Objectives: Acute respiratory failure is a frequent complication of Guillain-Barré syndrome, associated with high morbidity and mortality. Adjuvant treatments are needed to improve the outcome of Guillain-Barré syndrome. Since dysglycemia is a risk factor for development of axonal polyneuropathy in critically ill patients and since insulin therapy may be neuroprotective, we sought to explore the association between dysglycemia and neurologic status in Guillain-Barré syndrome patients. Design: Retrospective study. Setting: Single-center study. Interventions: All plasma levels of glycemia measured by enzymatic technique as well as capillary glycemia were collected in a cohort of mechanically ventilated Guillain-Barré syndrome patients. Insulin administration and dysglycemia were correlated to neurologic status at discharge defined by disability grade and arm grade. Measurements and Main Results: In a multivariate analysis, disability grade and arm grade at ICU discharge were independently and inversely correlated with mean blood glucose. Disability grade and arm grade did not correlate with any other dysglycemic variables or with insulin administration or length of stay. Conclusions: In the present study, we found that neurologic disability at ICU discharge correlated with dysglycemia in mechanically ventilated Guillain-Barré syndrome patients. These finding indicates that dysglycemia may delay motor recovery and impact the functional outcome of Guillain-Barré syndrome. Blood glucose control might be an adjuvant therapy for improving Guillain-Barré syndrome recovery. Drs. Heming and Sharshar contributed equally. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: t.sharshar@ch-sainte-anne.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
http://bit.ly/2AgFrIF
Τρίτη 25 Δεκεμβρίου 2018
Effects of Baseline Thrombocytopenia and Platelet Decrease Following Renal Replacement Therapy Initiation in Patients With Severe Acute Kidney Injury
Objectives: Thrombocytopenia is common in critically ill patients with severe acute kidney injury and may be worsened by the use of renal replacement therapy. In this study, we evaluate the effects of renal replacement therapy on subsequent platelet values, the prognostic significance of a decrease in platelets, and potential risk factors for platelet decreases. Design: Post hoc analysis of the Acute Renal Failure Trial Network Study. Setting: The Acute Renal Failure Trial Network study was a multicenter, prospective, randomized, parallel-group trial of two strategies for renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 Veterans Affairs and university-affiliated medical centers. Subjects: The Acute Renal Failure Trial Network study evaluated 1,124 patients with severe acute kidney injury requiring renal replacement therapy. Interventions: Predictor variables were thrombocytopenia at initiation of renal replacement therapy and platelet decrease following renal replacement therapy initiation. Measurements and Main Results: Outcomes were mortality at 28 days, 60 days, and 1 year, renal recovery, renal replacement therapy free days, ICU-free days, and hospital-free days. Baseline thrombocytopenia in patients requiring renal replacement therapy was associated with increased mortality and was also associated with lower rates of renal recovery. A decrease in platelet values following renal replacement therapy initiation was associated with increased mortality. Continuous renal replacement therapy was not an independent predictor of worsening thrombocytopenia compared with those treated with intermittent hemodialysis. Conclusions: Baseline thrombocytopenia and platelet decrease following renal replacement therapy initiation were associated with increased mortality, and baseline thrombocytopenia was associated with decreased rates of renal recovery. Continuous renal replacement therapy did not decrease platelets compared with hemodialysis. The analyses presented in this article were not prepared in conjunction with the Acute Renal Failure Trial Network (ATN) Study investigators and do not represent the opinions or views of the ATN study, the Veterans Affairs, or the National Institute of Diabetes and Digestive and Kidney Diseases. Drs. Griffin, Jovanovich, Palevsky, Faubel, Jalal contributed to research idea and study design and data analysis/interpretation. Dr. Griffin contributed to data acquisition. Dr. You contributed to statistical analysis. Drs. Jovanovich, Palevsky, Faubel, Jalal contributed to supervision or mentorship. Each author contributed important intellectual content during article drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). The Department of Veterans Affairs (VA)/National Institutes of Health Acute Renal Failure Trial Network study was supported, in part, by the Cooperative Studies Program (CSP) of the VA Office of Research and Development as CSP number 530 and by the National Institute of Diabetes and Digestive and Kidney Diseases under interagency agreement Y1-DK-3508-01. Dr. Griffin's institution received funding from National Kidney Foundation, and he received funding from the Nephrology Young Investigators Meeting (travel). Dr. Griffin is supported by a National Research Service Award Institutional Predoctoral Training Grant (T32), grant number T32 DK 007135. Dr. Jovanovich's institution received funding from Veterans Affairs, and she disclosed government work. Dr. Jovanovich is supported by Veterans Affairs CDA 5IK2CX001030-04. Drs. Palevsky and Jalal received support for article research from the National Institutes of Health. Dr. Palevsky also received support for article research from the United States Department of Veterans Affairs. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: benjamin.griffin@ucdenver.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
http://bit.ly/2SqdQvO
http://bit.ly/2SqdQvO
Extracorporeal Membrane Oxygenation Use in Cardiogenic Shock: Impact of Age on In-Hospital Mortality, Length of Stay, and Costs
Objectives: Increasing age is a well-recognized risk factor for in-hospital mortality in patients receiving extracorporeal membrane oxygenation for cardiogenic shock, but the shape of this relationship is unknown. In addition, the impact of age on hospital length of stay, patterns of patient disposition, and costs has been incompletely characterized. Design: Retrospective analysis of the National Inpatient Sample. Setting: U.S. nonfederal hospitals, years 2004–2016. Patients: Adults with cardiogenic shock treated with extracorporeal membrane oxygenation (3,094; weighted national estimate: 15,415). Interventions: None. Measurements and Main Results: The mean age of extracorporeal membrane oxygenation recipients was 54.8 ± 15.4 years (range, 18–90 yr). Crude in-hospital mortality was 57.7%. Median time-to-death was 8 days (interquartile range, 3–17 d). A linear relationship between age and in-hospital mortality was observed with a 14% increase in the adjusted odds of in-hospital mortality for every 10-year increase in age (adjusted odds ratio, 1.14; 95% CI, 1.08–1.21; p
http://bit.ly/2AhLtZp
http://bit.ly/2AhLtZp
Hospital Mechanical Ventilation Volume and Patient Outcomes: Too Much of a Good Thing?
