Horses afflicted with degenerative suspensory ligament desmitis (DSLD) suffer from progressive leg pain and lameness without history of trauma. DSLD is a systemic disorder caused by abnormal accumulation of pr...
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Τετάρτη 19 Σεπτεμβρίου 2018
Does BMP2 play a role in the pathogenesis of equine degenerative suspensory ligament desmitis?
Effects of mutations in the effector domain of influenza A virus NS1 protein
The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, ...
https://ift.tt/2DfWgqX
Cancers, Vol. 10, Pages 342: Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer
Cancers, Vol. 10, Pages 342: Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer
Cancers doi: 10.3390/cancers10100342
Authors: Babak Nami Hamid Maadi Zhixiang Wang
Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20–30% of breast cancers. HER2 is a preferred target for treating HER2-positive breast cancer. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved by the Food and Drug Administration (FDA) to use as adjuvant therapy in combination with docetaxel to treat metastatic HER2-positive breast cancer. Adding the monoclonal antibodies to treatment regimen has changed the paradigm for treatment of HER2-positive breast cancer. Despite improving outcomes, the percentage of the patients who benefit from the treatment is still low. Continued research and development of novel agents and strategies of drug combinations is needed. A thorough understanding of the molecular mechanisms underlying the action and synergism of trastuzumab and pertuzumab is essential for moving forward to achieve high efficacy in treating HER2-positive breast cancer. This review examined and analyzed findings and hypotheses regarding the action and synergism of trastuzumab and pertuzumab and proposed a model of synergism based on available information.
https://ift.tt/2Oz7fwW
Both ETFDH mutations and FAD homeostasis disturbance are essential for developing riboflavin‐responsive multiple Acyl‐CoA dehydrogenation deficiency
Annals of Neurology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2xA6Xih
A super-resolution method-based pipeline for fundus fluorescein angiography imaging
Fundus fluorescein angiography (FFA) imaging is a standard diagnostic tool for many retinal diseases such as age-related macular degeneration and diabetic retinopathy. High-resolution FFA images facilitate the...
https://ift.tt/2QIGo2S
The effect of virtual reality-based balance training on motor learning and postural control in healthy adults: a randomized preliminary study
Adults with sedentary lifestyles seem to face a higher risk of falling in their later years. Several causes, such as impairment of strength, coordination, and cognitive function, influence worsening health con...
https://ift.tt/2xyPKWb
Comparative mechanical analysis of deep brain stimulation electrodes
The new field of neuro-prosthetics focuses on the design and implementation of neural prostheses to restore some of the lost neural functions. The electrode-tissue contacts remain one of the major obstacles of...
https://ift.tt/2QPU3p8
Correction to: The study of human Y chromosome variation through ancient DNA
The following sentence on the 11th page of the article.
https://ift.tt/2plbQb6
Atypical sensory processing pattern following median or ulnar nerve injury — a case-control study
Due to brain plasticity a transection of a median or ulnar nerve results in profound changes in the somatosensory areas in the brain. The permanent sensory deprivation after a peripheral nerve injury might inf...
https://ift.tt/2PPfTrq
Epidemiological characteristics and influential factors of hand, foot, and mouth disease reinfection in Wuxi, China, 2008–2016
Hand, foot, and mouth disease (HFMD) is a viral disease caused by human enteroviruses. Although HFMD reinfection is common, studies investigating this phenomenon are insufficient.
https://ift.tt/2ODhZKS
Effects of a clinical pathway on antibiotic use in patients with community-acquired pneumonia: a multi-site study in China
Community-acquired pneumonia (CAP) is a common condition with high mortality, morbidity and healthcare costs. This study aimed to determine whether clinical pathway (CP) implementation in different hospitals i...
https://ift.tt/2NTWgkO
California Lawsuit Claims AbbVie Paid Doctors to Prescribe Humira
WEDNESDAY, Sept. 19, 2018 -- A lawsuit filed Tuesday in California claims that pharmaceutical company AbbVie used cash, gifts, and services to induce doctors to overprescribe the widely used drug Humira (adalimumab), ignoring the medicine's...
https://ift.tt/2xCsV3W
Medicaid Expansion Linked to Gains in Insurance Coverage
WEDNESDAY, Sept. 19, 2018 -- Medicaid expansion was associated with gains in insurance among low-income adults with substance use disorders, but corresponding treatment gains were not seen, according to a study published in the August issue of...
https://ift.tt/2QE1uzD
No Clear Benefit for Rivaroxaban After Hospital Discharge
WEDNESDAY, Sept. 19, 2018 -- Rivaroxaban does not lower risk of symptomatic venous thromboembolism and related death in medical patients after hospital discharge, compared to placebo, according to a study published in the Sept. 20 issue of the New...
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Pediatricians Have Role in Supporting Transgender Youth
WEDNESDAY, Sept. 19, 2018 -- In an American Academy of Pediatrics policy statement published online Sept. 17 in Pediatrics, recommendations are presented to ensure comprehensive care and support for youth who identify as transgender and gender...
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A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarkers
Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. Experimental Design: Sixty men were treated with alisertib50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; 50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival (rPFS). Pre-treatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed. Results: Median PSA was 1.13 ng/ml (0.01-514.2), number of prior therapies was three, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%),AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3-13). Four exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption. Conclusions: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.
https://ift.tt/2xIilsv
Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma
Purpose: Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with ex vivo-activated human natural killer (aNK) cells. Experimental Design: The effect of combining dinutuximab with human aNK cells was determined in vitro with cellular cytotoxicity and Matrigel invasion assays. The in vivo efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient derived xenograft (PDX) in immune deficient NOD-scid gamma (NSG) mice. Results: In vitro, the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared to that of untreated mice. Conclusions: The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immune deficient mice.
https://ift.tt/2QHAcbz
Outcomes of Older Hospitalized Patients Requiring Rapid Response Team Activation for Acute Deterioration
Objectives: Rapid response teams are groups of healthcare providers that have been implemented by many hospitals to respond to acutely deteriorating patients admitted to the hospital wards. Hospitalized older patients are at particular risk of deterioration. We sought to examine outcomes of older patients requiring rapid response team activation. Design: Analysis of a prospectively collected registry. Setting: Two hospitals within a single tertiary care level hospital system between 2012 and 2016. Patients: Five-thousand nine-hundred ninety-five patients were analyzed. Comparisons were made between older patients (defined as ≥ 75 yr old) and younger patients. Interventions: None. Measurements and Main Results: All patient information, outcomes, and rapid response team activation information were gathered at the time of rapid response team activation and assessment. The primary outcome was in-hospital mortality, analyzed using multivariate logistic regression. Two-thousand three-hundred nine were older patients (38.5%). Of these, 835 (36.2%) died in-hospital, compared with 998 younger patients (27.1%) (adjusted odds ratio, 1.83 [1.54–2.18]; p
https://ift.tt/2pn7qAI
https://ift.tt/2pn7qAI
Effects of Polyethylene Glycol-20k on Postresuscitation Myocardial and Cerebral Function in a Rat Model of Cardiopulmonary Resuscitation
Objectives: Polyethylene glycol-20k is a hybrid cell impermeant that reduces ischemia injury and improves microcirculatory flow during and following low flow states through nonenergy-dependent water transfer in the microcirculation. We investigated the effects of polyethylene glycol-20k on postresuscitation microcirculation, myocardial and cerebral function, and duration of survival in a rat model of cardiopulmonary resuscitation. Design: Ventricular fibrillation was induced in 20 male Sprague Dawley rats and untreated for 6 minutes. Animals were randomized into two groups (n = 10 for each group): polyethylene glycol-20k and control. Polyethylene glycol-20k (10% solution in saline, 10% estimated blood volume) and vehicle (saline) were administered at the beginning of cardiopulmonary resuscitation by continuous IV infusion. Resuscitation was attempted after 8 minutes of cardiopulmonary resuscitation. Setting: University-Affiliated Research Laboratory. Subjects: Sprague Dawley Rats. Interventions: Polyethylene glycol-20k. Measurements and Main Results: Buccal microcirculation was measured at baseline, 1, 3, and 6 hours after return of spontaneous circulation using a side-stream dark-field imaging device. Myocardial function was measured by echocardiography at baseline and every hour postresuscitation for 6 hours. The animals were then returned to their cage and observed for an additional 72 hours. Neurologic Deficit Scores were recorded at 24, 48, and 72 hours after resuscitation. Postresuscitation ejection fraction, cardiac output, and myocardial performance index were significantly improved in animals treated with polyethylene glycol-20k (p
https://ift.tt/2MMndlF
https://ift.tt/2MMndlF
Reconsidering Sham in Transcutaneous Vagus Nerve Stimulation studies
In their most recent study, Keute and colleagues demonstrated that transcutaneous vagus nerve stimulation (tVNS) induced a GABAergic neuromodulation during automatic motor inhibition (Keute et al., 2018). They chose to monitor the Negative Compatibility Effect (NCE) as a behavioral marker of automatic motor inhibition. Nevertheless, the tVNS-induced increase of NCE found was totally unexpected, going into the opposite direction of the decrease they had hypothesized, according to previous results.
https://ift.tt/2NUTnQI
Assessment of the Influence on Spontaneous Pregnancy of Hysterosalpingo-Contrast Sonography
Objective. Our objective was to explore whether the pregnancy rate (PR) was higher than usual after hysterosalpingo-contrast sonography (HyCoSy). Methods. We conducted a prospective observational study of 1,008 infertility patients, all of whom were examined by HyCoSy. The expected time for spontaneous pregnancy was at least 180 days after the HyCoSy exams. There were three types of HyCoSy results: type I, defined as both fallopian tubes patent; type II, defined as one fallopian tube patent with obstruction in the other; and type III, defined as both fallopian tubes obstructed. During the HyCoSy examinations, we recorded the mobility of the ovaries, injective resistance, and contrast agent venous intravasation. Before the examinations, we recorded each patient's medical history, including maternal age, infertility type, median duration of menstrual cycle, dysmenorrhea, and parity number. Results. The PR was 19.44% within 180 days after HyCoSy and it was significantly higher in the first 30 days (6.35%) (P <.01 the pr of type i was highest with a rate followed by ii and iii univariate analysis showed that younger age patency both fallopian tubes good ovarian mobility absence injective resistance were positively related to initiation pregnancy infertility median duration menstrual cycle dysmenorrhea parity number contrast agent venous intravasation identity sonographer unrelated>.05). However, multivariate analysis showed that patency of both fallopian tubes and the absence of injective resistance were independently associated with pregnancy. Conclusion. Some infertility patients conceived successfully and naturally not long after HyCoSy, most often in the first month after the examination. Multivariate analysis showed that patency of both fallopian tubes and the absence of injective resistance were independently factors associated with the ability to conceive after HyCoSy examination.
