Introduction. Less is known about fertility intention of men and family planning (FP) use pattern among men or their spouses who do not want to have more children in Nepal. The objective of the current research was to assess whether number and sex composition of living children determine contraceptive use and method mix among Nepalese men who expressed not wanting to have more children. Methods. We used couple dataset from NDHS 2016 for the analysis. The sample consisted of 1551 (weighted) men aged 20 or older who had at least one living child and said they wanted no more children. Multinomial logistic regression analysis was conducted to identify determinants of sterilization, traditional, temporary contraceptive use. Analysis was conducted considering clustering and stratification in NDHS 2016 survey. Results. Of the total respondents, more than 80% mentioned they do not want to have any more children. However, only one-third of the men or their spouses who expressed desire not to have children were using sterilization methods at the time of survey. Contraceptive use showed a strong association with number and sex composition of children with men favouring to have at least 1 or 2 sons. Multinomial logistic regression analysis showed that use of sterilization method (especially female sterilization) was strongly associated with having at least 1 or 2 sons. Men with daughters only and one son with daughters were more likely to use temporary methods. Conclusion. Among men who do not want to have more children, FP use was associated with number and sex composition of living children. Use of sterilization methods was associated with having at least 1 or 2 sons. Nepal's family planning program can be further strengthened by joining hands with initiatives aimed at promoting the value of girl child.
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Σάββατο 22 Δεκεμβρίου 2018
Fertility Limiting Intention and Contraceptive Use among Currently Married Men in Nepal: Evidence from Nepal Demographic and Health Survey 2016
Cartilage and Bone Serum Biomarkers as Novel Tools for Monitoring Knee Osteochondritis Dissecans Treated with Osteochondral Scaffold
Knee osteochondritis dissecans (OCD) is a focal disease of the joint characterized by modifications of bone and cartilage tissues. Biomimetic osteochondral scaffolds are used to restore these tissues. The aim of this prognostic prospective cohort study was to evaluate serum biomarkers of cartilage (fragments or propeptide of type II collagen: CTXII, C2C, and CPII) and bone (tartrate-resistant acid phosphatase (TRAP) 5b and osteocalcin (OC)) turnover during follow-up of patients treated with an osteochondral scaffold, to identify which were related to healing outcome and clinical score. We found that cartilage (CPII) and bone (OC) synthetic biomarkers were significantly increased during the first-year follow-up, while the respective degradative markers (CTXII, C2C, and TRAP5b) were not modulated. Only CTXII/CPII and C2C/CPII cartilage ratios were significantly modulated, evidencing a higher remodeling of cartilage compared to bone tissue. Cartilage and bone single biomarkers or ratios at one-year follow-up showed values close to or similar to those of healthy subjects. International Knee Documentation Committee (IKDC) score significantly increased from T0 to T2, while the Tegner score did not. Taking into consideration an IKDC score > 70 as clinical success, we found that all OCD cases with both CPII (> 300 pg/ml) and C2C/CPII (
http://bit.ly/2rSLdM6
Wait and you shall see: sexual delay discounting in hypersexual Parkinson’s disease
http://bit.ly/2BFqf7Y
Elucidation of the Intestinal Absorption Mechanism of Loganin in the Human Intestinal Caco-2 Cell Model
Loganin, iridoid glycosides, is the main bioactive ingredients in the plant Strychnos nux-vomica L. and demonstrates various pharmacological effects, though poor oral bioavailability in rats. In this study, the intestinal absorption mechanism of loganin was investigated using the human intestinal Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction; additionally, transport characteristics were systematically investigated at different concentrations, pHs, temperatures, and potential transporters. The absorption permeability (AB) of loganin, which ranged from 12.17 to 14.78 × 10−6cm/s, was high at four tested concentrations (5, 20, 40, and 80μM), while the major permeation mechanism of loganin was found to be passive diffusion with active efflux mediated by multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP). In addition, it was found that loganin was not the substrate of efflux transporter P-glycoprotein (P-gp) since the selective inhibitor (verapamil) of the efflux transporter exhibited little effects on the transport of loganin in the human intestinal Caco-2 cells. Meanwhile, transport from the apical to the basolateral side increased 2.09-fold after addition of a MRP inhibitor and 2.32-fold after addition of a BCRP inhibitor. In summary, our results clearly demonstrate, for the first time, a good permeability of loganin in the human intestinal Caco-2 cell model and elucidate, in detail, the intestinal absorption mechanism and the effects of transporters on iridoid glycosides compounds.
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Combining and Using the Utrecht Method and the Analytic Hierarchy Process to Facilitate Professional and Ethical Deliberation and Decision Making in Complementary and Alternative Medicine: A Case Study among a Panel of Stakeholders
Background. In daily practice, healthcare practitioners face many challenges in ethical and professional decision making. Currently, little is known on the ethical and professional deliberations and weighing benefits against risks in daily complementary and alternative medicine (CAM) practice. The aim of this study was to combine the Utrecht method and the Analytic Hierarchy Process (AHP) in deliberations, weighing benefits against risks of using ginger for a pregnant woman suffering nausea and vomiting of pregnancy (NVP) along with other comorbidities. Methods. A hypothetical case was constructed using the twelve tips for constructing dilemma case-based assessment. Three CAM practitioners, two physicians, three pharmacists, and two patients were recruited, and the Utrecht and the AHP methods were combined and used to deliberate and weigh benefits against risks of using ginger for the presented case. Results. Responses from the ten panelists were obtained. Priority ratings showed significantly higher scores (p-value
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Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the ‘U’ out of ‘CUP’
Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the 'U' out of 'CUP'
Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the 'U' out of 'CUP', Published online: 23 December 2018; doi:10.1038/s41416-018-0332-2
Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the 'U' out of 'CUP'https://go.nature.com/2PYuNuY
Gene Expression Patterns Analysis in the Supraspinatus Muscle after a Rotator Cuff Tear in a Mouse Model
Rotator cuff tear is a muscle-tendinous injury representative of various musculoskeletal disorders. In general, rotator cuff tear occurs in the tendon, but it causes unloading of the muscle resulting in muscle degeneration including fatty infiltration. These muscle degenerations lead to muscle weakness, pain, and loss of shoulder function and are well known as important factors for poor functional outcome after rotator cuff repair. Given that rotator cuff tear in various animal species results in similar pathological changes seen in humans, the animal model can be considered a good approach to understand the many aspects of the molecular changes in injured muscle. To comprehensively analyze changes in gene expression with time following a rotator cuff tear, we established a rotator cuff tear in mouse supraspinatus tendon of shoulder. At weeks 1 and 4 after the tear, the injured muscles were harvested for RNA isolation, and microarray analysis was performed. Expression patterns of genes belonging to 10 muscle physiology-related categories, including aging, apoptosis, atrophy, and fatty acid transport, were analyzed and further validated using real-time PCR. A total of 39,429 genes were analyzed, and significant changes in expression were observed for 12,178 genes at 1 week and 2,370 genes at 4 weeks after the tear. From the list of top 10 significantly up- and downregulated genes at the 2 time periods and the network evaluation of relevant genes according to the 10 categories, several important genes in each category were observed. In this study, we found that various genes are significantly altered after rotator cuff tear, and these genes may play key roles in controlling muscle degeneration after a rotator cuff tear.
http://bit.ly/2EDpHCx
Prevalence and Antibiotic Resistance Patterns of Campylobacter spp. Isolated from Broiler Chickens in the North of Tunisia
The aim of the current study is to assess the prevalence of Campylobacter infection in broiler chickens, raised in intensive production conditions, and to evaluate the antimicrobial susceptibility of recovered Campylobacter isolates. A total of 590 cloacal swab samples were taken from 13 broiler chicken flocks in the North East of Tunisia. All samples were tested for the presence of thermophilic Campylobacter by culture and PCR, targeting the mapA and ceuE genes, respectively. Susceptibility to antimicrobial drugs was tested against 8 antibiotics. Prevalence of Campylobacter infection, relationship with geographic origins and seasons, antimicrobial resistance rates and patterns were analyzed. Total prevalence of Campylobacter infection in broiler flocks was in the range of 22.4%, with a predominance of C. jejuni (68.9%), followed by C. coli (31.1%). Positive association was highlighted between the infection level and the season (P
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Role of miRNAs in Immune Responses and Immunotherapy in Cancer
Abstract
In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune‐based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success versus failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory non‐coding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immune‐therapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA‐mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.
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http://bit.ly/2rPZTv9
Non‐leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma
Abstract
Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non‐leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro‐LBL 02. Paraffin embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n=7), fluorescence in situ hybridization (FISH) (n=7) or both (n=5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non‐leukemic B‐myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B‐cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18 and 21. One B‐T MPAL showed typical aberrations of T‐cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN‐LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2‐qter affecting the ATM gene. ATM was also mutated in a T‐myeloid MPAL case with additional loss at 7q21.2‐q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN‐LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow‐up 3‐10 years, median: 4.9 years). In summary, the present series of non‐leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances.
