Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

Hemophilia A (HA) is a genetic disorder of hemostasis associated with a deficiency or reduced activity of clotting factor VIII (FVIII). This disorder remains unacceptably underdiagnosed in India. Early diagnosis and appropriate management of HA can substantially prevent morbidity and mortality. Currently, HA is managed with regular replacement therapy using standard or extended half-life FVIII concentrates or non-factor drug products. The challenges associated with FVIII concentrates include plateauing of drug effect, issues with its administration and adherence to treatment, breakthrough bleeds, and the development of inhibiting antibodies against administered clotting factors. Emicizumab is a bispecific antibody, launched in India in April 2019, for managing patients with HA. To investigate the role of emicizumab in Indian patients with HA, opinions were sought from 13 eminent hematologists and experts from India on the effectiveness of emicizumab in preventing all bleeds, spontaneous bleeds, perioperative bleeds, and intracranial hemorrhage; resolving target joints; and reducing the rate of hospitalizations and fatality associated with HA in children and adults, with or without inhibitors. The benefits of emicizumab over traditional FVIII concentrates include the subcutaneous route of delivery, less frequent dosing, and a lack of inhibitor development, in addition to providing sustained hemostasis without in-depth monitoring. It is a safe and effective management option for all HA patients, especially for patients with certain archetypes, such as those with inhibitors, those with high annualized bleed rates, those living far away from hemophilia care centers, pediatric patients and infants with intravenous access challenges, and those with a history of life-threatening bleeding events.

Correction: Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

[This corrects the article DOI: 10.7759/cureus.58941.].

Performance and usability evaluation of a mobile health data capture application in clinical cancer trials follow-up.

Mobile health data capture applications (mHDA's) may improve communication between healthcare providers and patients. However, there is limited literature about the use of mHDA's facilitating clinical trials. In this study, the effectiveness of an application, supporting follow-up visits of cancer trial participants was investigated. Twenty participants were provided with an e-questionnaire via the mHDA. Participants rated the usability of the application as high performing (mean Systems Usability Scale 87 points). The research team rated the mHDA as highly applicable and efficient in preparing visits. Anamnesis, physical examination and agreement on further policy were performed within an average of 31 min.

Assessing technical and biological variation in SWATH-MS-based proteomic analysis of chronic lymphocytic leukaemia cells.

Chronic lymphocytic leukaemia (CLL) exhibits variable clinical course and response to therapy, but the molecular basis of this variability remains incompletely understood. Data independent acquisition (DIA)-MS technologies, such as SWATH (Sequential Windowed Acquisition of all THeoretical fragments), provide an opportunity to study the pathophysiology of CLL at the proteome level. Here, a CLL-specific spectral library (7736 proteins) is described alongside an analysis of sample replication and data handling requirements for quantitative SWATH-MS analysis of clinical samples. The analysis was performed on 6 CLL samples, incorporating biological (IGHV mutational status), sample preparation and MS technical replicates. Quantitative information was obtained for 5169 proteins across 54 SWATH-MS acquisitions: the sources of variation and different computational approaches for batch correction were assessed. Functional enrichment analysis of proteins associated with IGHV mutational status showed significant overlap with previous studies based on gene expression profiling. Finally, an approach to perform statistical power analysis in proteomics studies was implemented. This study provides a valuable resource for researchers working on the proteomics of CLL. It also establishes a sound framework for the design of sufficiently powered clinical proteomics studies. Indeed, this study shows that it is possible to derive biologically plausible hypotheses from a relatively small dataset.

Esterified cellulose nanofibres from saw dust using vegetable oil.

In this work, cellulose nanofibres (CNFs) were extracted from sawdust, which is an underutilized by-product from the wood and timber industry. The extracted CNFs by chemical and mechanical treatments had a web-like structure with diameters ranging between 2 nm and 27 nm and lengths reaching a few microns. The obtained CNFs were further chemically modified with vegetable canola oil using two different esterification processes. In order to compare the effect of the surface modification of CNFs, the nanopapers were prepared from their prospective suspensions through solvent evaporation method, and then characterize with Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), UV-vis spectroscopy and tensile tester. FTIR results indicated that both methods led to a successful grafting of the long chain hydrocarbon structure onto the CNFs, and became more hydrophobic when compared to unmodified CNFs-based nanopapers. The crystallinity, mechanical, light transmittance and thermal properties were significantly affected primarily by the esterification method employed, thus the degree of substitution. It was found that high degree of substitution adversely affected the crystallinity, light transmittance, mechanical and thermal properties. The crystallinity decreased from 70% to <40% when the degree of substation was about 0.8.