https://ift.tt/2Ntwvsd
Nonintegrating Direct Conversion Using mRNA into Hepatocyte-Like Cells
Recently, several researchers have reported that direct reprogramming techniques can be used to differentiate fibroblasts into hepatocyte-like cells without a pluripotent intermediate step. However, the use of viral vectors for conversion continues to pose important challenges in terms of genome integration. Herein, we propose a new method of direct conversion without genome integration with potential clinical applications. To generate hepatocyte-like cells, mRNA coding for the hepatic transcription factors Foxa3 and HNF4α was transfected into mouse embryonic fibroblasts. After 10-12 days, the fibroblasts converted to an epithelial morphology and generated colonies of hepatocyte-like cells (R-iHeps). The generated R-iHeps expressed hepatocyte-specific marker genes and proteins, including albumin, alpha-fetoprotein, HNF4α, CK18, and CYP1A2. To evaluate hepatic function, indocyanine green uptake, periodic acid-Schiff staining, and albumin secretion were assessed. Furthermore, mCherry-positive R-iHeps were engrafted in the liver of Alb-TRECK/SCID mice, and we confirmed FAH enzyme expression in /RJ models. In conclusion, our data suggest that the nonintegrating method using mRNA has potential for cell therapy.
https://ift.tt/2DaCsp3
Effect of Aspirin on All-Cause Mortality in the Healthy Elderly
The Aspirin in Reducing Events in the Elderly (ASPREE) trial was a primary prevention trial that was established to investigate whether the daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults. The trial, which was conducted in Australia and the United…
https://ift.tt/2xn4QPy
Effect of Aspirin on All-Cause Mortality in the Healthy Elderly
The Aspirin in Reducing Events in the Elderly (ASPREE) trial was a primary prevention trial that was established to investigate whether the daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults. The trial, which was conducted in Australia and the United…
https://ift.tt/2xn4QPy
Effect of Aspirin on Disability-free Survival in the Healthy Elderly
Several large, randomized trials have shown the efficacy of aspirin for the secondary prevention of cardiovascular disease among persons with a history of coronary heart disease or stroke. The evidence supporting a benefit of aspirin therapy in the primary prevention of cardiovascular or other…
https://ift.tt/2MNMwDK
Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly
Dramatic increases in life expectancy over the past century have led to a substantial demographic shift toward an aging society in many countries. Thus, maintaining good health in older persons is an increasingly important public health aim. Cardiovascular diseases are among the principal causes of…
https://ift.tt/2MNI9J3
235 Push-Dose Vasopressors: A Time Motion Study
In recent years, push-dose vasopressors (PDP) utilization has increased amongst providers in the emergency department (ED). In theory, PDPs are faster to prepare, compared to vasopressor drips, therefore being able to increase a patient's blood pressure to promote organ perfusion faster. The time to preparation of PDPs has yet to be described, as there are few studies looking at the benefit and utility of this therapy as a whole. This study was intended to provide a time comparison for the preparation of PDP to the time for preparation of continuous infusion vasopressors.
https://ift.tt/2MMGnIe
340 Can Serial Central Nervous System Biomarkers Predict Neuro-Worsening in Mild Traumatic Brain Injury?
Determine if serial serum concentrations of glial fibrillary acidic protein (GFAP) or ubiquitin-C-terminal Hydrolase L1 (UCH-L1) predict neurologic worsening in patients with mild traumatic brain injury (mTBI)
https://ift.tt/2MMGiUW
276 No Evidence of Sedation of Tolperisone Compared to Cyclobenzaprine in a Crossover Driving Simulation Study
Tolperisone is a centrally acting muscle relaxant being developed in the US as a treatment for acute and painful symptoms of neck and low back muscle spasms. This study explores the impact of tolperisone on driving simulation endpoints, sedation, and cognition compared to placebo (PBO) and cyclobenzaprine (CYC). The CYC half-life is long (>19 hours) and accumulated over the 3 days of the trial. Tolperisone has a Tmax of 1 hour, and a 2- to 3-hour half-life.
https://ift.tt/2pkNRsA
308 Timeliness of Inter-Facility Transfer for Patients With Acute Large Vessel Occlusion Stroke
Ischemic stroke is a leading cause of morbidity and mortality in the U.S. and an estimated 11-46% of stroke patients have a large vessel occlusion (LVO). LVOs are associated with increased disability and mortality, particularly when the preferred treatment, mechanical thrombectomy (MT), is delayed. A delay as short as 15 minutes can impact both morbidity and mortality in acute ischemic stroke, and delays diminish both MT effectiveness and potential eligibility for MT. With nearly half of the U.S.
https://ift.tt/2MPQLie
356 Pharmaceutical Drug Poisoning After Deregulation of Over-the-Counter Drugs Sales: Emergency Department Based Injury In-Depth Injury Surveillance
The Korean government approved selected nonprescription drugs (over-the-counter drug; OTC drug) to be distributed in convenience stores from 15. Nov. 2012. The aim of this study is to describe the changes of incidence and the clinical outcome of acute therapeutic drug poisoning after the deregulation of OTC drugs sales.
https://ift.tt/2pmkw0Q
292 Assessing the Impact of Telemedicine on Nursing Home Transfers
The aim of this pilot was to implement a telemedicine program in the nursing home setting and to measure the effect of telemedicine in reducing preventable hospital transfers. Our data reports on a pilot initiated at a skilled nursing facility in Staten Island, New York participating in the Delivery System Reform Incentive Payment (DSRIP) program.
https://ift.tt/2pmkp5q
50 Influential Predictors of Suicide Attempt Among Suicidal Ideators Following an Emergency Department Visit
Recent research has found that many traditionally studied psychiatric risk factors do not significantly differ between individuals who think about suicide and those who act on their thoughts (Klonsky & May, 2015; Zalsman et al., 2016), an important distinction as only one-third of those who think about suicide carry out a suicide attempt (Nock et al., 2009). While there is support for some psychiatric factors (eg, anxiety, substance use disorders, sleep disturbance; Beghi et al, 2013; Pigeon et al., 2016; Walsh et al., 2017) being useful in differentiating these groups, limited research has utilized a longitudinal framework to identify risk factors that predict suicide attempts (SA) among those with suicidal ideation (SI) over time.
https://ift.tt/2MN6I99
348 Predictive Modeling for Poor Neurologic Outcome After Cardiac Arrest Using Multimodal Approach
Assessment of the accurate prognosis with spontaneous circulation after cardiac arrest is crucial in deciding to withdrawal of life sustaining treatment for patients predicted poor neurologic outcome. We investigated the accuracy of systemic multimodal approach to predict the poor neurologic outcome of patients applied targeted temperature management (TTM).
https://ift.tt/2pjwNDo
332 “Opt-Out” HIV Screening in the Emergency Department Discovers a High Prevalence of Undiagnosed HIV in the Upstate of South Carolina: Brief Report on the Conclusion of an 8-Year Emergency Department Collaboration With South Carolina Department of Health and Environmental Control
With over 1.2 million Americans living with HIV, the HIV/AIDS epidemic remains a large public health threat, particularly among underserved populations. Because emergency departments (EDs) are often the only access that many US citizens utilize for health care, EDs are in a unique position to identify HIV positive individuals from high-risk populations and have been selectively emphasized as critical capture points in multiple studies. This study reviews a 8-year collaboration with the South Carolina Department of Health and Environmental Control (DHEC) and local HIV clinics to establish a generalized "opt-out" HIV screening program in the only Level I Trauma Center ED serving the Upstate region of South Carolina (∼95K adult visits/year).
https://ift.tt/2MNUFrY
316 Prospective Assessment of Pediatric Medical Emergencies and Risk Factors for Traumatic Injuries in the Pediatric Emergency Unit of Kenyatta National Hospital, Nairobi, Kenya
The epidemiology and presence of risk factors for pediatric traumatic and medical emergencies in Kenya and resource-limited settings are not well understood. This is a barrier to providing quality, acute care within the local health systems. We performed a prospective, cross-sectional study that aimed to (1) describe the epidemiology of visits to the Pediatric Emergency Unit (PEU) at Kenyatta National Hospital (KNH) in Nairobi, Kenya; and (2), to describe the risk factors for traumatic injuries among PEU patients.
https://ift.tt/2pmkeHi
300 The Effect of Reviewing Health Information Exchange Data on Emergency Department Care Times and Imaging
Establishing interoperability through health information exchange (HIE) is expected to reduce health care costs and improve quality of care. These benefits are presumed to be associated with reductions in repeat testing and reduced rates of admission. Our institution utilizes Epic's Care Everywhere, an HIE which functions on a combination of push and pull data exchanges with multiple neighboring institutions including 3 of the 4 regional academic institutions. When HIE data is available, an activity tab becomes viewable to the end user, but there are no prompts to review this information.
https://ift.tt/2MNsnhd
284 Acute Ischemic Stroke and Hospital Discharge Outcomes after tPA
To examine the risk of short term outcomes after tPA for acute ischemic stroke.
https://ift.tt/2poidKR
268 A Simulation-Based Mastery Learning Ultrasound Guided IV Insertion Curriculum for Emergency Medicine Trainees
Establishing venous access in difficult IV access (DIVA) patients is a Accreditation Council for Graduate Medical Education (ACGME) milestone for emergency medicine trainees. Ultrasound-guided IV (USGIV) insertion is a safe and effective procedure to obtain access in DIVA patients; however, at our institution, most residents receive only informal instruction. Simulation-based mastery learning (SBML) is an educational model that engages learners in simulated scenarios and involves deliberate practice until a predetermined standard is achieved.
https://ift.tt/2MSiuPC
360 Characteristics of Posts of Opioid Users on Reddit, an Online Social Media Forum, an Area for Improved Harm Reduction
To characterize postings made on the reddit.com forum titled "opiates." In particular, we tested the hypothesis that the proportion of online posts glorifying opiate use is greater than the proportion advocating harm reduction. We further characterized posts across a variety of categories.