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http://bit.ly/2LufGZT
BCC developing independently from BAP1‐tumor predisposition syndrome in a patient with bilateral uveal melanoma
Abstract
Basal cell carcinomas (BCC) have been recently included into the spectrum of BAP1‐tumor predisposition syndrome (TPDS). Uveal melanoma (UM) is also a tumor often observed in patients with this hereditary tumor syndrome, in particular bilateral UM is highly suspicious for BAP1‐TPDS although no patient has been reported yet. Based on our index patient with BAP1‐TPDS with bilateral uveal melanoma (iris OS, choroid OD), several BCCs and thyroid cancer as well as a family history for cancer, this paper analyzes hints and pitfalls to diagnose this syndrome clinically and histologically. A previously undescribed germline variant, namely a heterozygous deletion of a single nucleotide on position 2001 (c.2001delG;p.[Thr668Profs*24] in exon 16 of the BAP1 gene), was identified. Structural changes in the C‐terminal of the BAP1 protein were observed by in silico analysis. While the excised iris melanoma showed loss of BAP1 nuclear staining by immunohistochemical staining, the BCCs of our patient (and in the control group, n = 13) were BAP1 positive. Genetic analysis of the BCC of the ocular adnexae confirmed a remaining intact BAP1 copy. The constellation of (bilateral) uveal melanoma in combination with BCC should raise suspicion for a BAP1‐TPDS. As our BCCs probably developed independently from the BAP1‐TPDS and uveal melanomas frequently show loss of nuclear BAP1 staining, genetic analysis is mandatory to diagnose this syndrome.
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http://bit.ly/2rPZPLV
CRLF2 expression associates with ICN1 stabilisation in T‐cell acute lymphoblastic leukaemia
Abstract
T‐cell acute lymphoblastic leukaemia (T‐ALL) is an aggressive haematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high‐risk T‐ALL patients. For these cases no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonises IKZF1 in T‐ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T‐ALL. We evaluated two independent series of paediatric T‐ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T‐ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T‐ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly we show that patients with mutations affecting NOTCH1‐PEST domain and/or FBXW7 had higher CRLF2 expression (P = 0.04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilisation are associated with CRLF2 overexpression.
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http://bit.ly/2LAS6uA
The cubital tunnel syndrome caused by intraneural ganglion cyst of the ulnar nerve at the elbow: a case report
Cubital tunnel syndrome is common nerve compression syndrome among peripheral nerve compression diseases. However, the syndrome caused by intraneural ganglion cysts has been rarely reported. Medical approaches...
http://bit.ly/2BzFrTY
Implementation of a Clinical Decision Support System for Children With Minor Blunt Head Trauma Who Are at Nonnegligible Risk for Traumatic Brain Injuries
To determine the effect of providing risk estimates of clinically important traumatic brain injuries and management recommendations on emergency department (ED) outcomes for children with isolated intermediate Pediatric Emergency Care Applied Research Network clinically important traumatic brain injury risk factors.
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Foramen ovale blood flow and cardiac function after main pulmonary artery occlusion in fetal sheep
New Findings
What is the central question of this study? At near term gestation, foramen ovale blood flow accounts for a significant proportion of fetal left ventricular output. Can foramen ovale increase its volume blood flow, when right ventricular afterload is increased by main pulmonary artery occlusion? What is the main finding and its importance? Foramen ovale volume blood flow increased during main pulmonary artery occlusion. However, this increase was attributable to a rise in fetal heart rate, because left ventricular stroke volume remained unchanged. These findings suggest that foramen ovale has a limited capacity to increase its volume blood flow.
Abstract
Foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular (RV) afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near term sheep fetuses. We hypothesised that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures, and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (p < 0.05) from 158(7) to 188(23) bpm and LVCO (p < 0.0001) from 629(198) to 776(283) ml/min. Combined cardiac output fell (p < 0.0001) from 1524(341) to 720(273) ml/min. During main pulmonary artery occlusion, FO volume blood flow increased (p < 0.001) from 507(181) to 776(ml/min). This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aorta blood pressure remained stable. Central venous pressure was higher (p < 0.05) during the occlusion than after it was released. During the occlusion fetal pH decreased and pCO2 increased. LV systolic dysfunction developed while LV diastolic function was preserved. RV systolic and diastolic function deteriorated following the occlusion. In conclusion, FO has a limited capacity to increase its volume blood flow at near term gestation.
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Decrement in resting and insulin‐stimulated soleus muscle mitochondrial respiration is an early event in diet‐induced obesity in mice
New Findings
What is the central question of this study? What are the temporal responses on mitochondrial respiration, and insulin mitochondrial responsivity in soleus muscle‐fibres from mice during the development of obesity and insulin resistance? What are the main finding and its importance? Short‐ and long‐term exposition of high‐fat diet (HFD) markedly reduced soleus mitochondrial respiration and mitochondrial insulin responsivity prior any change in glycogen synthesis. Muscle glycogen synthesis and whole‐body insulin resistance were present after 14 and 28 days, respectively. Our findings highlight the plasticity of mitochondria during the development of obesity and insulin resistance.
Abstract
Recently, significant attention has been given to the role of muscle mitochondrial function in the development of insulin resistance associated with obesity. Our aim was to investigate temporal alterations in mitochondrial respiration, H2O2 emission, and mitochondrial responsivity to insulin in permeabilized skeletal muscle‐fibres during the development of obesity in mice. Swiss male mice (5‐6 weeks old) were fed with a high‐fat diet (60% calories from fat) or standard diet for 7, 14 and 28 days to induce obesity and insulin resistance. Diet‐induced obese (DIO) mice presented reduced glucose tolerance and hyperinsulinemia after 7 days of HFD. After 14 days, the expected increase in muscle glycogen content after systemic injection of glucose and insulin was not observed in DIO mice. At 28 days, blood glucose decay after insulin injection was significantly impaired. Complex I (pyruvate + malate) and II (succinate) linked respiration, and oxidative phosphorylation (ADP) were decreased after 7 days of HFD and remained low in DIO mice after 14 and 28 days of treatment. Moreover, mitochondria from DIO mice were incapable of increasing respiratory coupling and ADP responsivity after insulin‐stimulation in all observed periods. Mitochondrial content markers were reduced only after 28 days of treatment. Mitochondrial H2O2 emission profile varied during the time course of DIO, with a reduction of H2O2 emission in the early stages of DIO and an increased emission after 28 days of treatment. Our data demonstrate that DIO promotes transitory alterations in mitochondrial physiology during the early and late stages of insulin‐resistance related to obesity.
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Ischaemia‐induced muscle metabolic abnormalities are poorly alleviated by endurance training in a mouse model of sickle cell disease
New Findings
The aim of this study was to evaluate the potential beneficial effects of endurance training during an ischemia/reperfusion paradigm in sickle cell disease mice. Endurance training would not reverse the metabolic defects induced by a simulated vaso‐occlusive crisis in sickle cell mice, whether it is with regard to intramuscular acidosis, mitochondrial dysfunction or anatomical properties. Our results suggest that endurance training would reduce vaso‐occlusive crisis number rather than the complications related to vaso‐occlusive crisis.
Abstract
The aim of this study was to investigate whether endurance training could limit the abnormalities described in sickle cell disease (SCD) mice in response to an ischemia/reperfusion (I/R) paradigm. Ten sedentary (HbSS‐SED) and 9 endurance trained (HbSS‐END) SCD mice were submitted to a standardized protocol of I/R of the leg during which ATP, phosphocreatine and inorganic phosphate concentrations as well as intramuscular pH were measured using magnetic resonance spectroscopy. Forty‐eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured. While the time‐course of intramuscular pH was slightly different between trained and sedentary mice (p < 0.05), the extent of acidosis was similar at the end of the ischemic period. The initial rate of phosphocreatine resynthesis measured at blood flow restoration, illustrating mitochondrial function, was not altered in trained mice compared to sedentary mice. Although several oxidative stress markers were not different between groups (p > 0.05), the I/R‐related increase of uric acid concentration observed in sedentary SCD mice (p < 0.05) was not present in the trained group. The spleen weight, generally used as a marker of the severity of the disease, was not different between groups (p > 0.05). In conclusion, endurance training did not limit the metabolic consequences of an I/R paradigm in skeletal muscle of SCD mice, suggesting that the reduction in the severity of the disease previously demonstrated at the basal state would be attributable to a reduction of vaso‐occlusive crisis (VOC) occurrence rather than a decrease of the deleterious effects of VOC.
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http://bit.ly/2R9ps93
Sex differences in the circulatory responses to an isocapnic cold pressor test
New Findings
What is the central question of this study?
