Near-miss Thoracic Spine Solitary Plasmacytoma with Neurological Deficit during Pregnancy: A Case Report.

Solitary plasmacytoma (SPC) account for only 5% of plasma cell neoplasms, and the literature hardly reports spinal SPC with a neurological deficit. Furthermore, spinal surgical intervention during pregnancy is rarely encountered and often requires multidisciplinary collaboration and management. The objective of this case report is to highlight this near-miss diagnosis and spinal surgical intervention during pregnancy. A 31-year-old woman with 24 weeks gestation presented with sudden paralysis and incontinence, with an underlying history of chronic backpain over a two-month period. Initially, she was treated for musculoskeletal back pain by obstetric colleagues during an antenatal visit, and no radiograph was performed. A non-contrasted spinal MRI was eventually requested when she started to show bilateral lower limb weakness, numbness and incontinence. The MRI highlighted thoracic vertebrae T11 vertebra plana with kyphotic deformity and a paraspinal soft tissue mass compressing the spinal cord causing spinal cord oedema. Our initial working diagnosis was spinal tuberculosis (TB), considering TB is highly endemic in Malaysia. However, TB workup was negative, and we proceeded with spinal surgery and transpedicular biopsy. Neurology improved significantly after surgery. Eventually, serum protein electrophoresis reported plasma dyscrasia, and HPE confirmed plasmacytoma. The patient was referred to a haematologist for steroidal and chemotherapy treatment.

Viral stimulation modulates endotype-related ACE2 expression in eosinophilic chronic rhinosinusitis.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2), a receptor targeted by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the nasal mucosa. Chronic rhinosinusitis (CRS) shows diverse endotypes and is aggravated by viral infection. Whether viral stimulation and CRS endotype influence ACE2 expression remains unclear. We investigated the expression of ACE2 and the transmembrane protease, serine 2 (TMPRSS2), which mediate the entry of SARS-CoV-2 into cells, and assessed polyinosinic:polycytidylic acid (poly[I:C])-induced changes based on CRS endotype. METHODOLOGY: ACE2 and TMPRSS2 expression was evaluated based on CRS phenotype, endotype, and tissue type. Correlations between ACE2/TMPRSS2 expression and inflammatory mediators in nasal polyps (NP) were examined. Air-liquid interface culture experiments were performed to assess the effects of major cytokines or poly(I:C) stimulation on ACE2/TMPRSS2 expression in primary epithelial cells from healthy nasal mucosa, eosinophilic NP (ENP), and non-eosinophilic NP (NENP). RESULTS: In primary nasal epithelial cells, interleukin (IL)-13 decreased ACE2 expression but increased TMPRSS2. Eosinophilic CRS showed lower ACE2 expression than non-eosinophilic CRS, regardless of CRS phenotype. CRS endotype was an independent factor associated with ACE2/TMPRSS2 expression in NP. Serum and tissue eosinophilic marker levels were inversely correlated with ACE2 expression, whereas tissue neutrophilic marker levels and ACE2 expression were positively correlated in NP. ACE2 expression was suppressed in ENP tissues; however, a combination of poly(I:C) and IL-13 induced ACE2/TMPRSS2 upregulation in ENP. CONCLUSIONS: ENP tissues have lower ACE2 expression than NENP; however, viral stimulation promotes ACE2/TMPRSS2 upregulation in ENP.

Subepithelial neutrophil infiltration as a predictor of the surgical outcome of chronic rhinosinusitis with nasal polyps.

BACKGROUND: Neutrophils present as major inflammatory cells in refractory chronic rhinosinusitis with nasal polyps (CRSwNP), regardless of the endotype. However, their role in the pathophysiology of CRSwNP remains poorly understood. We investigated factors predicting the surgical outcomes of CRSwNP patients with focus on neutrophilic localization. METHODS: We employed machine-learning methods such as the decision tree and random forest models to predict the surgical outcomes of CRSwNP. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE), Bcl-2, and Ki-67 in NP tissues. We counted the immunofluorescence-positive cells and divided them into three groups based on the infiltrated area, namely, epithelial, subepithelial, and perivascular groups. RESULTS: On machine learning, the decision tree algorithm demonstrated that the number of subepithelial HNE-positive cells, Lund-Mackay (LM) scores, and endotype (eosinophilic or non-eosinophilic) were the most important predictors of surgical outcomes in CRSwNP patients. Additionally, the random forest algorithm showed that, after ranking the mean decrease in the Gini index or the accuracy of each factor, the top three ranking factors associated with surgical outcomes were the LM score, age, and number of subepithelial HNE-positive cells. In terms of cellular proliferation, immunofluorescence analysis revealed that Ki-67/HNE-double positive and Bcl-2/HNE-double positive cells were significantly increased in the subepithelial area in refractory CRSwNP. CONCLUSION: Our machine-learning approach and immunofluorescence analysis demonstrated that subepithelial neutrophils in NP tissues had a high expression of Ki-67 and could serve as a cellular biomarker for predicting surgical outcomes in CRSwNP patients.

