bluuebunny/crossref_metadata_2025 huggingface dataset:
Properties of von Zeipel–Lidov–Kozai oscillations in triple systems at the quadrupole order: relaxing the test particle approximation
Authors: Hamers Adrian S
Published: November 2020

Von Zeipel–Lidov–Kozai (ZLK) oscillations in hierarchical triple systems have important astrophysical implications such as triggering strong interactions and producing, e.g. Type Ia supernovae and gravitational wave sources. When considering analytic properties of ZLK oscillations at the lowest (quadrupole) expansion order, as well as complications due to higher order terms, one usually assumes the test particle limit, in which one of the bodies in the inner binary is massless. Although this approximation holds well for, e.g. planetary systems, it is less accurate for systems with more comparable masses such as stellar triples. Although non-test-particle effects are usually taken into account in numerical simulations, a more analytic approach focusing on the differences between the test particle and general case (at quadrupole order) has, to our knowledge, not been presented. Here, we derive several analytic properties of secular oscillations in triples at the quadruple expansion order. The latter applies even to relatively compact triples, as long as the inner bodies are similar in mass such that octupole-order effects are suppressed. We consider general conditions for the character of the oscillations (circular versus librating), minimum and maximum eccentricities, and time-scales, all as a function of $\gamma \equiv (1/2) \, L_1/G_2$, a ratio of inner-to-outer orbital angular momenta variables (γ = 0 in the test particle limit). In particular, eccentricity oscillations are more effective at retrograde orientations for non-zero γ; assuming zero initial inner eccentricity, the maximum eccentricity peaks at $\cos (i_{\mathrm{rel},0}) = -\gamma$, where $i_{\mathrm{rel},0}$ is the initial relative inclination. We provide a python script that can be used to quickly compute these properties.
Parametric instability in a free-evolving warped protoplanetary disc
Authors: Deng Hongping , Ogilvie Gordon I , Mayer Lucio
Published: November 2020

Warped accretion discs of low viscosity are prone to hydrodynamic instability due to parametric resonance of inertial waves as confirmed by local simulations. Global simulations of warped discs, using either smoothed particle hydrodynamics or grid-based codes, are ubiquitous but no such instability has been seen. Here, we utilize a hybrid Godunov-type Lagrangian method to study parametric instability in global simulations of warped Keplerian discs at unprecedentedly high resolution (up to 120 million particles). In the global simulations, the propagation of the warp is well described by the linear bending-wave equations before the instability sets in. The ensuing turbulence, captured for the first time in a global simulation, damps relative orbital inclinations and leads to a decrease in the angular momentum deficit. As a result, the warp undergoes significant damping within one bending-wave crossing time. Observed protoplanetary disc warps are likely maintained by companions or aftermath of disc breaking.
LnCeCell: a comprehensive database of predicted lncRNA-associated ceRNA networks at single-cell resolution
Authors: Wang Peng , Guo Qiuyan , Hao Yangyang , Liu Qian , Gao Yue , Zhi Hui , Li Xin , Shang Shipeng , Guo Shuang , Zhang Yunpeng , Ning Shangwei , Li Xia
Published: November 2020

Within the tumour microenvironment, cells exhibit different behaviours driven by fine-tuning of gene regulation. Identification of cellular-specific gene regulatory networks will deepen the understanding of disease pathology at single-cell resolution and contribute to the development of precision medicine. Here, we describe a database, LnCeCell (http://www.bio-bigdata.net/LnCeCell/ or http://bio-bigdata.hrbmu.edu.cn/LnCeCell/), which aims to document cellular-specific long non-coding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) networks for personalised characterisation of diseases based on the ‘One Cell, One World’ theory. LnCeCell is curated with cellular-specific ceRNA regulations from >94 000 cells across 25 types of cancers and provides >9000 experimentally supported lncRNA biomarkers, associated with tumour metastasis, recurrence, prognosis, circulation, drug resistance, etc. For each cell, LnCeCell illustrates a global map of ceRNA sub-cellular locations, which have been manually curated from the literature and related data sources, and portrays a functional state atlas for a single cancer cell. LnCeCell also provides several flexible tools to infer ceRNA functions based on a specific cellular background. LnCeCell serves as an important resource for investigating the gene regulatory networks within a single cell and can help researchers understand the regulatory mechanisms underlying complex microbial ecosystems and individual phenotypes.
The Effects of Perceived Pain in the Past Month on Prefrontal Cortex Activation Patterns Assessed During Cognitive and Motor Performances in Older Adults
Authors: Pakray Hannah , Seng Elizabeth , Izzetoglu Meltem , Holtzer Roee
Published: November 2020

Objective

Pain is prevalent and functionally impactful in older adults. The prefrontal cortex is involved in pain perception, attentional control, and cortical control of locomotion. Although pain is a known moderator of attentional capacity, its moderating effect on cortical control of locomotion has not been assessed. This study aimed to examine the effects of subjective pain on changes in functional near-infrared spectroscopy–derived measurements of oxygenated hemoglobin (HbO2), gait velocity, and cognitive accuracy from single- to dual-task walking conditions among older adults.

