Characterization of effective, simple, and low-cost precipitation methods for depleting abundant plasma proteins to enhance the depth and breadth of plasma proteomics.

Plasma is an abundant source of proteins and potential biomarkers to aid in the detection, diagnosis, and prognosis of human diseases. These proteins are often present at low levels in the blood and difficult to identify and measure due to the large dynamic range of proteins. The goal of this work was to characterize and compare various protein precipitation methods related to how they affect the depth and breadth of plasma proteomic studies. Abundant protein precipitation with perchloric acid (PerCA) can increase protein identifications and depth of plasma proteomic studies. Three acid- and four solvent-based precipitation methods were evaluated. All methods tested provided excellent plasma proteomic coverage (>600 identified protein groups) and detected protein in the low pg/mL range. Functional enrichment analysis revealed subtle differences within and larger changes between the precipitant groups. Methanol-based precipitation outperformed the other methods based on identifications and reproducibility. The methods' performance was verified using eight lung cancer patient samples, where >700 protein groups were measured and proteins with an estimated plasma concentration of ∼10 pg/mL were detected. Various protein precipitation agents are amenable to extending the depth and breadth of plasma proteomes. These data can guide investigators to implement inexpensive, high-throughput methods for their plasma proteomic workflows.

A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817.

GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.

The Pediatric Epilepsy Surgery Interest Group (PESIG) under the auspice of the ISPN Research Committee: Availability of relevant technology and geographical distribution.

PURPOSE: Epilepsy surgery for pediatric drug-resistant epilepsy has been shown to improve seizure control, enhance patient and family QoL, and reduce mortality. However, diagnostic tools and surgical capacity are less accessible worldwide. The International Society Pediatric Neurosurgery (ISPN) has established a Pediatric Epilepsy Surgery Interest Group (PESIG), aiming to enhance global collaboration in research and educational aspects. The goals of this manuscript are to introduce PESIG and analyze geographical differences of epilepsy surgery and technology availability. METHODS: PESIG was established (2022) following an ISPN executive board decision. Using a standardized form, we surveyed the PESIG members, collecting and analyzing data regarding geographical distribution, and availability of various epilepsy treatment-related technologies. RESULTS: Two hundred eighty-two members registered in PESIG from 70 countries, over 6 continents, were included. We categorized the countries by GDP as follows: low, lower-medium, upper-medium, and high income. The most commonly available technology was vagus nerve stimulation 68%. Stereoelectroencephalography was available for 58%. North America had statistically significant greater availability compared to other continents. Europe had greater availability compared to Africa, Asia, and South (Latin) America. Asia had greater availability compared to Africa. High-income countries had statistically significant greater availability compared to other income groups; there was no significant difference between the other income-level subgroups. CONCLUSION: There is a clear discrepancy between countries and continents regarding access to epilepsy surgery technologies. This strengthens the need for collaboration between neurologists and neurosurgeons from around the world, to enhance medical education and training, as well as to increase technological availability.

Organosulfur Compounds, S-Allyl-L-Cysteine and S-Ethyl-L-Cysteine, Target PCSK-9/LDL-R-Axis to Ameliorate Cardiovascular, Hepatic, and Metabolic Changes in High Carbohydrate and High Fat Diet-Induced Metabolic Syndrome in Rats.

