Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro
Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro, Published online: 17 September 2018; doi:10.1038/s41419-018-0996-9
Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitroAutophagy-independent induction of LC3B through oxidative stress reveals its non-canonical role in anoikis of ovarian cancer cells
Autophagy-independent induction of LC3B through oxidative stress reveals its non-canonical role in anoikis of ovarian cancer cells, Published online: 17 September 2018; doi:10.1038/s41419-018-0989-8
Autophagy-independent induction of LC3B through oxidative stress reveals its non-canonical role in anoikis of ovarian cancer cellsIdelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma
Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma, Published online: 17 September 2018; doi:10.1038/s41419-018-0960-8
Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinomaMiR-423-5p in brain metastasis: potential role in diagnostics and molecular biology
MiR-423-5p in brain metastasis: potential role in diagnostics and molecular biology, Published online: 17 September 2018; doi:10.1038/s41419-018-0955-5
MiR-423-5p in brain metastasis: potential role in diagnostics and molecular biologyPreconditioning the uterine unfolded protein response maintains non-apoptotic Caspase 3-dependent quiescence during pregnancy
Preconditioning the uterine unfolded protein response maintains non-apoptotic Caspase 3-dependent quiescence during pregnancy, Published online: 17 September 2018; doi:10.1038/s41419-018-1000-4
Preconditioning the uterine unfolded protein response maintains non-apoptotic Caspase 3-dependent quiescence during pregnancyEstablishment of stable iPS-derived human neural stem cell lines suitable for cell therapies
Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies, Published online: 17 September 2018; doi:10.1038/s41419-018-0990-2
Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapiesChaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR
Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR, Published online: 17 September 2018; doi:10.1038/s41419-018-0970-6
Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTORThe abuse of synthetic opioids has become a major threat in recent years. Several clinical reports and fatal case reports exist discussing life-threatening hypoventilation and fatal respiratory depression following the abuse of trans-3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide (U-47700). The reported concentration of U-47700 in peripheral blood varies between 0.01 μg/mL and 1.46 μg/mL. These values depend on the mode of administration and whether the drug was used in combination with other drugs and/or pharmaceuticals. In the past, U-47700 was predominantly insufflated and not injected. The current study presents a non-targeted liquid chromatography/mass spectrometry (LC/MS)-based screening approach of urine and cerebrospinal fluid samples after intravenous injection of U-47700. Furthermore, quantitative values on U-47700 as obtained by liquid chromatography coupled to a linear ion trap (LC/ESI-QTRAPMS) are presented concerning femoral blood (0.29 μg/mL), urine (0.24 μg/mL), gastric contents (0.57 μg/mL), bile fluid (2.3 μg/mL), heart blood (1.25 μg/mL), liver (9.9 μg/g), cerebrospinal fluid (0.4 μg/mL), and hair (0.14 ng/mg). Thereof, concentrations in hair, gastric contents, bile fluid and cerebrospinal fluid have never been reported before. Drug paraphernalia were also analyzed by liquid chromatography coupled to a diode array detector (LC/DAD) and nuclear magnetic resonance spectrometer (NMR). The analyses show that the powder had a relatively high purity and was adulterated to a low degree. This is the first case report which lists concentration distributions of various specimens after intravenous injection. These findings as well as the U-47700 concentration are important to evaluate autopsy cases of U-47700 intoxication in the future.
In fire scenarios, the application and accuracy of traditional odontological methods are often limited. Crystalline studies and elemental profiling have been evaluated for their applicability in determining biological profiles (age and sex) from human dentition, particularly fire- and heat-affected dental remains. Thirty-seven teeth were paired according to tooth type and donor age/sex for the analysis of crown and root surfaces pre- and post-incineration using X-ray diffraction (XRD) and scanning electron microscopy (SEM/EDX). In unburned crowns, carbon (C) content showed a positive correlation with age, whereas phosphorus (P) and calcium (Ca) contents showed a negative correlation with age. In unburned roots, C, P and Ca contents also showed significant changes that were opposite of those observed in the crowns. In relation to sex, females exhibited a higher C ratio than males, whereas males showed significantly higher levels of oxygen (O), P and Ca in unburned roots. Incineration resulted in an increase in the crystallite size that correlated with increasing temperature. No differences in hydroxyapatite (HA) crystallite size were found between age groups; however, unburned teeth from females exhibited a larger crystallite size than did those from males. The challenges of using XRD with a 3D sample were overcome to allow analysis of whole teeth in a nondestructive manner. Further studies may be useful in helping predict the temperature of a fire.