https://ift.tt/2pnFI6D
352 Combining Quick Sepsis-Related Organ Failure Assessment Criteria and Lactate Levels for Screening of Septic Patients for Critical Illness
Screening patients for critical illness is a cornerstone of care for sepsis patients in the emergency department (ED). We previously showed that the quick Sepsis related Organ Failure Assessment (qSOFA) criteria thresholds had slightly better ED-centered screening performance for early critical illness than traditional systemic inflammatory response syndrome (SIRS)/sepsis criteria and lactate levels. Yet, with relatively low sensitivity (86%), qSOFA criteria may still miss a substantial number of patients when used alone for critical illness screening.
https://ift.tt/2MMcOqb
344 Prognostic Indicators of Being Discharged Home After an Ischemic Stroke
Acute ischemic stroke is a high-stakes diagnosis, after which fully 20% are dead at 90 days, and more than 50% cannot return to their previous functional ability or employment. It is thus important to understand what, if any, are prognostic markers for discharge to home after acute ischemic stroke. In this study we sought to determine which clinical and demographic variables are associated with a favorable prognosis, as characterized by discharge to home (with or without home health care).
https://ift.tt/2poQs4U
336 The Effect of Implementing Electronic Health Record Default Prescribing Preferences on Opioid Prescriptions Written in the Emergency Department
The United States is in the midst of an opioid epidemic. Of more than 42,000 opioid deaths in 2016, 40% were related to prescription medications. Emergency department (ED) visit prescriptions may provide the initial exposure for many patients who subsequently misuse or develop opioid use disorder (OUD). Physician prescribing patterns can vary extensively, however ED physicians are among the top 5 opioid prescribers in all medical specialties in almost all age groups. It is well documented that a larger quantity of tablets or prolonged prescription duration is associated with increased risk of chronic opioid use.
https://ift.tt/2MMcF67
Development of a Dietary Methyl Donor Food Frequency Questionnaire to Assess Folate and Vitamin B12 Status in Children with Chronic Hepatitis B Virus Infection
To develop a dietary methyl donor food frequency questionnaire (DMD-FFQ) that is validated in a cohort of US children and to determine whether the consumption of folate and vitamin B12, principal DMDs, correlates with HBV DNA levels and its methylation density.
https://ift.tt/2DeJQzB
Executive Function and Psychosocial Quality of Life in School Age Children with Congenital Heart Disease
To test a model to predict psychosocial quality of life (QOL) in children with congenital heart disease (CHD) via executive dysfunction.
https://ift.tt/2pkIbPi
Tumor trailing for liver SBRT on the MR-Linac
and purpose: Tumor trailing is a treatment delivery technique which continuously adjusts the beam aperture according to the last available time-averaged position of the target. This study investigates whether tumor trailing on the MR-Linac can improve target coverage in liver SBRT in the case of baseline motion.
https://ift.tt/2OF5LRM
p53-loss mitigates early volume deficits in the brains of irradiated young mice
In the brain, radiation-induced apoptosis is largely mediated by p53. We used longitudinal magnetic resonance imaging in a mouse model to map radiation-induced changes in neuroanatomy and quantified the impact of knocking out p53. We observed mitigation of radiation-induced volume loss by p53-knockout one week after treatment, but this was not maintained to adulthood due to decreased growth.
https://ift.tt/2NUEEoU
Using DNA Immunization to Elicit Monoclonal Antibodies in Mice, Rabbits, and Humans
Human Gene Therapy, Volume 29, Issue 9, Page 997-1003, September 2018.
https://ift.tt/2OBA8Zj
Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine
Human Gene Therapy, Volume 29, Issue 9, Page 1011-1028, September 2018.
https://ift.tt/2NWbENh
A Synthetic Micro-Consensus DNA Vaccine Generates Comprehensive Influenza A H3N2 Immunity and Protects Mice Against Lethal Challenge by Multiple H3N2 Viruses
Human Gene Therapy, Volume 29, Issue 9, Page 1044-1055, September 2018.
https://ift.tt/2OAhzF6
Targeting of Influenza Viral Epitopes to Antigen-Presenting Cells by Genetically Engineered Chimeric Molecules in a Humanized NOD SCID Gamma Transfer Model
Human Gene Therapy, Volume 29, Issue 9, Page 1056-1070, September 2018.
https://ift.tt/2NVLTwN
DNA Vaccination in 2018: An Update
Human Gene Therapy, Volume 29, Issue 9, Page 963-965, September 2018.
https://ift.tt/2OynASy
“The Same Thing That Makes You Live Can Kill You in the End”: Exploring the Effects of Growth Rates and Longevity on Cellular Metabolic Rates and Oxidative Stress in Mammals and Birds
Abstract
All aerobic organisms are subjected to metabolic by-products known as reactive species (RS). RS can wreak havoc on macromolecules by structurally altering proteins and inducing mutations in DNA, among other deleterious effects. To combat accumulating damage, organisms have an antioxidant system to sequester RS before they cause cellular damage. The balance between RS production, antioxidant defences, and accumulated cellular damage is termed oxidative stress. Physiological ecologists, gerontologists, and metabolic biochemists have turned their attention to whether oxidative stress is the principal, generalized mechanism that mediates and limits longevity, growth rates, and other life-history trade-offs in animals, as may be the case in mammals and birds. At the crux of this theory lies the regulation and activities of the mitochondria with respect to the organism and its metabolic rate. At the whole-animal level, evolutionary theory suggests that developmental trajectories and growth rates can shape the onset and rate of aging. Mitochondrial function is important for aging since it is the main source of energy in cells, and the main source of RS. Altering oxidative stress levels, either increase in oxidative damage or reduction in antioxidants, has proven to also decrease growth rates, which implies that oxidative stress is a cost of, as well as a constraint on, growth. Yet, in nature, many animals exhibit fast growth rates that lead to higher loads of oxidative stress, which are often linked to shorter lifespans. In this article, I summarize the latest findings on whole-animal life history trade-offs, such as growth rates and longevity, and how these can be affected by mitochondrial cellular metabolism, and oxidative stress.https://ift.tt/2QGBi7z
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. The authors declare no conflicts of interest. Reprints: Robert J. Amdur, MD, 2000 SW Archer Road, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: amdurr@shands.ufl.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2pmGosV
https://ift.tt/2pmGosV
An Efficient Strategy for Generating Tissue-specific Binary Transcription Systems in Drosophila by Genome Editing
https://ift.tt/2NWuX9p
LncRNA-135528 inhibits tumor progression by up-regulating CXCL10 through the JAK/STAT pathway
Abstract
Spontaneous tumor regression can be observed in many tumors, however, studies related to the altered expression of lncRNA in spontaneous glioma regression are limited, and the potential contributions of lncRNAs to spontaneous glioma regression remain unknown. To investigate the biological roles of lncRNA-135528 in spontaneous glioma regression. The cDNA fragment of lncRNA-135528 was obtained by rapid-amplification of cDNA ends (RACE) technology and cloned into the plvx-mcmv-zsgreen-puro vector. Additionally, we stably silenced or overexpressed lncRNA-135528 in G422 cells by transfecting with siRNA against lncRNA-135528 or lncRNA-135528 overexpression plasmid. Then, we examined lncRNA-135528 overexpressing and lncRNA-135528 silencing on glioma cells and its effects on CXCL10 and JAK/STAT pathways. The main findings indicated that lncRNA-135528 promoted glioma cell apoptosis, inhibited cell proliferation and arrested cell cycle progression; the up-regulation of lncRNA135528 led to significantly increased CXCL10 levels and the differential expression of mRNA associated with JAK/STAT pathway in glioma cells. lncRNA-135528 can inhibit tumor progression by up-regulating CXCL10 through the JAK/STAT pathway.
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Giant craniopharyngioma in an adult presenting with new onset seizure
Description
A 43-year-old man presented to the emergency department after experiencing a first episode seizure. No further information was available at presentation as the patient was confused on his arrival. On physical examination, vital signs were normal. The patient was confused, and his Glasgow Coma Score was 12(E3V4M5). Initial workup included complete blood count, electrolytes and ECG were normal. Thyroid function tests, insulin growth factor-1 and plasma random cortisol level were within the normal range. Testosterone levels were low, and luteinising hormone was inappropriately normal. CT demonstrated a cystic mass with peripheral calcification measuring 6.0x4.5x3.9 cm. The lesion originated from the pituitary fossa and expanded superiorly distorting the third ventricle and the left lateral ventricle causing hydrocephalus (figure 1). A pituitary MRI confirmed these findings (figure 2). The patient underwent a craniotomy with mass resection. The procedure was uneventful. Pathology demonstrated nodular whorls and...
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Partial mid-portion Achilles tear resulting in substantial improvement in pain and function in an amateur long-distance runner
This case presents symptom resolution for a long-distance runner with chronic Achilles tendinopathy (AT), following a partial tear of his Achilles tendon. The patient reported a sudden pain during a morning run, with preserved function. Three hours postinjury, he was reviewed in a musculoskeletal clinic. An ultrasound scan confirmed a partial Achilles tear, associated with significant Doppler activity. His index of AT severity The Victorian Institute of Sports Assessment - Achilles Questionnaire (VISA-A) 4 hours postinjury was markedly higher compared with 2 weeks preinjury, indicating reduced symptom severity. A follow-up scan 4 weeks postinjury showed minimal mid-portion swelling and no signs of the tear. His VISA-A score showed continued symptom improvement. This case represents resolution of tendinopathic symptomatology post partial Achilles tear. While the natural histories of AT and Achilles tears remain unknown, this case may indicate that alongside the known role of loading, inflammation may be a secondary mediator central to the successful resolution of AT pain.
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87-year-old woman with improved pulmonary function following accidental long-term inhalation therapy with dabigatran
Accidental long-term dabigatran etexilate inhalation was associated with subtherapeutic dabigatran serum concentrations in an elderly female patient with restrictive lung disease. A significant improvement in her pulmonary function was noted without other therapy directed towards her bronchopulmonary disease.
https://ift.tt/2QJpQI7
Unusual case of levamisole-induced dual-positive ANCA vasculitis and crescentic glomerulonephritis
Cocaine adulterated levamisole is an increasingly reported cause of skin necrosis, arthralgia and systemic vasculitis, but renal involvement is uncommon. We present a case of a 40-year-old Hispanic man with a history of cocaine abuse who presented with acute kidney injury to the rheumatology clinic where he was being treated for chronic inflammatory arthritis. He was found to have a serum creatinine of 2.5 mg/dL, microscopic haematuria and subnephrotic proteinuria, along with positive proteinase 3, myeloperoxidase, anticardiolipin antibodies and an elevated antinuclear antibody titre. The renal pathology revealed focal necrotising glomerulonephritis with crescentic features and mild immune type deposition. The patient was treated with cocaine abstinence, pulse dose steroids followed by maintenance prednisone, rituximab and cyclophosphamide. His renal function subsequently improved but did not normalise. We believe that his incomplete improvement was due to the degree of kidney injury on presentation as well as recidivism with cocaine use.