Metabolic syndrome (MetS) is an ever-evolving set of diseases that poses a serious health risk in many countries worldwide. Existing evidence illustrates that individuals with MetS have a 30%-40% higher chance of acquiring type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or both. This study was undertaken to uncover the regulatory role of natural organosulfur compounds (OSCs), S-allyl-L-cysteine (SAC), and S-ethyl-L-cysteine (SEC), in targeting high carbohydrate high fat (HCHF)-diet-induced MetS-associated risk management. Our findings suggested that SAC and SEC ameliorated HCHF-diet-induced diabetic profiles, plasma lipid and lipoprotein level, liver function, oxidative-stress, inflammatory cytokines, and chemokines including monocyte chemoattractant protein-1 (MCP-1), lipid peroxidation, plasma proprotein convertase subtilisin/kexin type-9 (PCSK-9), and high-sensitivity C-reactive protein (hs-CRP). Moreover, the assessment of the hepatic mRNA expression of the key genes involved in cholesterol homeostasis depicted that SAC and SEC downregulated the PCSK-9 mRNA expression via targeting the expression of HNF-1α, a transcriptional activator of PCSK-9. On the other hand, the LDL-receptor (LDL-R) expression was upregulated through the activation of its transcriptional regulator sterol regulatory element binding protein-2 (SREBP-2). In addition, the activity and the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductases (HMG-R) and peroxisome proliferator-activated receptors (PPARs) were also improved by the treatment of SAC and SEC. We concluded that SAC and SEC can protect against MetS via improving the lipid and lipoprotein content, glycemic indices, hepatic function, targeting the inflammatory cascades, and oxidative imbalance, regulation of the mRNA expression of PCSK-9, LDL-R, SREBP-2, HNF-1α, PPARs, and inflammatory biomarkers.

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

Bone marrow plasma metabonomics of idiopathic acquired aplastic anemia patients using 1H nuclear magnetic resonance spectroscopy.

INTRODUCTION: Idiopathic acquired aplastic anemia (AA) is a bone marrow failure disorder where aberrant T-cell functions lead to depletion of hematopoietic stem and progenitor cells in the bone marrow (BM) microenvironment. T-cells undergo metabolic rewiring, which regulates their proliferation and differentiation. Therefore, studying metabolic variation in AA patients may aid us with a better understanding of the T-cell regulatory pathways governed by metabolites and their pathological engagement in the disease. OBJECTIVE: To identify the differential metabolites in BM plasma of AA patients, AA follow-up (AAF) in comparison to normal controls (NC) and to identify potential disease biomarker(s). METHODS: The study used 1D 1H NMR Carr-Purcell-Meiboom-Gill (CPMG) spectra to identify the metabolites present in the BM plasma samples of AA (n = 40), AAF (n = 16), and NC (n = 20). Metabolic differences between the groups and predictive biomarkers were identified by using multivariate analysis and receiver operating characteristic (ROC) module of Metaboanalyst V5.0 tool, respectively. RESULTS: The AA and AAF samples were well discriminated from NC group as per Principal Component analysis (PCA). Further, we found significant alteration in the levels of 17 metabolites in AA involved in amino-acid (Leucine, serine, threonine, phenylalanine, lysine, histidine, valine, tyrosine, and proline), carbohydrate (Glucose, lactate and mannose), fatty acid (Acetate, glycerol myo-inositol and citrate), and purine metabolism (hypoxanthine) in comparison to NC. Additionally, biomarker analysis predicted Hypoxanthine and Acetate can be used as a potential biomarker. CONCLUSION: The study highlights the significant metabolic alterations in the BM plasma of AA patients which may have implication in the disease pathobiology.

Development of a Preliminary Question Prompt List as a Communication Tool for Adults With Achalasia: A Modified Delphi Study.

BACKGROUND: Question prompt lists (QPLs) are structured sets of disease-specific questions that enhance patient-physician communication by encouraging patients to ask questions during consultations. AIM: The aim of this study was to develop a preliminary achalasia-specific QPL created by esophageal experts. METHODS: The QPL content was derived through a modified Delphi method consisting of 2 rounds. In round 1, experts provided 5 answers to the prompts "What general questions should patients ask when given a new diagnosis of achalasia" and "What questions do I not hear patients asking, but given my expertise, I believe they should be asking?" In round 2, experts rated questions on a 5-point Likert scale. Questions considered "essential" or "important" were accepted into the QPL. Feedback regarding the QPL was obtained in a pilot study wherein patients received the QPL before their consultation and completed surveys afterwards. RESULTS: Nineteen esophageal experts participated in both rounds. Of 148 questions from round 1, 124 (83.8%) were accepted into the QPL. These were further reduced to 56 questions to minimize redundancy. Questions were categorized into 6 themes: "What is achalasia," "Risks with achalasia," "Symptom management in achalasia," "Treatment of achalasia," "Risk of reflux after treatment," and "Follow-up after treatment." Nineteen patients participated in the pilot, most of whom agreed that the QPL was helpful (84.2%) and recommended its wider use (84.2%). CONCLUSIONS: This is the first QPL developed specifically for adults with achalasia. Although well-received in a small pilot, follow-up studies will incorporate additional patient feedback to further refine the QPL content and assess its usability, acceptability, and feasibility.