To determine whether sex differences exist in the cardiorespiratory responses to an isocapnic cold pressor test (CPT).
What is the main finding and its importance?
During the CPT, there were no sex differences in the respiratory response; however, females demonstrated a reduced mean arterial pressure and reduced dilation of the common carotid artery. Since the CPT is predictive of future cardiovascular events, these data have clinical implications for improving the utility of the CPT to determine cardiovascular health risk. Sex differences should be taken into consideration when conducting and interpreting a CPT.
Abstract
The cold pressor test (CPT) elicits a transient increase in sympathetic nervous activity, minute ventilation (VE), mean arterial pressure (MAP), and common carotid artery (CCA) diameter in healthy individuals. Although the extent of dilation of the CCA in response to the CPT has been used as a clinical indicator of cardiovascular health status, the potential sex differences have yet to be explored. In response to a CPT, we hypothesized that elevations in VE, MAP and dilation of the CCA would be attenuated in females compared to males. In 20 young healthy participants (10 females), we measured the respiratory, cardiovascular, and CCA responses during a CPT, which consisted of a three‐minute right foot immersion into 0–1 °C water. Blood pressure (via finger photo plethysmography), heart rate (via electrocardiogram), and CCA diameter and velocity (via Duplex ultrasound) were simultaneously recorded immediately before and during the CPT. During the CPT, while controlling end‐tidal gases to baseline values, the main findings were: 1) no sex differences were present in absolute or relative changes in VE (P = 0.801 and P = 0.179, respectively); 2) the relative MAP and CCA diameter response were reduced in females by 51% and 55%, respectively (P = 0.008 and P = 0.029 vs. males, respectively); and 3) the relative MAP responses was positively correlated to the dilation of the CCA in males (r = 0.42, P = 0.019), females (r = 0.43, P = 0.019), and in males and females combined (r = 0.55, P < 0.001). Since the CPT is used as a clinical tool to assess cardiovascular health status, sex differences should be considered in future studies.
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http://bit.ly/2GLsxI6
Acupuncture decreased the risk of coronary heart disease in patients with rheumatoid arthritis in Taiwan: a Nationwide propensity score-matched study
Patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease (CHD). Acupuncture, a commonly used treatment for patients with RA, has not been reported to prevent CHD in patients with RA...
http://bit.ly/2EKJoJh
High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis
Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high‐dimensional single‐cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems‐wide analyses of immune cell frequencies and cell type‐specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK‐cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK‐cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.
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http://bit.ly/2T5sqIR
ID2 and ID3 are indispensable for Th1 cell differentiation during influenza virus infection in mice
Antigen‐specific Th1 cells could traffic to the infection sites during infection to execute effector functions, such as help CD8+ T cells to localize in these sites by secretion of anti‐viral cytokines‐IFN‐γ or direct cytotoxicity of antigen‐bearing cells. However, the molecular components that modulate Th1 cell differentiation and function in response to viral infection remain incompletely understood. Here, we reported that both inhibitor of DNA binding 3(Id3) protein and inhibitor of DNA binding 2(Id2) protein promoted Th1 cell differentiation. Depletion of Id3 or Id2 led to severe defect of Th1 cell differentiation during influenza virus infection. Whereas depletion of both Id3 and Id2 in CD4+ T cells restrained Th1 cell differentiation to a greater extent, indicating that Id3 and Id2 nonredundantly regulate Th1 cell differentiation. Moreover, deletion of E‐proteins, the antagonists of Id proteins, greatly enhanced Th1 cell differentiation. Mechanistic study indicated that E‐proteins suppressed Th1 cell differentiation by directly binding to the regulatory elements of Th1 cell master regulator T‐bet and regulate T‐bet expression. Thus, our findings identified Id‐protein's importance for Th1 cells and clarified the non‐redundant role of Id3 and Id2 in regulating Th1 cell differentiation, providing novel insight that Id3‐Id2‐E protein axis are essential for Th1 cell polarization.
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Activation of integrated stress response pathway regulates IL‐1β production through post‐transcriptional and translational reprogramming in macrophages
Immune cells sense and programme its cellular machinery appropriately to the environmental changes through the activation of cytoprotective adaptive pathway so‐called the "integrated stress response (ISR)". However, the mechanisms implicated in ISR‐induced protective responses are poorly understood. Here, we show that ISR activation by arsenite (Ar) results in suppression of IL‐1β production in macrophages and inhibition of DSS‐induced colitis in a murine model through a novel post‐ transcriptional and translation regulatory (PTR) mechanism. Ar triggers PTR events through eIF2α‐phosphorylation, which results in the attenuation of active polysome formation leading to the accumulation of translationally stalled IL‐1β mRNAs. Translationally stalled IL‐1β mRNAs recruit RNA‐binding proteins (TIA‐1/TIAR), resulting in the formation of RBP‐RNA complexes known as stress granules (SGs). The SGs bound IL‐1β mRNAs might undergo degradation through induction of autophagy. Also, we show that Ar post‐translationally impairs processing and secretion of IL‐1β by diminishing inflammasome activation. Altogether, this study unveils a novel mechanism of IL‐1β regulation and further suggests that pharmacological activation of cytoprotective ISR pathway might provide an effective therapeutic intervention against inflammatory diseases.
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Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer
Abstract
Background and Aim
Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti‐CTLA4 inhibitor, could be combined safely with microwave ablation to enhance the effect of anti‐CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10mg/kg, intravenously) for 6 doses, followed by infusions every 3 months until off‐treatment criteria were met. Thirty‐six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole exome sequencing.
Results
Twenty patients with refractory BTC were enrolled. Median age 56.5 years. No dose‐limiting toxicities were encountered. The common treatment related adverse events included lymphopenia, diarrhea and elevated transaminases. Among sixteen patients evaluable for efficacy analysis, two (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively), 5 patients (31.3%) achieved stable disease. Median progression free survival, and overall survival were 3.4 months (95% CI 2.5‐5.2 months), and 6.0 months (95% CI 3.8‐8.8 months), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated (HLA‐DR positive) CD8+ T cells. TCRβ screening showed tremelimumab expanded TCR repertoire but not reaching statistical significance (P=0.057).
Conclusions
Tremelimumab in combination with tumor ablation is a potential new treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.
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http://bit.ly/2CvLgn3
Disruption of sialic acid metabolism drives tumor growth by augmenting CD8+ T cell apoptosis
Sialylated glycan structures are known for their immunomodulatory capacities and their contribution to tumor immune evasion. However, the role of aberrant sialylation in colorectal cancer and the consequences of complete tumor desialylation on anti‐tumor immunity remain unstudied. Here, we report that CIRSPR/Cas9‐mediated knock out of the CMAS gene, encoding a key enzyme in the sialylation pathway, in the mouse colorectal cancer MC38 cell line completely abrogated cell surface expression of sialic acids (MC38‐Sianull) and, unexpectedly, significantly increased in vivo tumor growth compared to the control MC38‐MOCK cells. This enhanced tumor growth of MC38‐Sianull cells could be attributed to decreased CD8+ T cell frequencies in the tumor microenvironment only, as immune cell frequencies in tumor‐draining lymph nodes remained unaffected. In addition, MC38‐Sianull cells were able to induce CD8+ T cell apoptosis in an antigen‐independent manner. Moreover, low CMAS gene expression correlated with reduced recurrence‐free survival in a human colorectal cancer cohort, supporting the clinical relevance of our work. Together, these results demonstrate for the first time a detrimental effect of complete tumor desialylation on colorectal cancer tumor growth, which greatly impacts the design of novel cancer therapeutics aimed at altering the tumor glycosylation profile.
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Detection of lyssavirus antigen and antibody levels among apparently healthy and suspected rabid dogs in South-Eastern Nigeria
Domestic dogs are the main reservoir of rabies virus (RABV) infection in Nigeria, thus surveillance of rabies in dog populations is crucial in order to understand the patterns of spread of infection and ultima...
http://bit.ly/2BBoPLD
Improving the wellbeing and resilience of health services staff via psychological skills training
Health services staff work in a stressful environment, which can negatively impact their mental health and wellbeing, and as a result can affect psychosocial and professional functioning. The implementation of...