Subjects

The sample consisted of 383 healthy older adults (55% female).

Methods

Participants completed two single tasks (Single-Task-Walk [STW] and Cognitive Interference [Alpha]) and the Dual-Task-Walk (DTW), during which participants performed the two single tasks simultaneously. The Medical Outcomes Study Pain Severity Scale and Pain Effects Scale were used to assess pain severity and interference. ProtoKinetics Movement Analysis Software was used to assess gait velocity and rate of correct letter generation to assess cognitive accuracy. Functional Near-Infrared Spectroscopy (fNIRS) was used to assess HbO2 during active walking.

Results

Linear mixed-effects models revealed that HbO2 increased from single- to dual-task conditions. Perceived pain presence was associated with an attenuated increase in HbO2 from Alpha to DTW. Among those with pain, worse pain severity was associated with an attenuated increase in HbO2 from STW to DTW. Pain interference did not moderate the increase in HbO2 from single to dual tasks. Pain did not have a moderating effect on behavioral outcomes.

Conclusions

Task-related changes in the hemodynamic response in the prefrontal cortex during walking may be a sensitive marker of the effects of subjective pain on brain function in healthy older adults.
Markers of Cardiovascular Health in Older Adults with and Without Chronic Low Back and Radicular Leg Pain: A Comparative Analysis
Authors: Coyle Peter C , O’Brien Victoria A , Edwards David G , Pohlig Ryan T , Hicks Gregory E
Published: November 2020

Objectives

There is considerable overlap in risk profiles between chronic low back pain with radiculopathy (CLBPR) and cardiovascular health among older adults; obesity and smoking are related to both conditions and may largely drive the potential relationship. We sought to explore the impact of CLBPR on cardiovascular health outcomes, independent of body mass index (BMI) and current smoking status.

Methods

Age- and sex-matched older adults (60–85 years of age) with (n = 21) and without (n = 21) CLBPR were recruited. Current smokers were excluded. Blood samples were collected to measure cholesterol levels and pro-inflammatory markers (i.e., C-reactive protein and interleukin-6). Vascular endothelial function, a marker of cardiovascular health, was evaluated by measuring brachial artery flow-mediated dilation (FMD). General linear models with multifactorial designs were evaluated; group membership, BMI, education, and their respective two-way interaction terms were included as independent variables.

Results

Older adults with CLBPR had significantly higher BMIs (P = 0.004) and lower educational levels (P = 0.013) than did those without pain. There was a significant group-by-education interaction effect (P = 0.049) for endothelial function. Older adults without pain who were highly educated had higher FMD values, indicating better endothelial function (9.2%), whereas the following combinations all had lower FMD values: no pain plus low education, CLBPR plus high education, and CLBPR plus low education (5.9%, 6.1%, and 6.6%, respectively).

Conclusions

Among older adults, CLBPR is linked with worse endothelial function, regardless of educational level and independent of BMI and smoking. These findings suggest that older adults with CLBPR may be at a higher risk of cardiovascular disease.
Characteristic Cohomology I: Singularities of Given Type
Authors: Damon James
Published: November 2020

For a germ of a variety $\mathcal{V}, 0 \subset \mathbb C^N, 0$, a singularity $\mathcal{V}_0$ of ‘type $\mathcal{V}$’ is given by a germ $f_0 : \mathbb C^n, 0 \to \mathbb C^N, 0$ which is transverse to $\mathcal{V}$ in an appropriate sense so that $\mathcal{V}_0 = f_0^{\,-1}(\mathcal{V})$. If $\mathcal{V}$ is a hypersurface germ, then so is $\mathcal{V}_0 $, and by transversality ${\operatorname{codim}}_{\mathbb C} {\operatorname{sing}}(\mathcal{V}_0) = {\operatorname{codim}}_{\mathbb C} {\operatorname{sing}}(\mathcal{V})$ provided $n \gt {\operatorname{codim}}_{\mathbb C} {\operatorname{sing}}(\mathcal{V})$. So $\mathcal{V}_0, 0$ will exhibit singularities of $\mathcal{V}$ up to codimension n.

For singularities $\mathcal{V}_0, 0$ of type $\mathcal{V}$, we introduce a method to capture the contribution of the topology of $\mathcal{V}$ to that of $\mathcal{V}_0$. It is via the ‘characteristic cohomology’ of the Milnor fiber (for $\mathcal{V}, 0$ a hypersurface), and complement and link of $\mathcal{V}_0$ (in the general case). The characteristic cohomology of the Milnor fiber $\mathcal{A}_{\mathcal{V}}(\,f_0; R)$, and respectively of the complement $\mathcal{C}_{\mathcal{V}}(\,f_0; R)$, are subalgebras of the cohomology of the Milnor fibers, respectively the complement, with coefficients R in the corresponding cohomology. For a fixed $\mathcal{V}$, they are functorial over the category of singularities of type $\mathcal{V}$. In addition, for the link of $\mathcal{V}_0$ there is a characteristic cohomology subgroup $\mathcal{B}_{\mathcal{V}}(\,f_0, \mathbf{k})$ of the cohomology of the link over a field $\mathbf{k}$ of characteristic 0. The cohomologies $\mathcal{C}_{\mathcal{V}}(\,f_0; R)$ and $\mathcal{B}_{\mathcal{V}}(\,f_0, \mathbf{k})$ are shown to be invariant under the $\mathcal{K}_{\mathcal{V}}$-equivalence of defining germs f0, and likewise $\mathcal{A}_{\mathcal{V}}(\,f_0; R)$ is shown to be invariant under the $\mathcal{K}_{H}$-equivalence of f0 for H the defining equation of $\mathcal{V}, 0$.

