosphere resilience remote sensing can monitor, critically reviewing existing studies. Then we present illustrative, global results for vegetation resilience and trends in resilience over the last 20 years, from both satellite data and model simulations. We close by discussing how resilience sensing nested across global, biome-ecoregion, and local ecosystem scales could aid management and governance at these different scales, and identify priorities for further work.

This article is part of the theme issue ‘Ecological complexity and the biosphere: the next 30 years’.
Scaling up our understanding of tipping points
Authors: Kéfi Sonia , Saade Camille , Berlow Eric L. , Cabral Juliano S. , Fronhofer Emanuel A.
Published: June 2022

Anthropogenic activities are increasingly affecting ecosystems across the globe. Meanwhile, empirical and theoretical evidence suggest that natural systems can exhibit abrupt collapses in response to incremental increases in the stressors, sometimes with dramatic ecological and economic consequences. These catastrophic shifts are faster and larger than expected from the changes in the stressors and happen once a tipping point is crossed. The primary mechanisms that drive ecosystem responses to perturbations lie in their architecture of relationships, i.e. how species interact with each other and with the physical environment and the spatial structure of the environment. Nonetheless, existing theoretical work on catastrophic shifts has so far largely focused on relatively simple systems that have either few species and/or no spatial structure. This work has laid a critical foundation for understanding how abrupt responses to incremental stressors are possible, but it remains difficult to predict (let alone manage) where or when they are most likely to occur in more complex real-world settings. Here, we discuss how scaling up our investigations of catastrophic shifts from simple to more complex—species rich and spatially structured—systems could contribute to expanding our understanding of how nature works and improve our ability to anticipate the effects of global change on ecological systems.

This article is part of the theme issue ‘Ecological complexity and the biosphere: the next 30 years’.
Risks to biodiversity from temperature overshoot pathways
Authors: Meyer Andreas L. S. , Bentley Joanne , Odoulami Romaric C. , Pigot Alex L. , Trisos Christopher H.
Published: June 2022

Temperature overshoot pathways entail exceeding a specified global warming level (e.g. 1.5°C or 2°C) followed by a decline in warming, achieved through anthropogenically enhanced CO
2
removal from the atmosphere. However, risks to biodiversity from temperature overshoot pathways are poorly described. Here, we explore biodiversity risks from overshoot by synthesizing existing knowledge and quantifying the dynamics of exposure and de-exposure to potentially dangerous temperatures for more than 30 000 species for a 2°C overshoot scenario. Our results suggest that climate risk to biodiversity from temperature overshoot pathways will arrive suddenly, but decrease only gradually. Peak exposure for biodiversity occurs around the same time as peak global warming, but the rate of de-exposure lags behind the temperature decline. While the global overshoot period lasts around 60 years, the duration of elevated exposure of marine and terrestrial biodiversity is substantially longer (around 100 and 130 years, respectively), with some ecological communities never returning to pre-overshoot exposure levels. Key biodiversity impacts may be irreversible and reliance on widespread CO
2
removal to reduce warming poses additional risks to biodiversity through altered land use. Avoiding any temperature overshoot must be a priority for reducing biodiversity risks from climate change, followed by limiting the magnitude and duration of any overshoot. More integrated models that include direct and indirect impacts from overshoot are needed to inform policy.

This article is part of the theme issue ‘Ecological complexity and the biosphere: the next 30 years’.
Encoding of a transgene in-frame with a Newcastle disease virus protein increases transgene expression and stability
Authors: Elbehairy Mohamed A. , Samal Siba K. , Belov George A.
Published: June 2022