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Utilization of intra uterine contraceptive device and associated factors among reproductive age group of family planning users in Han Health Center, Bahir Dar, North West Amhara, Ethiopia, 2018
Aim was to assess utilization of IUCD and factors among family planning users in Han health center, Bahir Dar, Ethiopia, 2018. Two hundred forty-one participants were selected by Systematic sampling technique ...
http://bit.ly/2Bx6L52
Genome of Tenualosa ilisha from the river Padma, Bangladesh
Hilsa shad (Tenualosa ilisha), is a popular fish of Bangladesh belonging to the Clupeidae family. An anadromous species, like the salmon and many other migratory fish, it is a unique species that lives in the sea...
http://bit.ly/2QOpfIY
Sepsis prediction during outbreaks at neonatal intensive care units through body surface screening for Gram-negative bacteria: systematic review and meta-analysis
This systematic review focusses on the prognostic accuracy of neonatal body surface screening during outbreaks caused by Gram-negative bacteria for prediction of sepsis. In a previous systematic review we repo...
http://bit.ly/2BEKbI6
Detection of bacterial DNA from central venous catheter removed from patients by next generation sequencing: a preliminary clinical study
Catheter-related infection (CRI) is one of the serious challenges in clinical practice. This preliminary clinical study aimed to examine whether next-generation sequencing (NGS) targeting 16S rDNA, which was P...
http://bit.ly/2LwI6lT
Self-contamination during doffing of personal protective equipment by healthcare workers to prevent Ebola transmission
Healthcare workers (HCWs) use personal protective equipment (PPE) in Ebola virus disease (EVD) situations. However, preventing the contamination of HCWs and the environment during PPE removal crucially require...
http://bit.ly/2AeE0dJ
Leptospirosis complicated with Guillain Barre syndrome, papillitis and thrombotic thrombocytopenic Purpura; a case report
Leptospirosis is a zoonosis commonly prevalent in tropical countries. Clinical course of leptospirosis varies from mild to severe disease. Here we present a case of leptospirosis complicated with Guillain-Barr...
http://bit.ly/2EE2iRj
Droplet digital PCR for the quantification of Alu methylation status in hematological malignancies
Alu repeats, belonging to the Short Interspersed Repetitive Elements (SINEs) class, contain about 25% of CpG sites in the human genome. Alu sequences lie in gene-rich regions, so their methylation is an import...
http://bit.ly/2BEFm1s
Genetic and molecular origins of colorectal Cancer among the Iranians: an update
Colorectal cancer (CRC) is one the leading causes of cancer related deaths among Iranians. Despite the various progresses in new therapeutic methods, it has still a low rate of survival. This high ratio of mor...
http://bit.ly/2QPEzF5
An autopsy case of epignathus (immature teratoma of the soft palate) with intracranial extension but without brain invasion: case report and literature review
Epignathus is a rare congenital orofacial teratoma infrequently associated with intracranial extension. Intracranial extension of an epignathus indicates a poor prognosis; however, only a small number of such ...
http://bit.ly/2Bx7V0y
Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer
Background: Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. Patients and Methods: Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. Results: A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (Phttp://bit.ly/2rNoCQU
Survival Outcome and Prognostic Factors After Pulmonary Metastasectomy in Sarcoma Patients: A 18-Year Experience at a Single High-volume Referral Center
Background: Metastatic sarcoma patients have a poor prognosis with 3-year survival rate of 25%. About 30% of them present isolated lung metastases. We aimed to analyze the clinical outcome of sarcoma patients undergoing pulmonary metastasectomy (PM) and prognostic factors associated with local control, disease-free, and overall survival (OS). Patients and Methods: All sarcoma patients undergoing PM at Humanitas Cancer Center were retrospectively reviewed. Analyzed variables included clinicopathologic, surgical, and survival data. Exclusion criterion comprised a follow-up period inferior to 1 year. A univariable and multivariable Cox regression analysis was performed (Phttp://bit.ly/2rSBQfj
Utilization of an Alternative Docetaxel-based Intraperitoneal Chemotherapy Regimen in Patients With Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma: A Continued Need for Ovarian Cancer Patients
Objective: The objective of this study was to report the tolerability and toxicity of a regimen consisting of intravenous (IV) docetaxel and intraperitoneal (IP) cisplatin and paclitaxel with granulocyte colony-stimulating factor support. Materials and Methods: We conducted a retrospective cohort study of patients with surgical stage II-IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated with an outpatient IP chemotherapy regimen consisting of docetaxel 75 mg/m2 IV and cisplatin 75 mg/m2 IP day 1 followed by paclitaxel 60 mg/m2 IP day 8 every 21 days. Grade 3 and 4 toxicity, dose delays and reductions, port complications, and tolerability are reported. Outcomes, including response rate, progression-free survival (PFS), overall survival (OS) are also reported. Results: A total of 60 patients received this IP regimen. Most common toxicities included neutropenia (47%), gastrointestinal (28%), and anemia (25%). Most patients (85%) experienced no IP port complications. Dose delay or reduction was required in 30% of patients. Two-thirds completed all prescribed cycles, with 80% of total planned cycles completed. Complete response was achieved for 88%, and 43% are currently without evidence of disease. Median PFS for all patients was 25.5 months (95% confidence interval [CI], 20.4-30.5 mo) while OS for all patients was 56.8 months (95% CI, 47.7-65.9 mo). For the 44 patients with stage III disease, median PFS was 22.1 months (95% CI, 16.3-28.0 mo), while median OS was 56.8 months (95% CI, 47.3-66.3 mo). Conclusions: This docetaxel-based IP chemotherapy regimen demonstrates an improved tolerability profile compared with GOG172. Additional evaluations on alternative IP regimens remain warranted. Short follow-up time limits survival assessment, but results are encouraging.http://bit.ly/2Lv50Ks
The University of Florida Department of Radiation Oncology Guidelines for Treatment of Differentiated Thyroid Cancer With I-131 or External-beam Radiotherapy
The purpose of this paper is to summarize the University of Florida Department of Radiation Oncology guidelines for treatment of differentiated thyroid cancer with I-131 or external-beam radiotherapy. This article is not meant to compete with the many excellent book chapters and consensus guidelines that present comprehensive discussions of treatment options. This is a streamlined, "How we do it?" reference without substantial discussion of background or supporting data. To serve as a treatment reference, the great majority of the information is presented in topic-specific tables.http://bit.ly/2rODApP
Patterns of Care and Outcomes of Elderly Esophageal Cancer Patients Not Meeting Age-based Criteria of the CROSS Trial
Objectives: The CROSS trial established neoadjuvant chemoradiation followed by surgery (nCRT-S) as superior to surgery alone (S) for locally advanced esophageal cancer (EC). However, because patients above 75 years of age were excluded, this comparison cannot be extrapolated to older patients. This study of a large, contemporary national database evaluated practice patterns in elderly patients ineligible for CROSS, and analyzed overall survival (OS) between nCRT+S, S, and definitive CRT (dCRT). Materials and Methods: The National Cancer Data Base was queried for EC patients with cT1N1M0/T2-3N0-1M0 EC (per the CROSS trial) but 76 years and above of age. Multivariable logistic regression ascertained factors associated with nCRT+S (vs. S). Kaplan-Meier analysis evaluated OS; Cox multivariate analysis determined variables associated with OS. Propensity matching aimed to address group imbalances and indication biases. Results: Of 4099 total patients, 594 (14%) underwent nCRT+S, 494 (12%) underwent S, and 3011 (73%) underwent dCRT. Since 2010, trimodality management has risen, corresponding to declines in S and dCRT. Median OS in the respective groups were 26.7, 20.3, and 17.8 months (P0.05), with lower 30-day readmission and postoperative hospital stay (Phttp://bit.ly/2rQ7ev1
Neoadjuvant Chemotherapy Treatment Modifications in Ovarian Carcinoma: The Impact on Surgical Outcome and Progression-free Survival
Objective: Little is known on the impact of neoadjuvant chemotherapy (NACT) treatment modifications on surgical outcome and progression-free survival (PFS) in patients with ovarian carcinoma. We aimed to report the changes we made during NACT and to evaluate its impact on patient outcome. Methods: A retrospective cohort study of all women with advanced stage ovarian carcinoma treated with NACT followed by interval cytoreduction in one university-affiliated medical center (January 2005 to June 2017). We excluded those who were treated with NACT without any surgical intervention. NACT modifications included delay in treatment, change in chemotherapy, and dose reduction. Demographics, tumor characteristics, surgical outcome, and PFS were compared between patients exposed to NACT treatment modifications and those who received standard treatment. Results: Seventy-nine patients met inclusion criteria of whom, 59 patients received standard, nonmodified treatment and 20 patients modified NACT. There were no intergroup differences with respect to age at diagnosis (59.5±11.6 vs. 64.70±8.09, P=0.09) and stage of disease (P=0.13). Radiologic complete response rates (25.0% vs. 32.2%, P=0.545) and optimal cytoreduction rates (75.0% vs. 86.4%, P=0.23) were similar in both treatment groups. Mean PFS (in months) was comparable between patients receiving standard treatment and those who required NACT modifications (18.5 vs. 12.2, P=0.125). Conclusions: NACT treatment modifications did not affect surgical outcome and PFS. We conclude that when clinically indicated, dose alteration and scheduling can be implemented without apparent detriment to outcome.http://bit.ly/2rSBPIh
