Writing scientific articles is a daunting task for novice researchers. In this qualitative study carried out in 2007, the authors evaluated the experiences of a group of novice researchers engaged in ...the writing process, to elucidate the main difficulties and sources of encouragement they encountered.
Sixteen novice researchers were interviewed. Most were women (10), and most were enrolled in programs of medicine (9), followed by nursing (4) and physical therapy (3). These were drawn via convenience sampling from a randomized control trial in which 48 of them were equally assigned to either an online or a face-to-face course of instruction. On completion, interviews were conducted in focus groups of four students each. The interviews were transcribed and read independently by two of the authors, who then encoded the material based on the principles of grounded theory. Initial categories were converted to major emerging themes, which were validated when participants were asked to review the findings. Triangulation of results was carried out by discussing the emerging themes in an online forum with five specialists in college writing education.
Classifying the diverse responses of participants led to the emergence of four major themes: cognitive burden, group support and mentoring, difficulty in distinguishing between content and structure, and backward design of manuscripts.
The themes produced by this study provide some insight into the challenges faced by novice researchers in their early attempts at scientific writing. Remedies that address these challenges are needed to substantially improve scientific writing instruction.
A simultaneous operative approach to patients with significant carotid and coronary disease has been suggested as a safe, lower cost, and more convenient alternative to a staged approach. During the ...last three decades, spanning the career of our senior author, our group has pursued simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) in limited circumstances. We previously reported on our results in series from 1984 to 1994 and 1994 to 1999. Based on these prior results and the current literature, we liberalized our inclusion criteria. We are now reporting on a contemporary cohort of 91 patients operated on from 2006 to 2018.
All patients who underwent combined CEA/CABG in 2006 to 2018 were entered into the Vascular Quality Initiative database. We compared the current series of 91 patients (group 3) with the 74 patients (group 2) from 1994 to 1999 and the 100 patients (group 1) from 1984 to 1994 who also underwent combined CEA/CABG. We examined demographic and comorbid factors, presence of cerebrovascular symptoms, degree of contralateral carotid stenosis, perioperative stroke, and death. Statistical comparison was made with χ2 analysis.
The groups had similar demographics and comorbidities. Significant differences were noted in the preoperative diagnosis of hyperlipidemia (42%, 51%, 75%; P = .005) and the proportion of patients requiring urgent operations (24%, 47%, 56%; P = .002) during successive time periods. Patients in group 3 were much less likely to have preoperative symptoms from carotid stenosis before operation (55%, 31%, 4.4%; P < .001). Correspondingly, patients in group 3 were more likely to have asymptomatic unilateral carotid stenosis (20%, 55%, 78%; P < .001). The 30-day mortality rate remained stable compared with the first interval (8%, 3%, 2.2%; P = .11). Likewise, the overall stroke rate decreased in the later periods compared with the first series (9%, 1.4%, 2.2%; P = .016). Of the two perioperative strokes recorded for group 3, only one event was ipsilateral to the carotid artery operated on compared with the four ipsilateral strokes of nine total reported in group 1 and no ipsilateral stroke reported in group 2.
Based on the favorable results of the previously reported series of CEA/CABG from our group, we continued to liberalize selection criteria for the combined procedure to essentially mirror the standard recommendations for CEA in patients without coronary disease. The current series using this treatment algorithm demonstrates the safety of this approach, with stroke and death rates equivalent to those of CABG alone. These excellent results were achieved in the face of increasingly urgent cardiac procedures. The fact that the majority of the perioperative strokes were contralateral to the carotid artery operated on reinforces the safety of our approach but underscores the significant burden of atherosclerosis in these patients.
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of ...infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis.
Synopsis
Whilst calcineurin inhibition is common during organ transplantation, it also increases susceptibility to life‐threatening invasive pulmonary aspergillosis. Calcineurin is found here to mediate phagocytosis‐dependent innate immune responses to Aspergillus fumigatus in macrophages.
Phagocytosis‐dependent activation of TLR9 by the human mould pathogen A. fumigatus drives calcineurin–NFAT transcriptional responses in macrophages.
Activation of calcineurin–NFAT by TLR9 is independent of MyD88 and Dectin‐1–spleen tyrosine kinase, but dependent on Bruton's tyrosine kinase.
This pathway is critical for macrophage TNF‐α production and subsequent chemotaxis of neutrophil to the airway during pulmonary aspergillosis.
Direct inhibition of the TLR9–BTK–calcineurin–NFAT pathway by calcineurin inhibitors is a key mechanism that increases clinical susceptibility to pulmonary aspergillosis.