We give a geometric criterion involving ‘vanishing compact models’ for both the Milnor fibers and complements which detect non-vanishing subalgebras of the characteristic cohomologies, and subgroups of the characteristic cohomology of the link. Also, we consider how in the hypersurface case the cohomology of the Milnor fiber is a module over the characteristic cohomology $\mathcal{A}_{\mathcal{V}}(\,f_0; R)$. We briefly consider the application of these results to a number of cases of singularities of a given type. In part II, we specialize to the case of matrix singularities and using results on the topology of the Milnor fibers, complements and links of the varieties of singular matrices obtained in another paper allow us to give precise results for the characteristic cohomology of all three types.
A cross-sectional study to evaluate depression and quality of life among patients with lymphoedema due to podoconiosis, lymphatic filariasis and leprosy
Authors: Ali Oumer , Deribe Kebede , Semrau Maya , Mengiste Asrat , Kinfe Mersha , Tesfaye Abraham , Bremner Stephen , Davey Gail , Fekadu Abebaw
Published: November 2020

Background

Podoconiosis, lymphatic filariasis (LF) and leprosy are neglected tropical diseases (NTDs) that cause lymphoedema. When left untreated, they lead to substantial disability. This study determined the quality of life (QOL) and depression associated with lymphoedema in patients with podoconiosis, LF and leprosy. The study was conducted in northwestern Ethiopia.

Methods

This baseline cross-sectional study, nested within an interventional, non-comparative, longitudinal study, included patients with lymphoedema. Depression and QOL were assessed using versions of the 9-item Patient Health Questionnaire and Dermatologic Life Quality Index (DLQI), respectively, that had been translated into Amharic and validated. Factors associated with depression and QOL were assessed using multivariate linear regression analysis.

Results

Of the 251 patients with lymphoedema included in the study, 119 (47.4%) had moderate to severe depression and overall QOL was poor (mean±standard deviation [SD] DLQI score: 11.4±4.2). Disability was significantly associated with depression (β=0.26 [95% confidence interval {CI} 0.19 to 0.33]). Currently receiving treatment (β=−3.05 [95% CI −5.25 to −0.85), disability (β=−0.08 [95% CI −0.15 to −0.01]) and social support (moderate support: β=−2.27 [95% CI −3.66 to −0.89] and strong support: β=−2.87 [95% CI −5.35 to −0.38]) were significantly associated with better QOL.

Conclusion

High levels of depression and low QOL were found among patients with lymphoedema due the three NTDs in Ethiopia.
Review of the extinct ‘shrew-opossums’ (Marsupialia: Caenolestidae), with descriptions of two new genera and three new species from the Early Miocene of southern South America
Authors: Abello María Alejandra , Martin Gabriel M , Cardoso Yamila
Published: November 2020

We present a systematic review of the extinct species included in the family Caenolestidae, one of the few South American metatherian groups that has survived to the present. We perform a cladistic analysis based on a data matrix consisting of all extant and extinct species that have been referred to this family, 100 morphological characters and two sets of molecular data (cytochrome b and cytochrome c oxidase I). Morphological and molecular data were analysed separately and in combination, under maximum parsimony and maximum likelihood methods. As a result, caenolestids are recovered as a monophyletic group within which we formally recognize three new taxa: Caenolestoides miocaenicus gen. & sp. nov., Gaimanlestes pascuali gen. & sp. nov. and Stilotherium parvum sp. nov. from the Early Miocene of Patagonia, Argentina. Stilotherium is the earliest diverging lineage of caenolestids followed by Gaimanlestes, while C. miocaenicus was recovered as the extinct species most closely related to extant caenolestids.
Insights into Metabolic Changes Caused by the Trichoderma virens–Maize Root Interaction
Authors: Schweiger Rabea , Padilla-Arizmendi Fabiola , Nogueira-López Guillermo , Rostás Michael , Lawry Robert , Brown Chris , Hampton John , Steyaert Johanna M. , Müller Caroline , Mendoza-Mendoza Artemio
Published: November 2020