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Microangiopathic haemolytic anaemia with thrombocytopenia induced by vitamin B12 deficiency long term after gastrectomy
Microangiopathic haemolytic anaemia with thrombocytopenia, called pseudo-thrombotic microangiopathy (TMA), is a clinically important complication in patients with vitamin B12 deficiency. We herein present a case of an 80-year-old woman with pseudo-TMA after gastrectomy. She was initially suspected with thrombotic thrombocytopenic purpura based on rapid progression of anaemia with schistocytes and thrombocytopenia; however, her anaemia and thrombocytopenia were improved by vitamin B12 supplementation alone, with a single session of plasma exchange. Vitamin B12 deficiency was finally confirmed by low vitamin B12 levels from the patient's initial blood sample. In addition, normal ADAMTS13 activity was proven, lowering the likelihood of thrombotic thrombocytopenic purpura. Therefore, this patient was diagnosed with pseudo-TMA caused by vitamin B12 deficiency. Pseudo-TMA can occur in patients with vitamin B12 deficiency post-gastrectomy.
https://ift.tt/2QJpMIn
Herpes simplex virus keratitis mimicking Acanthamoeba keratitis: a clinicopathological correlation
A 36-year-old male, soft contact lens wearer was referred by his primary ophthalmologist for corneal ulcer of the right eye (OD), which was persistent despite topical fluoroquinolone therapy for 1 month. A ring-shaped infiltrate typically seen in Acanthamoeba infection was noted, and topical therapy with chlorhexidine and polyhexamethylene biguanide was initiated. However, the patient's condition deteriorated over the next several weeks; thus, diagnostic and therapeutic penetrating keratoplasty was performed. The postoperative immunohistochemical analysis suggested a diagnosis of herpes simplex virus (HSV) keratitis. The patient ultimately improved after initiation of oral valacyclovir following penetrating keratoplasty. We report a case of a commonly encountered clinical entity, HSV keratitis, with an atypical clinical presentation, masquerading as Acanthamoeba keratitis.
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Acute testicular pain secondary to a leaking abdominal aortic aneurysm (AAA)
We present the case of a 56-year-old male smoker with a background of hypertension who presented with acute onset right testicular pain secondary to a leaking abdominal aortic aneurysm. Following urgent surgical repair and a complicated intensive care recovery, the patient was discharged with no residual disability. This case highlights an atypical presentation of what is a devastating illness.
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Isolated Fourniers gangrene of the penis with penile autoamputation
Description
A 65-year-old non-diabetic man presented to us with blackish discolouration of his penile shaft for 10 days (figures 1 and 2). He had undergone total thyroidectomy for follicular carcinoma of the thyroid gland 2 weeks previously. Intraoperatively, failed attempts were made to catheterise the patient. These attempts were traumatic, and a suprapubic catheter was hence placed. Following this, he developed inflammation and oedema on his penile shaft which then gradually started turning black for which he came to us. A diagnosis of isolated Fournier's gangrene of penis was made. Debridement was done, and the patient was advised regular dressings. During the initial debridement, the tunica albuginea and corpus cavernosa were not excised although the patient had slight gangrenous changes over the cavernosa. Later, gradually, a line of demarcation developed, and there was autoamputation of the involved shaft, 2 weeks after the initial debridement. The patient...
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Positron emission tomography and reframing vasculitis as a spectrum of disease when investigating a patient with a fever of unknown origin
A retired businessman presented to the infectious diseases department with a history of ongoing fevers and myalgia and raised inflammatory markers. This continued despite adequate antibiotic treatment of an epididymo-orchitis. Extensive investigations, including bone marrow and liver biopsies and a positron emission tomography, did not reveal a cause but showed reactive change in the bone marrow. Later, he developed a vasculitic rash and vision loss due to non-arteritic anterior ischaemic optic neuropathy. High-dose steroids were immediately initiated. A temporal artery biopsy was performed, which confirmed a healing large vessel vasculitis, possibly giant cell arteritis. He has responded very well to therapy. We must better appreciate the limitations of positron emission tomography in investigating a fever of unknown origin. The case also encourages awareness of autoimmune disorders as the leading category of causative diseases for this in older age groups.
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Rare cause of ovarian mass
Pelvic actinomycosis is a rare entity that occurs almost exclusively in women, the presentation of which is usually non-specific and variable. Pelvic actinomycosis is almost always associated with the use of an intrauterine contraceptive device (IUD). Pelvic actinomycosis unrelated to IUD use is almost always associated with previous surgical procedures. The symptoms, clinical signs and radiological findings are usually non-specific, mimicking an ovarian malignancy. So an awareness of this rare condition and a proper diagnosis can avoid unnecessary surgeries because these cases can be treated with a prolonged course of antibiotics. We present a case of pelvic actinomycosis which masqueraded as an ovarian malignancy.
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Chemogenetic Isolation Reveals Synaptic Contribution of {delta} GABAA Receptors in Mouse Dentate Granule Neurons
Two major GABAA receptor classes mediate ionotropic GABA signaling, those containing a subunit and those with a 2 subunit. The classical viewpoint equates 2-containing receptors with IPSCs and -containing receptors with tonic inhibition because of differences in receptor localization, but significant questions remain because the populations cannot be pharmacologically separated. We removed this barrier using gene editing to confer a point mutation on the subunit in mice, rendering receptors containing the subunit picrotoxin resistant. By pharmacologically isolating -containing receptors, our results demonstrate their contribution to IPSCs in dentate granule neurons and weaker contributions to thalamocortical IPSCs. Despite documented extrasynaptic localization, we found that receptor localization does not preclude participation in isolated IPSCs, including mIPSCs. Further, phasic inhibition from subunit-containing receptors strongly inhibited summation of EPSPs, whereas tonic activity had little impact. In addition to any role that -containing receptors may play in canonical tonic inhibition, our results highlight a previously underestimated contribution of -containing receptors to phasic inhibition.
SIGNIFICANCE STATEMENT GABAA receptors play key roles in transient and tonic inhibition. The prevailing view suggests that synaptic 2-containing GABAA receptors drive phasic inhibition, whereas extrasynaptic -containing receptors mediate tonic inhibition. To re-evaluate the impact of receptors, we took a chemogenetic approach that offers a sensitive method to probe the synaptic contribution of -containing receptors. Our results reveal that localization does not strongly limit the contribution of receptors to IPSCs and that receptors make an unanticipated robust contribution to phasic inhibition.
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AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission
Mitochondrial fission and fusion impact numerous cellular functions and neurons are particularly sensitive to perturbations in mitochondrial dynamics. Here we describe that male mice lacking the mitochondrial A-kinase anchoring protein 1 (AKAP1) exhibit increased sensitivity in the transient middle cerebral artery occlusion model of focal ischemia. At the ultrastructural level, AKAP1–/– mice have smaller mitochondria and increased contacts between mitochondria and the endoplasmic reticulum in the brain. Mechanistically, deletion of AKAP1 dysregulates complex II of the electron transport chain, increases superoxide production, and impairs Ca2+ homeostasis in neurons subjected to excitotoxic glutamate. Ca2+ deregulation in neurons lacking AKAP1 can be attributed to loss of inhibitory phosphorylation of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) at the protein kinase A (PKA) site Ser637. Our results indicate that inhibition of Drp1-dependent mitochondrial fission by the outer mitochondrial AKAP1/PKA complex protects neurons from ischemic stroke by maintaining respiratory chain activity, inhibiting superoxide production, and delaying Ca2+ deregulation. They also provide the first genetic evidence that Drp1 inhibition may be of therapeutic relevance for the treatment of stroke and neurodegeneration.
SIGNIFICANCE STATEMENT Previous work suggests that activation of dynamin-related protein 1 (Drp1) and mitochondrial fission contribute to ischemic injury in the brain. However, the specificity and efficacy of the pharmacological Drp1 inhibitor mdivi-1 that was used has now been discredited by several high-profile studies. Our report is timely and highly impactful because it provides the first evidence that genetic disinhibition of Drp1 via knock-out of the mitochondrial protein kinase A (PKA) scaffold AKAP1 exacerbates stroke injury in mice. Mechanistically, we show that electron transport deficiency, increased superoxide production, and Ca2+ overload result from genetic disinhibition of Drp1. In summary, our work settles current controversies regarding the role of mitochondrial fission in neuronal injury, provides mechanisms, and suggests that fission inhibitors hold promise as future therapeutic agents.
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Sphingosine Kinase Regulates Neuropeptide Secretion During the Oxidative Stress-Response Through Intertissue Signaling
The Nrf2 antioxidant transcription factor promotes redox homeostasis in part through reciprocal signaling between neurons and neighboring cells, but the signals involved in intertissue signaling in response to Nrf2 activation are not well defined. In Caenorhabditis elegans, activation of SKN-1/Nrf2 in the intestine negatively regulates neuropeptide secretion from motor neurons. Here, we show that sphingosine kinase (SPHK-1) functions downstream of SKN-1/Nrf2 in the intestine to regulate neuropeptide secretion from motor neurons during the oxidative stress response in C. elegans hermaphrodites. SPHK-1 localizes to mitochondria in the intestine and SPHK-1 mitochondrial localization and kinase activity are essential for its function in regulating motor neuron function. SPHK-1 is recruited to mitochondria from cytosolic pools and its mitochondrial abundance is negatively regulated by acute or chronic SKN-1 activation. Finally, the regulation of motor function by SKN-1 requires the activation of the p38 MAPK cascade in the intestine and occurs through controlling the biogenesis or maturation of dense core vesicles in motor neurons. These findings show that the inhibition of SPHK-1 in the intestine by SKN-1 negatively regulates neuropeptide secretion from motor neurons, revealing a new mechanism by which SPHK-1 signaling mediates its effects on neuronal function in response to oxidative stress.