Newcastle disease virus (NDV) has been extensively explored as a vector for vaccine and oncolytic therapeutic development. In conventional NDV-based vectors, the transgene is arranged as a separate transcription unit in the NDV genome. Here, we expressed haemagglutinin protein (HA) of an avian influenza virus using an NDV vector design in which the transgene ORF is encoded in-frame with the ORF of an NDV gene. This arrangement does not increase the number of transcription units in the NDV genome, and imposes a selection pressure against mutations interrupting the transgene ORF. We placed the HA ORF upstream or downstream of N, M, F and HN ORFs of NDV so that both proteins are encoded in-frame and are separated by either a self-cleaving 2A peptide, furin cleavage site or both. Only constructs in which HA was placed downstream of the NDV HN were viable. These constructs expressed the transgene at a higher level compared to the vector encoding the same transgene in the same position in the NDV genome but as a separate transcription unit. Furthermore, the transgene expressed in one ORF with the NDV protein proved to be more stable over multiple passages. Thus, this design may be useful for applications where the stability of the transgene expression is highly important for a recombinant NDV vector.
Preclinical model for the study of immune responses specific for a hepatic self-antigen
Authors: Cardon Anaïs , Judor Jean-Paul , Guinebretière Thomas , Danger Richard , Nicot Arnaud , Brouard Sophie , Conchon Sophie , Renand Amédée
Published: June 2022

The liver displays a strong capacity to induce tolerance toward hepatic antigens. However, hepatic tolerance can be overcome with the development of local autoimmune diseases such as autoimmune hepatitis (AIH). This chronic inflammatory disorder leads to a progressive destruction of liver parenchyma if non-treated. Although the CD4+ T cell response seems a key player of this immune disorder, the dynamics and biology of emerging liver antigen-specific CD4+ T cells are poorly described. Here, we developed a new murine model which mimics hepatic autoreactivity allowing the study and monitoring of antigen-specific CD4+ T cells from their emergence to local immune response. We show that the induction of the expression of an antigen in the liver in non-inflammatory condition leads to antigen tolerance. In inflammatory condition, using viral vector transduction, we observe the development of a complete adaptive immune response concomitant with the antigen expression in the liver. The presence of antigen-specific CD4+ T cells in the liver is associated to transient hepatic damages. Interestingly, the neo-antigen expression by hepatocytes after peripheral immunisation induces the recruitment of antigen-specific CD4+ T cells and hepatic damages. These data demonstrate that the recruitment of antigen-specific CD4+ T cells in the liver is conditioned by an immune coordination between surface antigen expression by hepatocytes and peripheral immune response and mimics the first step of a local autoreactive process. In the long-term, we observe that the hepatic environment has the capacity to control the local, but not the systemic, antigen-specific CD4+ T cells. Additional immune events might be involved in the long-term chronic immune reactivity in the liver, following the first steps described in this study.

Key points

Antigen expression in the liver in non-inflammatory condition leads to antigen tolerance

Antigen expression in the liver in immunization condition (concomitant or pre-existing) is sufficient to induce liver recruitment of antigen-specific CD4+ T cells and hepatic damages

This model mimics the first step of an autoreactive process against a liver antigen

In the long-term, the hepatic environment induces a local tolerance toward the antigen expression and the clearance of liver-infiltrating, but not peripheral, antigen-specific CD4+ T cells

This new murine model can be of interest for the analysis of the immunomodulatory pathways implicated in liver tolerization of autoreactive CD4+ T cells and identification of potential extrinsic factors implicated in an acute-to-chronic transition as observed during autoimmune hepatitis
Mass Enhanced Node Embeddings for Drug Repurposing
Authors: Chatzianastasis Michail , Nikolentzos Giannis , Vazirgiannis Michalis
Published: June 2022

Graph representation learning has recently emerged as a promising approach to solve pharmacological tasks by modeling biological networks. Among the different tasks, drug repurposing, the task of identifying new uses for approved or investigational drugs, has attracted a lot of attention recently. In this work, we propose a node embedding algorithm for the problem of drug repurposing. The proposed algorithm learns node representations that capture the influence of nodes in the biological network by learning a mass term for each node along with its embedding. We apply the proposed algorithm to a multiscale interactome network and embed its nodes (i. e., proteins, drugs, diseases and biological functions) into a low-dimensional space. We evaluate the generated embeddings in the drug repurposing task. Our experiments show that the proposed approach outperforms the baselines and offers an improvement of 53.33% in average precision over typical walk-based embedding approaches.
Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype
Authors: Sung Jin Hee , Ou Yang , Barger Steven W.
Published: June 2022

The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimer’s disease, wherein the ε4 allele confers a dramatically elevated risk compared to the more common ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murineApoegene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without Aβ accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry anAPOEε4 allele. The fact that ApoE4 generally failed to exacerbate the effects of Aβ on glucose further highlights the growing distinction between the glycemic effects of Aβ versus those of peripheral insulin resistance.
The ExtRA Capacity Test: Reliability and validity study of a new tool for assessing shoulder muscle performance
Authors: Ford Harry , Lewis Jeremy , Tyros Vasileios , Davare Marco , Low Daniel , Shaheen Aliah
Published: June 2022

Objectives

The primary objective was to evaluate the reliability of a new tool for assessing shoulder muscle performance: The ExtRA Capacity Test. The secondary objective was to assess whether this tool was a valid measure for assessing shoulder strength.