The interactions of crops with root-colonizing endophytic microorganisms are highly relevant to agriculture, because endophytes can modify plant resistance to pests and increase crop yields. We investigated the interactions between the host plant Zea mays and the endophytic fungus Trichoderma virens at 5 days postinoculation grown in a hydroponic system. Wild-type T. virens and two knockout mutants, with deletion of the genes tv2og1 or vir4 involved in specialized metabolism, were analyzed. Root colonization by the fungal mutants was lower than that by the wild type. All fungal genotypes suppressed root biomass. Metabolic fingerprinting of roots, mycelia, and fungal culture supernatants was performed using ultrahigh performance liquid chromatography coupled to diode array detection and quadrupole time-of-flight tandem mass spectrometry. The metabolic composition of T. virens-colonized roots differed profoundly from that of noncolonized roots, with the effects depending on the fungal genotype. In particular, the concentrations of several metabolites derived from the shikimate pathway, including an amino acid and several flavonoids, were modulated. The expression levels of some genes coding for enzymes involved in these pathways were affected if roots were colonized by the ∆vir4 genotype of T. virens. Furthermore, mycelia and fungal culture supernatants of the different T. virens genotypes showed distinct metabolomes. Our study highlights the fact that colonization by endophytic T. virens leads to far-reaching metabolic changes, partly related to two fungal genes. Both metabolites produced by the fungus and plant metabolites modulated by the interaction probably contribute to these metabolic patterns. The metabolic changes in plant tissues may be interlinked with systemic endophyte effects often observed in later plant developmental stages.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Chronic rhinosinusitis: phenotypes and endotypes
Authors: Bailey Luke N. , Garcia Jaime A. Pena , Grayson Jessica W.
Published: November 2020

Purpose of review

Chronic rhinosinusitis (CRS) is a broad classification of airway inflammation that affects a significant portion of the population. The current model of delineating patients suffering from CRS is dated and is no longer as simple as the presence of polyps or no polyps. Continued advances in the endotype descriptions of CRS have allowed for new phenotypic descriptions that aid in driving management and research efforts.

Recent findings

Geographic differences exist between patient presentations, which require a molecular evaluation of the driving forces. Increased understanding of these differences allows for patient-specific treatment decisions.

New descriptions of CRS phenotypes allow for more targeted therapy for patients, particularly to those with difficult to control disease. The previously broad classification of CRS with or without nasal polyps is no longer sufficient at driving these treatment decisions.
L-bupivacaine Inhibition of Nociceptive Transmission in Rat Peripheral and Dorsal Horn Neurons
Authors: Uta Daisuke , Koga Kohei , Furue Hidemasa , Imoto Keiji , Yoshimura Megumu
Published: November 2020

Background

Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified.

Methods

The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo.

Results

In the dorsal root ganglion, these anesthetics decreased the amplitudes of action potentials. The half-maximum inhibitory concentrations of D-enantiomer D-bupivacaine were almost equal for Aβ (29.5 μM), Aδ (29.7μM), and C (29.8 μM) neurons. However, the half-maximum inhibitory concentrations of L-bupivacaine was lower for Aδ (19.35 μM) and C (19.5 μM) neurons than for A β (79.4 μM) neurons. Moreover, D-bupivacaine almost equally inhibited tetrodotoxin-resistant (mean ± SD: 15.8 ± 10.9% of the control, n = 14, P < 0.001) and tetrodotoxin-sensitive (15.4 ± 15.6% of the control, n = 11, P = 0.004) sodium currents. In contrast, L-bupivacaine suppressed tetrodotoxin-resistant sodium currents (26.1 ± 19.5% of the control, n = 18, P < 0.001) but not tetrodotoxin-sensitive sodium currents (74.5 ± 18.2% of the control, n = 11, P = 0.477). In the spinal dorsal horn, L-bupivacaine decreased the area of pinch-evoked excitatory postsynaptic currents (39.4 ± 11.3% of the control, n = 7, P < 0.001) but not touch-evoked responses (84.2 ± 14.5% of the control, n = 6, P = 0.826). In contrast, D-bupivacaine equally decreased pinch- and touch-evoked responses (38.8 ± 9.5% of the control, n = 6, P = 0.001, 42.9 ± 11.8% of the control, n = 6, P = 0.013, respectively).

Conclusions

These results suggest that the L-enantiomer of bupivacaine (L-bupivacaine) effectively inhibits noxious transmission to the spinal dorsal horn by blocking action potential conduction through C and Aδ afferent fibers.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Comparison of K-wire versus screw fixation after open reduction of transitional (Tillaux and triplane) distal tibia fractures
Authors: Mishra Neeraj , Wang Shiyao , Chua Zackary Kerk Hsiang , Lam Kai Yet , Mahadev Arjandas
Published: November 2020