SIGNIFICANCE STATEMENT Neurons are highly susceptible to damage by oxidative stress, yet have limited capacity to activate the SKN-1/Nrf2 oxidative stress response, relying instead on astrocytes to provide redox homeostasis. In Caenorhabditis elegans, intertissue signaling from the intestine plays a key role in regulating neuronal function during the oxidative stress response. Here, through a combination of genetic, behavioral, and fluorescent imaging approaches, we found that sphingosine kinase functions in the SKN-1/Nrf2 pathway in the intestine to regulate neuropeptide biogenesis and secretion in motor neurons. These results implicate sphingolipid signaling as a new component of the oxidative stress response and suggest that C. elegans may be a genetically tractable model to study non-cell-autonomous oxidative stress signaling to neurons.
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A Novel Alternative Splicing Mechanism That Enhances Human 5-HT1A Receptor RNA Stability Is Altered in Major Depression
The serotonin-1A (5-HT1A) receptor is a key regulator of serotonergic activity and is implicated in mood and emotion. However, its post-transcriptional regulation has never been studied in humans. In the present study, we show that the "intronless" human 5-HT1A gene (HTR1A) is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a ~1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human HTR1A, the mouse HTR1A lacks the splice donor/accepter sites. Thus, in the mouse HTR1A, splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced downregulation, and have greater translational output than the unspliced variant. Moreover, alternative HTR1A RNA splicing is oppositely regulated by the splice factors PTBP1 and nSR100, which inhibit or enhance its splicing, respectively. In postmortem human brain tissue from both sexes, HTR1A mRNA splicing was prevalent and region-specific. Unspliced HTR1A was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, HTR1A RNA splicing and nSR100 levels were reduced in the PFC of individuals with major depression compared with controls. Our unexpected findings uncover a novel mechanism to regulate HTR1A gene expression through alternative splicing of microRNA sites. Altered levels of splice factors could contribute to changes in regional and depression-related gene expression through alternative splicing.
SIGNIFICANCE STATEMENT Alternative splicing, which is prevalent in brain tissue, increases gene diversity. The serotonin-1A receptor gene (HTR1A) is a regulator of serotonin, which is implicated in mood and emotion. Here we show that human HTR1A RNA is alternately spliced. Splicing removes a microRNA site to generate ultrastable RNA and increase HTR1A expression. This splicing varies in different brain regions and is reduced in major depression. We also identify specific splice factors for HTR1A RNA, showing they are also reduced in depression. Thus, we describe a novel mechanism to regulate gene expression through splicing. Altered levels of splice factors could contribute to depression by changing gene expression.
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Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse
Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. However, the functions of mGluRs in the auditory system under normal and diseased states are not well understood. The medial nucleus of the trapezoid body (MNTB) is a critical nucleus in the auditory brainstem nuclei involved in sound localization. In addition to the classical calyx excitatory inputs, MNTB neurons also receive synaptic inhibition and it remains entirely unknown how this inhibition is regulated. Here, using whole-cell voltage clamp in brain slices, we investigated group I mGluR (mGluR I)-mediated modulation of the glycinergic and GABAergic inputs to MNTB neurons in both WT mice and a fragile X syndrome (FXS) mouse model (both sexes) in which the fragile X mental retardation gene 1 is knocked out (Fmr1 KO), causing exaggerated activity of mGluR I and behavioral phenotypes. Activation of mGluR I by (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) increased the frequency and amplitude of glycinergic spontaneous IPSCs (sIPSCs) in both WT and Fmr1 KO neurons in a voltage-gated sodium channel-dependent fashion, but did not modulate glycinergic evoked IPSCs (eIPSCs). In contrast, 3,5-DHPG did not affect GABAergic sIPSCs, but did suppress eIPSCs in WT neurons via endocannabinoid signaling. In the KO, the effect of 3,5-DHPG on GABAergic eIPSCs was highly variable, which supports the notion of impaired GABAergic signaling in the FXS model. The differential modulation of sIPSC and eIPSC and differential modulation of glycinergic and GABAergic transmission suggest distinct mechanisms responsible for spontaneous and evoked release of inhibitory transmitters and their modulation through the mGluR I signaling pathway.
SIGNIFICANCE STATEMENT Neurons communicate with each other through the release of neurotransmitters, which assumes two basic modes, spontaneous and evoked release. These two release modes are believed to function using the same vesicle pool and machinery. Recent works have challenged this dogma, pointing to distinct vesicle release mechanisms underlying the two release modes. Here, we provide the first evidence in the central auditory system supporting this novel concept. We discovered neural-transmitter- and release-mode-specific neuromodulation of inhibitory transmission by metabotropic glutamate receptors and revealed part of the signaling pathways underlying this differential modulation. The results establish the foundation for a multitude of directions to study physiological significance of different release modes in auditory processing.
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{alpha}-Neurexins Together with {alpha}2{delta}-1 Auxiliary Subunits Regulate Ca2+ Influx through Cav2.1 Channels
Action potential-evoked neurotransmitter release is impaired in knock-out neurons lacking synaptic cell-adhesion molecules α-neurexins (αNrxns), the extracellularly longer variants of the three vertebrate Nrxn genes. Ca2+ influx through presynaptic high-voltage gated calcium channels like the ubiquitous P/Q-type (CaV2.1) triggers release of fusion-ready vesicles at many boutons. α2 Auxiliary subunits regulate trafficking and kinetic properties of CaV2.1 pore-forming subunits but it has remained unclear if this involves αNrxns. Using live cell imaging with Ca2+ indicators, we report here that the total presynaptic Ca2+ influx in primary hippocampal neurons of αNrxn triple knock-out mice of both sexes is reduced and involved lower CaV2.1-mediated transients. This defect is accompanied by lower vesicle release, reduced synaptic abundance of CaV2.1 pore-forming subunits, and elevated surface mobility of α2-1 on axons. Overexpression of Nrxn1α in αNrxn triple knock-out neurons is sufficient to restore normal presynaptic Ca2+ influx and synaptic vesicle release. Moreover, coexpression of Nrxn1α together with α2-1 subunits facilitates Ca2+ influx further but causes little augmentation together with a different subunit, α2-3, suggesting remarkable specificity. Expression of defined recombinant CaV2.1 channels in heterologous cells validates and extends the findings from neurons. Whole-cell patch-clamp recordings show that Nrxn1α in combination with α2-1, but not with α2-3, facilitates Ca2+ currents of recombinant CaV2.1 without altering channel kinetics. These results suggest that presynaptic Nrxn1α acts as a positive regulator of Ca2+ influx through CaV2.1 channels containing α2-1 subunits. We propose that this regulation represents an important way for neurons to adjust synaptic strength.
SIGNIFICANCE STATEMENT Synaptic transmission between neurons depends on the fusion of neurotransmitter-filled vesicles with the presynaptic membrane, which subsequently activates postsynaptic receptors. Influx of calcium ions into the presynaptic terminal is the key step to trigger vesicle release and involves different subtypes of voltage-gated calcium channels. We study the regulation of calcium channels by neurexins, a family of synaptic cell-adhesion molecules that are essential for many synapse properties. Using optical measurements of calcium influx in cultured neurons and electrophysiological recordings of calcium currents from recombinant channels, we show that a major neurexin variant facilitates calcium influx through P/Q-type channels by interacting with their α2-1 auxiliary subunits. These results propose a novel way how neurons can modulate the strength of distinct synapses.
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Substrates specificity of tannase from Streptomyces sviceus and Lactobacillus plantarum
Tannases can catalyze the hydrolysis of galloyl ester and depside bonds of hydrolysable tannins to release gallic acid and glucose, but tannases from different species have different substrate specificities. O...
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Application of Design Aspects in Uniaxial Loading Machine Development
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Manufacturing Abdominal Aorta Hydrogel Tissue-Mimicking Phantoms for Ultrasound Elastography Validation
Here we describe a method to manufacture aneurysmal, aortic tissue-mimicking phantoms for the use in testing ultrasound elastography. The combined use of computer-aided design (CAD) and 3-dimensional (3D) printing techniques produce aortic phantoms with predictable, complex geometries to validate the elastographic imaging algorithms with controlled experiments.
https://ift.tt/2QKdnEf
Supplementation in mushroom crops and its impact on yield and quality
Mushroom supplementation is an agronomic process which consists of the application of nutritional amendments to the substrates employed for mushroom cultivation. Different nitrogen and carbohydrate rich supple...
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EPA Plan Will Maintain Carbon Emissions From Power Plants
WEDNESDAY, Sept. 19, 2018 -- The U.S. Environmental Protection Agency (EPA) has formally released its proposal to replace the Clean Power Plan with the Affordable Clean Energy Rule, which will keep carbon emissions from power plants constant,...
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HTN Tx Intensification Common Upon Discharge in U.S. Vets
WEDNESDAY, Sept. 19, 2018 -- Fourteen percent of older adults hospitalized with non-cardiac conditions are discharged with intensified antihypertensive treatment, of whom more than half had previously well-controlled outpatient blood pressure,...
https://ift.tt/2pnDpR0
Second HPV-Related Primary Cancers Common in Survivors
WEDNESDAY, Sept. 19, 2018 -- The risk of human papillomavirus-associated second primary cancers (HPV-SPCs) among survivors of HPV-associated cancers is significant, according to a study published online Sept. 7 in JAMA Network Open. Ryan Suk, from...
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Patient Health Information Often Shared Electronically
WEDNESDAY, Sept. 19, 2018 -- The most common electronically sent and received types of patient health information (PHI) include laboratory results and medication lists, according to a report published Aug. 15 by the U.S. Centers for Disease Control...
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Global Prevalence of Insufficient Activity 27.5 Percent
WEDNESDAY, Sept. 19, 2018 -- In 2016 the age-standardized prevalence of insufficient physical activity was 27.5 percent, according to a study published in the October issue of The Lancet Global Health. Regina Guthold, Ph.D., from the World Health...
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20% of Children, Adolescents Use Prescription Medications
WEDNESDAY, Sept. 19, 2018 -- Almost 20 percent of children and adolescents used prescription medications in 2013 to 2014, and 8.2 percent of concurrent users of prescription medications in 2009 to 2014 were at risk for a potentially major drug-drug...
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Quarterly Canakinumab Reduces Risk for Gout Attacks
WEDNESDAY, Sept. 19, 2018 -- Quarterly canakinumab administration is associated with significantly reduced risk for gout attacks without any change in serum uric acid levels, according to a study published online Sept. 18 in the Annals of Internal...