Objectives: Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. Design: Retrospective cohort study. Setting: The California Patient Discharge Database 2016. Patients: Adult nonsurgical patients receiving mechanical ventilation. Interventions: The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. Measurements and Main Results: We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17–1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21–2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67–0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (ρ = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. Conclusions: Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary. This work was performed at the National Jewish Health, Denver, CO. Dr. Mehta helped to study design, statistical analysis, data interpretation, and article preparation. Dr. Walkey helped to data interpretation and article preparation. Dr. Curran-Everett helped to statistical analysis and article preparation. Dr. Matlock helped to data interpretation and article preparation. Dr. Douglas helped to study design, data interpretation, and article preparation. Dr. Mehta takes full responsibility for the content of the article, data analysis, and data interpretation. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Dr. Mehta is supported, in part, by National Institutes of Health (NIH) K12HL137862. Dr. Walkey is supported by NIH K01HL116768 and R01HL136660. Dr. Curran-Everett is supported by NIH RHL089897B-08. Dr. Matlock is supported by NIH R01HL136403-01. Dr. Douglas is supported by NIH 1R01NR016459-01. Drs. Mehta and Matlock received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mehtaa@njhealth.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
http://bit.ly/2SlO77x
http://bit.ly/2SlO77x
Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study
Objective: To investigate immunostimulatory effects of acetylsalicylic acid during experimental human endotoxemia and in sepsis patients. Design: Double-blind, randomized, placebo-controlled study in healthy volunteers and ex vivo stimulation experiments using monocytes of septic patients. Setting: Intensive care research unit of an university hospital. Subjects: Thirty healthy male volunteers and four sepsis patients. Interventions: Healthy volunteers were challenged IV with endotoxin twice, at a 1-week interval, with each challenge consisting of a bolus of 1 ng/kg followed by continuous administration of 1 ng/kg/hr during 3 hours. Volunteers were randomized to acetylsalicylic acid prophylaxis (80 mg acetylsalicylic acid daily for a 14-d period, starting 7 d before the first endotoxin challenge), acetylsalicylic acid treatment (80 mg acetylsalicylic acid daily for the 7-d period in-between both endotoxin challenges), or the control group (receiving placebo). Furthermore, monocytes of sepsis patients were incubated with acetylsalicylic acid preexposed platelets and were subsequently stimulated with endotoxin. Measurements and Main Results: Acetylsalicylic acid prophylaxis enhanced plasma tumor necrosis factor-α concentrations upon the first endotoxin challenge by 50% compared with the control group (p = 0.02) but did not modulate cytokine responses during the second endotoxin challenge. In contrast, acetylsalicylic acid treatment resulted in enhanced plasma levels of tumor necrosis factor-α (+53%; p = 0.02), interleukin-6 (+91%; p = 0.03), and interleukin-8 (+42%; p = 0.02) upon the second challenge, whereas plasma levels of the key antiinflammatory cytokine interleukin-10 were attenuated (–40%; p = 0.003). This proinflammatory phenotype in the acetylsalicylic acid treatment group was accompanied by a decrease in urinary prostaglandin E metabolite levels (–27% ± 7%; p = 0.01). Ex vivo exposure of platelets to acetylsalicylic acid increased production of tumor necrosis factor-α (+66%) and decreased production of interleukin-10 (–23%) by monocytes of sepsis patients. Conclusions: Treatment, but not prophylaxis, with low-dose acetylsalicylic acid partially reverses endotoxin tolerance in humans in vivo by shifting response toward a proinflammatory phenotype. This acetylsalicylic acid–induced proinflammatory shift was also observed in septic monocytes, signifying that patients suffering from sepsis-induced immunoparalysis might benefit from initiating acetylsalicylic acid treatment. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Leijte, Netea, Kox, and Pickkers designed the study. Drs. Leijte, Kiers, Jansen, and Boerrigter included the subjects, performed the experiments, and processed the samples. Drs. Leijte and van der Heijden performed the ex vivo experiments. Drs. van der Heijden and Gerretsen performed the laboratory analyses. Dr. Leijte performed the statistical analyses and drafted the article. Drs. Kiers, van der Heijden, Netea, Kox, and Pickkers critically revised the article and supervised the research. All authors read and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Dr. Netea was funded by a Spinoza grant of the Netherlands Organization for Scientific Research, and a Competitiveness Operational Program Grant of the Romanian Ministry of European Funds. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Matthijs Kox, PhD, Department of Intensive Care Medicine, Radboud University Medical Center, internal mail 710, PO Box 9101, Nijmegen, The Netherlands. E-mail: matthijs.kox@radboudumc.nl Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
http://bit.ly/2AeRA0M
http://bit.ly/2AeRA0M
What Does the Word “Treatable” Mean? Implications for Communication and Decision-Making in Critical Illness
Objectives: To explore how nonphysicians and physicians interpret the word "treatable" in the context of critical illness. Design: Qualitative study using in-depth interviews. Setting: One academic medical center. Subjects: Twenty-four nonphysicians (patients and community members) purposively sampled for variation in demographic characteristics and 24 physicians (attending physicians and trainees) purposively sampled from four specialties (critical care, palliative care, oncology, and surgery). Interventions: None. Measurements and Main Results: We identified two distinct concepts that participants used to interpret the word "treatable": 1) a "good news" concept, in which the word "treatable" conveys a positive message about a patient's future, thereby inspiring hope and encouraging further treatment and 2) an "action-oriented" concept, in which the word "treatable" conveys that physicians have an action or intervention available, but does not necessarily imply an improved prognosis or quality of life. The overwhelming majority of nonphysicians adopted the "good news" concept, whereas physicians almost exclusively adopted the "action-oriented" concept. For some nonphysicians, the word "treatable" conveyed a positive message about prognosis and/or further treatment, even when this contradicted previously stated negative information. Conclusions: Physician use of the word "treatable" may lead patients or surrogates to derive unwarranted good news and false encouragement to pursue treatment, even when physicians have explicitly stated information to the contrary. Further work is needed to determine the extent to which the word "treatable" and its cognates contribute to widespread decision-making and communication challenges in critical care, including discordance about prognosis, misconceptions that palliative treatments are curative, and disputes about potentially inappropriate or futile treatment. Mr. Batten received funding from Stanford Medical Scholars for research time (Project No 11635, "What Does 'Treatable' Mean? An Empirical Study of Physician-Patient Communication"). The Stanford Center for Biomedical Ethics provided funds for transcription of audio recordings. Mr. Batten received funding from The Social Science Matrix at the University of California, Berkeley for collaborative interdisciplinary discussions that informed this work (Prospecting Team, "Expert Language, Native Language: Toward a Framework for Translation in Clinical (Mis)communication"). The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Stanford Hospital and Clinics. For information regarding this article, E-mail: jbatten@stanford.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