VE-MMODE - A randomized controlled trial of Venlafaxine versus Escitalopram for treatment of mild to moderate depression in persons with epilepsy.

OBJECTIVES: Depression in persons with epilepsy (PWE) goes undiagnosed and untreated. Despite being common, there are no direct efficacy comparisons of available antidepressants in PWE. Our aim was to compare the effectiveness of Venlafaxine (VEN) and Escitalopram (ESCIT) in comorbid depression in PWE. METHODS: In a single-center, prospective, double-blinded randomized controlled trial (RCT) 90 PWE (age ≥18 years) with mild to moderate depression, were randomized in a 1:1 ratio to receive ESCIT (5-20 mg/day) or VEN (37.5-150 mg/day) for 8 weeks. The primary outcome was to study differences in the efficacy, based on the change in scores of the Hamilton depression rating scale (HAM-D) at 8 weeks. Seizure frequency, QOLIE-31, adverse event profile, and medication adherence were secondary outcome measures. RESULTS: Using the NDDI-E scale, we screened 350 PWE, 90 were enrolled. ITT analysis included all participants and the PP analysis included 40 participants to VEN group and 42 to ESCIT group. Baseline mean (±SD) HAM-D scores for both groups were similar (13.53 ± 3.27; 13.02 ± 3.57). The mean difference (95%CI) on HAM-D scores at 8 weeks was found to be significant within both groups (ITT/PP- VEN: 7.75(6.75, 8.79)/7.92 (7.06, 8.78); p < 0.001, ESCIT: 8.21 (7.39, 9.03)/8.23(7.43, 9.04); p < 0.001). However, there was no significant difference in the efficacy of VEN versus ESCIT at 8 weeks. A significant improvement in QOLIE-31 index and seizure frequency was observed from baseline in both the groups. 90% of those on VEN and 92.9% of those using ESCITadhered to the treatment at week 8. Adverse events were more in VEN group than the ESCIT group. CONCLUSIONS: This study found that HAMD scores improved significantly in the ESCIT and VEN groups, despite the fact that there was no clinically meaningful difference observed between the two groups. Trials with a larger sample size and longer duration are required to establish whether ESCIT or VEN is superior.

Intracranial myeloid sarcoma as the first presentation of acute myeloid leukemia and literature review.

INTRODUCTION: Intracranial myeloid sarcoma is a rare extramedullary presentation of acute myeloid leukemia (AML). It can involve the meninges and ependyma presenting as extra-axial mass lesion. Rarely, it can also invade the brain parenchyma. It is commonly seen in children. It is usually misdiagnosed due to its close resemblance to other intracranial tumors (meningioma, metastasis, Ewing's sarcomas, and lymphoma). These are underdiagnosed if they precede the diagnosis of leukemia. CASE REPORT: A 7-year-old boy with isolated intracranial myeloid sarcoma who presented with raised intracranial pressure (ICP) which was successfully managed by surgical excision. CONCLUSION: Isolated intracranial myeloid sarcoma is a rare presentation of AML. Leukemia can be diagnosed early during the postoperative period and can be started on therapy timely. These patients requires regular follow-ups (clinical, laboratory and radiological) to detect relapses early.

Comparative analysis of biochemical, hormonal, and mineral compositions of preovulatory and cystic ovarian follicles in buffalo during the non-breeding season.