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USPSTF Recommends Intensive Behavioral Change for Obesity
WEDNESDAY, Sept. 19, 2018 -- Primary care physicians should offer or refer obese patients to intensive behavioral interventions, according to a U.S. Preventive Services Task Force (USPSTF) final recommendation statement published in the Sept. 18...
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Opioid Deaths 1999 to 2015 May Be Dramatically Underestimated
WEDNESDAY, Sept. 19, 2018 -- States may be greatly underestimating the effect of opioid-related overdose deaths because of incomplete cause-of-death reporting, according to a study recently published in Public Health Reports. Jeanine M. Buchanich,...
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Cardiac MR With Contrast Feasible in Developing World
WEDNESDAY, Sept. 19, 2018 -- A cardiac magnetic resonance (CMR) with contrast protocol is feasible for implementation in the developing world and can impact management, according to a study published in the Sept. 4 issue of the Journal of the...
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Neurophysiological correlates of motor planning and movement initiation in ACL-reconstructed individuals: a case-control study
Introduction
Current evidence suggests that the loss of mechanoreceptors after anterior cruciate ligament (ACL) tears might be compensated by increased cortical motor planning. This occupation of cerebral resources may limit the potential to quickly adapt movements to unforeseen external stimuli in the athletic environment. To date, studies investigating such neural alterations during movement focused on simple, anticipated tasks with low ecological validity. This trial, therefore, aims to investigate the cortical and biomechanical processes associated with more sport-related and injury-related movements in ACL-reconstructed individuals.
Methods and analysisACL-reconstructed participants and uninjured controls will perform repetitive countermovement jumps with single leg landings. Two different conditions are to be completed: anticipated (n=35) versus unanticipated (n=35) successful landings. Under the anticipated condition, participants receive the visual information depicting the requested landing leg prior to the jump. In the unanticipated condition, this information will be provided only about 400 msec prior to landing. Neural correlates of motor planning will be measured using electroencephalography. In detail, movement-related cortical potentials, frequency spectral power and functional connectivity will be assessed. Biomechanical landing quality will be captured via a capacitive force plate. Calculated parameters encompass time to stabilisation, vertical peak ground reaction force, and centre of pressure path length. Potential systematic differences between ACL-reconstructed individuals and controls will be identified in dependence of jumping condition (anticipated/ unanticipated, injured/uninjured leg and controls) by using interference statistics. Potential associations between the cortical and biomechanical measures will be calculated by means of correlation analysis. In case of statistical significance (α<0.05.) further confounders (cofactors) will be considered.
Ethics and disseminationThe independent Ethics Committee of the University of Frankfurt (Faculty of Psychology and Sports Sciences) approved the study. Publications in peer-reviewed journals are planned. The findings will be presented at scientific conferences.
Trial statusAt the time of submission of this manuscript, recruitment is ongoing.
Trial registration numberNCT03336060; Pre-results.
https://ift.tt/2NVbRk1
Classic e-Delphi survey to provide national consensus and establish priorities with regards to the factors that promote the implementation and continued development of non-medical prescribing within health services in Wales
Objective
To provide national consensus and establish priorities with regards to the factors that promote the implementation and continued development of non-medical prescribing within health services.
DesignClassic e-Delphi survey.
SettingNational study in Wales.
ParticipantsPharmacists, nurses and allied health professionals with the independent/supplementary prescribing qualification.
ResultsA total of 55 non-medical prescribers agreed to become members of the expert panel of whom 42 (76%) completed the round 1 questionnaire, 40/42 (95%) completed round 2 and 34/40 (85%) responded to round 3. Twenty-one statements were developed, and consensus was achieved on nine factors representing those necessary for the successful implementation of non-medical prescribing and five representing actions required for its continued development. Strategic fit between non-medical prescribing and existing service provision, organisation preparedness, visible benefits, good managerial and team support, and a clear differentiation of roles were each important influences.
ConclusionGiven the high degree of consensus, this list of factors and actions should provide guidance to managers and commissioners of services wishing to initiate or extend non-medical prescribing. This information should be considered internationally by other countries outside of the UK wishing to implement prescribing by non-medical healthcare professionals.
https://ift.tt/2OAizsE
Comparison of high flow nasal cannula oxygen and conventional oxygen therapy on ventilatory support duration during acute-on-chronic respiratory failure: study protocol of a multicentre, randomised, controlled trial. The 'HIGH-FLOW ACRF study
Introduction
This study protocol describes a trial designed to investigate whether high-flow heated and humidified nasal oxygen (HFHO) therapy in patients with hypercapnic acute respiratory failure (ARF) reduces the need of non-invasive ventilation (NIV).
Methods and analysisThis is an open-label, superiority, international, parallel-group, multicentre randomised controlled two-arm trial, with an internal feasibility pilot phase. 242 patients with hypercapnic ARF requiring NIV admitted to an intensive care unit, an intermediate care or a respiratory care unit will be randomised in a 1:1 ratio to receive HFHO or standard oxygen in between NIV sessions. Randomisation will be centralised and stratified by centre and pH at admission (pH ≤7.25 or >7.25). The primary outcome will be the number of ventilator-free days (VFDs) and alive at day 28 postrandomisation. The secondary outcomes will encompass parameters related to the VFDs, comfort and tolerance variables, hospital length of stay and mortality. VFDs at 28 days postrandomisation will be compared between the two groups by Wilcoxon-Mann-Whitney two-sample rank-sum test in the intention-to-treat population. A sensitivity analysis will be conducted in the population of patients for whom the criteria of switching from NIV to spontaneous breathing, or conversely, are not strictly verified.
Ethics and disseminationThe protocol has been approved by the Comité de Protection des Personnes (CPP) Sud-Ouest & Outre-Mer IV (ref CPP17-049a/2017-A01830-53) and will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. A trial steering committee will oversee the progress of the study. Findings will be disseminated through national and international scientific conferences, and publication in peer-reviewed journals.
Trial registration numberhttps://ift.tt/2NSaF0R
Lets talk numbers: a qualitative study of community-dwelling US adults to understand the role of numeracy in the management of heart failure
Objective
To examine the perspectives of adults with heart failure (HF) about numerical concepts integral to HF self-care.
SettingThis qualitative study took place at an urban academic primary care practice.
ParticipantsThirty men and women aged 47–89 years with a history of HF were recruited to participate. Eligibility criteria included: a history of HF (≥1 year), seen at the clinic within the last year, and a HF hospitalisation within the last 6 months. Non-English speakers and those with severe cognitive impairment were excluded.
MethodsIn-depth semistructured interviews were conducted. Participants were interviewed about numeracy across three domains of HF self-care: (1) monitoring weight,(2) maintaining a diet low in salt and (3) monitoring blood pressure. Interviews were audio-taped, transcribed verbatim and analysed using grounded theory and word cloud techniques.
ResultsFive key themes reflecting participants' attitudes towards numerical concepts pertaining to weight, diet and blood pressure were identified: (1) Communication between healthcare providers and patients is a complex, multistage process; (2) Patients possess a wide range of knowledge and understanding; (3) Social and caregiver support is critical for the application of numerical concepts; (4) Prior health experiences shape outlook towards numerical concepts and instructions and (5) Fear serves as a barrier and a facilitator to carrying out HF self-care tasks that involve numbers. The findings informed a theoretical framework of health numeracy in HF.
ConclusionEffective communication of numerical concepts which pertain to HF self-care is highly variable. Many patients with HF lack basic understanding and numeracy skills required for adequate self-care. As such, patients rely on caregivers who may lack HF training. HF-specific training of caregivers and research that seeks to elucidate the intricacies of the patient–caregiver relationship in the context of health numeracy and HF self-care are warranted.
https://ift.tt/2OEzVVg
'Mind your Moles study: protocol of a prospective cohort study of melanocytic naevi
Introduction
Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults.
Methods and analysisThis is a population-based cohort study of melanocytic naevi in 200 adults aged 20–69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment.
Ethics and disseminationThis study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.
https://ift.tt/2NUwA7j
The UALE project: a cross-sectional approach for trends in HIV/STI prevalence among key populations attending STI clinics in Guatemala
Objective
To describe and compare trends in prevalence, sexual behaviour and HIV transmission knowledge data related to sexually transmitted infections (STI) and HIV in patients attending three STI clinics over an 8-year period in Escuintla Department, Guatemala.
MethodsSTI clinic attendees were classified into transmission groups as follows: female sex workers (FSW), men who have sex with men (MSM) and 'high-risk heterosexuals' (HRH). Annual cross-sectional analysis and multivariable Poisson regression adjusted for sociodemographic variables were used for prevalence comparisons and adjusted prevalence trends for HIV/STI outcomes and used for adjusted trends in proportions in sexual behaviour and HIV transmission knowledge outcomes. Endocervical swabs were obtained to detect trichomonas, chlamydia and neisseria infections. Serologies for syphilis and HIV were performed using rapid tests. For reactive HIV samples, positivity was confirmed by an ELISA. All reactive syphilis samples were further confirmed for diagnosis of active syphilis disease.
ResultsFrom a total of 4027 clinic attendees, 3213 (79.78%) were FSW, 229 (5.69%) were MSM and 585 (14.53%) were HRH. The proportion of FSW, MSM and HRH who had a single visit was 56.42%, 57.23% and 91.10%, respectively. Overall, HIV prevalence was 2.10% in FSW, 8.17% in MSM and 4.12% in HRH. Prevalence trends in HIV and syphilis decreased in FSW. Prevalence trends in gonorrhoea did not decrease over time neither in FSW nor in HRH. Chlamydia and trichomonas infections in HRH showed an increase prevalence trend. In FSW, trends in condom use in last sexual intercourse with regular and occasional clients were above 93%.
ConclusionsFSW show a decreasing trend in HIV, syphilis and chlamydia prevalence. Gonorrhoea prevalence in FSW and HRH did not decrease over time. HRH is a hard to engage population with low follow-up rates and high potential to act as a bridge population.
https://ift.tt/2OEzOJk
Examining protective and buffering associations between sociocultural factors and adverse childhood experiences among American Indian adults with type 2 diabetes: a quantitative, community-based participatory research approach
Objectives
The purpose of this study was to determine the frequency of select adverse childhood experiences (ACEs) among a sample of American Indian (AI) adults living with type 2 diabetes (T2D) and the associations between ACEs and self-rated physical and mental health. We also examined associations between sociocultural factors and health, including possible buffering processes.