Mapping the Transcriptional and Fitness Landscapes of a Pathogenic E. coli Strain: The Effects of Organic Acid Stress under Aerobic and Anaerobic Conditions.

Several methods are available to probe cellular responses to external stresses at the whole genome level. RNAseq can be used to measure changes in expression of all genes following exposure to stress, but gives no information about the contribution of these genes to an organism's ability to survive the stress. The relative contribution of each non-essential gene in the genome to the fitness of the organism under stress can be obtained using methods that use sequencing to estimate the frequencies of members of a dense transposon library grown under different conditions, for example by transposon-directed insertion sequencing (TraDIS). These two methods thus probe different aspects of the underlying biology of the organism. We were interested to determine the extent to which the data from these two methods converge on related genes and pathways. To do this, we looked at a combination of biologically meaningful stresses. The human gut contains different organic short-chain fatty acids (SCFAs) produced by fermentation of carbon compounds, and Escherichia coli is exposed to these in its passage through the gut. Their effect is likely to depend on both the ambient pH and the level of oxygen present. We, therefore, generated RNAseq and TraDIS data on a uropathogenic E. coli strain grown at either pH 7 or pH 5.5 in the presence or absence of three SCFAs (acetic, propionic and butyric), either aerobically or anaerobically. Our analysis identifies both known and novel pathways as being likely to be important under these conditions. There is no simple correlation between gene expression and fitness, but we found a significant overlap in KEGG pathways that are predicted to be enriched following analysis of the data from the two methods, and the majority of these showed a fitness signature that would be predicted from the gene expression data, assuming expression to be adaptive. Genes which are not in the E. coli core genome were found to be particularly likely to show a positive correlation between level of expression and contribution to fitness.

Astrocytes in the Pathogenesis of Multiple Sclerosis: An In Situ MicroRNA Study.

Astrocytes are increasingly recognized as active contributors to the disease process in multiple sclerosis (MS), rather than being merely reactive. We investigated the expression of a selected microRNA (miRNA) panel that could contribute both to the injury and to the recovery phases of the disease. Individual astrocytes were laser microdissected from brain sections. We then compared the miRNAs' expressions in MS and control brain samples at different lesional stages in white versus grey matter regions. In active MS lesions, we found upregulation of ischemia-related miRNAs in white but not grey matter, often with reversion to the normal state in inactive lesions. In contrast to our previous findings on MS macrophages, expression of 2 classical inflammatory-related miRNAs, miRNA-155 and miRNA-146a, was reduced in astrocytes from active and chronic active MS lesions in white and grey matter, suggesting a lesser direct pathogenetic role for these miRNAs in astrocytes. miRNAs within the categories regulating aquaporin4 (-100, -145, -320) and glutamate transport/apoptosis/neuroprotection (-124a, -181a, and -29a) showed some contrasting responses. The regional and lesion-stage differences of expression of these miRNAs indicate the remarkable ability of astrocytes to show a wide range of selective responses in the face of differing insults and phases of resolution.

The invasive proteome of glioblastoma revealed by laser-capture microdissection.

BACKGROUND: Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery. METHODS: Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and invasive areas of patient-derived xenografts. RESULTS: Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays. CONCLUSIONS: In summary, our results identify new networks and molecules that may play an important role in glioblastoma development and may constitute potential novel therapeutic targets.

Principles of haemophilia care: The Asia-Pacific perspective.