This study is a comparative analysis of the biochemical, hormonal, and mineral compositions of follicular fluid in preovulatory and cystic follicles of water buffalo (Bubalus bubalis). In total, reproductive tracts from 215 buffalo along with intact ovaries were collected randomly from an abattoir. The incidence of cystic conditions found in this study was 3.72% (8/215), involving the right ovary in 62.5% of instances and the left ovary in 37.5% of instances during the non-breeding season. Follicular fluid was aspirated from preovulatory follicles (12-15 mm diameter, oestrogen-active, follicular phase or stage IV corpus luteum on one of the two ovaries, n = 10) and cystic follicles (at least 20 mm diameter, no corpus luteum on any one of the two ovaries, n = 8). The follicular fluid samples were assayed for biochemical components (uric acid, creatinine, blood urea nitrogen, cholesterol, total protein, glucose, ascorbic acid, and alkaline phosphatase), hormones (progesterone, estradiol, and insulin), and minerals (calcium, magnesium, phosphorus, copper, zinc, and cobalt). Cystic follicles had greater (P < 0.05) concentrations of creatinine, blood urea nitrogen, cholesterol, progesterone, copper, zinc, and cobalt, and lesser (P < 0.05) concentrations of uric acid, glucose, ascorbic acid, estradiol, insulin, calcium, magnesium, and phosphorus compared with preovulatory follicles. These results indicated the marked differences in follicular fluid composition between preovulatory and cystic follicles in buffalo. Some of the changes were indicative of oxidative stress and disturbed steroidogenesis, two important mechanisms shown to be associated with cystic ovarian disease in various species. Further studies are warranted to investigate whether these differences are directly or indirectly involved in the formation of cystic follicles or are mere manifestations of the condition.

Optimizing data-independent acquisition (DIA) spectral library workflows for plasma proteomics studies.

Traditional data-independent acquisition (DIA) workflows employ off-column fractionation with data-dependent acquisition (DDA) to generate spectral libraries for data extraction. Recent advances have led to the establishment of library-independent approaches for DIA analyses. The selection of a DIA workflow may affect the outcome of plasma proteomics studies. Here, we establish a gas-phase fractionation (GPF) workflow to create DIA libraries for DIA with parallel accumulation and serial fragmentation (diaPASEF). This workflow along with three other workflows, fractionated DDA libraries, fractionated DIA libraries, and predicted spectra libraries, were evaluated on 20 plasma samples from nonsmall cell lung cancer patients with low or high levels of IL-6. We sought to optimize protein identification and total experiment time. The novel GPF workflow for diaPASEF outperformed the traditional ddaPASEF workflow in the number of identified and quantified proteins. A library-independent workflow based on predicted spectra identified and quantified the most proteins in our experiment at the cost of computational power. Overall, the choice of DIA library workflow seemed to have a limited effect on the overall outcome of a plasma proteomics experiment, but it can affect the number of proteins identified and the total experiment time.

Transcriptomic profiling of nonneoplastic cortical tissues reveals epileptogenic mechanisms in dysembryoplastic neuroepithelial tumors.

Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a frequent cause of drug-refractory epilepsy. Molecular mechanisms underlying seizure generation in these tumors are poorly understood. This study was conducted to identify altered genes in nonneoplastic epileptogenic cortical tissues (ECTs) resected from DNT patients during electrocorticography (ECoG)-guided surgery. RNA sequencing (RNAseq) was used to determine the differentially expressed genes (DEGs) in these high-spiking ECTs compared to non-epileptic controls. A total of 477 DEGs (180 upregulated; 297 downregulated) were observed in the ECTs compared to non-epileptic controls. Gene ontology analysis revealed enrichment of genes belonging to the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: (i) glutamatergic synapse; (ii) nitrogen metabolism; (iii) transcriptional misregulation in cancer; and (iv) protein digestion and absorption. The glutamatergic synapse pathway was enriched by DEGs such as GRM4, SLC1A6, GRIN2C, GRM2, GRM5, GRIN3A, and GRIN2B. Enhanced glutamatergic activity was observed in the pyramidal neurons of ECTs, which could be attributed to altered synaptic transmission in these tissues compared to non-epileptic controls. Besides glutamatergic synapse, altered expression of other genes such as GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration) could be linked to epileptogenesis in ECTs. Also, upregulation of GABRA6 gene in ECTs could underlie benzodiazepine resistance in these patients. Neural cell-type-specific gene set enrichment analysis (GSEA) revealed transcriptome of ECTs to be predominantly contributed by microglia and neurons. This study provides first comprehensive gene expression profiling of nonneoplastic ECTs of DNT patients and identifies genes/pathways potentially linked to epileptogenesis.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