Differential Outcomes Among Immunosuppressed Patients With Merkel Cell Carcinoma: Impact of Immunosuppression Type on Cancer-specific and Overall Survival
Objectives: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with higher incidence among whites, elderly, and immunosuppressed patients. Although immunosuppressed MCC patients are at higher risk of recurrence and MCC-related death, it is unknown whether immunosuppression type is associated with differential outcomes. Materials and Methods: We retrospectively evaluated 89 nonmetastatic MCC patients with a diagnosis of chronic immunosuppression. Immunosuppression was categorized as chronic lymphocytic leukemia (31% of cohort), other hematologic malignancies (18%), solid organ transplant (21%), autoimmune disease (21%), and human immunodeficiency virus acquired deficiency syndrome (8%). Progression-free survival (PFS) and MCC-specific survival (MSS) were estimated with the cumulative incidence function. Overall survival (OS) was estimated by the Kaplan-Meier method. Results: With a median follow-up of 52 months, 53 deaths occurred (42 from MCC, 7 unknown, and 4 non-MCC). Two-year PFS, MSS, and OS were 30%, 55%, and 52%, respectively. Human immunodeficiency virus/acquired deficiency syndrome and solid organ transplant patients were diagnosed with MCC at a younger age (median 55 and 59 y, respectively) and with more advanced stage disease compared with other immunosuppressed subgroups. PFS did not significantly differ among the 5 immunosuppression subgroups (P=0.30), but significant differences were observed in MSS and OS (both P=0.01). Controlling for potential confounders for OS, including age and stage, immunosuppression type was still significantly associated with risk of death (P=0.01). Conclusions: Among immunosuppressed MCC patients, recurrent MCC is the major cause of mortality. The risk of death from MCC differs among immunosuppression types, suggesting important biological differences in host-tumor immune interactions.http://bit.ly/2rSm1oK
Disparities Predict for Higher Rates of Cut-through Hysterectomies in Locally Advanced Cervical Cancer
Objectives: The treatment of choice for locally advanced cervical cancer is definitive chemoradiation (CRT). Hysterectomy is not indicated due to higher-rates of cut-through resections leaving gross disease behind, requiring additional therapy with increasing morbidity and no benefit in overall survival (OS). The objectives of this study were to determine factors associated with cut-through hysterectomies and evaluate OS outcomes. Materials and Methods: The National Cancer Database (NCDB) was queried for patients 18 years and older with clinical Federation of Gynecology and Obstetrics stage IB2 to IVA. All patients underwent upfront hysterectomy and had known margin status. Cut-through hysterectomy was classified as presence of microscopic or macroscopic disease at the margin. Results: A total of 11,638 patients were included; 993 (8.5%) had positive margins. In patients with positive margins, 560 (56.4%) received postoperative CRT and 148 (14.9%) underwent postoperative radiation. Five-year OS was worse for those with cut-through resections when compared with those with negative margins, 66.0% versus 86.7%, respectively (hazard ratios, 3.08; Phttp://bit.ly/2Lv50dq
Neoadjuvant Interdigitated Chemoradiotherapy Using Mesna, Doxorubicin, and Ifosfamide for Large, High-grade, Soft Tissue Sarcomas of the Extremity: Improved Efficacy and Reduced Toxicity
Objectives: Patients with large, high-grade extremity soft tissue sarcoma (STS) are at high risk for both local and distant recurrence. RTOG 95-14, using a regimen of neoadjuvant interdigitated chemoradiotherapy with mesna, doxorubicin, ifosfamide, and dacarbazine followed by surgery and 3 cycles of adjuvant mesna, doxorubicin, ifosfamide, and dacarbazine, demonstrated high rates of disease control at the cost of significant toxicity (83% grade 4, 5% grade 5). As such, this regimen has not been widely adopted. Herein, we report our institutional outcomes utilizing a modified interdigitated chemoradiotherapy regimen, without dacarbazine, and current radiotherapy planning and delivery techniques for high-risk STS. Materials and Methods: Adults with large (≥5 cm; median, 12.9 cm), grade 3 extremity STS who were prospectively treated as part of our institutional standard of care from 2008 to 2016 are included. Neoadjuvant chemoradiotherapy consisted of 3 cycles of mesna, doxorubicin, and ifosfamide (MAI) and 44 Gy (22 Gy in 11 fractions between cycles of MAI) after which patients underwent surgical resection and received 3 additional cycles of MAI. Results: Twenty-six patients received the MAI treatment protocol. At a median follow-up of 47.3 months, 23 (88.5%) patients are still alive. Three year locoregional recurrence-free survival, disease-free survival, and overall survival are 95.0%, 64.0%, and 95.0%, respectively. There have been no therapy-related deaths or secondary malignancies. The nonhematologic grade 4 toxicity rate was 7.7%. Conclusions: Neoadjuvant interdigitated MAI radiotherapy followed by resection and 3 cycles of adjuvant MAI has resulted in acceptable and manageable toxicity and highly favorable survival in patients at greatest risk for treatment failure.http://bit.ly/2Lv52ly
Clinical and Molecular Recursive Partitioning Analysis of High-grade Glioma Treated With IMRT
Introduction: Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables. Methods: Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. Results: We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (Phttp://bit.ly/2rQ7hHd
Treatment Patterns and Survival of Elderly Patients With Breast Cancer Brain Metastases
Objectives: The main objective of this study was to analyze treatment patterns of elderly patients with breast cancer brain metastases (BCBM), evaluate characteristics associated with treatment selection, and to analyze trends in overall survival (OS) over time. Materials and Methods: We included women with BCBM reported to the Surveillance, Epidemiology, and End Results Medicare Program from 1992 to 2012. Treatments were recorded from Medicare claims from the date of brain metastases diagnosis until 60 days after. Treatments included resection, radiation, and chemotherapy. Cochran-Armitage tests were used for analysis of treatment patterns. Multinomial logistic regression was applied to determine factors associated with treatment selection. Cox regression modelled OS trends within each treatment modality across time. Results: Among 5969 patients included, treatment rates increased from 50% in 1992 to 64.1% in 2012 (Phttp://bit.ly/2LAlQI0
Comparison of Outcomes in Patients With Muscle-invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder Preservation
Purpose: Radical cystectomy currently remains the standard of care for muscle-invasive bladder cancer. However, surgery can be associated with considerable morbidity and mortality, including the removal of the bladder. An alternative strategy is to preserve the bladder through concurrent chemoradiation following a maximal transurethral resection of the tumor. National protocols using a bladder-preservation approach have demonstrated disease-specific outcomes comparable to radical cystectomy in selected patients, but these results have not been replicated in previously reported population-based series. Here, we describe an outcomes analysis of patients with muscle-invasive bladder cancer treated with either radical surgery or bladder-preserving chemoradiation (BPCRT) for those patients meeting BPCRT criterion using the National Cancer Database (NCDB). Materials and Methods: Using the NCDB, patients with American Joint Commission on Cancer clinical T2-3, N0, M0 urothelial carcinoma diagnosed between 2004 and 2013 were included for analysis. Only patients treated with definitive intent with either radical cystectomy or concurrent chemotherapy and radiation after a maximal transurethral tumor resection were included. Propensity-score matching was used. Results: Among 8454 eligible patients, 7276 (86%) underwent radical cystectomy, and 1178 (14%) underwent BPCRT. Patients undergoing BPCRT were significantly older (median age, 77 vs. 68 y; Phttp://bit.ly/2Lv4YCk
Comparison of Clinical Characteristics and Outcomes in Relapsed Versus De Novo Metastatic Non–Small Cell Lung Cancer
Objectives: To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non–small cell lung cancer (NSCLC). Materials and Methods: We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed. Results: A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, Phttp://bit.ly/2LAlP6U
Safety and Efficacy of Cabozantinib for Metastatic Nonclear Renal Cell Carcinoma: Real-world Data From an Italian Managed Access Program
Objective: The activity of cabozantinib in nonclear cell histologies has not been evaluated. Materials and Methods: Data were collected across 24 Italian hospitals. Patients were aged 18 years and older with advanced nonclear cell renal cell carcinoma (RCC), with an Eastern Cooperative Oncology Group Performance Status 0 to 2, who had relapsed after previous systemic treatments for metastatic disease. Cabozantinib was administered orally at 60 mg once a day in 28 days cycles. Dose reductions to 40 or 20 mg were made due to toxicity. Adverse events (AEs) were monitored using CTCAE version 4.0. Results: Seventeen patients were enrolled. Three (18%) patients were diagnosed type I papillary RCC, 9 (53%) type II papillary, 3 (18%) chromophobe, and 2 (11%) with Bellini duct carcinoma. In total, 11 patients started with 60 mg. Six patients started a lower dose of 40 mg. Median progression-free survival was 7.83 months (0.4 to 13.4 mo), while median overall survival was not reached but 1-year overall survival was about 60%. Six patients (35%) experienced a partial response to treatment and 6 patients (35%) showed a stable disease. In the remaining 5 (30%), we observed a progressive disease. Grade 3 and 4 AEs were observed in 41% of patients. Among 20 patients, only 1 (6%) discontinued treatment due to AEs. Asthenia (41%), diarrhea (35%), aminotransferase increasing (35%), mucosal inflammation (35%), hand and foot syndrome (24%), and hypothyroidism (24%) were the most frequently AEs. Conclusions: Our data showed that, cabozantinib is a active and feasible treatment in patient with nonclear cell RCC.http://bit.ly/2rQ7hab