Our study aimed to compare the clinical and radiographic outcomes of transitional distal tibia fractures treated with K-wire fixation versus screw fixation after open reduction. A retrospective study was performed on all displaced transitional distal tibia fractures that underwent operative fixation. Following open reduction, surgical fixation was performed using either percutaneously inserted 2.0 mm K-wires, or 4.0 mm partially-threaded cannulated cancellous screws. Clinical and radiographic outcomes between the two groups were assessed using the modified Weber score. Other outcome measures assessed were surgical time, casting duration, follow-up duration and duration before return-to-sports. We recruited 49 patients with transitional distal tibia fractures requiring open reduction and surgical fixation. There were 18 patients in the K-wiring group (KWG), and 31 patients in the screw fixation group (SFG). All patients in both groups had excellent clinical and radiographic outcome based on the modified Weber’s scoring, full radiological healing, and no residual displacement upon final follow up. The KWG had significantly shorter surgical time (41.0 min versus 75.1 min, P < 0.0001) and shorter follow-up duration needed before discharge (5.4 months versus 8.7 months, P = 0.024). However, they required a longer post-operative casting duration (7.3 weeks versus 5.3 weeks, P = 0.006). No significant difference was found for the duration before return to sports between both groups. Complications were few in this study group. Superficial pin site infection was noted in one patient in the KWG, and valgus deformity of the ankle was noted in one patient in the SFG. In our study, surgical treatment of transitional distal tibia fractures demonstrated equally excellent outcomes when treated by open reduction with either K-wire or cannulated screw fixation. Level of evidence: III.
RNA editing enzyme ADAR1 is required for early T cell development
Authors: Xufeng Richard , Nie Daibang , Yang Qiong , Wang Wang , Cheng Tao , Wang Qingde
Published: November 2020

The RNA editing enzyme ADAR1 has been shown to be an essential molecule for hematopoietic cell differentiation, embryonic development, and regulation of immune responses. Here, we present evidence in a T-cell-specific gene knockout mouse model that ADAR1 is required for early T cell development. Loss of ADAR1 led to cell death of the progenitors at the double negative stage and prevented T cell maturation in the thymus. Furthermore, ADAR1 deletion in pre-T cells preferentially affected TCRβ-expressing cells causing TCRβ positive cell depletion. Interruption of IFN signaling occurred in the premature T cells, indicating a role of IFN signaling in the survival of TCRβ-expressing cells regulated by ADAR1. This study demonstrated an essential role for the RNA editing enzyme ADAR1 as a potential regulator for T-cell fate determination during clonal selection, which, in turn, contributes to immunologic homeostasis.
Preleukemic stem cells: leave it or not?
Authors: Su Minhua , Cheng Hui , Cheng Tao
Published: November 2020

Acute myeloid leukemia (AML) has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent. The early stage of AML (before it becomes clinically recognizable) may be characterized by acquisition of some, but not all, leukemia-related somatic mutations in hematopoietic stem cells (HSCs). The physiological roles of these mutations remain puzzling. These HSCs have been termed as preleukemic HSCs. However, those frequent acquired somatic mutations are also found in healthy aging adults, namely, “age-related clonal hematopoiesis.” Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML. Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined. This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.
Zebrafish for thrombocytopoiesis- and hemostasis-related researches and disorders
Authors: Meng Panpan , Wu Liangliang , Lin Qing , Zhang Yiyue
Published: November 2020

Platelets play vital roles in hemostasis, inflammation, and vascular biology. Platelets are also active participants in the immune responses. As vertebrates, zebrafish have a highly conserved hematopoietic system in the developmental, cellular, functional, biochemical, and genetic levels with mammals. Thrombocytes in zebrafish are functional homologs of mammalian platelets. Here, we summarized thrombocyte development, function, and related research techniques in zebrafish, and reviewed available zebrafish models of platelet-associated disorders, including congenital amegakaryocytic thrombocytopenia, inherited thrombocytopenia, essential thrombocythemia, and blood coagulation disorders such as gray platelet syndrome. These elegant zebrafish models and methods are crucial for understanding the molecular and genetic mechanisms of thrombocyte development and function, and provide deep insights into related human disease pathophysiology and drug development.
BECN1 modulates hematopoietic stem cells by targeting Caspase-3-GSDME-mediated pyroptosis
Authors: Yang Xiuxiu , Ge Liang , Wang Jianwei
Published: November 2020

Hematopoietic stem cells (HSCs) maintain the blood system throughout the lifespan. However, the molecular mechanism maintaining HSC character remains not fully understood. In this study, we observed that the targeted deletion of Becn1 disrupts the blood system and impairs the reconstitution capacity of HSCs. Interestingly, Becn1 deletion did not lead to dysfunction of autophagy in HSCs, indicating a non-classical role of BECN1 in regulating HSCs function. While we observed the increase of Caspase-3-GSDME-mediated pyroptosis in Becn1 deficient hematopoietic stem and progenitor cells. Forced expression of the full-length GSDME compromises the function of HSCs. In brief, we identified a novel role of Becn1 in modulating HSCs by regulating pyroptosis, but not through autophagy. This study provides a new link between BECN1-Caspase-3-GSDME signaling and HSC maintenance.
Current modalities of sickle cell disease management
Authors: Sanyaolu Adekunle , Agiri Ejoke , Bertram Carl , Brookes Latasha , Choudhury Jesy , Datt Dorina , Ibrahim Amira , Maciejko Anna , Mansfield Anna , Nkrumah Jasmine , Williams Martina
Published: November 2020