Methods

The ExtRA Capacity test involves two measures: maximal scapular plane lateral raises to 90° abduction with 2.5kg of external load and the maximal number of prone lying unsupported external rotations with the shoulder at 90° abduction. Both capacity tests are completed to a metronome set to 30 beats per minute 20 asymptomatic participants were sampled on 2 separate sessions, 1 week apart. The ExtRA Capacity Test was completed by the lead researcher and an independent physiotherapist. Shoulder strength was also measured using isokinetic dynamometry.

Results

The test showed excellent inter-rater reliability (mean abduction ICC= 0.969, mean external rotation ICC= 0.822, with a 95% CI). Mean intra-rater variability was 3.96± 4.09 for the abduction measure and 1.70± 1.17 for the external rotation measure. Validity was calculated using Pearson correlation coefficient. The abduction measure showed good/ moderate correlation for the majority of strength measurements taken using isokinetic dynamometry however the external rotation capacity test did not correlate closely to isokinetic dynamometry strength measures.

Conclusion

The abduction component of the ExtRA Capacity Test is a suitable measure for assessing shoulder strength in clinical practice. The external rotation measure is of suitable reliability however if used in clinical practice, it should not be used to assess shoulder strength, instead it may be suitable to assess movement control of the shoulder.

Various methods of measuring shoulder strength exist, ranging from cost free, relatively inaccurate methods to costly, complex methods which are of high reliability and validity but are challenging to use in a fast-pace, clinical environment. Objective outcome measures are used within a rehabilitation setting however at present there is no upper limb muscle performance test that is suitable to use on all people, regardless of strength or fitness level. Capacity testing of movements provides a functional, insight into strength specific to a real world/ sporting environment with lower limb capacity tests providing clear objective baselines that can be used for goal setting and providing return to play criteria following injury. This study proves the reliability and validity of the ExtRA Capacity Test which is a measure of shoulder muscle performance, suitable for people of all physical activity levels and upper limb strength.
The Optimal Combination of Scanning Speed and Fiber-to-Stone Distance for Effective and Efficient Dusting during Holmium: YAG Laser Lithotripsy
Authors: Chen Junqin , Li Daiwei , Yu Wenjun , Ma Zhiteng , Li Chenhang , Xiang Gaoming , Wu Yuan , Yao Junjie , Zhong Pei
Published: June 2022

Objectives

To investigate mechanistically the effects of fiber scanning speed (vfiber) and fiber tip-to-stone standoff distance (SD) on dusting efficiency during Holmium (Ho): YAG laser lithotripsy (LL)

Materials and Methods

Pre-soaked BegoStone samples (23 × 23 × 4 mm, W x L x H) were treated in water using a clinical Ho:YAG laser in dusting mode (0.2 J pulse energy delivered at 20 Hz frequency) at three different SDs (0.10, 0.25 and 0.50 mm) with vfiber in the range of 0 to 10 mm/s. Stone damage was quantified by optical coherence tomography, bubble dynamics were captured by high-speed imaging, and associated pressure transients were measured using a needle hydrophone. To compare photothermal ablation vs. cavitation in stone dusting, the experiments were further repeated in air (photothermal ablation only), and in water with the fiber tip advanced at a short (0.25 mm) offset distance (OSD) from a ureteroscope to mitigate the bubble collapse toward the stone surface, thus eliminating cavitation-induced damage.