Challenging the Requirement to Treat the Contralateral Neck in Cases With >4 mm Tumor Thickness in Patients Receiving Postoperative Radiation Therapy for Squamous Cell Carcinoma of the Oral Tongue or Floor of Mouth
Hypothesis: While treating patients with postoperative radiotherapy (RT) for squamous cell carcinoma of the oral tongue or floor of mouth, we hypothesized a low risk of tumor recurrence in the contralateral neck in the absence of contralateral neck RT when the primary tumor is >1 cm from the midline regardless of tumor thickness (TT) or depth of invasion (DOI)>4 mm. Objective: The policy at our institution for many years has been to limit postoperative RT to the ipsilateral side when the primary tumor does not cross the midline, regardless of TT or DOI. We report the rate of isolated contralateral neck failure in this group. Materials and Methods: We retrospectively reviewed all patients treated with postoperative RT at our institution between 1998 and 2014 for pathologic stage T1-T4 N1-N2b squamous cell carcinoma of the oral tongue or floor of mouth that did not cross the midline and thus were treated with RT limited to the primary site +/− ipsilateral neck. Results: Our study population included 32 patients: 75% with close (5 mm in 68% of patients. There were no isolated contralateral neck recurrences with a median follow-up of 5 years. Conclusion: While delivering postoperative RT for oral tongue or floor of mouth cancer with pathologic neck stage N0-2b, the risk of not irradiating the contralateral neck is very low when the primary tumor does not cross the midline, regardless of other factors at the primary site, such as TT and DOI.http://bit.ly/2LAlMYM
Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Meta-Analysis
Objective: To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer. Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED. Results: There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10200 Gy. Conclusions: SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity ofhttp://bit.ly/2Lv4Y5i
Nuclear Medicine Therapy With 223Radium-dichloride for Osseous Metastases in Prostate Carcinoma
Painful osseous metastasis resulting from castration-resistant prostate carcinoma is a common clinical problem. Historically, nuclear medicine offered several palliative beta-emitting radiopharmaceuticals targeting the skeleton with the goal of decreasing pain. However, these have largely been replaced by the alpha-emitting agent 223radium (Ra). 223Ra received Food and Drug Administration approval in 2013 for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases without visceral metastases. 223Ra offers an improved therapeutic profile due to its alpha-particle emissions resulting in a relatively higher linear energy transfer and lower particle range compared with beta-emitters. 223Ra also has demonstrated to increase overall survival in patients and to delay adverse skeletal events. Running a successful clinical nuclear therapy program with 223Ra requires a multidisciplinary team approach and this article suggests an implementation strategy from the authors' institution. Potential new nuclear radiopharmaceuticals still under investigation offering the future possibility of radioligand therapy are also discussed briefly.http://bit.ly/2LAlLUI
Advanced endoscopic techniques in the assessment of inflammatory bowel disease: new technology, new era
Endoscopic assessment of inflammation and mucosal healing is crucial for appropriate management in IBD. Current definition of endoscopic mucosal healing has been derived using previous generation of standard white light endoscopes. New endoscopy technologies widely available provide much more detailed images of mucosal and vascular patterns. Novel endoscopic techniques with high definition image, optical and digital enhancement have enhanced the quality and fine details of vascular and mucosal pattern so that endoscopic images have started to reflect histological changes for lesions and inflammation/healing. These technologies can now define subtle inflammatory changes and increase detection and characterisation of colonic lesions in patients with IBD. The best endoscopic technique to detect dysplasia in IBD is still debated. Dye chromoendoscopy with targeted biopsies is considered by Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in inflammatory Bowel Disease Patients: International Consensus Recommendations (SCENIC consensus the standard of care and recommended for adoption by gastroenterologists in practice. In future, it is possible that well-trained colonoscopists using high definition equipment with image enhancements may be able to obtain equivalent yield without pan-colonic dye spraying and characterise lesions. Finally, SCENIC introduced endoscopic resectability of some dysplastic colonic lesions—new techniques may now better characterise endoscopic resectability and limit the number of colectomies. In this review, we will provide a state-of-the-art opinion on the direction of technological advances in the assessment of IBD and how new concepts will refine clinical practice.
http://bit.ly/2GBp0we
Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection
Objective
Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control.
DesignThe phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection.
ResultsWe detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities.
ConclusionHBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.
http://bit.ly/2RbTg4R
Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity
Objective
Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.
DesignFollowing phenotypic characterisation, we performed RNA sequencing on CD14+CD16– monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.
ResultsMonocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16– monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.
ConclusionIn ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.
http://bit.ly/2GCvx9J
A 100 KW Class Applied-field Magnetoplasmadynamic Thruster
http://bit.ly/2V2kolO
Kinetically selective and potent inhibitors of HDAC8
Journal Name: Biological Chemistry
Issue: Ahead of print
http://bit.ly/2EIOuVA
An engineered lipocalin that tightly complexes the plant poison colchicine for use as antidote and in bioanalytical applications
Journal Name: Biological Chemistry
Issue: Ahead of print
http://bit.ly/2EJeyRr
Directed evolution of the 3C protease from coxsackievirus using a novel fluorescence-assisted intracellular method
Journal Name: Biological Chemistry
Issue: Ahead of print
http://bit.ly/2EIOq8i
Pleuropulmonary tuberculosis with spinal lesions due to metastatic malignancy differentiated definitively on imaging
A healthy 31-year-old man presenting with back pain was found to have multiple spinal enhancing lesions on MRI. An incidental asymptomatic large pleural effusion was identified on investigations for the back pain and pleural and pulmonary tuberculosis (TB) was subsequently diagnosed. The radiographical features on MRI spine were not typical of spinal TB and a Ga68 DOTATATE Positron Emission Tomography (PET)/CT confirmed metastatic paraganglioma with multiple bone metastases. Although metastatic paraganglioma is rare, this case highlights that even in young patients dual pathology needs to be considered. Most importantly, it is a reminder to physicians managing TB of the clues that help distinguish spinal TB from important alternative causes, including metastatic malignancy.
http://bit.ly/2EJacK5
Chlamydia ascites: a call for sexually transmitted infection testing
A 26-year-old gravida 2, para 2-0-0-2 woman with a recent uncomplicated vaginal delivery 10 weeks prior presented to our hospital with 5 weeks of abdominal swelling and discomfort. Four weeks after delivery, the patient began having right upper quadrant pain and was found to have cholelithiasis. She underwent an elective laparoscopic cholecystectomy 6 weeks prior to admission, but started to develop worsening abdominal swelling 1 week postoperatively. Abdominal distension and shifting dullness were present on examination. CT of the abdomen and pelvis was remarkable for moderate-volume ascites and mild enhancement of the pelvic peritoneum. Paracentesis removed 2.46 L of ascites fluid with 76% lymphocytic predominance. Results for Chlamydia trachomatis were positive in urine, cervical swab and ascitic fluid. Doxycycline was prescribed for a diagnosis of pelvic inflammatory disease exudative ascites. Since discharge, she has completed her antibiotic course and reports resolution of all symptoms without recurrence of ascites.
http://bit.ly/2ECyDbj
Removing the problem: parathyroidectomy for calciphylaxis
Calcific uremic arteriolopathy (CUA), widely known as calciphylaxis, is a rare and lethal disease that usually affects patients with end-stage renal disease. It is characterised by widespread vascular calcification leading to tissue ischaemia and necrosis and formation of characteristic skin lesions with black eschar. Treatment options include sodium thiosulfate, cinacalcet, phosphate binders and in resistant cases, parathyroidectomy. We report a case of recurrent, treatment-resistant CUA successfully treated with parathyroidectomy. Her postoperative course was complicated by hungry bone syndrome and worsening of her wounds before they completely healed. We then discuss the morbidity of CUA, including the controversy around the use of parathyroidectomy and risk of aggressive management of hungry bone syndrome.
