Medicine by Alexandros G.Sfakianakis: 11/10/17

Παρασκευή 10 Νοεμβρίου 2017

Modern Surgeons: Still Masters of Their Trade or Just Operators of Medical Equipment?

No abstract available

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Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.

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Risk of Type 2 Diabetes Mellitus Development in the Native Population of Low- and High-Altitude Regions of Kyrgyzstan: Finnish Diabetes Risc Score Questionnaire Results

High Altitude Medicine & Biology , Vol. 0, No. 0.

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Seismology and Advances in Trauma Resuscitation

Trauma is a disease that imparts an almost unspeakable burden of illness on a global population of patients. Over the past decade, advances in the science of trauma resuscitation have changed the landscape of trauma resuscitation dramatically. Trauma is a team sport, and the science of teams has greatly advanced our ability to deliver rapid, effective multidisciplinary trauma care. Traumatic cardiac arrest, once believed to be a terminal event, is now believed to contain a population of patients with excellent survival, provided a thoughtful approach is followed.

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The Kids Are Alright

Pediatric patients with trauma pose unique challenges, both practical and cognitive, to front-line care providers. The combination of anatomic, physiologic, and metabolic factors leads to unique injury patterns with different approaches and responses to treatment compared with adults. A similar traumatic mechanism can lead to slightly different internal injuries with unique management and treatment strategies between the two groups. This article is intended for community, nonpediatric trauma centers, and emergency physicians who are frequently required to assess, resuscitate, and stabilize injured children before they can be safely transferred to a pediatric trauma center for ongoing definitive care and rehabilitation.

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Secondary Gains

Neurotrauma is a leading cause of death and is associated with many secondary injuries. A balance of mean arterial pressure (MAP) and intracranial pressure (ICP) is required to ensure adequate cerebral blood flow and cerebral perfusion pressure. Evaluation and management in the emergency department entails initial stabilization and resuscitation while assessing neurologic status. ICP management follows a tiered approach. Intubation requires consideration of preoxygenation, head of bed elevation, first pass success, and adequate analgesia and sedation. Early consultation with neurosurgery is needed for definitive therapy. Focused evaluation and management play a significant role in optimizing patient outcomes.

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The Tragically Hip

Old age is a risk factor for poor outcome in trauma patients, as a result of undertriage and the presence of occult life-threatening injuries. The mechanisms of injury for geriatric trauma differ from those in younger patients, with a much higher incidence of low-impact trauma, especially falls from a low height. Frailty is a risk factor for severe injury after minor trauma, and caring for these patients require a multidisciplinary team with both trauma and geriatric expertise. With early recognition and aggressive management, severe injuries can still be associated with good outcomes, even in very elderly patients.

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Resuscitation Resequenced

Trauma resuscitation is a complex and dynamic process that requires a high-performing team to optimize patient outcomes. More than 30 years ago, Advanced Trauma Life Support was developed to formalize and standardize trauma care; however, the sequential nature of the algorithm that is used can lead to ineffective prioritization. An improved understanding of shock mandates an updated approach to trauma resuscitation. This article proposes a resequenced approach that (1) addresses immediate threats to life and (2) targets strategies for the diagnosis and management of shock causes. This updated approach emphasizes evidence-based resuscitation principles that align with physiologic priorities.

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Management of Major Vascular Injuries

Vascular injuries represent a significant burden of mortality and disability. Blunt injuries to the neck vessels can present with signs of stroke either immediately or in a delayed fashion. Most injuries are detected with computed tomography angiography and managed with either antiplatelet medications or anticoagulation. In contrast, patients with penetrating injuries to the neck vessels require airway management, hemorrhage control, and damage control resuscitation before surgical repair. The keys to diagnosis and management of peripheral vascular injury include early recognition of the injury; hemorrhage control with direct pressure, packing, or tourniquets; and urgent surgical consultation.

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Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay–Sachs Disease

Human Gene Therapy , Vol. 0, No. 0.

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Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer

Abstract

Background

Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP).

Methods

We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment.

Results

Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index ≥ 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791).

Conclusions

Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

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Tasigna (nilotinib) in chronic myeloid leukemia treatment-free remission after nearly 2 years: an interview with Adam Mead

Future Oncology, Ahead of Print.