Objective: To perform a comprehensive assessment of long-term quality of life (QOL) and gastrointestinal (GI) function in patients following pancreaticoduodenectomy (PD). Summary of Background Data: Survival after PD has greatly improved and thus has resulted in a larger population of survivors, yet long-term QOL and GI function after PD is largely unknown. Methods: Patients were identified from a global online support group. QOL was measured using the Short Form-36, while GI function was assessed using the Gastrointestinal Symptom Rating Scale. QOL and GI function were analyzed across subgroups based on time after PD. QOL was compared with preoperative measurements and with established values of a general healthy population (GHP). Multivariate linear regression was used to identify predictors of QOL. Results: Of the 7605 members of the online support group, 1102 responded to the questionnaire with 927 responders meeting inclusion criteria. Seven hundred seventeen (77.3%) of these responders underwent PD for malignancy. Mean age was 57 ± 12 years and 327 (35%) were male. At the time of survey, patients were 2.0 (0.7, 4.3) years out from surgery, with a maximum 30.7-year response following PD. Emotional and physical domains of QOL improved with time and surpassed preoperative levels between 6 months and 1 year after PD (both P 5 years) included total GSRS score [β = −1.70 (−1.91, −1.50)], female sex [β = 3.58 (0.67, 6.46)], and being a cancer survivor [β = 3.93 (0.60, 7.25)]. Conclusions: Long-term QOL following PD improves over time, however never approaches that of a GHP. GI dysfunction persists in long-term survivors and is an independent predictor of poor QOL. Long-term physical, psychosocial, and GI functional support after PD is encouraged.Inadequate nutrient consumption causes protein energy malnutrition and micronutrient deficiencies and related consequences, including poor physical growth and intellectual development. However, literatures sho...
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The study was aimed at determining the prevalence of unintended pregnancy and associated factors in Arsi Negele Woreda from May 01, 2017 to July 30, 2017.
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Monosodium glutamate (MSG) has been marred by a lot of controversy on its safety. In a majority of experimental studies, administration of the compound has been parenteral, and yet little is known about MSG sa...
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Pancreatic cancer is one of the most aggressive and mortal cancers. Although several drugs have been proposed for its treatment, it remains resistant and new alternatives are needed. In this context, plants an...
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Euphorbia supina (ES) has been widely used in folk medicine owing to its antibacterial, hemostatic, and anti-inflammatory properties. The aim of this study was to evaluate the antioxidant and skin-whitening effec...
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The male reproductive system is a sensitive and intricate process that can be distressed following exposure to various toxicants. Therapeutic drugs, especially chemotherapeutics, can also adversely affect male...
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Mitochondrial dysfunction has been implicated in the pathogenesis of ischemic heart disease, exacerbating cardiomyocytes injury in myocardial infarction (MI). Peroxisome proliferator-activated receptor gamma c...
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Cancers, Vol. 10, Pages 336: Revisiting Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Cancer: Saint or Sinner?
Cancers doi: 10.3390/cancers10090336
Authors: Brigitte Bauvois Santos A. Susin
Human neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein present in a wide variety of tissues and cell types. NGAL exists as a 25 kDa monomer, a 46 kDa homodimer (the most abundant form in healthy subjects) and a 130 kDa disulfide-linked heterodimer bound to latent matrix metalloproteinase-9. Dysregulated expression of NGAL in human malignancies suggests its value as a clinical marker. A growing body of evidence is highlighting NGAL’s paradoxical (i.e., both beneficial and detrimental) effects on cellular processes associated with tumor development (proliferation, survival, migration, invasion, and multidrug resistance). At least two distinct cell surface receptors are identified for NGAL. This review (i) summarizes our current knowledge of NGAL’s expression profiles in solid tumors and leukemias, and (ii) critically evaluates the beneficial and detrimental activities of NGAL having been documented in a diverse range of cancer-derived cell lines. A better understanding of the causal relationships between NGAL dysregulation and tumor development will require a fine analysis of the molecular aspects and biological role(s) of NGAL both in primary tumors and at different stages of disease. Having an accurate picture of NGAL’s contribution to tumor progression is a prerequisite for attempting to modulate this protein as a putative therapeutic target.
Annals of Clinical and Translational Neurology, EarlyView.
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Annals of Clinical and Translational Neurology, EarlyView.
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Annals of Clinical and Translational Neurology, EarlyView.
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Human Gene Therapy, Ahead of Print.
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Human Gene Therapy, Ahead of Print.
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Low-grade serous ovarian cancer (LGSOC) is a rare subtype of ovarian cancer, accounting for approximately 10% of cases of serous ovarian cancer. Patients typically present at a younger age have a protracted clinical course with survival for those with recurrent disease nearing 10 years, and have a high prevalence of somatic (tumor-specific) mutations affecting the mitogen-activated protein kinase (MAPK) pathway. Initial treatment of patients with stage IC–IV disease is similar to that of high-grade serous ovarian cancer with surgery and platinum/taxane-based chemotherapy. Selected patients may benefit from hormonal maintenance therapy following chemotherapy, in particular those with evidence of residual disease at completion of therapy. In the recurrent setting, the highest response rates to chemotherapy have been noted in those patients receiving chemotherapy in combination with bevacizumab. While hormonal therapies may offer disease stabilization with relatively low toxicity, objective response rates remain low. The use of targeted therapies such as MEK inhibitors remains an active area of investigation and those patients with MAPK pathway alterations may derive the greatest benefit from these agents.
Future Oncology, Ahead of Print.
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Future Oncology, Ahead of Print.
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International Endodontic Journal, Volume 0, Issue ja, -Not available-.
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Annals of Neurology, Volume 0, Issue ja, -Not available-.
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Annals of Neurology, Volume 0, Issue ja, -Not available-.
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Annals of Neurology, Volume 0, Issue ja, -Not available-.
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ANZ Journal of Surgery, EarlyView.
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ANZ Journal of Surgery, EarlyView.
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ANZ Journal of Surgery, EarlyView.
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ANZ Journal of Surgery, EarlyView.