Sickle cell disease (SCD) affects nearly 100,000 people in the United States of America and the sickle gene is present in approximately 8% of black Americans. Among Africans, the prevalence of sickle cell trait (heterozygosity) is as high as 30%. While SCD occurs among varying racial and ethnic groups, it is more commonly prevalent in individuals of African or African-American descent. This inherited blood disorder causes varying symptoms and complications among affected children and adults and early diagnosis and treatment are essential to help reduce mortality rates. Because there is no cure for SCD, management is vital to survival. Hence, there are different approaches in use to aid those living with SCD; thus, this paper provides insight into the current methods that are implemented in the management and maintenance of this disease.
The single-cell landscape of immunological responses of CD4+ T cells in HIV versus severe acute respiratory syndrome coronavirus 2
Authors: Collora Jack A. , Liu Runxia , Albrecht Kristen , Ho Ya-Chi
Published: November 2020

Purpose of review

CD4+ T cell loss is the hallmark of uncontrolled HIV-1 infection. Strikingly, CD4+ T cell depletion is a strong indicator for disease severity in the recently emerged coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We reviewed recent single-cell immune profiling studies in HIV-1 infection and COVID-19 to provide critical insight in virus-induced immunopathogenesis.

Recent findings

Cytokine dysregulation in HIV-1 leads to chronic inflammation, while severe SARS-CoV-2 infection induces cytokine release syndrome and increased mortality. HIV-1-specific CD4+ T cells are dysfunctional, while SARS-CoV-2-specific CD4+ T cells exhibit robust Th1 function and correlate with protective antibody responses. In HIV-1 infection, follicular helper T cells (TFH) are susceptible to HIV-1 infection and persist in immune-sanctuary sites in lymphoid tissues as an HIV-1 reservoir. In severe SARS-CoV-2 infection, TFH are absent in lymphoid tissues and are associated with diminished protective immunity. Advancement in HIV-1 DNA, RNA, and protein-based single-cell capture methods can overcome the rarity and heterogeneity of HIV-1-infected cells and identify mechanisms of HIV-1 persistence and clonal expansion dynamics.

Single-cell immune profiling identifies a high-resolution picture of immune dysregulation in HIV-1 and SARS-CoV-2 infection and informs outcome prediction and therapeutic interventions.
Role of Hydrogen Sulfide in Myocardial Ischemia–Reperfusion Injury
Authors: Zhang Peng , Yu Yue , Wang Pei , Shen Hua , Ling Xinyu , Xue Xiaofei , Yang Qian , Zhang Yufeng , Xiao Jian , Wang Zhinong
Published: November 2020

Hydrogen sulfide (H2S), generally known as a new gas signal molecule after nitric oxide and carbon monoxide, has been found as an important endogenous gasotransmitter in the last few decades, and it plays a significant role in the cardiovascular system both pathologically and physiologically. In recent years, there is growing evidence that H2S provides myocardial protection against myocardial ischemia–reperfusion injury (MIRI), which resulted in an ongoing focus on the possible mechanisms of action accounting for the H2S cardioprotective effect. At present, lots of mechanisms of action have been verified through in vitro and in vivo models of I/R injury, such as S-sulfhydrated modification, antiapoptosis, effects on microRNA, bidirectional effect on autophagy, antioxidant stress, or interaction with NO and CO. With advances in understanding of the molecular pathogenesis of MIRI and pharmacology studies, the design, the development, and the pharmacological characterization of H2S donor drugs have made great important progress. This review summarizes the latest research progress on the role of H2S in MIRI, systematically explains the molecular mechanism of H2S affecting MIRI, and provides a new idea for the formulation of a myocardial protection strategy in the future.
A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators
Authors: Yoo Hyounggyoon , Chun Ji Sang , Cho Joo-Youn , Kim Sang-Heon , Yoon Jihoon G. , Goo Lee Min , Yu Kyung-Sang , Jang In-Jin , Oh Jaeseong
Published: November 2020

Isoniazid is a therapeutic agent for the treatment of latent tuberculosis infection. Genetic variants in the N-acetyltransferase 2 (NAT2) are associated with the safety and pharmacokinetics of isoniazid. The study aimed to evaluate the safety and pharmacokinetics of a NAT2 genotype-guided regimen of isoniazid monotherapy. A randomized, open-label, parallel-group and multiple-dosing study was performed in healthy subjects. The subjects received isoniazid for 29 days. The NAT2 slow acetylators (NAT2*5/*5, -*5/*6, -*5/*7, -*6/*6, -*6/*7, -*7/*7) randomly received standard dose (300 mg, standard-treatment group) or reduced dose (200 mg, PGx-treatment group) of isoniazid. Also, all the NAT2 rapid acetylators (NAT2*4/*4) received isoniazid 300 mg (reference group). The safety and pharmacokinetics were evaluated during the study. The PGx-treatment group showed a more stable serum liver enzyme profile and a lower incidence of adverse drug reactions (ADRs) than the standard-treatment group. The emergence rates of ADRs were 12.5, 60 and 33.3% in the reference, standard-treatment and PGx-treatment groups, respectively. The PGx-treatment group showed higher plasma isoniazid concentrations than the reference group, although the PGx-treatment group received a reduced dose of isoniazid. Our results showed that a NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.
Quantitative Method for the Analysis of Ivacaftor, Hydroxymethyl Ivacaftor, Ivacaftor Carboxylate, Lumacaftor, and Tezacaftor in Plasma and Sputum Using Liquid Chromatography With Tandem Mass Spectrometry and Its Clinical Applicability
Authors: Vonk Steffie E. M. , van der Meer-Vos Marloes , Bos Lieuwe D. J. , Neerincx Anne H. , Majoor Christof J. , Maitland-van der Zee Anke-Hilse , Mathôt Ron A. A. , Kemper E. Marleen ,   on behalf of the Amsterdam Mucociliary Clearance Disease (AMCD) research group
Published: November 2020