Whilst calcineurin inhibition is common during organ transplantation, it also increases susceptibility to life‐threatening invasive pulmonary aspergillosis. Calcineurin is found here to mediate phagocytosis‐dependent innate immune responses to Aspergillus fumigatus in macrophages.
Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected ...with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
Calcineurin has also been shown to directly interact with TWICK-related spinal cord K+ channel (TRESK), which is important in nociception 8; with Kinase Suppressor of RAS (KSR2), a protein scaffold ...that enables signaling from RAS to Extra-cellular signal-Regulated Kinase (ERK) and subsequent ERK activation 9; as well as with A Kinase Anchoring Protein 79 (AKAP79; an anchoring molecular enabling colocalization of calcineurin with protein kinase A PKA and protein kinase C PKC) 10, 11 and the regulator of calcineurin 1 (RCAN1) family of endogenous calcineurin negative regulators (11). RNAseq analysis of the human macrophage calcineurin-dependent response to A. fumigatus infection revealed regulatory control of caspase pathways, nucleotide-binding oligomerization domain-containing protein (NOD) pathways, interleukin 1 (IL-1) signaling, and the Activator Protein 1 (AP-1) transcriptional network, and calcineurin was found to regulate tumor necrosis factor (TNF)-alpha , granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1) levels 12. For particulate LPS, endocytosis via CD14 leads to PLCgamma-dependent calcineurin-NFAT activation. https://doi.org/10.1371/journal.ppat.1006627.g001 Subsequent analysis of the role of calcineurin in human myeloid cells revealed that calcineurin inhibits the proliferation of myeloid granulocyte-monocyte progenitors via FMS-like Tyrosine Kinase 3 Ligand (Flt3-L) 21. ...accumulating evidence places calcineurin as a central regulator of both cellular differentiation, proliferation, and cell death decisions in myeloid immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel ...phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.
Recommendations regarding performance of magnetic resonance imaging (MRI) in non-MRI conditional pacemaker and defibrillator recipients are evolving. Previous studies have suggested low adverse event ...rates with MRI in nonconditional cardiac implantable electronic device (CIED) recipients, but low power limits optimal characterization of risk.
The purpose of this study was to perform a systematic review and meta-analysis to characterize the clinical risk associated with MRI in CIED recipients in order to improve power.
PubMed and CINAHL indexed articles from 1990 to 2017 were queried. A random effects model was used for meta-analysis of continuous variables. Safety outcomes were evaluated with descriptive statistics.
Seventy studies of non-MRI conditional devices undergoing MRI were identified, allowing for analysis of 5099 patients who underwent a total of 5908 MRI studies. Heterogeneity in lead parameter changes was observed within studies, although smaller variances were noted between studies. All lead characteristics and battery voltages showed very small, clinically insignificant changes when assessed as a pooled cohort, although cases of clinically relevant outcomes were also noted (lead failure 3, implantable cardioverter-defibrillator shock 1, electrical reset 94). Electrical resets were found only in older devices. Defibrillator function was unchanged, and inappropriate shocks were avoided with pre-MRI programming changes.
This review demonstrated low lead failure and clinical event rates in non-MRI conditional pacemaker and defibrillator recipients undergoing MRI. Observed changes were small and interstudy variance was low, suggesting that the composite event rates offer a reasonable estimate of true effect. The observed adverse events reinforce the need for ongoing vigilance and caution, particularly with older devices.
Introduction
Transvenous leads have been implicated in tricuspid valve (TV) dysfunction, but limited data are available regarding the effect of extracting leads across the TV on valve regurgitation. ...The aim of this study is to quantify tricuspid regurgitation (TR) before and after lead extraction and identify predictors of worsening TR.
Methods
We studied 321 patients who had echocardiographic data before and after lead extraction. TR was graded on a scale (0 = none/trivial, 1 = mild, 2 = moderate, 3 = severe). A change of >1 grade following extraction was considered significant.
Results
A total of 321 patients underwent extraction of a total of 338 leads across the TV (1.05 ± 0.31 leads across the TV per patient). There was no significant difference on average TR grade pre‐ and postextraction (1.18 ± 0.91 vs. 1.15 ± 0.87; p = 0.79). TR severity increased after extraction in 84 patients, but was classified as significantly worse (i.e., >1 grade change in severity) in only 8 patients (2.5%). Use of laser lead extraction was associated with a higher rate of worsening TR postextraction (44.0% vs. 31.6%, p = 0.04).
Conclusion
In our single‐center analysis, extraction of leads across the TV did not significantly affect the extent of TR in most patients. Laser lead extraction was associated with a higher rate of worsening TR after extraction.
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