Harnessing lipid signaling pathways to target specialized pro-angiogenic neutrophil subsets for regenerative immunotherapy.

To gain insights into neutrophil heterogeneity dynamics in the context of sterile inflammation and wound healing, we performed a pseudotime analysis of single-cell flow cytometry data using the spanning-tree progression analysis of density-normalized events algorithm. This enables us to view neutrophil transitional subsets along a pseudotime trajectory and identify distinct VEGFR1, VEGFR2, and CXCR4 high-expressing pro-angiogenic neutrophils. While the proresolving lipid mediator aspirin-triggered resolvin D1 (AT-RvD1) has a known ability to limit neutrophil infiltration, our analysis uncovers a mode of action in which AT-RvD1 leads to inflammation resolution through the selective reprogramming toward a therapeutic neutrophil subset. This accumulation leads to enhanced vascular remodeling in the skinfold window chamber and a proregenerative shift in macrophage and dendritic cell phenotype, resulting in improved wound closure after skin transplantation. As the targeting of functional immune subsets becomes the key to regenerative immunotherapies, single-cell pseudotime analysis tools will be vital in this field.

Adapting re-usable elastomeric respirators to utilise anaesthesia circuit filters using a 3D-printed adaptor - a potential alternative to address N95 shortages during the COVID-19 pandemic.

The COVID-19 pandemic has increased the demand for disposable N95 respirators. Re-usable elastomeric respirators may provide a suitable alternative. Proprietary elastomeric respirator filters may become depleted as demand increases. An alternative may be the virus/bacterial filters used in anaesthesia circuits, if they can be adequately fitted onto the elastomeric respirators. In addition, many re-usable elastomeric respirators do not filter exhaled breaths. If used for sterile procedures, this would also require modification. We designed a 3D-printed adaptor that permits elastomeric respirators to interface with anaesthesia circuit filters and created a simple modification to divert exhaled breaths through the filter. We conducted a feasibility study evaluating the performance of our modified elastomeric respirators. A convenience sample of eight volunteers was recruited. Quantitative fit testing, respiratory rate and end-tidal carbon dioxide were recorded during fit testing exercises and after 1 h of wear. All eight volunteers obtained excellent quantitative fit testing throughout the trial. The mean (SD) end-tidal carbon dioxide was 4.5 (0.5) kPa and 4.6 (0.4) kPa at baseline and after 1 h of wear (p = 0.148). The mean (SD) respiratory rate was 17 (4) breaths.min-1 and 17 (3) breaths.min-1 at baseline and after 1 h of wear (p = 0.435). Four out of eight subjects self-reported discomfort; two reported facial pressure, one reported exhalation resistance and one reported transient dizziness on exertion. Re-usable elastomeric respirators to utilise anaesthesia circuit filters through a 3D-printed adaptor may be a potential alternative to disposable N95 respirators during the COVID-19 pandemic.

The interaction of Lolium latent virus major coat protein with ankyrin repeat protein NbANKr redirects it to chloroplasts and modulates virus infection.

The Lolium latent virus (LoLV) major coat protein sequence contains a typical chloroplast transit peptide (cTP) domain. In infected Nicotiana benthamiana leaf tissue, LoLV coat proteins can be detected at the chloroplast. In transient expression, several N-terminal deletions of the CP sequence, increasing in length, result in disruption of the domain functionality, markedly affecting intracellular localization. A yeast two-hybrid-based study using LoLV CP as bait identified several potentially interacting Arabidopsis host proteins, most of them with chloroplast-linked pathways. One of them, an ankyrin repeat protein, was studied in detail. The N. benthamiana homologue (NbANKr) targets chloroplasts, is able to co-localize with LoLV CP at chloroplast membranes in transient expression and shows a robust interaction with LoLV CP in vivo by BiFC, which has been confirmed by yeast two-hybrid data. Silencing NbANKr genes in N. benthamiana plants, prior to challenging with LoLV by mechanical inoculation, affects LoLV infection, significantly reducing the level of viral RNA in young leaves, compared to levels in control plants, and suggesting an inhibition of virus movement. Silencing of NbANKr has no obvious effect on plant phenotype, but is able to interfere with LoLV infection, opening the way for a new strategy for virus infection control.