Background:

The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry.

Methods:

The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability.

Results:

The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF.

Conclusions:

The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators.
Prospective Evaluation of Childhood Encephalitis
Authors: Fowler Åsa , Ygberg Sofia , Svensson Eva , Bergman Kristian , Cooray Gerald , Wickström Ronny
Published: November 2020

Background:

Acute encephalitis in childhood is a serious condition. The severity varies between studies, partly reflecting differences in study design where only severe cases from referral centers often are reported. The aim of this study was to prospectively study the clinical picture and etiology of acute encephalitis in childhood at a primary and tertiary pediatric hospital in Sweden.

Methods:

All children with acute encephalitis were prospectively included from 2011 to 2016. Laboratory tests, investigations and follow-up were performed according to standardized study protocols.

Results:

Eighty-nine children were included (46 female and 43 male) with a median age of 53 months. An etiology was established in 61/89. Tick-borne encephalitis virus, enterovirus and rotavirus dominated and 34% were caused by a virus preventable by vaccination. Immune-mediated encephalitis was seen in 7 children. An abnormal electroencephalography picture was seen in 77/86, pathologic findings on neuroimaging in 13/49, and 38/89 children had seizures. Sequelae were reported by 49%. A high prevalence of previous contact with child and adolescent psychiatry was seen and, although not statistically significant, the need for extra support at school before encephalitis and the presence of central nervous system disease in the family seemed to predispose for a longer hospital stay.

Conclusion:

Encephalitis is a condition with long-term consequences. Most children need admission to hospital, and many need surveillance in the intensive care unit. The etiology can be determined in a majority of cases, and 1/3 could have been prevented by vaccination. This study corroborates electroencephalography as a cornerstone in diagnosis.
Hypersensitivity Myocarditis Due to Antitubercular Drugs in Children
Authors: Dhochak Nitin , Ram Jat Kana , Sankar Jhuma , Kabra Sushil K. , Lodha Rakesh
Published: November 2020

Background:

Drug-related hypersensitivity myocarditis is a rare acute hypersensitivity reaction to therapeutic agents. Reports of antitubercular drugs causing hypersensitivity myocarditis are not described in literature.

Methods:

Retrospective chart review of children admitted between January 1, 2016, and March 31, 2019, was conducted to identify children receiving antitubercular drugs who were diagnosed with hypersensitivity myocarditis.

Results:

Three children (2 girls), who had hypersensitivity myocarditis due to antitubercular therapy, were identified. Cases 1 and 2 developed hypersensitivity myocarditis due to rifampicin, and isoniazid-rifampicin combination, respectively, on reintroduction of drugs, while case 3 developed hypersensitivity to streptomycin on first exposure. All children developed symptoms within minutes to hours of starting the offending drugs. Severe myocardial dysfunction leading to shock and pulmonary edema was seen in cases 1 and 3, while case 2 presented with wide QRS complex ventricular rhythm with bradycardia and hypotensive shock. Cases 1 and 2 were treated with steroids. Cases 1 and 3 received intravenous immunoglobulin therapy. First 2 children survived while third died of refractory shock. Total serum IgE levels were elevated in all children (range: 161–3053 kU/L).

Conclusion:

Hypersensitivity myocarditis is a rare but life-threatening adverse effect of antitubercular drugs. Prompt diagnosis of hypersensitivity myocarditis and timely steroid therapy can be lifesaving.
Missed Opportunity Encounters for Early Diagnosis of HIV Infection in Adolescents
Authors: Most Zachary M. , Warraich Gohar J. , James Lorraine , Costello Kathleen , Dietz Stephen , Lamb Gabriella S. , Evans Amanda S.
Published: November 2020

Background:

Early diagnosis of HIV infection improves patient outcomes and reduces transmission. Adolescents make up one-fifth of new HIV diagnoses in the United States. We sought to quantify the number of missed opportunity encounters (MOEs) before HIV diagnosis for adolescents at a pediatric hospital (PediHosp) and a proximate adult hospital which employs universal HIV screening in its emergency department (ED) (CountyHosp).