Results

Compared to the craters produced by a stationary fiber, the damage troughs produced by a scanning fiber after 100 pulses were significantly larger in volume. The optimal vfiber for maximum dusting efficiency was found to be 3.5 mm/s for SD = 0.10 ∼ 0.25 mm, resulting in long (17.5 mm), shallow (0.14 – 0.15 mm) and narrow (0.3 – 0.4 mm) troughs. In contrast, the maximum stone damage was produced at an optimal vfiber of 0.5 mm/s for SD = 0.50 mm, which generates much shorter (2.5 mm), yet deeper (0.35 mm) and wider (1.4 mm) troughs. Greater stone damage was produced in water than in air, especially at vfiber = 0 – 3.5 mm/s. With the scope end placed near the fiber tip, stone damage could be significantly reduced in water by 29% - 58% for SD = 0.10 mm, by 51% - 82% for SD = 0.25 mm, and by 66% - 100 % for SD = 0.50 mm, compared to those produced without the scope. Together, these findings suggest that cavitation plays an indispensable role in stone dusting by scanning treatment. Moreover, under clinically relevant vfiber (1 ∼ 3 mm/s), dusting at SD = 0.5 mm (i.e., non-contact mode) may leverage higher frequency of the laser (e.g., 40 to 120 Hz) to harvest the full potential of cavitation damage while significantly reducing the procedure time, compared to its counterpart at SD = 0.1 mm (i.e., contact mode) that promotes photothermal ablation.

Conclusion

Dusting efficiency during Ho:YAG LL may be substantially improved by utilizing the optimal combination of vfiber and SD for a given frequency.
Are asymmetric inheritance systems an evolutionary trap? Transitions in the mechanism of genome loss in the scale insect family Eriococcidae
Authors: Hodson Christina N , Toon Alicia , Cook Lyn , Ross Laura
Published: June 2022

Haplodiploidy and paternal genome elimination (PGE) are examples of asymmetric inheritance, where males transmit only maternally inherited chromosomes to their offspring. Under haplodiploidy this results from males being haploid, whereas under PGE males inherit but subsequently eliminate paternally inherited chromosomes during meiosis. Their evolution involves changes in the mechanisms of meiosis and sex determination, and sometimes also dosage compensation. As a result, these systems are thought to be an evolutionary trap, meaning that once asymmetric chromosome transmission evolves, it is difficult to transition back to typical Mendelian transmission. We assess whether there is evidence for this idea in the scale insect family Eriococcidae, a lineage with PGE and the only clade with a suggestion that asymmetric inheritance has transitioned back to Mendelian inheritance. We conduct a cytological survey of 13 eriococcid species, and a cytological, genetic, and gene expression analysis of species in the genusCystococcus, to investigate whether there is evidence for species in this clade evolving Mendelian chromosome transmission. Although we find that all species we examined exhibit PGE, the mechanism is extremely variable within Eriococcidae. WithinCystococcus, in fact, we uncover a previously undiscovered type of PGE in scale insects, where in males paternally inherited chromosomes are present, uncondensed, and expressed in somatic cells, but are eliminated prior to meiosis. Broadly, we fail to find evidence for a reversion from PGE to Mendelian inheritance in Eriococcidae, supporting the idea that asymmetric inheritance systems such as PGE may be an evolutionary trap.
DNA sequencing and gene-expression profiling assists in making a tissue of origin diagnosis in cancer of unknown primary
Authors: Posner Atara , Prall Owen W.J. , Sivakumaran Tharani , Etemadamoghadam Dariush , Thio Niko , Pattison Andrew , Balachander Shiva , Fisher Krista , Webb Samantha , Wood Colin , DeFazio Anna , Wilcken Nicholas , Gao Bo , Karapetis Christos S , Singh Madhu , Collins Ian M , Richardson Gary , Steer Christopher , Warren Mark , Karanth Narayan , Wright Gavin , Williams Scott , George Joshy , Hicks Rodney J , Boussioutas Alex , Gill Anthony J , Solomon Benjamin J. , Xu Huiling , Fellowes Andrew , Fox Stephen B , Schofield Penelope , Bowtell David , Mileshkin Linda , Tothill Richard W.
Published: June 2022