Nitazoxanide potentiates linezolid against linezolid-resistant Staphylococcus aureus in vitro and in vivo.

BACKGROUND: Antimicrobial resistance is a growing menace, claiming millions of lives all over the world. In this context, drug repurposing is one approach gaining interest as a suitable alternative to conventional drug discovery and development. METHODS: Whole-cell assays were used to screen FDA-approved drugs to identify novel antimicrobial agents active against bacterial pathogens. Following identification of nitazoxanide, its various characteristics, such as antimicrobial activity against MDR isolates, time-kill kinetics, ability to synergize with approved drugs, antibiofilm activity and ability to generate resistance in Staphylococcus aureus, were determined, followed by determination of its in vivo potential against MDR S. aureus. RESULTS: Nitazoxanide demonstrated a potent in vitro antistaphylococcal profile, including equipotent activity against clinical drug-resistant S. aureus and Enterococcus spp. Nitazoxanide exhibited concentration-dependent killing, significantly eradicated preformed S. aureus biofilm and S. aureus did not generate resistance to it. Nitazoxanide strongly synergized with linezolid both in vitro and in vivo against linezolid-susceptible and -resistant S. aureus, displaying superior activity to untreated control and drug-alone treatment groups. CONCLUSIONS: Nitazoxanide can be utilized in combination with linezolid against infections caused by linezolid-resistant S. aureus as it exhibits strong synergism in vitro and in vivo.

Role of Altered Expression, Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy.

Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34+ hematopoietic stem and progenitor cells.

Mesenchymal stromal cells (MSC) regulate hematopoiesis in the bone marrow (BM) niche and extracellular vesicles (EVs) released by BM-MSC are important mediators of the cross-talk between BM-MSC and hematopoietic stem and progenitor cells (HSPC). We have previously demonstrated that BM-MSC of severe aplastic anemia (SAA) patients have an altered expression of hematopoiesis regulatory molecules. In the present study, we observed that CD34+ HSPC when cocultured with BM-MSC EVs from aplastic anemia patients exhibited a significant reduction in colony-forming units (p = .001), cell proliferation (p = .002), and increased apoptosis (p > .001) when compared to coculture with BM-MSC EVs from controls. Collectively, our results highlight that EVs derived from the BM-MSC of SAA patients impair the hematopoiesis supporting function of HSPC.

Implementing FCTC Article 17 Through Participatory Research With Bidi Workers in Tamil Nadu, India.

INTRODUCTION: The exploitation, poor conditions, and precarity in the bidi (hand-rolled leaf cigarette) industry in India make it ripe for the application of the FCTC's Article 17, "Provision of support for economically viable alternative activities". "Bottom-up", participatory approaches give scope to explore bidi rollers' own circumstances, experiences, and aspirations. METHODS: A team of six community health volunteers using a participatory research orientation developed a questionnaire-based semi-structured interview tool. Forty-six bidi rolling women were interviewed by pairs of volunteers in two northern Tamil Nadu cities. Two follow-up focus groups were also held. A panel of 11 bidi rollers attended a workshop at which the findings from the interviews and focus groups were presented, further significant points were made and possible alternatives to bidi rolling were discussed. RESULTS: Bidi workers are aware of the adverse impact of their occupation on them and their families, as well as the major risks posed by the product itself for the health of consumers. However, they need alternative livelihoods that offer equivalent remuneration, convenience, and (in some cases) dignity. Alternative livelihoods, and campaigns for better rights for bidi workers while they remain in the industry, serve to undercut industry arguments against tobacco control. Responses need to be diverse and specific to local situations, i.e. "bottom-up" as much as "top-down", which can make the issue of scaling up problematic. CONCLUSION: Participatory approaches involving bidi workers themselves in discussions about their circumstances and aspirations have opened up new possibilities for alternative livelihoods to tobacco. IMPLICATIONS: Progress with the FCTC's Article 17 has generally been slow and has focussed on tobacco cultivation rather than later stages in the production process. The bidi industry in India is ripe for the application of an alternative livelihoods approach. This study is one of the first to use participatory methods to investigate the circumstances, experiences, and aspirations of bidi workers themselves.