Methods:

An observational study at 2 academic tertiary care hospitals in the United States that included all adolescents 13–20 years old with a new diagnosis of behaviorally-acquired HIV infection from 2006 to 2017. MOE were defined as any encounter at PediHosp or CountyHosp after the latter of the individual’s 13th birthday or the date 3 months after the individual’s most recent negative HIV screen, and before the encounter of HIV diagnosis. Comparisons were made by site of diagnosis and location of MOE.

Results:

Two-hundred five subjects met inclusion criteria: 68% male, 76% Black and 81% men who have sex with men. There were 264 MOE, the proportion of adolescent ED encounters that were MOE at the PediHosp ED was 8.3 MOE per 10,000 encounters and the proportion at the CountyHosp ED was 1.2 (relative risk = 6.7; 95% CI: 4.1–11.0; P < 0.001).

Conclusions:

MOE for HIV diagnosis in adolescents occur frequently and are greater in number at a PediHosp as compared with a similar adult setting with universal screening. Universal HIV screening protocols at PediHosp may identify HIV-positive adolescents earlier.
Radiomics-Based Prediction of Long-Term Treatment Response of Vestibular Schwannomas Following Stereotactic Radiosurgery
Authors: Langenhuizen Patrick P. J. H. , Zinger Svetlana , Leenstra Sieger , Kunst Henricus P. M. , Mulder Jef J. S. , Hanssens Patrick E. J. , de With Peter H. N. , Verheul Jeroen B.
Published: November 2020

Objective:

Stereotactic radiosurgery (SRS) is one of the treatment modalities for vestibular schwannomas (VSs). However, tumor progression can still occur after treatment. Currently, it remains unknown how to predict long-term SRS treatment outcome. This study investigates possible magnetic resonance imaging (MRI)-based predictors of long-term tumor control following SRS.

Study Design:

Retrospective cohort study.

Setting:

Tertiary referral center.

Patients:

Analysis was performed on a database containing 735 patients with unilateral VS, treated with SRS between June 2002 and December 2014. Using strict volumetric criteria for long-term tumor control and tumor progression, a total of 85 patients were included for tumor texture analysis.

Intervention(s):

All patients underwent SRS and had at least 2 years of follow-up.

Main Outcome Measure(s):

Quantitative tumor texture features were extracted from conventional MRI scans. These features were supplied to a machine learning stage to train prediction models. Prediction accuracy, sensitivity, specificity, and area under the receiver operating curve (AUC) are evaluated.

Results:

Gray-level co-occurrence matrices, which capture statistics from specific MRI tumor texture features, obtained the best prediction scores: 0.77 accuracy, 0.71 sensitivity, 0.83 specificity, and 0.93 AUC. These prediction scores further improved to 0.83, 0.83, 0.82, and 0.99, respectively, for tumors larger than 5 cm3.

Conclusions:

Results of this study show the feasibility of predicting the long-term SRS treatment response of VS tumors on an individual basis, using MRI-based tumor texture features. These results can be exploited for further research into creating a clinical decision support system, facilitating physicians, and patients to select a personalized optimal treatment strategy.
Vestibular Schwannoma Practice Patterns: An International Cross-specialty Survey
Authors: Macielak Robert J. , Driscoll Colin L.W. , Link Michael J. , Haynes David S. , Lohse Christine M. , Carlson Matthew L.
Published: November 2020

Objective:

To assess vestibular schwannoma (VS) practice patterns among providers.

Study Design:

Cross-sectional survey.

Setting:

8th Quadrennial International Conference on Vestibular Schwannoma and Other CPA Tumors.

Subjects:

Clinicians who specialize in the management of VS.

Main Outcome Measures:

Responses to questions on the management and anticipated outcomes of VS for a series of common clinical scenarios were compared by specialty (otolaryngology versus neurosurgery), level of experience, scope of practice (surgery versus radiation and surgery), and geographic location of practice (United States versus international).

Results:

Responses from 110 participants were analyzed. Overall, 53% of respondents were otolaryngologists, 60% had greater than 10 years of experience, and 57% practiced within the United States. In total, 86% of respondents would pursue initial observation for themselves if diagnosed with a 4 mm distal intracanalicular VS; however, practicing radiosurgeons were more likely to select stereotactic radiosurgery for this scenario compared with providers who solely practice surgery (14 versus 0%; p = 0.032). Otolaryngologists and neurosurgeons alike report that radiosurgery should not be considered a long-term hearing preservation strategy.

Otolaryngologists were more optimistic regarding microsurgical hearing preservation outcomes for small distal intracanalicular tumors compared with neurosurgeons (11 versus 3% selected a high likelihood of maintaining class A/B hearing; p = 0.007). Ninety-five percent of respondents prioritized facial nerve outcome over complete disease removal in the context of microsurgical resection of large tumors.

Conclusions:

Management decision-making and expected outcomes for various clinical scenarios were largely similar among providers; however, variances in several key clinical areas exist. This study points to the feasibility of developing a widely accepted consensus statement among VS experts across specialties.