http://bit.ly/2EMkycn
PIBIDS syndrome in two Brazilian siblings
Trichothiodystrophy is a rare condition associated with autosomal recessive or X-linked dominant variants in the ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A or GTF2E2 genes. The genes associated to photosensitive trichothiodystrophy encode subunits of transcription factor IIH, involved in the nucleotide excision repair pathway. The disease is characterised by cysteine-deficient brittle hair along with other neuroectodermal abnormalities. It has a variable clinical expression and some cases might be associated with photosensitivity, resulting in the acronym PIBIDS (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature). We report clinical findings of two siblings diagnosed with trichothiodystrophy associated with marked photosensitivity.
http://bit.ly/2EFE21q
Early presentation of vertebral osteomyelitis following a transrectal ultrasound-guided prostate biopsy with delayed radiological findings
A transrectal ultrasound-guided (TRUS) prostate biopsy is a common diagnostic procedure which carries an expected risk of iatrogenic infections. These range from simple urinary tract infections to rare but serious infections requiring an admission to hospital. Here we present a rare case of vertebral osteomyelitis following a TRUS biopsy, with normal initial MRI and bone scintigraphy scans and delayed radiological findings on repeat MRI of the spine.
http://bit.ly/2EDNwdm
Multiple melanoma in a burns scar
It is well known that up to 2% of chronic burn scar lesions can transform into malignant tumours, however, melanoma formation at these sites is extremely rare. This case report describes a burns case, which progressed to four melanomas in a 78-year-old male patient's little finger, 40 years after the initial incident. The patient underwent 3 mm punch biopsies, then digital amputation of the finger with pathology-proven melanoma. Histopathology investigation demonstrated three melanoma in situ and one invasive melanoma with a Breslow thickness of 1 mm. These findings are rare with few reports of melanoma in burn scars in the literature. This case report highlights the vigilance required from clinicians when performing skin examinations, and the importance of biopsies to newly pigmented lesions.
http://bit.ly/2ECmCmi
Bishop-Koop jejunostomy in an adult following proximal small bowel anastomotic breakdown
This case involves a proximal penetrating small bowel injury and the use of a Bishop-Koop anastomosis in a 33-year-old man. This case highlights the use of alternative methods used to prevent a proximal small bowel stoma in a rural setting. The Bishop-Koop anastomosis was originally designed for neonates in cases of intestinal anomalies such as atresia, volvulus and apple-peel syndrome. A literature search for the use of the Bishop-Koop anastomosis in adults, although scanty, is included in this article. We believe this article will benefit readers and that this method may be considered in breakdown of proximal small bowel injuries, to prevent a high-output stoma.
http://bit.ly/2EIcbOJ
Pars plana vitrectomy in management of giant retinal tear and retinal detachment following iris-fixated anterior chamber phakic intraocular lens implantation
This case report describes a 26-year-old man presenting with a giant retinal tear (GRT) with retinal detachment (RD) following implantation of iris-fixated anterior chamber phakic intraocular lens (AC-PIOL) for high myopia and occurrence of intraoperative aberrations during vitrectomy due to the presence of AC-PIOL in situ. Posterior chamber PIOL have been well reported to be associated with GRT with RD. Very few reports exist of GRT with RD following AC-PIOL. Moreover, the presence of iris-fixated AC-PIOL, in this case, led to the formation of ghost images intraoperatively especially during crucial steps like induction of posterior vitreous detachment which has never been reported.
http://bit.ly/2EJDE2v
IgA nephropathy with diffuse alveolar haemorrhage
Immunoglobulin (Ig)A nephropathy is the most common cause of primary glomerulonephritis worldwide. While IgA nephropathy has been associated with a variety of other diseases, pulmonary complications are extremely rare. A 58-year-old man presented with a 2-week history of fever and exertional dyspnoea. A chest imaging revealed bilateral consolidation predominantly in upper lungs. Laboratory findings showed elevated serum creatinine with proteinuria and haematuria. Flexible bronchoscopy revealed diffuse alveolar haemorrhage, and IgA nephropathy was confirmed on a renal biopsy. He received prednisone with good effect. This case highlights the need to consider IgA nephropathy in the differential diagnosis of pulmonary renal syndrome.
http://bit.ly/2EF3JPp
Unusual presentation of eosinophilic fasciitis (EF) with a raised ALT
Eosinophilic fasciitis (EF) is a syndrome of unknown aetiology characterised by progressive collagenous thickening of the subcutaneous fascia. Limb oedema can precede the skin thickening and induration classically associated with EF. We describe a case of EF in a 31-year-old woman who presented to her general practitioner with lower limb oedema and stiffness. Blood tests in primary care showed a persistently raised alanine transferase (ALT). No hepatic cause for her raised ALT was found despite investigation. The unusual manner of her presentation led to delay in her referral to the autoimmune connective tissue disease (CTD) clinic. This case illustrates the importance of considering autoimmune CTD such as EF in young patients presenting with limb oedema and raised ALT, as early treatment influences prognosis and functional recovery.
http://bit.ly/2EJDyrF
Acute on chronic anaemia with a haemoglobin of 18 g/L (1.8 g/dL) and haematocrit of 7.2%
Anaemia can present with symptoms of fatigue, shortness of breath, weakness, malaise, tachycardia and skin pallor. If left untreated, this can progress to life-threatening complications such as arrhythmias, cardiac hypertrophy and myocardial infarction. In this report, a 43-year-old woman, who was ambulatory with no exertional dysponea, presented with weakness, fatigue, bilateral lower extremity oedema and intermittent right sided chest pain for several months. This patient was subsequently found to have a haemoglobin of 18 g/L (1.8 g/dL) and haematocrit of 7.2%. She was admitted to the hospital and treated with seven units of blood. CT scan showed a 9.6 cm uterine fibroid in addition to a 5.9x5.4 cm mass near the right kidney, which was later diagnosed as metastatic carcinoid tumour. This case deserves attention due to the importance of looking for multiple causes of blood loss and the effects of low haemoglobin levels.
http://bit.ly/2EKkpWv
Examination of Hemodynamics in Patients in Hemorrhagic Shock Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA)
Publication date: Available online 21 December 2018
Source: Injury
Author(s): Philip J Wasicek, Yao Li, Shiming Yang, William A Teeter, Thomas M Scalea, Peter Hu, Megan L Brenner
Abstract
Background
The objective of this study was to investigate the hemodynamic effects of aortic occlusion (AO) during Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) using a sophisticated continuous vital sign (CVS) monitoring tool.
Methods
Patients admitted between February 2013 and May 2017 at a tertiary center that received REBOA were included. Patients in cardiac arrest before or at the time of REBOA were excluded. Time of AO was documented by time-stamped videography and correlated with CVS data.
Results
28 patients were included, mean (standard deviation) ISS was 38 (11). 18 received Zone 1 (distal thoracic aorta) and 10 received Zone 3 (distal abdominal aorta) AO. Among Zone 1 patients the pre-AO systolic blood pressure (SBP) nadir was 64 (19) mmHg, which increased to a mean of 124 (29) mmHg within 5 minutes after AO (p < 0.01). Among Zone 3 patients the pre-AO SBP nadir was 75 (19) mmHg, which increased to a mean of 98 (14) mmHg within 5 minutes after AO (p < 0.01). 72% of Zone 1 patients had episodes during AO where SBP was less than 90 mmHg as compared to 80% of Zone 3 patients (p = 0.51). 100% of Zone 1 patients had periods during AO where SBP was greater than 140 mmHg as compared to 70% Zone 3 patients (p = 0.04). The overall mean decrease in SBP after balloon deflation was 13 (20) mmHg (p < 0.01), with similar decreases among groups (14 (21) mmHg vs 12 (18) mmHg for Zone 1 and 3 patients, respectively (p = 0.85)). Patients undergoing Zone 1 AO were more likely to have an acute change (increase or decrease) in their heart rate immediately after AO as compared to Zone 3 AO (p = 0.048).
Conclusions
Significant hemodynamic alterations occur before, during, and after AO. The effects of Zone 1 AO on blood pressure and heart rate appear different than Zone 3 AO. This may have important implications for cardiac or cerebral function and perfusion goals, particularly with concomitant injuries such as cardiac contusion or traumatic brain injury.
http://bit.ly/2GD1D5j
External validation of a modified Trauma and Injury Severity Score model in major trauma injury
Publication date: Available online 21 December 2018
Source: Injury
Author(s): W.S. Chen, J.H. Tan, Y. Mohamad, R. Imran
Abstract
Background
The establishment of an accurate prognostic model in major trauma patients is important mainly because this group of patients will benefit the most. Clinical prediction models must be validated internally and externally on a regular basis to ensure the prediction is accurate and current. This study aims to externally validate two prediction models, the Trauma and Injury Severity Score model developed using the Major Trauma Outcome Study in North America (MTOS-TRISS model), and the NTrD-TRISS model, which is a refined MTOS-TRISS model with coefficients derived from the Malaysian National Trauma Database (NTrD), by regarding mortality as the outcome measurement.