Cancer of unknown primary (CUP) constitutes a group of metastatic cancers in which standardized clinical investigations fail to identify a tissue of origin (TOO). Gene-expression profiling (GEP) has been used to resolve TOO, and DNA sequencing to identify potential targeted treatments; however, these methods have not been widely applied together in CUP patients. To assess the diagnostic utility of DNA and RNA tests for TOO classification, we applied GEP classification and/or gene-panel DNA sequencing in 215 CUP patients. Based on a retrospective review of pathology reports and clinical data, 77% of the cohort were deemed True-CUPs (T-CUP). Among the remaining cases, a latent primary diagnosis (10%) (LP-CUP) or TOO was highly suspected based on combined clinicopathological data (13%) (histology-resolved CUP, HR-CUP). High-medium confidence GEP classifications were made for 80% of LP/HR-CUPs, and these classifications were consistent with a pathologist-assigned diagnosis in 94% of cases, while only 56% of T-CUPs had high-medium confidence predictions. The frequency of somatic mutations in cancer genes was similar to 2,785 CUPs from AACR GENIE Project. DNA features, GEP classification, and oncovirus detection assisted making a TOO diagnosis in 37% of T-CUPs. Gene mutations and mutational signatures of diagnostic utility were found in 31% T-CUPs. GEP classification was useful in 13% of cases and viral detection in 4%. Among resolved T-CUPs, lung and biliary were the most frequently identified cancer types, while kidney cancer represented another minor subset. Multivariate survival analysis showed that unresolved T-CUPs had poorer overall survival than LP/HR-CUPs (Hazard ratio=1.9, 95% CI 1.1 − 3.2, p=0.016), while the risk of death was similar in genomically-resolved T-CUPs and LP/HR-CUPs. In conclusion, combining DNA and RNA profiling with clinicopathological data supported a putative TOO diagnosis in over a third of T-CUPs. DNA sequencing benefited T-CUP tumors with atypical transcriptional patterns that hindered reliable GEP classification.
Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune-inflammatory pathways and the onset of delirium following hip fracture surgery
Authors: Maes Michael , Thisayakorn Paul , Thipakorn Yanin , Tantavisut Saran , Sirivichayakul Sunee , Vojdani Aristo
Published: June 2022

Objectives

Activation of the immune-inflammatory response system (IRS) and a deficiency in the compensatory immunoregulatory system (CIRS), neuronal injuries, and alterations in the glutamate receptor (GlutaR), aquaporin-4 (AQP4), and heat shock protein 60 (HSP60) are involved in delirium. Increased serum levels of neurofilament protein (NFP), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) are biomarker of neuronal injury and post-surgery cognitive impairments. Polyreactive antibodies (PAbs) contribute to the development of immune-mediated disease. This investigation delineates whether elevated IgA and IgG reactivity against those self-antigens is associated with enhanced IRS responses and delirium severity.

Methods

We measured peak Delirium Rating Scale (DRS) scores on days 2 and 3 following surgery in 59 hip fracture older adults, and IgA/IgG antibody levels against MBP, NFP, GFAP and myelin oligodendrocyte glycoprotein (MOG), GlutaR, N-Methyl-D-Aspartate receptor (NMDAR), APQ4 and HSP60.

Results

The IgA antibody levels against those self-antigens, especially GFAP, MBP and HSP60, strongly predict peak DRS scores on days 2 and 3 post-surgery. IgA reactivity against NMDAR and baseline DRS scores explained 40.6% of the variance in peak DRS scores, whilst IgA against NMDAR, IgG against MBP and age explained 29.1% of the variance in the IRS/CIRS ratio. There was no correlation between DRS scores and IgG directed against these self-antigens.

Conclusions

Increased IgA levels against neuronal self-antigens, AQP4, and HSP60 are risk factors for delirium. PAb-associated breakdown of immune tolerance, IRS activation and injuries in the neuronal cytoskeleton, oligodendrocytes, astrocytes, glial cells, and myelin sheath are involved in the pathophysiology of delirium.
Missed opportunities for HIV testing among those who accessed sexually transmitted infection (STI) services, tested for STIs and diagnosed with STIs: a systematic review and meta-analysis.
Authors: Saleem Kanwal , Ting Ee Lynn , Loh Andre J.W. , Baggaley Rachel , Mello Maeve B , Jamil Muhammad S , Barr-Dichiara Magdalena , Johnson Cheryl , Gottlieb Sami L , Fairley Christopher K , Chow Eric P.F. , Ong Jason J
Published: June 2022

Introduction: Of 37.7 million people living with HIV in 2020, 6.1 million still do not know their HIV status. We synthesise evidence on concurrent HIV testing among people who tested for other sexually transmitted infections (STI).