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Glycoprotein nmb (GPNMB) is a type I transmembrane protein that contributes to the initiation and malignant progression of breast cancer through induction of epithelial-mesenchymal transition (EMT). Although it is known that EMT is associated with not only cancer invasion but also acquisition of cancer stem cell (CSC) properties, the function of GPNMB in this acquisition of CSC properties has yet to be elucidated. To address this issue, we utilized a three-dimensional (3D) sphere culture method to examine the correlation between GPNMB and CSC properties in breast cancer cells. 3D sphere cultures induced higher expression of CSC genes and EMT-inducing transcription factor (EMT-TF) genes than did the 2D monolayer cultures. 3D culture also induced cell surface expression of GPNMB on limited numbers of cells in the spheres, whereas the 2D cultures did not. Therefore, we isolated cell surface-GPNMBhigh and -GPNMBlow cells from the spheres. Cell surface-GPNMBhigh cells expressed high levels of CSC genes and EMT-TF genes, had significantly higher sphere-forming frequencies than the cell surface-GPNMBlow cells, and showed no detectable levels of proliferation marker genes. Similar results were obtained from transplanted breast tumors. Furthermore, wild-type GPNMB but not mutant GPNMB (YF), which lacks tumorigenic activity, induced CSC-like properties in breast epithelial cells. These findings suggest that GPNMB is exposed on the surface of dormant breast cancer cells and its activity contributes to the acquisition of stem cell-like properties.
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Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers (BC), a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes (TIL). Approaches that activate innate immunity in BC cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I interferons (IFN), and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene-I (RIG-I/DDX58) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of pro-inflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and modulate the tumor microenvironment in vivo.
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UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry-based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.
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Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here we developed a surgical approach to deliver STING ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that while control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T cell-mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo. We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands, and establishes the utility of the explant assay to personalize immunotherapies according to the local response.
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Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the anti-tumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice restored MPL/TDCM-induced protection in mice with B cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases.
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Null mutants are essential for analyzing gene function. Here, we describe a simple and efficient method to generate Caenorhabditis elegans null mutants using CRISPR/Cas9 and short single stranded DNA oligo repair templates to insert a universal 43-nucleotide-long knock-in cassette (STOP-IN) into the early exons of target genes. This STOP-IN cassette has stop codons in all three reading frames and leads to frameshifts, which will generate putative null mutations regardless of the reading frame of the insertion position in exons. The STOP-IN cassette also contains an exogenous Cas9 target site that allows further genome editing and provides a unique sequence that simplifies the identification of successful insertion events via PCR. As a proof of concept, we inserted the STOP-IN cassette right at a Cas9 target site in aex-2 to generate new putative null alleles by injecting preassembled Cas9 ribonucleoprotein and a short synthetic single stranded DNA repair template containing the STOP-IN cassette and two ~35-nucleotide-long homology arms identical to the sequences flanking the Cas9 cut site. We showed that these new aex-2 alleles phenocopied an existing loss-of-function allele of aex-2. We further showed that the new aex-2 null alleles could be reverted back to the wild-type sequence by targeting the exogenous Cas9 cut site included in the STOP-IN cassette and providing a single stranded wild-type DNA repair oligo. We applied our STOP-IN method to generate new putative null mutants for 20 additional genes, including three pharyngeal muscle-specific genes (clik-1, clik-2, and clik-3), and reported a high insertion rate (46%) based on the animals we screened. We showed that null mutations of clik-2 cause recessive lethality with a severe pumping defect and clik-3 null mutants have a mild pumping defect, while clik-1 is dispensable for pumping. We expect that the knock-in method using the STOP-IN cassette will facilitate the generation of new null mutants to understand gene function in C. elegans and other genetic model organisms.
Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.
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Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.
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Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.
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Legionellosis is a well-known cause of pneumonia. Primary cutaneous and subcutaneous infection caused by Legionella pneumophila is rare and the diagnosis is challenging.
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To prevent cross infection the surgical team perform preoperative hand disinfection before dressed in surgical gowns and gloves. Preoperative hand disinfection does not make hands sterile and the surgical glov...
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Most guidelines recommend 6 to 12 weeks of parenteral antibiotic treatment for pyogenic spondylodiscitis. When surgical debridement is adequately performed, further intravenous antibiotic treatment duration ca...
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Editor's note: Annals has partnered with a small group of selected journals of international emergency medicine societies to share from each a highlighted research study, as selected monthly by their editors. Our goals are to increase awareness of our readership to research developments in the international emergency medicine literature, promote collaboration among the selected international emergency medicine journals, and support the improvement of emergency medicine world-wide, as described in the WAME statement at https://ift.tt/2dmKsCb.
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Technologic advances have allowed miniaturization of ultrasound technology such that point-of-care ultrasound is available for use with modern tablets and smartphones. Since 2009, a multitude of products have become available in the US market for use with both iOS and Android operating systems. These "pocket devices" target both the inhospital and out-of-hospital markets. Some have the ability to store patient data, interface wirelessly with image archival systems, and insert information into electronic health records or electronic work-flow solutions.