Method
This retrospective study included patients with major trauma injuries reported to a trauma centre of Hospital Sultanah Aminah over a 6-year period from 2011 and 2017. Model validation was examined using the measures of discrimination and calibration. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC) and 95% confidence interval (CI). The Hosmer-Lemeshow (H-L) goodness-of-fit test was used to examine calibration capabilities. The predictive validity of both MTOS-TRISS and NTrD-TRISS models were further evaluated by incorporating parameters such as the New Injury Severity Scale and the Injury Severity Score.
Results
Total patients of 3,788 (3,434 blunt and 354 penetrating injuries) with average age of 37 years (standard deviation of 16 years) were included in this study. All MTOS-TRISS and NTrD-TRISS models examined in this study showed adequate discriminative ability with AUCs ranged from 0.86 to 0.89 for patients with blunt trauma mechanism and 0.89 to 0.99 for patients with penetrating trauma mechanism. The H-L goodness-of-fit test indicated the NTrD-TRISS model calibrated as good as the MTOS-TRISS model for patients with blunt trauma mechanism.
Conclusion
For patients with blunt trauma mechanism, both the MTOS-TRISS and NTrD-TRISS models showed good discrimination and calibration performances. Discrimination performance for the NTrD-TRISS model was revealed to be as good as the MTOS-TRISS model specifically for patients with penetrating trauma mechanism. Overall, this validation study has ascertained the discrimination and calibration performances of the NTrD-TRISS model to be as good as the MTOS-TRISS model particularly for patients with blunt trauma mechanism.
http://bit.ly/2ReJ0bU
A multi-institutional observational study on the effects of three-dimensional radiotherapy and weekly 40-mg/m 2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors
Abstract
Background
The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors.
Methods
We conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/m2 cisplatin from 2007 to 2012. Each participating hospital provided detailed information regarding patient characteristics, treatment outcomes, and treatment complications.
Results
The eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively.
Conclusions
The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m2 cisplatin are similar to those in the previous studies that used several chemotherapy regimens. However, postoperative CCRT using 3DRT had a high level of late GIT.
http://bit.ly/2Aa7yJC
Robot helps health workers train for emergencies
Hal is one of the most advanced human simulators and can replicate many human vital signs — heartbeat, blood pressure, pulse, blood oxygen levels and breathing
http://strib.mn/2rP0sWl
M-CSF and IL-34 expression as indicators for growth in sporadic vestibular schwannoma
Abstract
Macrophage colony stimulating factor and IL-34 are associated with clinical vestibular schwannoma progression. Investigating the biology behind vestibular schwannoma progression helps understanding tumor growth. Inflammation is important in the microenvironment of neoplasms. Macrophages are major players in the intratumoral infiltrate. These tumor-associated macrophages are known to stimulate angiogenesis and cell growth. M-CSF and IL-34 are cytokines that can regulate tumor-infiltrating macrophages. They are expressed by tumors and form potential targets for therapy. The goal of this study was to investigate these cytokines in vestibular schwannomas and to see if their expression is related to angiogenesis, macrophage numbers, cystic degeneration, and volumetric tumor progression. Immunohistochemical expression of M-CSF and IL-34 was analyzed in ten fast-growing vestibular schwannomas and in ten slow-growing vestibular schwannomas. Expression M-CSF and IL-34 were compared between fast- versus slow-growing and cystic versus non-cystic tumors. Data on macrophage numbers and microvessel density, known from earlier research, was also included. All tumors expressed M-CSF and its expression was higher in fast-growing tumors (p = 0.003) and in cystic tumors (p = 0.035). CD163 expression was higher in tumors with strong M-CSF expression (p = 0.003). All tumors expressed IL-34 as well, but no significant differences were found in relation to clinicopathological characteristics. This study demonstrated the expression of M-CSF and IL-34 in vestibular schwannomas. The results suggest that M-CSF is related to macrophage activity and tumor progression, making it a potential target for therapy. If a similar assumption can be made for IL-34 remains unclear.
http://bit.ly/2BAWRzn
Effect of RSK4 on biological characteristics of colorectal cancer
Abstract
Background
This study aimed to investigate the expression of P90 Ribosomal Protein S6 kinase 4 (RSK4) in colorectal cancer cells and its biological function.
Methods
We selected early SW480 and HCT116 colorectal cancer cell lines, using Lipofectamine™ 2000 transfection reagent carrying RSK4 gene transfected into cells to establish the colorectal cancer cell lines with high expression of RSK4. RT-PCR and western blot (WB) analysis confirmed RSK4 expression in SW480 and HCT116 cancer cell lines. We used methylthiazoltetrazolium (MTT) assay and flow cytometry to detect the proliferation of colorectal cancer cells. After transfection of RSK4, the effect of RSK4 on the RNA levels associated with epithelial–mesenchymal transition (EMT) of colorectal cancer cells was analyzed by real-time fluorescence quantitative PCR and the expression of EMT-related protein was detected by WB analysis.
Results
After transfection of RSK4 overexpression, the MTT assay detected that RSK4 could significantly inhibit the growth of colorectal cancer cells in vitro; flow cytometry detected that S-phase cells decreased significantly, and G0/1 cells increased significantly (P < 0.05). The invasion ability of SW480 and HCT116 cells transfected with RSK4 was markedly lower than that in the control group, and the difference was statistically significant (P < 0.05). Fluorescent quantitative PCR and WB analysis showed that the expression of EMT-associated molecular E-cadherin was remarkably increased and the expression of Snail was significantly decreased (P < 0.01).
Conclusion
RSK4 gene in colorectal cancer cell lines with low expression of RSK4 after transfection can inhibit the growth and invasion of tumor cells. RSK4 gene may inhibit EMT and inhibit metastasis of colorectal cancer cells, may be a potential tumor suppressor gene and inhibit tumor distant metastasis, and may provide the biological basis for new therapeutic targets.
http://bit.ly/2LvHQDE
Cancers, Vol. 11, Pages 16: Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma
Cancers, Vol. 11, Pages 16: Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma
Cancers doi: 10.3390/cancers11010016
Authors: Monserrat Llaguno-Munive Mario Romero-Piña Janeth Serrano-Bello Luis A. Medina Norma Uribe-Uribe Ana Maria Salazar Mauricio Rodríguez-Dorantes Patricia Garcia-Lopez
The standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the standard therapy are necessary. The aim of the present study was to evaluate whether mifepristone, an antihormonal agent, has a synergistic effect with temozolomide (used in standard therapy for gliomas). Whereas the mechanism of temozolomide involves damage to tumor DNA leading to apoptosis, tumor resistance is associated with DNA damage repair through the O6-methylguanine-DNA-methyltransferase (MGMT) enzyme. Temozolomide/mifepristone treatment, herein examined in Wistar rats after orthotopically implanting C6 glioma cells, markedly reduced proliferation. This was evidenced by a decreased level of the following parameters: a proliferation marker (Ki-67), a tumor growth marker (18F-fluorothymidine uptake, determined by PET/CT images), and the MGMT enzyme. Increased apoptosis was detected by the relative expression of related proteins, (e.g. Bcl-2 (B-cell lymphoma 2), Bax (bcl-2-like protein 4) and caspase-3). Thus, greater apoptosis of tumor cells caused by their diminished capacity to repair DNA probably contributed significantly to the enhanced activity of temozolomide. The results suggest that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide during chemotherapy for GBM.
http://bit.ly/2T9339f
Cancers, Vol. 11, Pages 17: Non-Coding RNAs in Glioma
Cancers, Vol. 11, Pages 17: Non-Coding RNAs in Glioma
Cancers doi: 10.3390/cancers11010017
Authors: Ryte Rynkeviciene Julija Simiene Egle Strainiene Vaidotas Stankevicius Jurgita Usinskiene Edita Miseikyte Kaubriene Ingrida Meskinyte Jonas Cicenas Kestutis Suziedelis
Glioma is the most aggressive brain tumor of the central nervous system. The ability of glioma cells to migrate, rapidly diffuse and invade normal adjacent tissue, their sustained proliferation, and heterogeneity contribute to an overall survival of approximately 15 months for most patients with high grade glioma. Numerous studies indicate that non-coding RNA species have critical functions across biological processes that regulate glioma initiation and progression. Recently, new data emerged, which shows that the cross-regulation between long non-coding RNAs and small non-coding RNAs contribute to phenotypic diversity of glioblastoma subclasses. In this paper, we review data of long non-coding RNA expression, which was evaluated in human glioma tissue samples during a five-year period. Thus, this review summarizes the following: (I) the role of non-coding RNAs in glioblastoma pathogenesis, (II) the potential application of non-coding RNA species in glioma-grading, (III) crosstalk between lncRNAs and miRNAs (IV) future perspectives of non-coding RNAs as biomarkers for glioma.
http://bit.ly/2Cu3q8Q
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