Methods: We conducted a systematic review using five databases, HIV conferences and clinical trial registries. We included publications between 2010 and May 2021 that reported primary data on concurrent HIV/STI testing. We conducted a random-effects meta-analysis and meta-regression of the pooled proportion for concurrent HIV/STI testing.

Results and discussion: We identified 96 eligible studies: the majority (73%) were from high-income countries (HIC), with a third from general populations (36%) and non-heterosexual populations (30%). Among the 96 studies, 18 studies had relevant data for a meta-analysis for the proportion of people tested for HIV among those attending a clinic with STI testing services, 15 studies among those tested for other STIs, 13 studies among those diagnosed with STI and three studies for people with STI symptoms. The remaining studies provided data on the acceptability, feasibility, barriers, facilitators, economic evaluation and social harms of concurrent HIV/STI testing. The pooled proportion of people tested for HIV among those attending an STI service (n=18 studies) was 71.0% [95% confidence intervals: 61.0-80.1, I2=99.9%], people tested for HIV among those who were tested for STIs (n=15) was 61.3% [53.9-68.4, I2=99.9%], people tested for HIV among those who were diagnosed with an STI (n=13) was 35.3% [27.1-43.9, I2=99.9%]. and people tested for HIV among those presenting with STI symptoms (n=3) was 27.1% [20.5-34.3, I2=92.0%]. The meta-regression analysis found that heterogeneity was driven mainly by identity as a sexual minority, the latest year of study, country-income level and region of the world.

Conclusions: Not testing for HIV amongst people using STI services presents a significant missed opportunity, particularly among those diagnosed with an STI. Stronger integration of HIV and STI services is urgently needed to improve prevention, early diagnosis, and linkage to care services.

PROSPERO Number: CRD42021231321
An individualized Bayesian method for estimating genomic variants of hypertension
Authors: Rahman Md. Asad , Cai Chunhui , McNamara Dennis M. , Ding Ying , Cooper Gregory F. , Lu Xinghua , Liu Jinling
Published: June 2022

Background

Genomic variants of disease are often discovered nowadays through population-based genome-wide association studies (GWAS). Identifying genomic variations potentially underlying a phenotype, such as hypertension, in an individual is important for designing personalized treatment; however, population-level models, such as GWAS, may not capture all of the important, individualized factors well. In addition, GWAS typically requires a large sample size to detect association of low-frequency genomic variants with sufficient power. Here, we report an individualized Bayesian inference (IBI) algorithm for estimating the genomic variants that influence complex traits such as hypertension at the level of an individual (e.g., a patient). By modeling at the level of the individual, IBI seeks to find genomic variants observed in the individual’s genome that provide a strong explanation of the phenotype observed in this individual.

Results

We applied the IBI algorithm to the data from the Framingham Heart Study to explore genomic influences of hypertension. Among the top-ranking variants identified by IBI and GWAS, there is a significant number of shared variants (intersection); the unique variants identified only by IBI tend to have relatively lower minor allele frequency than those identified by GWAS. In addition, we observed that IBI discovered more individualized and diverse variants that explain the hypertension patients better than did GWAS. Furthermore, IBI found several well-known low-frequency variants as well as genes related to blood pressure that were missed by GWAS in the same cohort. Finally, IBI identified top-ranked variants that predicted hypertension better than did GWAS, according to the area under the ROC curve.