http://bit.ly/2Aqh23B
http://bit.ly/2Aqh23B
National Performance on the Medicare SEP-1 Sepsis Quality Measure
Objectives: The Centers for Medicare and Medicaid Services requires hospitals to report compliance with a sepsis treatment bundle as part of its Inpatient Quality Reporting Program. We used recently released data from this program to characterize national performance on the sepsis measure, known as SEP-1. Design: Cross-sectional study of United States hospitals participating in the Centers for Medicare and Medicaid Services Hospital Inpatient Quality Reporting Program linked to Centers for Medicare and Medicaid Services' Healthcare Cost Reporting Information System. Setting: General, short-stay, acute-care hospitals in the United States. Measurements and Main Results: We examined the hospital factors associated with reporting SEP-1 data, the hospital factors associated with performance on the SEP-1 measure, and the relationship between SEP-1 performance and performance on other quality measures related to time-sensitive medical conditions. A total of 3,283 hospitals were eligible for the analysis, of which 2,851 (86.8%) reported SEP-1 performance data. SEP-1 reporting was more common in larger, nonprofit hospitals. The most common reason for nonreporting was an inadequate case volume. Among hospitals reporting SEP-1 performance data, overall bundle compliance was generally low, but it varied widely across hospitals (mean and SD: 48.9% ± 19.4%). Compared with hospitals with worse SEP-1 performance, hospitals with better SEP-1 performance tended to be smaller, for-profit, nonteaching, and with intermediate-sized ICUs. Better hospital performance on SEP-1 was associated with higher rates of timely head CT interpretation for stroke patients (rho = 0.16; p
http://bit.ly/2SjD3YD
http://bit.ly/2SjD3YD
MCPIP1 mediates inflammatory responses induced by lipopolysaccharide and lipoteichoic acid in bovine mammary epithelial cells
Abstract
Monocyte chemoattractant protein-induced protein 1 (MCPIP1) is a kind of zinc finger RNA binding protein, which exerts immune responses in a variety of cell types. However, the role of MCPIP1 in bovine mammary epithelial cells during mastitis has not been studied. In this study, we explored the functions of MCPIP1 in the inflammatory process induced by virulence factors of pathogens in bovine mammary alveolar cell-T (MAC-T) cell line. Our results showed that MCPIP1 was significantly highly expressed both in the mammary tissue of dairy cows with mastitis and in inflammatory MAC-T cells induced by lipopolysaccharide (LPS) or lipoteichoic acid (LTA). Furthermore, we found that overexpression of MCPIP1 in MAC-T cells abated the LPS-induced increase at the gene expression levels of inflammatory mediators tumor necrosis factor-α-α, interleukin (IL)-1β, IL-6 and IL-8, enhanced the LPS- and LTA-induced inhibition of epithelial proliferation and promoted the LPS- and LTA-induced oxidative and DNA damage. These findings indicated that MCPIP1 has an enormous potential in regulating the inflammatory response of bovine mammary epithelial cells during infection and may provide an effective therapeutic target for bovine mastitis to reduce the damage caused by inflammatory reactions.http://bit.ly/2SfI5oW
Systematic review with meta‐analysis: the prevalence of bile acid malabsorption and response to colestyramine in patients with chronic watery diarrhoea and previous cholecystectomy
Summary
Background
A limited number of small‐sized studies suggest that bile acid diarrhoea is frequent in patients with chronic watery diarrhoea and previous cholecystectomy.
Aim
To perform a systematic review and meta‐analysis to assess the prevalence of bile acid diarrhoea in patients with chronic watery diarrhoea and previous cholecystectomy, and their response to colestyramine, including a new consecutive series of patients.
Methods
MEDLINE and EMBASE were searched up to January 2018. Selected studies included patients with previous cholecystectomy and chronic watery diarrhoea assessed by the 23‐seleno‐25‐homotaurocholic acid (SeHCAT) test. We calculated the pooled rate of bile acid diarrhoea using the inverse double arcsine square root method. Additionally, the medical records of 291 consecutive patients with chronic watery diarrhoea in whom a SeHCAT test was performed were retrospectively reviewed and 74 with previous cholecystectomy were included in the meta‐analysis.
Results
The search strategy identified eight relevant studies, which, together with the data of the present series, comprise 361 individuals. The pooled bile acid diarrhoea rate was 70% (95% CI 56%‐82%), and was similar when using cut‐offs of 10% or 15%. There was substantial heterogeneity (I 2 = 84%). Five studies comprising 166 patients evaluated the effect of colestyramine in patients with bile acid diarrhoea. The pooled colestyramine response rate was 79% (95% CI 63%‐91%) with substantial heterogeneity (I 2 = 73%).
Conclusions
Two thirds of patients with chronic watery diarrhoea and previous cholecystectomy have bile acid diarrhoea. Response to colestyramine in these patients is good.
http://bit.ly/2EPEPxI
Quality of life measures predict mortality in patients with cirrhosis and severe ascites
Summary
Background
Severe ascites is associated with both a poor health‐related quality of life (HRQL) and a mortality in excess of that captured by current prognostic clinical scores.
Aim
To determine the association between HRQL and mortality in patients with severe ascites.
Methods
The HRQL data from previously published randomised controlled trials examining the efficacy of satavaptan in ascites were retrospectively evaluated.
Results
Of the 496 patients randomised who completed the SF‐36, 405 patients had complete datasets and were included in the analysis (difficult‐to‐treat ascites, n = 164 or refractory ascites, n = 241). Overall, patients reported poor HRQL, in particular the physical component score (PCS) of SF‐36. The physical component score (PCS) correlated with the mental component score (MCS) of SF‐36 (Spearman rank correlation = 0.68) but not with markers of severity of liver disease. The PCS, but not the MCS, was significantly lower in patients who died (P = 0.01 and P = 0.84, respectively). After confounder‐adjustment, the hazard ratio for a 10‐point increase in the physical component score was 0.83 (95% CI; 0.72‐0.97) for all‐cause mortality and 0.84 (95% CI; 0.71‐0.99) for cirrhosis‐related deaths only, indicating that patients with better physical HRQL live longer on average.