Optimal haemophilia care is best established and implemented through a well-coordinated plan guided by clearly defined principles and priorities. A document which enunciates those details is therefore important. A successful example of this approach is the definition of principles of haemophilia care (PHC) outlined by the European Association for Haemophilia and Associated Disorders (EAHAD) and also the World Federation of Hemophilia. A similar document applicable to the Asia-Pacific region must take into account not only the highly varied healthcare systems but also the tremendous socio-economic and cultural diversities which impact provision of such care. The Asia-Pacific Haemophilia Working Group (APHWG), representing the countries in this region, has prepared this perspective of the PHC. While endorsing the overall framework outlined by EAHAD, this APHWG document emphasizes regional priorities on education and training of healthcare personnel in the diagnosis and management of hereditary bleeding disorders. Central coordinating agencies with wide stakeholder input, networks of haemophilia treatment centres and national registries as well as robust processes for procurement and distribution of safe and effective clotting factor concentrates (CFCs), implementation of prophylaxis programmes and management of patients with inhibitors should also be developed. The implementation of these strategies should lead to establishment of good comprehensive care programmes. This document should also be an advocacy tool to lobby for improved care for people with haemophilia (PWH) in the region. We urge national healthcare policy makers to consider these principles and initiate strong and decisive action to reach these goals.

Thermoplastic Processing of PLA/Cellulose Nanomaterials Composites.

Over the past decades, research has escalated on the use of polylactic acid (PLA) as a replacement for petroleum-based polymers. This is due to its valuable properties, such as renewability, biodegradability, biocompatibility and good thermomechanical properties. Despite possessing good mechanical properties comparable to conventional petroleum-based polymers, PLA suffers from some shortcomings such as low thermal resistance, heat distortion temperature and rate of crystallization, thus different fillers have been used to overcome these limitations. In the framework of environmentally friendly processes and products, there has been growing interest on the use of cellulose nanomaterials viz. cellulose nanocrystals (CNC) and nanofibers (CNF) as natural fillers for PLA towards advanced applications other than short-term packaging and biomedical. Cellulosic nanomaterials are renewable in nature, biodegradable, eco-friendly and they possess high strength and stiffness. In the case of eco-friendly processes, various conventional processing techniques, such as melt extrusion, melt-spinning, and compression molding, have been used to produce PLA composites. This review addresses the critical factors in the manufacturing of PLA-cellulosic nanomaterials by using conventional techniques and recent advances needed to promote and improve the dispersion of the cellulosic nanomaterials. Different aspects, including morphology, mechanical behavior and thermal properties, as well as comparisons of CNC- and CNF-reinforced PLA, are also discussed.

Disgust but not Health Anxiety Graphic Warning Labels Reduce Motivated Attention in Smokers: A Study of P300 and Late Positive Potential Responses.

Background: Graphic health warning labels (GHWLs) on tobacco products attempt to leverage avoidance-promoting emotions, such as anxiety and disgust, to encourage cessation. Prior studies have relied on self-report or attentional metrics that may not accurately illuminate GHWLs' ability to motivate change. This report evaluates the impact of disgust- and anxiety-based GHWLs on electroencephalograph (EEG) measures of motivated attention among two groups of smokers-those that report higher versus lower cigarette dependence. We hypothesized that both anxiety and disgust GHWLs would reduce appetitive attention, as indexed by lowered P300 (P3) and late positive potential (LPP) activations. Methods: Sixty-one smokers provided demographic and smoking history before completing an oddball paradigm consisting of three counterbalanced stimuli blocks. Each block (100 trials) contained a neutral, GHWL-anxiety, or GHWL-disgust frequent image and a smoking cue as the oddball image (20%). Oddball trials for each block were averaged, P3 and LPP were identified at midline electrode positions (Fz, Cz, and Pz), and mean amplitude was analyzed. Results: Separate mixed-model ANOVAs of P3 and LPP reactivity revealed disgust-focused GHWLs reduced motivated attentional processing. Conversely, the anxiety-focused GHWL appeared to increase the salience of the smoking cue (Fz only). Less-dependent smokers showed lower P3 reactivity than those with higher dependence at Fz, but greater P3 reactivity at Cz and Pz. Conclusion: These results extend prior work in demonstrating that disgust, but not anxiety-based GHWLs, may reduce EEG-assessed motivated attention to smoking cues. Disgust may thus represent a more fruitful target for public health cessation efforts. Implications: Most GHWL evaluations have focused on fear (or anxiety) elicitation rather than disgust, an emotion that may have a unique link to smoking, having evolved specifically to facilitate the avoidance of contaminants via oral incorporation. Analyses of P300 and LPP responses to GHWLs suggest that disgust-focused images interfere with the EEG-indexed attentional processing of smoking cues and do so better than health anxiety-focused messages. However, interaction effects at different electrode sites indicated that GHWLs have complex effects in more versus less-dependent smokers and that an understanding of how smoking cues and anti-smoking imagery become associated over time is needed to identify relevant targets for public health efforts.