DesignSurvey data for this observational study were collected using computer-assisted survey interviewing techniques between 2013 and 2015.
SettingParticipants were randomly selected from AI tribal clinic facilities on five reservations in the upper Midwestern USA.
ParticipantsInclusion criteria were a diagnosis of T2D, age 18 years or older and self-identified as AI. The sample includes n=192 adults (55.7% female; mean age=46.3 years).
Primary measuresWe assessed nine ACEs related to household dysfunction and child maltreatment. Independent variables included social support, diabetes support and two cultural factors: spiritual activities and connectedness. Primary outcomes were self-rated physical and mental health.
ResultsAn average of 3.05 ACEs were reported by participants and 81.9% (n=149) said they had experienced at least one ACE. Controlling for gender, age and income, ACEs were negatively associated with self-rated physical and mental health (p<0.05). Connectedness and social support were positively and significantly associated with physical and mental health. Involvement in spiritual activities was positively associated with mental health and diabetes-specific support was positively associated with physical health. Social support and diabetes-specific social support moderated associations between ACEs and physical health.
ConclusionsThis research demonstrates inverse associations between ACEs and well-being of adult AI patients with diabetes. The findings further demonstrate the promise of social and cultural integration as a critical component of wellness, a point of relevance for all cultures. Health professionals can use findings from this study to augment their assessment of patients and guide them to health-promoting social support services and resources for cultural involvement.
https://ift.tt/2NTKCWZ
Geographical and socioeconomic differences in uptake of Pap test and mammography in Italy: results from the National Health Interview Survey
Objective
The Italian National Health Service instituted cervical and breast cancer screening programmes in 1999; the local health authorities have a mandate to implement these screening programmes by inviting all women aged 25–64 years for a Pap test every 3 years (or for an Human Papilloma Virus (HPV) test every 5 years) and women aged 50–69 years for a mammography every 2 years. However, the implementation of screening programmes throughout the country is still incomplete. This study aims to: (1) describe cervical and breast cancer screening uptake and (2) evaluate geographical and individual socioeconomic difference in screening uptake.
MethodsData both from the Italian National Health Interview Survey (NHIS) conducted by the National Institute of Statistics in 2012–2013 and from the Italian National Centre for Screening Monitoring (INCSM) were used. The NHIS interviewed a national representative random sample of 32 831 women aged 25–64 years and of 16 459 women aged 50–69 years. Logistic multilevel models were used to estimate the effect of socioeconomic variables and behavioural factors (level 1) on screening uptake. Data on screening invitation coverage at the regional level, taken from INCSM, were used as ecological (level 2) covariates.
ResultsTotal 3-year Pap test and 2-year mammography uptake were 62.1% and 56.4%, respectively; screening programmes accounted for 1/3 and 1/2 of total test uptake, respectively. Strong geographical differences were observed. Uptake was associated with high educational levels, healthy behaviours, being a former smoker and being Italian versus foreign national. Differences in uptake between Italian regions were mostly explained by the invitation coverage to screening programmes.
ConclusionsThe uptake of both screening programmes in Italy is still under acceptable levels. Screening programme implementation has the potential to reduce the health inequalities gap between regions but only if uptake increases.
https://ift.tt/2OEzIkW
Defining the prevalence and symptom burden of those with self-reported severe chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a two-phase community pilot study in the North East of England
Objectives
To define the prevalence of severe chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and its clinical characteristics in a geographically defined area of Northern England. To understand the feasibility of a community-based research study in the severely affected CFS/ME group.
DesignA two-phase clinical cohort study to pilot a series of investigations in participants own homes.
SettingParticipants were community living from the area defined by the Northern clinical network of the UK.
ParticipantsAdults with either a medical or a self-reported diagnosis of CFS/ME. Phase 1 involved the creation of a database. Phase 2: five participants were selected from database, dependent on their proximity to Newcastle.
InterventionsThe De Paul fatigue questionnaire itemised symptoms of CFS/ME, the Barthel Functional Outcome Measure and demographic questions were collected via postal return. For phase 2, five participants were subsequently invited to participate in the pilot study.
Results483 questionnaire packs were requested, 63 were returned in various stages of completion. 56 De Paul fatigue questionnaires were returned: all but 12 met one of the CFS/ME criteria, but 12 or 22% of individuals did not fulfil the Fukuda nor the Clinical Canadian Criteria CFS/ME diagnostic criteria but 6 of them indicated that their fatigue was related to other causes and they barely had any symptoms. The five pilot participants completed 60% of the planned visits.
ConclusionsSeverely affected CFS/ME individuals are keen to participate in research, however, their symptom burden is great and quality of life is poor. These factors must be considered when planning research and methods of engaging with such a cohort.
https://ift.tt/2NOOsAP
Effect of vitamin D supplementation on serum 25-hydroxyvitamin D concentration in children and adolescents: a systematic review and meta-analysis protocol
Introduction
The importance of vitamin D for bone health as well as its role in non-skeletal functions has long been documented. However, review investigations on the effect of vitamin D supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in children and adolescents are scarce. The aims of the current study were to assess the impact of various doses of vitamin D supplementation on serum 25(OH)D concentrations in children and adolescents, and to identify relevant determinants of variations in the effect of vitamin D supplementation.
MethodsPubMed, Scopus, ISI Web of Science and Cochrane Central Register of Controlled Trials databases up to 27 September 2017 will systematically be searched for randomised controlled trials of vitamin D supplementation. We considered articles with the following control groups as eligible: placebo control, control group without any supplementation or a comparative arm investigation. Two reviewers will assess articles for eligibility according to prespecified selection criteria, after which data extraction and quality appraisal will be conducted by two independent reviewers. The quality assessment will be assessed using the Jadad scale. Meta-analyses will be conducted where appropriate. We will express continuous measures (ie, serum 25(OH)D concentration) as mean differences with 95% CIs. Heterogeneity of the data will be investigated via visual inspection of the forest plots and using 2 test on N-1 df, with a significance level of α=0.1. We will also assess individual study and subgroup characteristics and perform a sensitivity analysis. Publication bias will be assessed using funnel plot and statistical analysis of Egger's test.
Ethics and disseminationEthics approval is not required because the work will be carried out on published documents. The authors will publish findings from this review through peer-reviewed publication or conference presentations.
PROSPERO registration numberCRD42017067179.
https://ift.tt/2OEzytQ
Telehealth for patients with chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis protocol
Introduction
Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic disease characterised by persistent respiratory symptoms. A focus of COPD interventional studies is directed towards prevention of exacerbations leading to hospital readmissions. Telehealth as a method of remote patient monitoring and care delivery may be implemented to reduce hospital readmissions and improve self-management of disease. Prior reviews have not systematically assessed the efficacies of various telehealth functionalities in patients with COPD at different stages of disease severity. We aim to evaluate which COPD telehealth interventions, classified by their functionalities, are most effective in improving patient with COPD management measured by both clinical and resource utilisation outcomes.
Methods and analysisWe will conduct a systematic review which will include randomised controlled trials comparing the efficacy of telehealth interventions versus standard care in patients with COPD with confirmed disease severity based on forced expiratory volume(%) levels. An electronic search strategy will be used to identify trials published since 2000 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINHAL. Telehealth is described as remote monitoring and delivery of care where patient data/clinical information is routinely or continuously collected and/or processed, presented to the patient and transferred to a clinical care institution for feedback, triage and intervention by a clinical specialist. Two authors will independently screen articles for inclusion, assess risk of bias and extract data. We will merge studies into a meta-analysis if the interventions, technologies, participants and underlying clinical questions are homogeneous enough. We will use a random-effects model, as we expect some heterogeneity between interventions. In cases where a meta-analysis is not possible, we will synthesise findings narratively. We will assess the quality of the evidence for the main outcomes using GRADE.
Ethics and DisseminationResearch ethics approval is not required. The findings will be disseminated through publication in a peer-reviewed journal.
PROSPERO registration numberCRD42018083671.
https://ift.tt/2NOOmZZ
Associations between understanding of current treatment intent, communication with healthcare providers, preferences for invasive life-sustaining interventions and decisional conflict: results from a survey of patients with advanced heart failure in Singapore
Objectives
To make informed choices about use of future invasive life-sustaining interventions (ILSI), patients with congestive heart failure (CHF) need to correctly understand the intent of their current treatments. However, healthcare providers may be wary of having these discussions due to fear of distressing patients. In this study, we assessed whether patients who understand their treatment intent are less willing to undergo ILSI and are indeed more psychologically distressed.
Design, participants and outcomesAs part of a cross-sectional survey conducted prior to randomising patients for a trial, we asked 282 patients with advanced CHF (New York Heart Association Class III and IV) whether they believe their existing treatments would cure their heart condition, their willingness to undergo ILSI and assessed their anxiety and depression using the Hospital Anxiety and Depression Scale.
ResultsApproximately half of patients reported a willingness to undergo ILSI if needed. Only 22% knew that their current treatments were not curative. These patients were far less willing to undergo ILSI (OR 0.28, 95% CI 0.15 to 0.56) and were not at a greater risk of having clinically significant anxiety (OR 0.72, 0.34 to 1.54) and depression (OR 0.70, 0.33 to 1.47) compared with those who did not understand their current treatment intent.
ConclusionsImproving patients' understanding of the intent of their current treatments can help patients make informed choices about ILSI.
Trial registration numberNCT02299180; Pre-results.
https://ift.tt/2OD2mTE
Association between bronchopulmonary dysplasia and cerebral palsy in children: a meta-analysis
Objective
To investigate the association between bronchopulmonary dysplasia (BPD) and the risk of cerebral palsy (CP) in children.
Data sourcesWe used EMBASE, PubMed and Web of Science to conduct a meta-analysis of studies published before 1 September 2017, written in English whose titles or abstracts discussed an association between BPD and CP.
Study selectionObservational studies, for example, case–control and cohort studies were included.
Data extraction and synthesisAll review stages were conducted by two reviewers independently. Data synthesis was undertaken via meta-analysis of available evidence.
Main outcomes and measuresThe prevalence of developing CP was measured after exposure to BPD.