Conclusions

The results provide support for IBI as a promising approach for complementing GWAS especially in detecting low-frequency genomic variants as well as learning personalized genomic variants of clinical traits and disease, such as the complex trait of hypertension, to help advance precision medicine.
Flexible positioning of a large area detector using an industrial robot
Authors: Reinhard Christina , Drakopoulos Michael , Charlesworth Christopher M. , James Andrew , Patel Hiten , Tutthill Paul , Crivelli Davide , Deyhle Hans , Ahmed Sharif I.
Published: June 2022

The DIAD beamline for Dual Imaging and Diffraction at Diamond Light Source has opted to use an industrial robot to position its Dectris Pilatus 2M CdTe diffraction detector. This setup was chosen to enable flexible positioning of the detector in a quarter-sphere around the sample position whilst reliably holding the large weight of 139 kg of detector, detector mount and cabling in a stable position. Metrology measurements showed that the detector can be positioned with a linear repeatability of <19.7 µm and a rotational repeatability of <16.3 µrad. The detector position stays stable for a 12 h period with <10.1 µm of movement for linear displacement and <3.8 µrad for rotational displacement. X-ray diffraction from calibration samples confirmed that the robot is sufficiently stable to resolve lattice d-spacings within the instrumental broadening given by detector position and beam divergence.
A new two-dimensional cadmium(II) coordination polymer based on Cd6(CHADC)6 clusters (H2CHADC is cyclohexane-1,2-dicarboxylic acid): synthesis, structure and properties
Authors: Shen Hong
Published: June 2022

The highly effective recognition and detection of metal ions and anions in water has attracted much attention with respect to environmental safety. Herein, a novel Cd-based coordination polymer, poly[[4,4′-bis(2-methylimidazol-1-yl)biphenyl]bis(cyclohexane-1,2-dicarboxylato)dicadmium(II)], [Cd2(C8H10O4)2(C20H18N4)]
n
or [Cd(CHADC)(4,4′-BMIBP)0.5]
n
, (I), has been synthesized employing cis-cyclohexane-1,2-dicarboxylic acid (H2CHADC) and 4,4′-bis(2-methyl-1H-imidazol-1-yl)biphenyl (4,4′-BMIBP). Single-crystal X-ray analysis reveals that (I) presents a 6-connected hxl two-dimensional layer based on Cd6(CHADC)6 clusters with the point symbol (36·46·53). Furthermore, (I) has been characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis and fluorescence spectroscopy, and exhibits good stability and excellent photoluminescence properties. Coordination polymer (I) was chosen as a fluorescent probe to sense different target analytes and shows an obvious selective recognition response to Fe3+ cations and Cr2O7
2−/CrO4
2− anions through luminescence-quenching effects in aqueous solution. The sensing mechanism was investigated and showed that the detection mechanism was resonance energy transfer between (I) and the Fe3+, Cr2O7
2− and CrO4
2− ions.
Asian perspective of capital market performance amid the COVID 19 pandemic
Authors: Adnan A.T.M.
Published: June 2022

Purpose

The purpose of this research is to investigate the short-term capital markets' reactions to the public announcement first local detection of novel corona virus (COVID 19) cases in 12 major Asian capital markets.

Design/methodology/approach

Using the constant mean return model and the market model, an event study methodology has been implied to determine the cumulative abnormal returns (CARs) of 10 pre and post-event trading days. The statistical significance of the data was assessed using both parametric and nonparametric test statistics.

Findings

First discovery of local COVID 19 cases had a substantial impact on all 12 Asian markets on the event day, as shown by statistically significant negative average abnormal return (AAR) and cumulative average abnormal return (CAAR). The single factor ANOVA result has also demonstrated that there is no variability among 12 regional markets in terms of short-term market responses. Furthermore, there is little evidence that these major Asian stock market indices differ significantly from the FTSE All-World Index which might suggest possible spillover impact and co-integration among the major Asian capital markets. The study further discovers that market capitalization and liquidity did not have any significant impact on market reaction to announcement.

Research limitations/implications

The study's contribution might have been compromised by the absence of socio-demographic, technical, financial and other significant policy factors from the analysis.

Practical implications

These findings will be considerably helpful in tackling this unprecedented epidemic issue for personal and institutional investors, industrial and economic experts, government and policymakers in assessing the market in special circumstances, diversifying risk and developing financial and monetary policy proposals.