Conclusions
Poor physical component score (PCS) of SF‐36 is an independent predictor of 12‐month mortality in patients with severe ascites independent of current prognostic clinical scores. It holds promise not only in prognostic modelling but also as an endpoint in the evaluation of therapies targeting ascites.
http://bit.ly/2ELsVDY
Mild malformations of cortical development in sleep‐related hypermotor epilepsy due to KCNT1 mutations
Abstract
Mutations in the sodium‐activated potassium channel gene KCNT1 have been associated with nonlesional sleep‐related hypermotor epilepsy (SHE). We report the co‐occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI‐negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies.
http://bit.ly/2Cyj2Ih
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours, Published online: 26 December 2018; doi:10.1038/s41416-018-0355-8
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours
https://go.nature.com/2Tard2Z
Co-targeting EGFR and IKKβ/NF-κB signalling pathways in head and neck squamous cell carcinoma: a potential novel therapy for head and neck squamous cell cancer
Co-targeting EGFR and IKKβ/NF-κB signalling pathways in head and neck squamous cell carcinoma: a potential novel therapy for head and neck squamous cell cancer
Co-targeting EGFR and IKKβ/NF-κB signalling pathways in head and neck squamous cell carcinoma: a potential novel therapy for head and neck squamous cell cancer, Published online: 26 December 2018; doi:10.1038/s41416-018-0351-z
Co-targeting EGFR and IKKβ/NF-κB signalling pathways in head and neck squamous cell carcinoma: a potential novel therapy for head and neck squamous cell cancer
https://go.nature.com/2TardA1
Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype
Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype
Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their <i>UGT1A 1</i> genotype, Published online: 26 December 2018; doi:10.1038/s41416-018-0348-7
Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype
https://go.nature.com/2Cxuzrd
Personal radio use and cancer risks among 48,518 British police officers and staff from the Airwave Health Monitoring Study
Personal radio use and cancer risks among 48,518 British police officers and staff from the Airwave Health Monitoring Study
Personal radio use and cancer risks among 48,518 British police officers and staff from the Airwave Health Monitoring Study, Published online: 26 December 2018; doi:10.1038/s41416-018-0365-6
Personal radio use and cancer risks among 48,518 British police officers and staff from the Airwave Health Monitoring Study
https://go.nature.com/2Cxux2z
Recent Advances in HBV Reactivation Research
Hepatitis B virus (HBV) is an important public health problem that poses a serious threat to human health. HBV reactivation generally occurs in overt or occult HBV infection patients who suffered DDAs, chemotherapy, or immunosuppressive therapy, especially when some solid tumors and leukemia patients are using hormones such as prednisolone and imatinib. The approximate incidence of HBV reactivation ranged from about 10% to 40%. Scientists often explore the molecular mechanisms from both the virus and the host. But some studies have reported that some drugs (cisplatin, rituximab, imatinib, and glucocorticoid) could induce HBV reactivation directly. However, the specific molecular mechanisms were unclear. With the emergence of new antiviral drugs and molecular targeted drugs, the risk of HBV reactivation will increase significantly. Therefore this review was expected to be used to provide recommendations for future research in HBV reactivation.
http://bit.ly/2EOK5RV
The Dantastic Mr. Tox & Howard – S02E06 – The Ergogenic Academic
Dantastic Live at NACCT 2018 . . . &Howard That's not a lump of coal in your stocking . . . Join Dan (@drusyniak) &Howard (@heshiegreshie) as they speak with Dr. Dan Rusyniak (@drusyniak) live on stage at the 2018 North American Congress of Clinical Toxicology Pre-Meeting Symposium. Dan cleverly tricked Howard into being the foil […]
EMCrit Project by Tox & Hound.
http://bit.ly/2T7HbuI
Exceptional longevity: why some people live to be more than 100-year old
Interventions that promote longevity, remembered by mnemonic: DEEP purple - "eat colorful plant foods: Dietary modification, Exercise, active Engagement, Purposeful living (click here to enlarge the image).
Based on a Mayo Clinic Proceedings article (https://www.mayoclinicproceedings.org/article/S0025-6196(18)30792-4/):
Exceptional Human Longevity: the oldest old have an extreme phenotype of delayed onset of age-related diseases and/or resistance to lethal illnesses occurring earlier in life.
Centenarians have delayed onset of chronic diseases
During the span of human history the likelihood of living from birth to age 100 rose from 1 in 20 million to 1 in 50 as of year 1995 (for females in low-mortality nations such as Japan and Sweden). By 2009, this probability increased to 1 in 2. About 1 in 5,000 persons in the United States is a centenarian or older. Human longevity now exceeds 115 years. However, maximum life span has remained largely unchanged. There is a limit to human longevity, and it may be around 120 years.
In centenarians, the age at onset of common age-associated diseases is delayed: 43% of both male and female centenarians reach the age of 80 years before experiencing age-associated illness.
There is an absence of any disease diagnosis in some 15% and 30% of female and male centenarians, respectively, at the age of 100 years!
As many as 25% of centenarians are cognitively intact.
Geographic Clusters
Geographic Clustering of Exceptionally Long-Lived Individuals: Countries with the world's oldest populations in 2015: Japan, followed by Germany, Italy, Greece, Finland, and Sweden.
Long-lived Okinawans subscribe to the nutritional behavior of "hara haci bu" or "eat until you are only 80% full." Their "rainbow diet" is based on diverse fruits and vegetables, with soy providing the bulk of protein intake. Their daily caloric intake is reduced, accounting for their low BMI of 20.
Life span is increased in regular churchgoers, whatever their faith. Seventh Day Adventists exhibit significantly lower levels of measured stress hormones.
Behavioral and environmental influences that may contribute to longevity in the so called "blue zones":
- Eating in moderation, mostly plant-based diet. Small-portioned "regular" meals. Lighter meals at the end of the day.