Arrhythmogenic response to isoproterenol testing vs. exercise testing in arrhythmogenic right ventricular cardiomyopathy patients.

Aims: To compare the arrhythmic response to isoproterenol and exercise testing in newly diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. Methods and results: We studied isoproterenol [continuous infusion (45 µg/min) for 3 min] and exercise testing (workload increased by 30 W every 3 min) performed in consecutive newly diagnosed ARVC patients. Both tests were evaluated with regard to the incidence of (i) polymorphic premature ventricular contractions (PVCs) and couplet(s) or (ii) sustained or non-sustained ventricular tachycardia (VT) with left bundle branch block [excluding right ventricular outflow tract VT]; and compared to a control group referred for the evaluation of PVCs without structural heart disease. Thirty-seven ARVC patients (63.5% male, age 38 ± 16 years) were included. The maximal sinus rhythm heart rate achieved during isoproterenol testing was significantly lower compared to exercise testing (149 ± 17 bpm vs. 166 ± 19 bpm, P < 0.0001). However, the incidence of polymorphic ventricular arrhythmias was much higher during isoproterenol testing compared to exercise testing [33/37 (89.2%) vs. 16/37 (43.2%), P < 0.0001]. Interestingly, isoproterenol testing was arrhythmogenic in all 15 patients in whom baseline PVCs were reduced or suppressed during exercise testing. During both isoproterenol and exercise testing, control group presented a low incidence of ventricular arrhythmias compared to ARVC patients (8.1% vs. 89.2%, P < 0.0001 and 2.7% vs. 43.2%, P < 0.0001, respectively). Conclusions: The incidence of polymorphic ventricular arrhythmias is significantly higher during isoproterenol compared to exercise testing in newly diagnosed ARVC patients, suggesting its potential utility for the diagnosis.

A Study on CYP2C19 and CYP2D6 Polymorphic Effects on Pharmacokinetics and Pharmacodynamics of Amitriptyline in Healthy Koreans.

We performed a double-blinded, genotype-based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty-four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N-demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19. The extent of hydroxylation of amitriptyline or nortriptyline was significantly reduced in subjects carrying two CYP2D6 decreased functional alleles compared with those with no or one decreased functional allele. The overall metabolic pathway of amitriptyline was more likely to be dominated by CYP2C19 than CYP2D6. The gene variations of CYP2C19 and CYP2D6 did not change the pharmacodynamic effect. The findings of this study will provide useful information on individualized drug treatment with amitriptyline considering both CYP2D6 and CYP2C19 gene variations.

Identification of a novel HLA-B*40 allele, HLA-B*40:332, in a Korean individual.

HLA-B*40:332 differs from B*40:01:02 by 1 nucleotide difference at nucleotide position 439.

Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.

In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7ΔCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARα) was consistently increased in the adipose tissues of Atg7ΔCD11c mice, B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity.

Population Pharmacokinetic and Pharmacodynamic Modeling Analysis of GCC-4401C, a Novel Direct Factor Xa Inhibitor, in Healthy Volunteers.

GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution. Relevant PD markers generally changed in a dose-dependent manner and were described well with sigmoid, simple maximum effect, or linear models. GCC-4401C was absorbed more rapidly than rivaroxaban. Comparisons based on simulations of PD marker changes over time suggest that 20 mg and 40 mg of GCC-4401C administered under fasted status are comparable to 10 mg and 20 mg of rivaroxaban under fed status.

Enhancement of spin-wave nonreciprocity in magnonic crystals via synthetic antiferromagnetic coupling.

Spin-wave nonreciprocity arising from dipole-dipole interaction is insignificant for magnon wavelengths in the sub-100 nm range. Our micromagnetic simulations reveal that for the nanoscale magnonic crystals studied, such nonreciprocity can be greatly enhanced via synthetic antiferromagnetic coupling. The nonreciprocity is manifested as highly asymmetric magnon dispersion curves of the magnonic crystals. Furthermore, based on the study of the dependence of the nonreciprocity on an applied magnetic field, the antiparallel alignment of the magnetizations is shown to be responsible for the enhancement. Our findings would be useful for magnonic and spintronics applications.