ResultsAmong 1234 initially identified studies, we selected those that addressed an association between BPD and CP according to our preselected inclusion criteria. Our meta-analysis included 11 studies. According to a random effect model, BPD was significantly associated with CP (ORs 2.10; 95% CI 1.57 to 2.82) in preterm infants. Factors explaining differences in the study results included study design, the definition of BPD, the time of diagnosis of CP and whether the studies adjusted for potential confounders.
ConclusionThis study suggests that BPD is a risk factor for CP. Further studies are required to confirm these results and to detect the influence of variables across studies.
https://ift.tt/2NOOgl5
Cross-sectional analysis of sleep-promoting and wake-promoting drug use on health, fatigue-related error, and near-crashes in police officers
Objectives
To examine sleep-promoting and wake-promoting drug use in police officers and associations between their use and health (excessive sleepiness, stress and burnout), performance (fatigue-related errors) and safety (near-crashes) outcomes, both alone and in combination with night-shift work.
DesignCross-sectional survey.
SettingPolice officers from North America completed the survey either online or via paper/pencil at a police station.
Participants4957 police participated, 3693 online (91.9%, participation rate) and 1264 onsite (cooperation rate 63.1%).
Main outcome measuresSleep-promoting and wake-promoting drug use, excessive sleepiness, near-crash motor vehicle crashes, dozing while driving, fatigue errors, stress and burnout.
ResultsOver the past month, 20% of police officers reported using sleep-promoting drugs and drugs causing sleepiness, while wake-promoting agents were used by 28% of police (5% used wake-promoting drugs, 23% used high levels of caffeine and 4% smoked to stay awake). Use of sleep-promoting drugs was associated with increased near-crashes (OR=1.61; 95% CI 1.21 to 2.13), fatigue-related errors (OR=1.75; 95% CI 1.32 to 2.79), higher stress (OR=1.41; 95% CI 1.10 to 1.82), and higher burnout (OR=1.83; 95% CI 1.40 to 2.38). Wake-promoting drug use, high caffeine and smoking to stay awake were associated with increased odds of a fatigue-related error, stress and burnout (ORs ranging from 1.68 to 2.56). Caffeine consumption was common, and while smoking was not, of those participants who did smoke, one-in-three did so to remain awake. Night-shift work was associated with independent increases in excessive sleepiness, near-crashes and fatigue-related errors. Interactions between night-shift work and wake-promoting drug use were also found for excessive sleepiness.
ConclusionsPolice who use sleep-promoting and wake-promoting drugs, especially when working night shifts, are most vulnerable to adverse health, performance and safety outcomes. Future research should examine temporal relationships between shift work, drug use and adverse outcomes, in order to develop optimal alertness management strategies.
https://ift.tt/2OEzhqO
Sarcopenic obesity associated with high-sensitivity C-reactive protein in age and sex comparison: a two-center study in South Korea
Objectives
To evaluate the association between high-sensitivity C-reactive protein (hs-CRP) and sarcopenic obesity, and to determine age or sex differences underlying the relationship between hs-CRP and sarcopenic obesity.
DesignObservational study.
ParticipantsThe study included 237 838 participants whose body composition and hs-CRP were analysed at the two health promotion centres in South Korea. Participants were divided into four groups based on body composition: normal, obesity only, sarcopenia only and sarcopenic obesity.
Primary measuresThe levels of hs-CRP and proportion of participants with high (≥1.0 mg/L) hs-CRP. Sarcopenic obesity was defined as subjects fulfilling the criteria for sarcopenia (below 2 SD of mean of Skeletal Muscle Mass Index for young adults) and obesity (waist circumference ≥90 cm for men and ≥85 cm for women).
ResultsThe level of hs-CRP was highest in the sarcopenic obesity group. Following adjustment for various confounders including age, sex, comorbidities, metabolic, health-related behaviour and demographic factors, the adjusted ORs (95% CI) for subjects with high hs-CRP associated with obesity, sarcopenia and sarcopenic obesity compared with normal group (reference) were 1.17 (1.05 to 1.31), 2.23 (1.21 to 4.07) and 3.23 (2.71 to 3.83), respectively. In age subgroup analyses, multivariate logistic regression analysis revealed that the association of high hs-CRP with sarcopenic obesity was stronger in younger (<60 years) participants than in older (≥60 years) participants (p for interaction <0.001). In subgroup analyses for sex, the association of high hs-CRP with sarcopenic obesity was higher in female participants than in males (p for interaction <0.001).
ConclusionsThis study demonstrated that high level of hs-CRP was independently associated with sarcopenic obesity in Korean population. We found for the first time that there was a strong association between increased hs-CRP and sarcopenic obesity in female and younger (<60 years) subjects.
https://ift.tt/2NOO9WH
Partners at Care Transitions: exploring healthcare professionals perspectives of excellence at care transitions for older people
Introduction
Hospital admissions are shorter than they were 10 years ago. Notwithstanding the benefits of this, patients often leave hospital requiring ongoing care. The transition period can therefore be risky, particularly for older people with complex health and social care needs. Previous research has predominantly focused on the errors and harms that occur during transitions of care. In contrast, this study adopts an asset-based approach to learn from factors that facilitate safe outcomes. It seeks to explore how staff within high-performing ('positively deviant') teams successfully support transitions from hospital to home for older people.
Methods and analysisSix high-performing general practices and six hospital specialties that demonstrate exceptionally low or reducing 30-day emergency hospital readmission rates will be invited to participate in the study. Healthcare staff from these clinical teams will be recruited to take part in focus groups, individual interviews and/or observations of staff meetings. Data collection will explore the ways in which teams successfully deliver exceptionally safe transitional care and how they overcome the challenges faced in their everyday clinical work. Data will be thematically analysed using a pen portrait approach to identify the manifest (explicit) and latent (abstract) factors that facilitate success.
Ethics and disseminationEthical approval was obtained from the University of Leeds. The study will help develop our understanding of how multidisciplinary staff within different healthcare settings successfully support care transitions for older people. Findings will be disseminated to academic and clinical audiences through peer-reviewed articles, conferences and workshops. Findings will also inform the development of an intervention to improve the safety and experience of older people during transitions from hospital to home.
https://ift.tt/2OzNh59
Can epinephrine therapy be detrimental to patients with hypertrophic cardiomyopathy with hypotension or cardiac arrest? a systematic review
Approximately 10% of sudden cardiac deaths among patients under 35 years of age is owing to hypertrophic cardiomyopathy (HCM)-related cardiac arrest (CA). CA is often associated with pre-arrest or peri-arrest hypotension and is treated by a set of interventions, including the administration of epinephrine. It is debated whether epinephrine increases or decreases survival to discharge following CA. HCM is associated with septal hypertrophy with a dynamic left ventricular outflow tract obstruction and impaired peripheral vasoconstriction in response to α1-adrenergic stimulation, both of which could cause epinephrine to have a different effect than in the general population. This systematic review of the literature aimed to investigate if patients with HCM in CA have a detrimental hemodynamic response to epinephrine. A literature search was performed in October 2016 using Medline (OVID), Embase (Elsevier), and Cochrane Library (Wiley). The initial search generated 2429 articles, of which 22 articles were found to meet inclusion criteria: four physiology studies, 13 case reports of hypotensive HCM patients, and five case reports of HCM patients in CA. The reviewed studies demonstrate that epinephrine effect varies in patients with HCM: in some cases, the expected hypertensive effect was obtained, but in others, a paradoxical hypotensive effect, or no effect, was observed. The probable mechanism of this effect is an increased left ventricular outflow tract obstruction. Other drugs were considered in several of these cases. In summary, the retrieved studies jointly suggest that patients with HCM may respond differently to epinephrine than patients without HCM. The suitability of epinephrine in HCM-associated CA is questionable. Correspondence to Therese Djärv, MD, PhD, Karolinska Institutet, Stockholm 17100, Sweden Tel: +46 851 770 000; fax: +46 851 770 000; e-mail: therese.djarv@ki.se Received October 12, 2017 Accepted August 25, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2MLrmpX
https://ift.tt/2MLrmpX
The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo
Abstract
Background
Multidrug resistance (MDR) is often responsible for the failure of chemotherapy treatment, and current strategies for cancer MDR are not adequately satisfying as to their efficacy and safety. In this study, we sought to determine the anti-MDR effects of ultrasound (US) irradiation and its underlying mechanisms against drug-resistance.
Methods
MDR variant MCF-7/ADR cell lines and endothelial cell lines were used to determine the appropriate ultrasound intensity for in vitro experiments. MCF-7/ADR cell and HEPG2/ADM cells were used to assess the anti-MDR effect of US irradiation. Intracellular adriamycin (ADM) accumulation, Cell viability, cell proliferation and cell apoptosis were evaluated after ADM + US treatment or ADM treatment alone. MCF-7/ADR xenograft mice were used to investigate the appropriate ultrasound intensity for in vivo experiments and its effect on the long-term prognosis. Underlining mechanisms by which ultrasound exposure reversing MDR phenotype were investigated both in vitro and in vivo.
Results
Combination of ADM and 0.74 W/cm2 US irradiation enhanced ADM intracellular concentration and nuclear accumulation in MCF-7/ADR and HEPG2/ADM cells, compared to those treated with ADM alone. Enhanced cellular ADM uptake and nuclei localization was associated with increased cytotoxicity of ADM to ADM-resistant cells, lower ADM-resistant cell viability and proliferative cell ratio, and higher apoptotic cell ratio. More importantly, US exposure increased the effectiveness of ADM to inhibit tumor growth in MCF-7/ADR xenograft mice. Mechanistically, US exposure promoted ADM accumulation in MDR cells mainly through down-regulation of P-glycoprotein (P-gp), which is dependent on US-induced intracellular reactive oxygen species (ROS) production. US-induced oxidative stress promoted miR-200c-3p and miR-34a-3p expression by forming miR-200c/34a/ZEB1 double-negative feedback loop. Finally, US-induced miR-200c/34a overexpression decreased P-gp expression and reversed MDR phenotype.
Conclusion
US irradiation could reverse MDR phenotype by activating ROS-ZEB1-miR200c/34a-P-gp signal pathway. Our findings offer a new and promising strategy for sensitizing cells to combat MDR and to improve the therapeutic index of chemotherapy.
https://ift.tt/2NXXmMf
Tobacco Carcinogen-Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer
Although smoking is a significant risk factor for pancreatic cancer (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here we show the role of cAMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared to non-smokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared to PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in PDAC patients. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared to control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor associated macrophages (TAM) and Treg expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for PDAC patients.
https://ift.tt/2xmTo6v
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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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