Bio-based coatings for reducing water sorption in natural fibre reinforced composites.

In this study, bio-based coatings were used for reducing water sorption of composites containing flame retardant treated natural fibres and phenolic resin. Two types of coatings; polyfurfuryl alcohol resin (PFA) and polyurethane (PU) were used on the composites and compared with a water resistant market product. Uncoated and coated samples were conditioned at 90 °C and relative humidity of 90% for three days and the relative moisture content and mechanical properties after conditioning were analysed. In addition, the changes in the weight loss of the conditioned samples were also investigated by thermogravimetric analysis. The moisture diffusion characteristics of coated laminates were also studied at room temperature under water immersion conditions. PFA coated samples showed better moisture resistance and mechanical performance than other bio-based coatings when subjected to long term environmental aging.

Acute kidney injury and mortality in hematopoietic stem cell transplantation: A single-center experience.

Hematopoietic stem cell transplant (HSCT) is a life-saving procedure for patients with several malignant and nonmalignant hematological disorders. Acute kidney injury (AKI) is a common complication after HSCT. The aim of the study was to identify the incidence and outcomes of AKI associated with HSCT in our center. Sixty-six HSCT recipients from October 2008 to March 2014 at Christian Medical College, Ludhiana, were followed up till July 31, 2014. RIFLE criteria utilizing serum creatinine was used to diagnose and stage AKI. Mortality and AKI were the primary outcomes studied. The risk of AKI in relation to conditioning regimen, type of HSCT (allogeneic and autologous), co-morbidities, graft versus host disease, drug toxicity, and veno-occlusive disease were analyzed. Sixty-five patients were included in the study. Male: Female ratio was 3.6:1 with a median age of 17 years (1.5-62). Forty-nine (75.4%) patients had AKI over 3 months, R 17 (26.2%), I 19 (29.2%), and F 13 (20%). AKI occurred at a mean of 19.4 ± 29.2 days after the HSCT. AKI was more commonly observed in patients undergoing allogeneic versus autologous HSCT (85.2% in allogeneic vs. 27.8% in autologous, P = 0.005). Mortality was seen in 20 patients (30.8%) in 3 months. AKI in the first 2 weeks (P < 0.016) was a significant risk factor for mortality. Incidence of AKI in HSCT is high and accounts for significant mortality and morbidity. RIFLE classification of AKI has prognostic significance among HSCT patients with an incremental trend in mortality.

Visual cue-specific craving is diminished in stressed smokers.

BACKGROUND: Craving among smokers is increased by stress and exposure to smoking-related visual cues. However, few experimental studies have tested both elicitors concurrently and considered how exposures may interact to influence craving. OBJECTIVE: The current study examined craving in response to stress and visual cue exposure, separately and in succession, in order to better understand the relationship between craving elicitation and the elicitor. METHOD: Thirty-nine smokers (21 males) who forwent smoking for 30 minutes were randomized to complete a stress task and a visual cue task in counterbalanced orders (creating the experimental groups); for the cue task, counterbalanced blocks of neutral, motivational control, and smoking images were presented. Self-reported craving was assessed after each block of visual stimuli and stress task, and after a recovery period following each task. RESULTS: As expected, the stress and smoking images generated greater craving than neutral or motivational control images (p < .001). Interactions indicated craving in those who completed the stress task first differed from those who completed the visual cues task first (p < .05), such that stress task craving was greater than all image type craving (all p's < .05) only if the visual cue task was completed first. Conversely, craving was stable across image types when the stress task was completed first. CONCLUSIONS: Findings indicate when smokers are stressed, visual cues have little additive effect on craving, and different types of visual cues elicit comparable craving. These findings may imply that once stressed, smokers will crave cigarettes comparably notwithstanding whether they are exposed to smoking image cues.

Recurrent hemoperitoneum secondary to haemorrhage from the corpus luteum unmasks factor V deficiency.