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[Flannery B, Chung JR, Belongia EA, et al. Interim estimates of 2017-18 seasonal influenza vaccine effectiveness—United States, February 2018. MMWR Morb Mortal Wkly Rep. 2018;67:180-185.][Because of the length of the original publication, it has been abridged. Readers are encouraged to read the full original publication, available at https://ift.tt/2pn5xE9]
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The American College of Emergency Physicians (ACEP) advocates tolerance and respect for the dignity of each individual and opposes all forms of discrimination against and harassment of patients and emergency medicine staff on the basis of an individual's race, age, religion, creed, color, ancestry, citizenship, national or ethnic origin, language preference, immigration status, disability, medical condition, military or veteran status, social or socioeconomic status or condition, sex, gender identity or expression, sexual orientation, or any other classification protected by local, state, or federal law.
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A previously healthy 13-year-old male adolescent presented to our hospital, complaining of intense chest pain and dyspnea after a bout of coughing. On examination, his vital signs were normal, but there were decreased sounds in the right hemithorax. A chest radiograph showed an apparent elevation of the right hemidiaphragm and a possible thoracic mass (Figure 1). Emergency thoracic computed tomography (CT) (Figure 2) and magnetic resonance imaging (MRI) (Figure 3) were performed, and the patient underwent thoracic surgery the following day.
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Q1. Cervantes et al1 report on a study of a vulnerable population, undocumented immigrants with end-stage renal disease.
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News flash: Often people who call 911 for medical help are not experiencing true emergencies, yet individuals experiencing no more than indigestion or paper cuts frequently end up in emergency departments (EDs). Thanks to an innovative new program in the nation's capital, however, emergency physicians in Washington, DC, are likely to find themselves prescribing fewer antacids and applying fewer Band-Aids in the future.
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The American College of Emergency Physicians (ACEP) believes that emergency physicians should assume a primary role in disaster preparedness and response throughout all phases of the disaster life cycle. The provision of effective disaster medical services requires previous training or experience, which is a component of emergency medicine residency training. Additionally, emergency physicians should be encouraged to pursue continued training enabling them to best fulfill this responsibility.
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A 7-year-old boy presented to the emergency department after sustaining a fall. He described pain on the lateral aspect of his left foot. On examination, there was mild swelling and point tenderness of the base of his left fifth toe. An anteroposterior radiograph of the foot revealed dislocation of the fifth metatarsophalangeal joint, although it was impossible to identify the injury on a medial 30-degree oblique view (Figure).
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Recognizing that significant changes are occurring in the physician workforce and in the financing of graduate medical education (GME), the American College of Emergency Physicians (ACEP) believes that:
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▮ Wilderness and Travel Medicine. October 1-15, 2018. Arusha, Tanzania. Contact: Amy Weiss. Email: kayakeramy@aol.com. Url: https://ift.tt/2peBvSD. (15.5)
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The American College of Emergency Physicians (ACEP) believes that patients with a medical emergency as defined with the prudent layperson standard must have universal access to 911-based emergency medical services (EMS) systems, and supports the following principles:
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Ads and complete payments must be received in writing by the issue's deadline date. These deadlines apply to insertions, cancellations, and changes.
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Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised consensus clustering revealed four distinct consensus clusters (CC). The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pre-treatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound-healing/ scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar-like tumors had the most favorable prognosis. Conclusion: This study expands our knowledge on muscle-invasive bladder cancer not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.
Purpose: Osteonecrosis (ON) is a devastating complication of high dose corticosteroid therapy in cancer patients. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in ON lesions. Experimental Design: In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MR imaging studies of nine hip joints of seven ON patients before and after core decompression. 24-48hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron labeled bone marrow cells were aspirated from the iliac crest, concentrated and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation. Results: Iron labeled cells could be detected in the access canal by a dark (negative) signal on T2*-weighted MR images. T2* relaxation times of iron labeled cell transplants were significantly lower compared to unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair. Conclusions: This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.
Purpose: To assess the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model; to assess the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx). Experimental Design: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and androgen receptor (AR), AR-splice variant7 and AR targets. A phase I trial had a 3x3 panobinostat dose-escalation design. The phase II randomized 55 patients to panobinostat 40mg (A-arm) or 20mg (B-arm) triweekly x2 weeks with bicalutamide 50mg/day in 3-week cycles. The primary endpoint was percent of patients radiographic progression-free (rPF) at 36 weeks versus historical high-dose bicalutamide. Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35% in the A- and B-arms (47.5%; 38.5%). The A-arm but not the B-arm exceeded expectations for times (medians) to rP (33.9 and 10 weeks), and from PSA progression to rP (24 and 5.9 weeks). A-arm/B-arm: adverse events (AEs), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%. Principal A-arm grade≥3 AEs: thrombocytopenia (31%), fatigue (14%). Conclusions: The 40mg panobinostat/bicalutamide regimen increased radiographic progression-free survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen.
Purpose: The tumor immune microenvironment determines clinical outcome. Whether the original tissue in which a primary tumor develops influences this microenvironment is not well understood. Experimental Design: We applied high-dimensional single-cell mass cytometry (CyTOF) analysis and functional studies to analyze immune cell populations in human papillomavirus (HPV)-induced primary tumors of the cervix (CxCa) and oropharynx (OPSCC). Results: Despite the same etiology of these tumors, the composition and functionality of their lymphocytic infiltrate substantially differed. CxCa displayed a 3-fold lower CD4:CD8 ratio, contained more activated CD8+CD103+CD161+ effector T-cells and less CD4+CD161+ effector memory T-cells than OPSCC. CD161+ effector cells produced the highest cytokine levels among tumor-specific T-cells. Differences in CD4+ T-cell infiltration between CxCa and OPSCC were reflected in the detection rate of intratumoral HPV-specific CD4+ T-cells and in their impact on OPSCC and CxCa survival. The PBMC composition of these patients, however, was similar. Conclusions: The tissue of origin significantly impacts the overall shape of the immune infiltrate in primary tumors.
Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anti-cancer drug development. Three selective CDK4/6 inhibitors are FDA and EMEA approved for hormone receptor positive/HER2 negative advanced breast cancer. A major emerging appreciation is that these inhibitors are not only cytostatic, but also play critical roles in the interaction between tumour cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anti-cancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anti-cancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immune-therapy.
Background: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus BV (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). Materials and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between 1) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and 2) plasma vascular endothelial growth factor A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Results: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS (HR=0.79; 95% CI: 0.61, 1.01; P=0.06) and OS (HR=0.76; 95% CI: 0.56, 1.04; P=0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR=0.84; 95% CI: 0.56, 1.26; P=0.40; OS, HR=0.80; 95% CI: 0.51, 1.26; P=0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR=1.19; 95% CI: 0.93, 1.53; P=0.17) and significantly shorter OS (HR=1.64; 95% CI: 1.20, 2.24; P<0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable to those reported previously. Conclusions: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these BV-containing regimens. ClinicalTrials.gov Identifier: NCT01374425
Purpose: Effective targeted therapies are lacking for refractory and relapsed T-cell Acute Lymphoblastic Leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSIs) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL. Experimental Design: We performed a comprehensive analysis of our high throughput drug screen across hundreds of human cell lines including fifteen T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both, in vitro experiments and in vivo studies on patient-derived xenograft models. Results: We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of anti-apoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacological inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax in vitro and leads to tumor regressions in vivo. Conclusions: Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
Purpose: BRAF mutations are divided into functional classes based on signaling mechanism and kinase activity: V600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), and kinase-inactivating heterodimers (class III). The relationship between functional class and disease characteristics in BRAF-mutant non-small cell lung cancer (NSCLC) has not been fully explored. Experimental Design: We performed a retrospective analysis of BRAF-mutant NSCLCs treated at two institutions from 2005-2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS). Results: We identified 236 patients with BRAF-mutant NSCLC (n=107 class I, n=75 class II, and n=54 class III). Patients with class II or III mutations were more likely to have brain metastases (p≤0.01) and RAS co-alterations (p≤0.001). Compared to class I, PFS on chemotherapy was shorter for class II (p=0.069) and class III (p=0.034). OS was shorter for class II and III (Class I: 40.1 months, Class II: 13.9 months, Class III: 15.6 months; I vs II: p<0.001, I vs III: p=0.023); however, this difference was driven by fewer extra-thoracic metastases and higher use of targeted therapies in class I patients. When patients treated with targeted therapy and those with thoracic-only metastases were excluded, there was no difference in OS across the three classes. Conclusions: BRAF-mutant NSCLC is a heterogeneous disease that encompasses three distinct functional classes. Classes II and III have aggressive clinical features leading to less favorable outcomes. The distinct biological characteristics of class II and III tumors suggest that class-specific therapies may be necessary to effectively target these molecular subsets.
Horm Metab Res
DOI: 10.1055/a-0651-5051
The roles of interleukin-10 (IL-10) gene polymorphisms in diabetes mellitus (DM) have been intensively analyzed earlier, but the results of these studies were conflicting. Hence, we performed this study to better assess the relationship between IL-10 genetic variations and DM. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess correlations between IL-10 polymorphisms and DM. A total of 32 studies were finally included in our analyses. Significant associations with the risk of DM were detected for the rs1800871, rs1800872, and rs1800896 polymorphisms. As for complications in DM, significant association with the risk of diabetic nephropathy (DN) was detected for the rs1800871 polymorphism. In addition, we also found that the rs1800896 polymorphism was significantly associated with the risk of diabetic retinopathy (DR). Further stratified analyses on the basis of type of disease demonstrated that the positive results were predominantly driven by the T2DM subgroup. When we stratified data based on ethnicity of participants, we found that the rs1800871 polymorphism was significantly correlated with DM in Caucasians, the rs1800872 polymorphism was significantly correlated with DM in Asians, and the rs1800896 polymorphism was significantly correlated with DM in both Caucasians and Asians. Our findings indicate that rs1800871, rs1800872, and rs1800896 polymorphisms may serve as genetic biomarkers of DM. Moreover, the rs1800871 and rs1800896 polymorphisms may also contribute to the development of complications in DM.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Horm Metab Res
DOI: 10.1055/a-0723-2807
Currently, the second-generation intact parathyroid hormone (iPTH) assay is commonly used for measuring PTH levels. The iPTH assay detects both full-length (1–84)PTH and (7–84)PTH fragments, which have antagonistic effects on (1–84)PTH in bones and kidneys. The third-generation PTH assay is specific for (1–84)PTH. This study examined the features of different PTH fragments in stage 5 chronic kidney disease (CKD) and the effects of parathyroidectomy (PTX) on the above markers in severe secondary hyperparathyroidism (SHPT) patients. The cross-sectional study included 262 stage 5 CKD patients and 90 controls. A prospective follow-up study was then conducted in 34 PTX patients. Second- and third-generation assays were used to measure plasma iPTH and (1–84)PTH levels, respectively. Circulating (7–84)PTH levels were calculated by subtracting the (1–84)PTH value from the iPTH value. Different plasma PTH fragments were higher, and (1–84)PTH/iPTH was lower in CKD patients than in controls. Plasma (1–84)PTH and (7–84)PTH concentrations increased as iPTH levels increased, and (7–84)PTH increased more evidently. Plasma iPTH, (1–84)PTH and (7–84)PTH levels were 1530.5 (885.0–2111.5) pg/ml, 683.1 (431.4–1018.0) pg/ml, and 739.3 (452.6–1261.0) pg/ml, respectively, in PTX patients. Plasma iPTH, (1–84)PTH and (7–84)PTH concentrations decreased considerably, and the (1–84)PTH/iPTH ratio increased after PTX (median follow-up interval: 10.9 months). Stage 5 CKD patients had higher plasma levels of different PTH fragments, and lower (1–84)PTH/iPTH ratio. PTX could significantly reverse these abnormalities in severe SHPT patients. The iPTH assay overestimated the function of the parathyroid glands; thus, the third-generation PTH assay is likely better for the management of CKD patients.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
MONDAY, Sept. 17, 2018 -- The PK Papyrus Covered Coronary Stent System has been approved by the U.S. Food and Drug Administration to treat acute coronary artery perforations. "An acute coronary artery perforation is a rare, but potentially...