- Purposeful living: life philosophy, volunteerism, "hard work" or "work ethic"
- Social support systems: interactions with family/friends, laughter/humor
- Exercise, especially walking, gardening
- Other nutritional factors: goat's milk, red wine, herbal teas
- Spirituality
- Maintenance of a healthy body mass index (BMI)
- Other possible factors: sunshine, adequate hydration, naps
Compression of Morbidity: diseases occur later in life. Fries' "compression of morbidity" hypothesis: chronic morbidity begins at a later age.
Why Are Some People Long-Lived?
Genes: Centenarians' offspring have an increased likelihood of surviving to 100 years and exhibit a diminished prevalence of age-associated diseases.
Environmental factors exert even greater effect than genes.
Sex Differences: Universally, women live longer than men. Despite the greater longevity of women, functional status is better in older men compared with older women.
Resiliency is the capacity to adequately respond to stressors. It helps resist age-related physiologic changes. Resiliency protects against insults that shorten life and health span. Resiliency can explain why some centenarians, despite onset of chronic disease before the age of 80 years, live exceptionally long.
How Is Exceptional Longevity Achieved?
Caloric restriction delays the aging phenotype in mammals. This is shown by abundant studies. Caloric restriction delayed the onset of diabetes, cancer, cardiovascular disease, and brain atrophy.
Reduced calorie intake by 20% to 60% retards aging. It only works if such reduction is quite substantial.
What about exercise? Regular physical activity promotes healthy human life span. However, it is unclear if exercise increases maximum longevity.
Normal body weight confers the most protection from mortality.
Active engagement and development of social networks and support systems confer longevity benefits. Lack of strong social relations is associated with a mortality risk roughly equivalent to smoking.
Interventions that promote longevity can be remembered by the mnemonic: DEEP purple - "eat colorful plant foods":
- Dietary modification
- Exercise
- active Engagement
- Purposeful living
How to Measure Successful Aging?
Several algorithms have been proposed to estimate biological age. They are based on functional as well as biochemical measurements.
Biomarkers of Aging Processes and Longevity:
Disease-free survival or disability-free survival at 6-month intervals
Time to impairment in the next activity of daily living
Length of stay after hospitalization
Height, especially in men
Facial features
Gait speed, grip strength, muscle mass, mobility stress test
Daily and instrumental activities of daily living
Cognitive tests such as the Digit Symbol Substitution Test or Montreal Cognitive Test
Blood glucose or hemoglobin A1c, hypertension and elevated lipids, interleukin 6, insulin-like growth factor 1, and insulin-like growth factor binding proteins
CD4+, CD28− and CD8+, CD28− T cells; percentage of T cells that are naive vs memory (CD4 cells, CD8 cells)
Antibody response to annual influenza vaccination; delayed hypersensitivity skin test
Cataracts
Threshold for hearing high-pitched tones; tests of taste and smell
Tests of proprioception and balance
Forced expiratory volume in 1 second
Number of remaining teeth
One or two parents reaching 90 years of age
Educational attainment
More speculative: DNA methylation indices; senescent cell burden
References:
https://www.mayoclinicproceedings.org/article/S0025-6196(18)30792-4/
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http://bit.ly/2EP3zW3
Association of low‐frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts
Genome‐wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low‐frequency variants may account for some of the "missing" heritability. Therefore, we scanned low‐frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP‐Seq studies in craniofacial tissues or cell lines contained multiple low‐frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low‐frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p‐value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p‐value = .001). These findings suggest that low‐frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.
http://bit.ly/2AeKt8D
Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships
The most frequent cause of isolated complex III deficits is mutations to the nuclear‐encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease‐causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype–phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under "BCS1L Mitopathies". Patterns in genotype–phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.
http://bit.ly/2SfhQz6
Parents' perceptions of functional abilities in people with Down syndrome
Abstract
A realistic assessment of the range of functional abilities found in people with Down syndrome (DS) may assist in counseling expectant parents. This study asked parents from the United States and the Netherlands to assess 11 functional skills of their sons and daughters with DS: walking, eating, speaking, grooming/personal hygiene, reading, writing, preparing meals, working at a job, going on dates, traveling independently, and living independently. We analyzed responses from 2,658 parents who have sons/daughters with DS of all ages. The majority of people with DS in the United States could walk by 25 months of age, speak reasonably well by 12 years, maintain their own personal hygiene by 13 years, and work independently by 20 years. By 31 years of age, 49% were reading reasonably well, and 46% were writing reasonably well. Approximately 30% could travel independently, and 34% were living independently. The results from parents in the Netherlands were similar for most measures. This normative data on function may contribute to anticipatory guidance and decision‐making. Furthermore, as parents and clinicians seek to assess the relative strengths and weakness of people with DS, resources and supports can be marshaled for those not meeting milestones at expected times.
http://bit.ly/2AeKLML
Role of the Death Receptor and Endoplasmic Reticulum Stress Signaling Pathways in Polyphyllin I-Regulated Apoptosis of Human Hepatocellular Carcinoma HepG2 Cells
Polyphyllin has been reported to exhibit anticancer effects against various types of cancer via the proapoptotic signaling pathway. The aim of the present study was to investigate the role of the endoplasmic reticulum stress and death receptor signaling pathways in PPI-induced apoptosis of human hepatocellular carcinoma HepG2 cells. Analysis demonstrated that PPI could significantly inhibit the proliferation and induce apoptosis of HepG2 cells in a dose- and time-dependent manner. Investigation into the molecular mechanism of PPI indicated that PPI notably mediated ER stress activation via IRE-1 overexpression and activation of the caspase-12 to protect HepG2 cells against apoptosis. In addition, PPI markedly induced the expression of death receptors signaling pathways-associated factors, including tumor necrosis factor (TNF) receptor 1/TNF-α and FAS/FASL. Additionally, suppression of the death receptor signaling pathways with a caspase-8 inhibitor, Z-IETD-FMK, revealed an increase in the death rate and apoptotic rate of HepG2 cells. Collectively, the findings of the present study suggested that the ER stress and death receptor signaling pathways were associated with PPI-induced HepG2 cell apoptosis; however, endoplasmic reticulum stress may serve a protective role in this process. The combination of PPI and Z-IETD-FMK may activate necroptosis, which enhances apoptosis. Therefore, the results of the present study may improve understanding regarding the roles of signaling pathways in PPI regulated apoptosis and contribute to the development of novel therapies for the treatment of HCC.
http://bit.ly/2RedUkU
Serum Metabolomics Analysis in Wasp Sting Patients
To analyze the dynamic changes of serum metabolomics in wasp sting victims, we collected serum from 10 healthy volunteers and 10 patients who had been stung 3 hours, 24 hours, and 72 hours before sample collection. We analyzed the metabolomics by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) techniques and then performed enrichment analysis. A total of 838 metabolites were identified. Serum metabolomics analysis using MetaboAnalyst revealed 289 metabolites that were significantly different among patients in the 3-hour group versus healthy controls (P
http://bit.ly/2GDsEW9
Cytomorphological spectrum and immunochemistry of cutaneous tuberculosis
Objectives
The diagnosis of cutaneous tuberculosis is challenging due to its diverse clinical manifestations, paucibacillary state and lack of proper diagnostic tests. Clinico‐pathological correlation is still frequently used for diagnosis. There is paucity of literature on cytomorphological features. Immunochemistry can help as an ancillary test.