The host galaxy of a fast radio burst.

In recent years, millisecond-duration radio signals originating in distant galaxies appear to have been discovered in the so-called fast radio bursts. These signals are dispersed according to a precise physical law and this dispersion is a key observable quantity, which, in tandem with a redshift measurement, can be used for fundamental physical investigations. Every fast radio burst has a dispersion measurement, but none before now have had a redshift measurement, because of the difficulty in pinpointing their celestial coordinates. Here we report the discovery of a fast radio burst and the identification of a fading radio transient lasting ~6 days after the event, which we use to identify the host galaxy; we measure the galaxy's redshift to be z = 0.492 ± 0.008. The dispersion measure and redshift, in combination, provide a direct measurement of the cosmic density of ionized baryons in the intergalactic medium of ΩIGM = 4.9 ± 1.3 per cent, in agreement with the expectation from the Wilkinson Microwave Anisotropy Probe, and including all of the so-called 'missing baryons'. The ~6-day radio transient is largely consistent with the radio afterglow of a short γ-ray burst, and its existence and timescale do not support progenitor models such as giant pulses from pulsars, and supernovae. This contrasts with the interpretation of another recently discovered fast radio burst, suggesting that there are at least two classes of bursts.

Comparison of a bolt-connected external ventricular drain with a tunneled external ventricular drain - a narrative review and meta-analysis.

External ventricular drain (EVD) is one of the most commonly performed neurosurgical procedures. EVD can be associated with high rates of complications like misplacement, iatrogenic hemorrhage, and CSF infection. Several modifications have been proposed in the EVD insertion techniques to decrease the risk of these complications. Bolt-connected EVD, one of these modifications which involves insertion of a bolt in the burr hole, has been proposed to have better chances of optimal placement of EVD tip, lesser risk of CSF infection, and accidental pullout. A comprehensive search of different databases was performed to retrieve studies comparing the bolt-connected EVD with tunneled EVD and meta-analysis was done. Seven studies met inclusion criteria and were included in the meta-analysis. Our analysis revealed that bolt-connected EVD is associated with significantly better chances of optimal placement than traditional tunneled EVD (MH OR-1.65, 95% CI 1.14 to 2.40, p = 0.008). We also observed that bolt-connected EVD is associated with significantly decreased risk of CSF infection (MH OR-0.60, 95% CI 0.39 to 0.94, p = 0.026), EVD malfunction (MH OR-0.31, 95% CI 0.16 to 0.58, p = 0.0003), and accidental disconnection (MH OR-0.09, 95% CI 0.03 to 0.26, p < 0.0001) as compared to traditional tunneled EVD. The difference between the two techniques was not statistically significant for complications, multiple punctures done for insertion of EVD, iatrogenic intracranial, and need of reoperation. Bolt-connected external ventricular drain is associated with significantly more chances of optimal placement and lesser chances of accidental discontinuation and CSF infection than tunneled EVD. There was no statistically significant difference noted between the two techniques for multiple punctures done for insertion of EVD, iatrogenic intracranial hemorrhage and need of reoperation. However, most of the included studies were retrospective. Thus, the results from the meta-analysis should be interpreted with caution as further prospective high-quality studies are needed.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.