Comparison of filter media materials for heavy metal removal from urban stormwater runoff using biofiltration systems.

The filter media in biofiltration systems play an important role in removing potentially harmful pollutants from urban stormwater runoff. This study compares the heavy metal removal potential (Cu, Zn, Cd, Pb) of five materials (potting soil, compost, coconut coir, sludge and a commercial mix) using laboratory columns. Total/dissolved organic carbon (TOC/DOC) was also analysed because some of the test materials had high carbon content which affects heavy metal uptake/release. Potting soil and the commercial mix offered the best metal uptake when dosed with low (Cu: 44.78 µg/L, Zn: 436.4 µg/L, Cd, 1.82 µg/L, Pb: 51.32 µg/L) and high concentrations of heavy metals (Cu: 241 µg/L, Zn: 1127 µg/L, Cd: 4.57 µg/L, Pb: 90.25 µg/L). Compost and sludge also had high removal efficiencies (>90%). Heavy metal leaching from these materials was negligible. A one-month dry period between dosing experiments did not affect metal removal efficiencies. TOC concentrations from all materials increased after the dry period. Heavy metal removal was not affected by filter media depth (600 mm vs. 300 mm). Heavy metals tended to accumulate at the upper 5 cm of the filter media although potting soil showed bottom-enriched concentrations. We recommend using potting soil as the principal media mixed with compost or sludge since these materials perform well and are readily available. The use of renewable materials commonly found in Singapore supports a sustainable approach to urban water management.

The fear-avoidance model of chronic pain: assessing the role of neuroticism and negative affect in pain catastrophizing using structural equation modeling.

BACKGROUND: Previous research on the fear-avoidance model (FAM) of chronic pain suggests that the personality traits of neuroticism and negative affect (NA) influence pain catastrophizing. However, the mechanisms of their influence on pain catastrophizing remain unclear. PURPOSE: This study examined four possible models of relationships between neuroticism, NA, and pain catastrophizing within the FAM framework using structural equation modeling. METHOD: A total of 401 patients with chronic musculoskeletal pain completed measures of neuroticism, NA, three core FAM components (pain catastrophizing, pain-related fear, and pain anxiety), and adjustment outcomes (pain-related disability and depression). RESULTS: Regression analyses refuted the possibility that neuroticism and NA moderated each other's effect on pain catastrophic thoughts (p > 0.05). Results of structural equation modeling (SEM) evidenced superior data-model fit for the collapsed models in which neuroticism and NA were two secondary traits underlying a latent construct, negative emotion (disability: comparative fit index (CFI) = 0.93; depression: CFI = 0.91). CONCLUSION: The results offer preliminary evidence that patients presenting with more neurotic symptom and heightened NA probably elicit more catastrophic thoughts about pain.

The effects of anxiety sensitivity, pain hypervigilance, and pain catastrophizing on quality of life outcomes of patients with chronic pain: a preliminary, cross-sectional analysis.

PURPOSE: In the fear-avoidance model (FAM) of chronic pain, pain-related fear is one of the most prominent predictors of negative adjustment outcomes. While existing data point to the effects of anxiety sensitivity, pain hypervigilance, and pain catastrophizing on pain-related fear, the nature of their multivariate relationships remains unclear. This study explored the possible mediating role of pain hypervigilance in the relationship of anxiety sensitivity and pain catastrophizing with pain-related fear, and their effects on quality of life (QoL) outcomes within the FAM framework. METHODS: A sample of 401 Chinese patients with chronic musculoskeletal pain completed the standardized measures assessing the FAM components and QoL. Structural equation modeling (SEM) was used to evaluate six hypothesized models. RESULTS: Results of SEM showed adequate data-model fit [comparative fit indexes (CFIs) ranging from 0.92 to 0.94] on models which specified pain hypervigilance as mediator of anxiety sensitivity and pain catastrophizing with pain-related fear on two QoL outcomes (QoL-Physical and QoL-Mental). Results consistent with net suppression effects of pain catastrophizing on anxiety sensitivity were found in SEM when both anxiety sensitivity and pain catastrophizing were included in the same full model to predict QoL-Physical (CFI = 0.95; Sobel z = 8.06, p < 0.001) and QoL-Mental (CFI = 0.93; Sobel z = 8.31, p < 0.001). CONCLUSIONS: These cross-sectional analyses gave results consistent with pain hypervigilance, mediating the relationship of pain catastrophic cognition and anxiety sensitivity with pain-related fear. The net suppression effects of pain catastrophizing point to anxiety sensitivity, enhancing the effect of pain catastrophic cognition on pain hypervigilance. These findings elucidate how the interdependence of dispositional factors might influence pain adjustment and functioning.