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MONDAY, Sept. 17, 2018 -- Over the last two decades, the proportion of women in the first and senior authorship positions has increased in academic cardiology literature, according to an article published in the Aug. 7 issue of the Journal of the...
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MONDAY, Sept. 17, 2018 -- Variables have been identified that predict escalated care for infants with bronchiolitis, according to a study published in the September issue of Pediatrics. Gabrielle Freire, M.D., from the University of Toronto, and...
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MONDAY, Sept. 17, 2018 -- A new report finds that foster children are often given powerful psychiatric medicines without regard for proper safeguards. The report, coming from the inspector general's office at the U.S. Department of Health and Human...
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MONDAY, Sept. 17, 2018 -- Following implementation of a federal mandatory safety standard on infant walkers in 2010, there was a decrease in the number of infant walker-related injuries, according to a study published online Sept. 17 in...
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by Chris Holstege Early in my career, I received a call from my emergency department (ED) that a local pest remover had an M44 cyanide device discharge in his face. He was hyperventilating while insufflating amyl nitrite. I began to look further into it and I was rather stunned at the number of markedly toxic […]
EMCrit Project by Tox & Hound.
Closed-loop resuscitation can improve personalization of care, decrease workload and bring expert knowledge in isolated areas. We have developed a new device to control the administration of fluid or simultane...
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The streptococcal toxic shock syndrome is a severe complication associated with invasive infections by group A streptococci. In spite of medical progresses in the care of patients with septic shock during the ...
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Criteria for the Sepsis-3 definition of septic shock include vasopressor treatment to maintain a mean arterial pressure > 65 mmHg and a lactate concentration > 2 mmol/L. The impact of hyperoxia in patients wit...
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Clinical and Translational Science, Volume 0, Issue ja, -Not available-.
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Postoperative complications, especially postoperative pancreatic fistulas, remain the major concern following pancreaticoduodenectomy (PD). Mesh-reinforced pancreatic anastomoses, including pancreatojejunostomy (PJ) and pancreatogastrostomy (PG), are a new effective technique in PD. This study was conducted to analyze the safety and efficacy of this new technique and to compare the results of mesh-reinforced PJ vs PG.
A total of 110 patients who underwent PD between August 2005 and January 2016 were eligible in this study. Perioperative and postoperative data of patients with a mesh-reinforced technique were analyzed. Data were also grouped according to the procedure performed: mesh-reinforced PJ and mesh-reinforced PG.
Among patients undergoing PD with the mesh-reinforced technique, 42 had postoperative complications, and the comprehensive complication index (CCI) was 32.7 ± 2.5. Only 10% of patients had pancreatic fistula; three were grade A, six were grade B, and two were grade C. Biliary fistula occurred in only 8.2% of patients. Patients undergoing mesh-reinforced PG showed a significantly lower rate of CCI than did mesh-reinforced PJ patients (27.0 ± 2.1 vs 37.0 ± 3.9, p < 0.05). The mesh-reinforced PG was also favored over mesh-reinforced PJ because of significant differences in intra-abdominal fluid collection (5.9% vs 18.6%, p < 0.05) and delayed gastric emptying (3.9% vs 15.3%, p < 0.05).
PD with the mesh-reinforced technique was a safe and effective method of decreasing postoperative pancreatic fistula. Compared with mesh-reinforced PJ, mesh-reinforced PG did not show significant differences in the rates of pancreatic fistula or biliary fistula. However, CCI, intra-abdominal fluid collection, and delayed gastric emptying were significantly reduced in patients with mesh-reinforced PG.
Frequent emergency department (ED) users are of interest to policymakers and hospitals. The objective of this study is to examine the effect of health information exchange size on the identification of frequent ED users.