Factor V deficiency is a rare autosomal recessive coagulation disorder. We report a case with inherited factor V deficiency presenting as life-threatening recurrent hemoperitoneum, following bleeding from ruptured corpus haemorrhagicum. Prolonged prothrombin and activated partial thromboplastin times, normal thrombin time and a normal platelet count pointed towards a disorder of coagulation. Mixing studies with factor V deficient plasma and coagulation factor assay revealed markedly reduced plasma factor V clotting activity. The management included blood, plasma and tranexamic acid. Family screening revealed low factor V levels in her parents. Although her brother had significant Factor V deficiency and epistaxis, he did not need hospitalization or replacement, indicating the varied manifestation of this bleeding defect in this family.

Measurement of back-bombardment temperature rise in microwave thermionic electron guns.

We describe a simple method to measure the back-bombardment heating temperature rise as a function of time in pulsed microwave thermionic guns using a fast rise-time InGaAs detector and optical pyrometer. Gaining knowledge of the nature of that temperature rise and the corresponding current out of the gun are the first steps in devising a scheme to counteract the back-bombardment heating which lengthens the micropulses, limits the macropulse length, and increases the energy spread of the emitted electron beam. We measured a temperature rise of 59 K in our LaB6 cathode which delivered a peak of 600 mA over a 5 µs RF pulse in our 0.33 MV/cm peak field, 2.856 GHz thermionic electron gun.

Mapping the extracellular and membrane proteome associated with the vasculature and the stroma in the embryo.

In order to map the extracellular or membrane proteome associated with the vasculature and the stroma in an embryonic organism in vivo, we developed a biotinylation technique for chicken embryo and combined it with mass spectrometry and bioinformatic analysis. We also applied this procedure to implanted tumors growing on the chorioallantoic membrane or after the induction of granulation tissue. Membrane and extracellular matrix proteins were the most abundant components identified. Relative quantitative analysis revealed differential protein expression patterns in several tissues. Through a bioinformatic approach, we determined endothelial cell protein expression signatures, which allowed us to identify several proteins not yet reported to be associated with endothelial cells or the vasculature. This is the first study reported so far that applies in vivo biotinylation, in combination with robust label-free quantitative proteomics approaches and bioinformatic analysis, to an embryonic organism. It also provides the first description of the vascular and matrix proteome of the embryo that might constitute the starting point for further developments.

Environmental friendly method for the extraction of coir fibre and isolation of nanofibre.

The objective of this work was to develop an environmental friendly method for the effective utilization of coir fibre by adopting steam pre-treatment. The retting of the coconut bunch makes strong environmental problems which can be avoided by this method. Chemical characterization of the fibre during each processing stages confirmed the increase of cellulose content from raw (40%) to final steam treated fibres (93%). Morphological and dynamic light scattering analyses of the fibres at different processing stages revealed that the isolation of cellulose nano fibres occur in the final step of the process as an aqueous suspension. FT-IR and XRD analysis demonstrated that the treatments lead to the gradual removal of lignin and hemicelluloses from the fibres. The existence of strong lignin-cellulose complex in the raw coir fibre is proved by its enhanced thermal stability. Steam explosion has been proved to be a green method to expand the application areas of coir fibre.

The experimental renal cell carcinoma model in the chick embryo.

The clear cell subtype of renal carcinoma (CCRCC) is highly vascularized and despite a slow progression rate, it is potentially a highly aggressive tumor. Although a doubling of median progression-free survival in CCRCC patients treated by targeted therapies has been observed, the fact that tumors escape after anti-VEGF treatment suggests alternative pathways. The chick chorioallantoic membrane (CAM) is a well-established model, which allows in vivo studies of tumor angiogenesis and the testing of anti-angiogenic molecules. However, only a few data exist on CCRCC grafted onto CAM. We aimed to validate herein the CAM as a suitable model for studying the development of CCRCC and the interactions with the surrounding stroma. Our study uses both CCRCC cell lines and fresh tumor samples after surgical resection. We demonstrate that in both cases CCRCC can be grafted onto the CAM, to survive and to induce an angiogenic process. We further provide insights into the transcriptional regulation of the model by performing a differential analysis of tumor-derived and stroma-derived transcripts.