Methods
Clinical diagnosis was made after thorough history and physical examination. Modified Fine Needle Aspiration technique was used to collect cytology samples and 3 mm punch biopsy for histological examination. Findings on histopathology were compared with cytomorphology. Immunochemical staining with anti‐TB polyclonal antibody using standard Polymer‐based‐HRP immunochemistry technique and comparison of cytology and histology findings.
Results
The morphological spectrum of biopsy and cytology showed high correlation using nine parameters: necrosis, granulomas, giant cells, AFB, neutrophilic infiltrate, presence of lymphocytes, histiocytes, collagen bundles, and immunochemistry. Diagnostic correlation of FNA compared to biopsy was found to be 90.3%. On comparing cytomorphology of scrofuloderma and lupus vulgaris, all the parameters were found more frequently in scrofuloderma except for granulomas, giant cells and immunochemistry. Immunochemistry showed sensitivity and specificity of 90.3% and 70% on biopsy, respectively, compared to 67.7% and 60% on FNA, respectively. Combined sensitivity of IHC and ICC was 96.8%.
Conclusions
The cytomorphological spectrum of cutaneous tuberculosis is comparable to clinicohistopathology with a high correlation of 90.3%. However, sub classification on FNA is difficult on cytology alone. While FNAC is a better diagnostic tool for finding AFBs hence confirming the diagnosis, biopsy is better for immunochemistry. Thus, biopsy and FNA complement each other.
http://bit.ly/2V70wOp
Sharing special birth stories. An explorative study of online childbirth narratives.
Publication date: Available online 24 December 2018
Source: Women and Birth
Author(s): José Sanders
Abstract
Background
Increasingly, pregnant women, as active online media users, incorporate media driven values on childbirth that may not agree with professional midwifery values. In Dutch midwifery practice, online searching for other women's stories is often discouraged. However, online birth stories attract women as a means to learn from one another's experiences of childbirth.
Aim
This study aims to explore Dutch women's use of an online social media platform (Instagram) to represent childbirth by analyzing their narrative strategies.
Method
A collection of 110 Instagram-linked childbirth narratives (2015–2017) were analyzed applying an approach of interpretative repertoires.
Findings
The Dutch women in this study linked birth stories on their Instagram accounts that represented impactful experiences of childbirth. In their narratives, three interconnected repertoires are played out: sharing your story, going into details, and doing it yourself. This study highlights that narrative details of the online birth stories illustrate the physical and procedural obstacles that women overcame in giving birth.
Discussion
Reporting their emotional experiences in detail, women's online sharing of birth stories puts a focus on their personal preferences and decision making, and may ease the way for medical interventions. Without giving explicit advice, personal online birth stories could be instrumental in reformulating the standards of what childbirth is, or should be, like.
Conclusion
Social media networks allow women to exchange stories that structure narrating women's childbirth experiences and offer a structure for the lived or future experiences of others. This may have an impact on women's decision-making during pregnancy and childbirth.
http://bit.ly/2QNo1xw
Bowel Obstruction and Ventral Hernia After Laparoscopic Versus Open Surgery for Rectal Cancer in A Randomized Trial (COLOR II)
Objective: The aim of this study was to evaluate the risk of bowel obstruction, incisional, and parastomal hernia following laparoscopic versus open surgery for rectal cancer. Summary Background Data: Laparoscopic surgery for rectal cancer has been adopted worldwide, after trials reported similar oncological outcomes compared with open surgery. Little is known about long-term morbidity, including bowel obstruction, incisional, and parastomal hernia following surgery. Methods: Patients included in the international, multicenter, noninferior, open-label, randomized COLOR II trial were followed for five years. Primary endpoint was local recurrence at 3-year follow-up. Secondary endpoints included bowel obstruction, incisional and parastomal hernia within 5 years, and the current article reports on these secondary endpoints. Results: All 1044 patients included in the COLOR II trial were analyzed. There was no difference in risk of bowel obstruction, incisional, or parastomal hernia following laparoscopic or open surgery for rectal cancer. Conclusion: Based on long-term morbidity outcomes, laparoscopic surgery for rectal cancer could be considered a routine technique as there are no differences with open surgery.http://bit.ly/2BCwn0r
Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without EGFR mutations
Abstract
Recent clinical trials of non‐small cell lung cancer with immune checkpoint inhibitors revealed that patients with EGFR mutations had more unfavorable outcome compared with those with wild‐type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with/without EGFR mutations to investigate the characteristics of TCR repertoire. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole‐exome sequencing (WES) and transcriptome analysis. TCR diversity index in EGFR‐mutant tumors was significantly higher than that in EGFR‐wild‐type (median [range] 552 [162‐1,135] vs. 230 [30‐764]; P < 0.01), suggesting higher T cell clonal expansion in EGFR‐wild‐type tumors than in EGFR‐mutant tumors. In WES, EGFR‐mutant tumors showed lower numbers of non‐synonymous mutations and predicted neoantigens than EGFR‐wild‐type tumors (P < 0.01, P = 0.03, respectively). The number of non‐synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRβ clonotypes of 1% or higher in tumors (r = 0.52, P = 0.04). The present study demonstrates significant differences in TCR repertoires and number of predicted neoantigens between EGFR‐mutant and wild‐type lung tumors. Our findings provide important information to understand the molecular mechanism that EGFR‐mutant patients show unfavorable responses to immune checkpoint inhibitors.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Ri3wZc
DANCR mediated miR‐665 regulates proliferation and metastasis of cervical cancer through ERK/SMADs pathway
Abstract
Emerging evidence has indicated that miRNAs play an important role in cervical cancer (CC). However, the role of miR‐665 in cervical cancer remains unclear. The aim of our present study was to investigate the potential functions of miR‐665 in CC and to identify the underlying mechanisms of action. In current study, we have shown that miR‐665 was down‐regulated in CC tissues and cell lines, which is negatively correlated with tumor size, distant metastasis, advanced TNM stage and poor prognosis. Functionally, miR‐665 inhibited cell proliferation, migration and invasion and the resistance for cis‐platinum of CC cells, as well as the tumor growth. We validated that TGFBR1 was a direct target of miR‐665 and mediated the ERK/SMADs pathway. In addition, we identified miR‐665 as the ceRNA for lnc‐DANCR. These observations suggested that lnc‐DANCR mediated miR‐665 downregulation regulates the malignant phenotype of CC cells by targeting TGFBR1 through the ERK/SMADs pathway, which may present a path to novel therapeutic stratagems for the CC therapy.