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Patients receiving direct oral anticoagulant medications commonly undergo computed tomography head scanning after mild traumatic brain injury, regardless of symptoms or signs. International guidelines have noted a lack of evidence to support management decisions for such patients. This systematic review aims to identify, appraise, and synthesize the current evidence for the risk of adverse outcome in patients receiving direct oral anticoagulants after mild head injury.
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Thrombolysis with tissue plasminogen activator should occur promptly after ischemic stroke onset. Various strategies have attempted to improve door-to-needle time. Our objective is to evaluate a strategy that uses an emergency physician–based protocol when no stroke neurologist is available.
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European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
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To describe the perceptions of caregivers of children with medical complexity (CMC) about their decision to pursue tracheostomy for their children, in particular the satisfaction with their decision.
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Cognitive Science, Volume 42, Issue 7, Page 2105-2107, September 2018.
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Histopathology, Volume 0, Issue ja, -Not available-.
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Advanced Healthcare Materials, EarlyView.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Hepatology, Volume 0, Issue ja, -Not available-.
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Hepatology, EarlyView.
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Advanced Healthcare Materials, EarlyView.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, Volume 30, Issue 38, September 20, 2018.
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Advanced Materials, EarlyView.
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Advanced Materials, EarlyView.
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Advanced Materials, EarlyView.
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Advanced Materials, EarlyView.
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Advanced Materials, EarlyView.
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Cancer Medicine, EarlyView.
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Cancer Medicine, EarlyView.
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Food Science &Nutrition, EarlyView.
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Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.
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European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.
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European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.
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Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.
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Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.
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Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.
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P. aeruginosa isolates (n = 1,909) were collected from 70 United Sates medical centers and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (MIC50/90, 2/8 mg/liter) and ceftolozane-tazobactam (MIC50/90, 0.5/2 mg/liter) were the most active (highest susceptibility rates) compounds after colistin, with national susceptibility rates of 96.9% and 97.5%, respectively. Overall, piperacillin-tazobactam (MIC50/90, 4/128 mg/liter) and meropenem (MIC50/90, 0.5/16 mg/liter) were active against 77.5% and 76.0%, respectively. Susceptibility variations across census divisions were documented for many antimicrobials.
Candida tropicalis isolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy.
Fluconazole efficacy against two weakly (≤25% growth), two moderately (26-50% growth), one resistant heavily (>70% growth) trailing, and one resistant (100% growth) isolates was investigated in vitro and in vivo (a Galleria mellonella survival model and two non-lethal murine models). CDR1 expression levels and ERG11 sequences were characterised.
Survival in fluconazole-treated G. mellonella was inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment. The CDR1 expression was significantly higher in trailing and resistant compared to wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibited ERG11 wild-type alleles.
Heavily trailing isolates were less responsive to fluconazole in all in vivo models indicating an impact on fluconazole efficacy. CDR1 upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole efficacy against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larvae model may be a reason for concern in selected vulnerable patient populations.
Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia, but induce hepatitis B surface antigen (HBsAg) loss in a very few patients and do not much affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, Tazarotene exhibited the most potent anti-HBV effect with an IC50 for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected dHepaRG models, but not in HepG2.215 cells, and HBV genotype A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA, RNAs and the activation of HBV promoters. Moreover, RNA-sequence analysis showed that Tazarotene did not induce an interferon response, but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by specific antagonist significantly attenuated the anti-HBV activity of Tazarotene, suggesting Tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of Tazarotene and Entecavir on HBV-DNA levels was observed. Therefore, RAR agonists as represented by Tazarotene were identified as potential novel anti-HBV agents.
Vancomycin-resistant enterococci (VRE) is an important cause of nosocomial infections in acute care hospitals (ACHs), intermediate- (ITCFs) and long-term care facilities (LTCFs). This study contemporaneously compared the epidemiology and risk factors for VRE colonization in different care settings in a healthcare network. We conducted a serial cross-sectional study in a 1700-bed ACH and its six closely-affiliated ITCFs and LTCFs in June-July, 2014–2016. Rectal swabs or stool were cultured for VRE. Multivariable logistic regression was used to assess for independent risk factors associated with VRE colonization. Of 5357 participants, 523 (9.8%) were VRE-colonized. VRE prevalence was higher in ACH (14.2%) than ITCFs (7.6%) and LTCFs (0.8%). Common risk factors between ACH and ITCFs included prior VRE carriage; a longer duration of antibiotic therapy; surgery in the preceding 90 days and presence of skin ulcer. Independent risk factors specific to ACH-admitted patients were prior MRSA carriage; a higher number of beds per room; prior proton pump inhibitors use and length of stay >14 days. For ITCFs, length of stay >14 days was inversely associated with VRE colonization. Similarities and differences in risk factors for VRE colonization were observed between healthcare settings. VRE prevention efforts should target the respective high-risk patients.
Beta-lactam therapy for severe staphylococcal infections is associated with superior outcomes when compared to non-beta-lactam therapy. In patients with immediate hypersensitivity to beta-lactams, desensitization has been widely employed to allow beta-lactam therapy, but published protocols for anti-staphylococcal beta-lactams such as flucloxacillin are lacking. Here, we report a case and the desensitization protocol successfully used for a patient with isolated flucloxacillin immediate hypersensitivity, where a penicillin desensitization protocol would likely have resulted in an adverse drug reaction.
High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response. In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival. A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%), 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12). Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.