Community-based wastewater treatment systems and water quality of an Indonesian village.

This paper examines the impact of community-based water treatment systems on water quality in a peri-urban village in Yogyakarta, Indonesia. Water samples were taken from the wastewater treatment plants (WWTPs), irrigation canals, paddy fields and wells during the dry and wet seasons. The samples were tested for biological and chemical oxygen demand, nutrients (ammonia, nitrate, total nitrogen and total phosphorus) and Escherichia coli. Water quality in this village is affected by the presence of active septic tanks, WWTP effluent discharge, small-scale tempe industries and external sources. We found that the WWTPs remove oxygen-demanding wastes effectively but discharged nutrients, such as nitrate and ammonia, into irrigation canals. Irrigation canals had high levels of E. coli as well as oxygen-demanding wastes. Well samples had high E. coli, nitrate and total nitrogen levels. Rainfall tended to increase concentrations of biological and chemical oxygen demand and some nutrients. All our samples fell within the drinking water standards for nitrate but failed the international and Indonesian standards for E. coli. Water quality in this village can be improved by improving the WWTP treatment of nutrients, encouraging more villagers to be connected to WWTPs and controlling hotspot contamination areas in the village.

Multiple regression analysis in modeling of columnar ozone in Peninsular Malaysia.

This study aimed to predict monthly columnar ozone (O3) in Peninsular Malaysia by using data on the concentration of environmental pollutants. Data (2003-2008) on five atmospheric pollutant gases (CO2, O3, CH4, NO2, and H2O vapor) retrieved from the satellite Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) were employed to develop a model that predicts columnar ozone through multiple linear regression. In the entire period, the pollutants were highly correlated (R = 0.811 for the southwest monsoon, R = 0.803 for the northeast monsoon) with predicted columnar ozone. The results of the validation of columnar ozone with column ozone from SCIAMACHY showed a high correlation coefficient (R = 0.752-0.802), indicating the model's accuracy and efficiency. Statistical analysis was utilized to determine the effects of each atmospheric pollutant on columnar ozone. A model that can retrieve columnar ozone in Peninsular Malaysia was developed to provide air quality information. These results are encouraging and accurate and can be used in early warning of the population to comply with air quality standards.

Exploration of optimal dosing regimens of vancomycin in patients infected with methicillin-resistant Staphylococcus aureus by modeling and simulation.

WHAT IS KNOWN AND OBJECTIVE: Vancomycin is the drug of choice for methicillin-resistant Staphylococcus aureus (MRSA) infection and shows time-dependent bacterial killing. The current study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of vancomycin and explored its optimal dosing regimens by modeling and simulation. METHODS: Pharmacokinetics study was performed for 20 patients who were treated with vancomycin intravenously, 1000 mg, every 12 h, and blood for PK was randomly drawn within prespecified time windows. PD study was in vitro time-kill experiment for vancomycin against 20 MRSA strains independent of the PK study, where bacterial titre was measured at 0, 2, 4, 8, 24 h after the beginning of vancomycin exposure at 0, 1, 2, 4, 8, 16, 32× minimum inhibitory concentrations. PK and PD models were built from each data set, and simulation for MRSA titre changes over time in human body was performed for various vancomycin dosing regimens using NONMEM(®) . RESULTS: Vancomycin followed a two-compartment PK model, and creatinine clearance was the significant covariate affecting the clearance of vancomycin. PD model described the in vitro time-kill data well. The PK/PD model predicted clear dose-response relationships of vancomycin. The therapeutic dosing regimens of vancomycin, suggested by the simulation studies, showed good agreement with the current clinical practice guidance, which indicates that this PK/PD modeling and simulation approach could prove useful for identifying optimal dosing regimens of other antibiotics and expediting novel antibiotic development. Using PD model from in vitro time-kill study and human PK model from phase 1 study, we could predict whether the drug is going to be efficacious or obtain insight into the optimal dosing regimens for a novel antibiotic agent in the early phases of drug development process.