This article is protected by copyright. All rights reserved.
http://bit.ly/2GEKrfE
E2F6 Functions as a Competing Endogenous RNA, and Transcriptional Repressor, to Promote Ovarian Cancer Stemness
Abstract
Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long‐term exposure to estrogen may increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen‐mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c‐Kit, by epigenetic silencing the tumor suppressor miR‐193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c‐KIT, but downregulated miR‐193a. Luciferase assays further confirmed that miR‐193a targets both E2F6 and c‐Kit. Interestingly, ChIP‐PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR‐193a, via recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, while E2F6 or EZH2 depletion derepressed miR‐193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR‐193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen‐mediated E2F6 ceRNA network epigenetically and competitively inhibits miR‐193a activity, promoting ovarian cancer stemness and tumorigenesis.
This article is protected by copyright. All rights reserved.
http://bit.ly/2RlxoEk
An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing
Abstract
The last decade has seen the majority of primary bone tumor subtypes become defined by molecular genetic alteration. Examples include giant cell tumour of bone (H3F3A p.G34W), chondroblastoma (H3F3B p.K36M), mesenchymal chondrosarcoma (HEY1‐NCOA2), chondromyxoid fibroma (GRM1 rearrangements), aneurysmal bone cyst (USP6 rearrangements), osteoblastoma/osteoid osteoma (FOS/FOSB rearrangements), and synovial chondromatosis (FN1‐ACVR2A and ACVR2A‐FN1). All such alterations are mutually exclusive. Many of these have been translated into clinical service using immunohistochemistry or FISH. 60% of central chondrosarcoma is characterised by either isocitrate dehydrogenase (IDH) 1 or IDH2 mutations distinguishing them from other cartilaginous tumours. In contrast, recurrent alterations which are clinically helpful have not been found in high grade osteosarcoma. High throughput next generation sequencing has also proved valuable in identifying germ line alterations in a significant proportion of young patients with primary malignant bone tumors. These findings will play an increasing role in reaching a diagnosis and in patient management.
http://bit.ly/2V7RgJQ
Comparison of pulse contour, aortic Doppler ultrasound and bioelectrical impedance estimates of stroke volume during rapid changes in blood pressure
New Findings
What is the central question of this study?
Pulse contour analysis of the finger arterial pressure by Windkessel modeling is commonly used to continuously estimate stroke volume; but, is it valid during dynamic changes in blood pressure?
What is the main finding and its importance?
Second‐by‐second analysis revealed that pulse contour analysis underestimated stroke volume by up to 25% after standing from a squat, and 16% after standing thigh cuff release when compared to aortic Doppler ultrasound estimates. These results reveal that pulse contour analysis of stroke volume should be interpreted with caution during rapid changes in physiological state.
Abstract
Dynamic measurements of stroke volume (SV) and cardiac output (Q̇) provide an index of central hemodynamics during transitional states, such as posture changes and onset of exercise. The most widely used method to assess dynamic fluctuations in SV is the Modelflow method, which uses the arterial blood pressure waveform along with age and sex specific aortic properties to compute beat‐to‐beat estimates of aortic flow. Modelflow has been validated against more direct methods in steady state conditions, but not during dynamic changes in physiological state, such as active orthostatic stress testing. The present study compared the dynamic SV responses from Modelflow (SVMF), aortic Doppler ultrasound (SVU/S), and bioelectrical impedance analysis (SVBIA) during two different orthostatic stress tests, a squat‐to‐stand (S‐S) transition, and standing bilateral thigh cuff release (TCR) in 15 adults (6 females). Second‐by‐second analysis revealed that when compared to estimates of SV by aortic Doppler ultrasound, Modelflow underestimated SV by up to 25% from 3 – 11 seconds after standing from the squat position and by up to 16% from 3 – 7 seconds following TCR (P < 0.05). SVMF and SVBIA were similar during the first minute of the S‐S transition but were different 3 seconds after TCR, and at intermittent time points between 34 and 44 seconds (P < 0.05). These findings indicate that the physiological conditions elicited by orthostatic stress testing violate some of the inherent assumptions of Modelflow and challenge models used to interpret bioelectrical impedance responses resulting in an underestimation in SV during rapid changes in physiological state.
This article is protected by copyright. All rights reserved
http://bit.ly/2PZdMAV
Paravascular spaces, entry or exit from the brain?
New Findings
What is the topic of this review?
In this symposium report we review the glymphatic clearance from the brain.
What advances does it highlight?
Evaluation of the evidence indicates that cerebrospinal fluid flows along paravascular spaces at the surface of the brain. However, bulk flow along penetrating arteries into the brain, followed by exit along veins, requires further confirmation. Clearance from the brain, based on mixing, may provide an alternative explanation for experimental findings.
Abstract
The interstitial fluid (ISF) of the brain provides the environment for proper neuronal function. Maintenance of volume and composition of ISF requires regulation of influx and removal of water, ions, nutritive and waste products. The recently described glymphatic pathway may contribute to some of these functions. It proposes that cerebrospinal fluid (CSF) enters the brain via paravascular spaces along arteries, mixes with ISF, and leaves the brain via paravascular spaces along veins. In this symposium report we review the glymphatic concept, its concerns, and alternative views on ISF‐CSF exchange.