The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli that produces colistin-resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501R, HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S. Experiments were conducted at a medium inoculum of ~107 CFU/mL over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic thigh-infected mouse model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. By contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in bacterial burden, albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings where a mean decrease of 0.38 to 0.90 log10 CFU and 1.27 to 1.78 log10 CFU was noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.
The in vitro activity of tavaborole, a FDA approved antifungal drug, was compared to four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine and fluconazole, the principal choices for the treatment of onychomycosis. Thus it appears that tavaborole is not a candidate for the treatment of onychomycosis due to Candida species, Aspergillus species and dermatophytes.
Mutations in the kelch-propeller domain (K13-propeller) of Plasmodium falciparum parasites from Southeast Asia are associated with reduced susceptibility to artemisinin. We exposed in vitro-cultured Stage V gametocytes from Cambodian K13-propeller mutant parasites to dihydroartemisinin and evaluated inhibition of male gamete formation in the in vitro exflagellation inhibition assay (EIA). Gametocytes with R539T and C580Y K13-propeller alleles were less susceptible to dihydroartemisinin and had significantly higher 50% inhibitory concentrations (IC50s) compared to gametocytes with wild-type alleles.
Vibrio alginolyticus is a Gram-negative halophilic and mesophilic bacterium, particularly associated with severe epidemic vibriosis, which causes high mortality for marine animals, including fish, shellfish and shrimp (1)....
Hepatic fungal abscesses are rare in the neonatal period and often constitute a severe complication of the catheterization of the umbilical vessels. Such life-threatening lesions are observed more frequently in preterm than in other newborn infants and the optimal treatment remains uncertain. We present the case of a preterm neonate, who developed an intrahepatic lesion due to parenteral extravasation, successively contaminated by Candida albicans. Despite the maximal pharmacological therapies, the treatment that led to the definitive resolution of the abscess was the placement of a surgical drainage followed by the direct intralesional administration of liposomal amphotericin B (AmBisome), never described in neonates in the literature, which turned out to be a safe and effective approach.
We evaluated the effect of rifampin co-administration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in clearance (0.53 vs 0.55 L/hr, P = 1.00), volume of distribution (7.0 vs 7.2 L, P = 0.62), or half-life (9.7 vs 9.6 hrs, P = 0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition.
Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single ascending dose study to assess safety and tolerability of chinfloxacin. The single dose pharmacokinetic study, food effect study and a multiple dose pharmacokinetics study was conducted in Part B, Part C and Part D, respectively. Part E was a randomized, placebo- and positive-controlled single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/QTc interval. The results suggest that single and multiple oral administration of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to Cmax (Tmax) was about 2 h and T1/2 was 14-16 h. Food slightly affected the drug's rate and extent of absorption, increasing the Tmax from 1.60 to 2.59 h and reducing the Cmax by 13.6% and AUC by 8.95%, respectively. Chinfloxacin 400 mg had no effect on prolongation of QT/QTc intervals. Although chinfloxacin 600 mg caused mild effect on prolongation of QT/QTc interval, the effect was less pronounced than that of the positive control, moxifloxacin 400 mg. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at ChiCTR.org.cn. Identifier of Part A to Part D: ChiCTR-TRC-10001619; Identifier of the Part E: ChiCTR1800015906.)
The capsid of hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, which is the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report herein a cell-based assay in which the formation of core dimers is indicated by the Split Luciferase Complementation (SLC). Making use of this model, 2 compounds, Arbidol and 20-Deoxyingenol, were identified as core dimerization regulators from a library containing 672 compounds. Arbidol and 20-Deoxyingenol inhibit the HBV DNA replication in vitro by decreasing and increasing the formation of core dimer and capsid, respectively. Our results provided a proof of concept for the cell model to be used to screen new agents targeting the step of core dimer and capsid formation.
Drug-induced liver and kidney injuries are threats to public health worldwide, but there are claims that medicinal plants may provide remedy. Protective effect of Dialium guineense leaf extract (DGE) against diclofenac (DF)-induced oxidative injuries to the liver and kidney was evaluated in rats. Extract was prepared by maceration of pulverized sample in a mixture of water and ethanol, filtration, and evaporation to dryness. Eighteen rats were divided into three groups with six rats per group. Group I rats received normal saline, group II rats received 10 mg/kg DF by intramuscular route for 7 days while group III rats were treated with 250 mg/kg DGE orally for 28 days and given DF as group II rats. At the end of treatment, blood was collected from each rat and the serum was separated and used for spectrophotometric estimations of biomarkers of hepatorenal injuries. Liver and kidneys were excised from euthanized rats, homogenized in phosphate buffer and the supernatants used for assays of biomarkers of oxidative injuries. There was a significant (p < 0.01) increase in levels of ALT, AST, GGT, MDA, creatinine, and urea, and significant (p < 0.01) decrease in SOD, CAT, GPx, GST, GSH, and G6Pase of DF-intoxicated rats when compared with normal control. Pretreatment of DF-intoxicated rats with DGE significantly (p < 0.01) reduced the levels of ALT, AST, GGT, MDA, creatinine, and urea, and significantly (p < 0.01) elevated the levels of SOD, CAT, GPx, GST, GSH, and G6Pase compared with DF control. These findings showed that DGE may protect against DF-induced oxidative stress and hepatorenal injuries in rats.