Originality/value

This paper is the first to examine the effects of local COVID 19 detection announcement on major Asian capital markets. This study will add to the literature by investigating unusual market returns generated by infectious illness outbreaks and the overall market efficiency and investors' behavioral pattern of major Asian capital markets.
The gradient discretisation method for the chemical reactions of biochemical systems
Authors: Alnashri Yahya , Alzubaidi Hasan
Published: June 2022

Purpose

The main purpose of this paper is to introduce the gradient discretisation method (GDM) to a system of reaction diffusion equations subject to non-homogeneous Dirichlet boundary conditions. Then, the authors show that the GDM provides a comprehensive convergence analysis of several numerical methods for the considered model. The convergence is established without non-physical regularity assumptions on the solutions.

Design/methodology/approach

In this paper, the authors use the GDM to discretise a system of reaction diffusion equations with non-homogeneous Dirichlet boundary conditions.

Findings

The authors provide a generic convergence analysis of a system of reaction diffusion equations. The authors introduce a specific example of numerical scheme that fits in the gradient discretisation method. The authors conduct a numerical test to measure the efficiency of the proposed method.

Originality/value

This work provides a unified convergence analysis of several numerical methods for a system of reaction diffusion equations. The generic convergence is proved under the classical assumptions on the solutions.
Human resource competency 4.0 and its impact on Bank Indonesia employees' readiness for transformational change
Authors: Lubis Anggia Sari , Lumbanraja Prihatin , Absah Yeni , Silalahi Amlys Syahputra
Published: June 2022

Purpose

The purpose of this paper is to analyze the influence of factors that affect human resource competency (HRC) 4.0, employee readiness for transformational change as well as analyzing the mediating and moderating factors that influence the relationship of factors such as soft skills training and individual characteristics on employee readiness for transformational change and HRC 4.0.

Design/methodology/approach

This research is a quantitative research with descriptive statistics. The analytical tool used is a structural equation model of partial least squares (PLS). This research was conducted at five Bank Indonesia Offices in Aceh and North Sumatra Provinces. Using a proportional random sampling technique, 200 respondents of employees were selected.

Findings

The results of this study are as follows: (1) both soft skill training and individual characteristics have a significant effect on HRC 4.0; (2) HRC 4.0, soft skill training and individual characteristic have a significant on employee readiness for transformational change; (3) soft skill training has significant effect on employee readiness for transformational change through HRC 4.0; (4) individual characteristic has a significant effect on employee readiness for transformational change through HRC 4.0; (5) the effect of HRC 4.0 on employee readiness for transformational change moderates by transformational leadership; (6) the effect of HRC 4.0 on employee readiness for transformational change moderates by employee commitment to change.

Originality/value

This research contains valuable novelty, which is a new concept of HRC 4.0 that is linked to soft skill training and individual characteristics variables, and employee readiness for transformational change. Furthermore, transformational leadership and employee commitment variables have significant effect in moderating the influence off HRC 4.0 on employee readiness for transformational change.
An examination of how personal characteristics moderate the relationship between startup intent and entrepreneurship education
Authors: Burch Tyler , Tocher Neil M. , Murphy Gregory
Published: June 2022

Purpose

While research has identified a consistent link between startup intent and entrepreneurship education (EE) intentions, studies also indicate that many entrepreneurs lack the EE they need. However, research examining factors that explain why certain individuals with high startup intent pursue EE while others do not is rare. Given this, the purpose of this paper is to examine how individual characteristics moderate the startup intent EE intentions relationship.

Design/methodology/approach

Survey data were gathered on 199 US adults. Moderators examined include attitudes toward education, perceived entrepreneurial efficacy, propensity for risk taking and the Big Five personality traits. Linear regression models were used to test each of the moderation relationships predicted.

Findings

Notable findings suggest that extroversion, openness to experience, agreeableness, perceived entrepreneurial efficacy and risk propensity reduce the chances that individuals with high startup intent will pursue EE, while viewing education as instrumental enhances the relationship.

Research limitations/implications

Study findings imply that EE programs might not be reaching critical target markets, suggest that EE programs might need to be modified to attract individuals with high startup intent and indicate that individual characteristics are key factors that determine why certain individuals with high startup intent pursue EE while others with the same desires do not pursue EE.

Originality/value

This study builds on previous work that looks at the relationship between startup intent and EE intentions by investigating how individual characteristics either amplify or diminish the relationship, increasing scholarly knowledge about why certain individuals with high startup intent pursue EE while others do not.