This article is protected by copyright. All rights reserved
http://bit.ly/2V8EQBD
Dynamic heart rate response to multi‐day unsupported ultra‐endurance cycle racing: A case report
New Findings
What is the main observation in this case?
Ultra‐endurance cycle racing is known to lead to suppressed heart rates as a product of time spent racing. This case report identifies a racer who experienced this phenomenon initially, but then uniquely experienced an overall increase in heart rate late in the race.
What insight does it reveal?
In this case, unique chronotropic disturbances to heart rate occurred as a result of the many extreme demands of ultra‐endurance racing. Work should now focus on identifying the frequency of this response in other racers and whether the causes are physiological, environmental or genetic in nature.
Abstract
Participation in ultra‐endurance cycling events such as the Transcontinental Race is increasing. These extremely demanding races provide a unique opportunity for field observation as to the limits of human endurance physiology and importantly, when these limits might be exceeded, and crossover into pathology. The heart is of special interest in this field and previous data suggest 'reverse drift' of heart rate occurs as a product of time and load in races of 24 ‐ 48 hrs, whilst transient structural abnormalities have been observed upon completion of running ultramarathons. Here, we report a unique case of a male cyclist racing in the Transcontinental Race over an extended period of 14 days characterised by extreme workloads and low quantity and quality of sleep. Heart rate response was dynamic over the course of the race and defined by a U‐shaped quadratic relationship. Larger scale study is required to determine the relevance of this information to the ultra‐endurance cycling community.
This article is protected by copyright. All rights reserved
http://bit.ly/2Q05CbG
Low Serum Hepcidin is Associated with Reduced Short‐term Survival in Adults with Acute Liver Failure
Abstract
Background and Aims
The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)‐induced ALF mouse model
Method
A representative subset of 121 ALF adults (including 66 APAP‐related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) vs. death/transplantation (NSS). Mice were assessed prior to (controls), four and 18 hours after injection of 300 mg/kg APAP
Results
ALF patients as well as APAP‐treated mice displayed increased ferritin, diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1 vs. 34.5 μmol/l; p<0.05) and transferrin saturation (60.9 vs. 79.1%; p<0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/ml; p<0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; p<0.001) than NSS. In a multivariate analysis, a log transformed hepcidin‐containing model displayed similar prognostic power as the established ALFSG index (C‐statistic 0.87 vs. 0.85) and was better than MELD score (C‐statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury
Conclusion
Our findings demonstrate that several serum iron parameters significantly associate with 3‐week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP‐induced ALF, and is an independent predictor and might be a useful component of future prognostic scores.
This article is protected by copyright. All rights reserved.
http://bit.ly/2EMfPal
Dual‐specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice through TAK1 Suppression
Abstract
Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low‐ grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study observed that the expression of Dusp26 (dual‐specificity phosphatase 26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses and insulin resistance were exacerbated in liver‐specific Dusp26‐knockout (KO) mice but ameliorated in liver‐specific Dusp26‐transgenic mice induced by a high‐fat diet (HFD). In addition, the degree of liver fibrosis was aggravated in high‐fat high‐cholesterol diet (HFHC)‐induced Dusp26‐KO mice. We further found that the binding of Dusp26 to TAK1 to block the phosphorylation of TAK1 regulated the TAK1‐p38/JNK signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusions
These findings suggest that Dusp26 is a good TAK1‐dependent therapeutic target for NAFLD.
This article is protected by copyright. All rights reserved.
http://bit.ly/2EMrYev
The role of 3D‐MRE in the diagnosis of NASH in obese patients undergoing bariatric surgery
Abstract
The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of 3D‐MRE, with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and MRI proton density fat fraction (MRI‐PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015‐2017 (prospective cohort, n=88) and 2010‐2013 (retrospective cohort, n=87). The imaging protocol consisted of multifrequency 3D‐MRE (mf3D‐MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH; and MRI‐PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D‐MRE technical parameters for NASH detection. The 2 cohorts were then combined to derive predictive models of NASH and disease activity by NAFLD activity score (NAS) using the 3 imaging parameters that correlated with NASH. A total of 175 patients, median age 45, 81% women, and 81 (46%) with histologic NASH were used for model derivation. From the complex shear modulus output generated by mf3D‐MRE, the damping ratio at 40Hz and shear stiffness at 60Hz best correlated with NASH. The fat fraction obtained from MRI‐PDFF correlated with steatosis (p<0.05 for all). These 3 parameters were fit into a logistic regression model which predicted NASH with cross‐validated AUROC=0.73, sensitivity=0.67, specificity= 0.80, PPV= 0.73 and NPV=0.74 and disease activity by NAS with cross‐validated AUROC=0.82.
Conclusion
Multifrequency 3D‐MRE allows identification of novel imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in non‐bariatric cohorts.
This article is protected by copyright. All rights reserved.
http://bit.ly/2ENvEhc
Involvement of non melanocytic skin cells in vitiligo
Abstract
Despite melanocytes are the key players in vitiligo, a continuous cross‐talk between epidermal and dermal cells may strictly affect their functionality, in both lesional and non‐lesional skin. Focusing on this interplay, we have reviewed existing literature supporting evidence on cellular and functional alterations of surrounding epidermal keratinocytes, extracellular matrix (ECM) proteins and fibroblasts in the underlying dermal compartment that may contribute to melanocyte disappearance in vitiligo. We have also examined some clinical and therapeutic aspects of the disease to sustain the non‐exclusive involvement of melanocytes within vitiligo. As a result, a different and more complex scenario has appeared that may enable to provide better understanding about origins and progress of vitiligo and that should be considered in the evaluation of new treatment approaches.
This article is protected by copyright. All rights reserved.
http://bit.ly/2T9WOlf
Phosphatidylinositol 3‐kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities
Background
The phosphatidylinositol 3‐kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co‐alterations serving as potential resistance/attenuation mechanisms.
Methods
Consecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment‐certified laboratory using comprehensive genomic profiling performed by next‐generation sequencing (315 genes). The co‐alterations evaluated included the Erb‐B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto‐oncogene tyrosine kinase (MET), and mitogen‐activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).
Results
Alterations in any of 18 PI3K‐pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co‐occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co‐occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.
Conclusions
Comprehensive genomic profiling reveals altered PI3K‐related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co‐occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.
http://bit.ly/2Q10OTt
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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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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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