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Current issues of preoperative radio(chemo)therapy and its future evolution in locally advanced rectal cancer

Future Oncology, Ahead of Print.

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Long noncoding RNA identification in lymphoma

Future Oncology, Ahead of Print.

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Treatment and prognostic factors of patients with thymic epithelial tumors at first recurrence or progression

Future Oncology, Ahead of Print.

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Fluorescence image-guided neurosurgery

Future Oncology, Ahead of Print.

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Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer?

Future Oncology, Ahead of Print.

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Electronic patient-reported outcomes: a revolutionary strategy in cancer care

Future Oncology, Ahead of Print.

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Developments in optical imaging for gastrointestinal surgery

Future Oncology, Ahead of Print.

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Intraoperative image-guided surgery in neuro-oncology with specific focus on high-grade gliomas

Future Oncology, Ahead of Print.

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Imaging in cutaneous surgery

Future Oncology, Ahead of Print.

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77. Altered H-reflex following pulsed radiofrequency in patients with lumbosacral radicular pain

Pulsed radiofrequency (PRF) short-lasting bursts allow pain modulation with no tissue necrosis. Neurophysiological evaluation of PRF possible effects has not been described yet. Objective of this study was to investigate the effects of PRF on sensory nerve conduction and H-reflex in patients with lumbosacral radicular pain.We evaluated 23 patients with unilateral L5-S1 root pain who underwent PRF at the corresponding level of radicular symptoms. PRF was applied through a multifunctional electrode introduced via trans-sacral access for 240s.

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76. Vestibular evoked myogenic potentials (c-VEMPS AND o-VEMPS) in the diagnosis of vestibular neuritis

Vestibular neuritis (VN) is a common neuro-otologic syndrome characterized by acute prolonged vertigo lasting several days, nausea, vomiting. Vestibular-evoked myogenic potentials (VEMPs) are becoming the better diagnostic tool in this pathology. VEMPs can be recorded from tonically contracted neck muscles by acoustic and galvanic stimulation or forehead tap (cervical VEMPs, c-VEMPs) or from extraocular muscles, using the same stimuli. (ocular VEMPs, o-VEMPs). The aim of our study was to assess the reliability of c-VEMPs and o-VEMPs in the diagnosis of VN.

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88. The sympathetic skin response as a predictor of recovery of ulnar nerve lesion at wrist

The aim of the study was to evaluate, in the ulnar nerve injuries, distally to the elbow, the role of monitoring the function of sudomotor fibers assessed by Sympathetic Skin Response (SSR) during recovery after surgical treatment and rehabilitation.We recruited 31 patients admitted for rehabilitation after traumatic wrist injury with ulnar nerve and artery lesions. Patients with other nerves or artery involved were excluded. All patients underwent surgical primary nerve repair within 72h and the same rehabilitative program.

http://ift.tt/2Aznfsp

46. Somatosensory evoked potentials in neonatal hypoxic-ischemic encephalopathy

Somatosensory evoked potentials (SEPs) are considered a useful exam for the prognosis of newborns with hypoxic-ischemic encephalopathy (HIE) treated with hypothermia. We examined our data in respect to the MRI, considering the repetitivity of the abnormalities of the SEPs in the time. Of a large number of newborns evaluated with HIE treated with hypothermia in both centers we considered a group of patients with SEPs and MRI just after the completion of hypothermia. 10 patients with abnormal SEPs have repeated the exam after a period ranging from 4days to 7months: in 7 cases the SEPs were normalized (in 3 newborns just after few weeks).

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1. Laser evoked potential in clinical practice: The diagnostic field in small fiber neuropathy

Small fiber neuropathy (SFN) is frequently encountered in clinical practice. Due to the small nerve fiber characteristics, the diagnosis requires the use of not conventional tests like skin biopsy, Quantitative sensory testing (QST) and Laser Evoked Potentials (LEPs). The aim of this study was to evaluate the diagnostic value of A-delta LEPs in clinical practice in a large cohort of patients with diagnosis of "definite" SFN.We screened 296 patients evaluated in our institution with confirmed diagnosis of sensory neuropathy.

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38. Different behavior of cerebrospinal fluid amyloid-β and tau levels in patients with post-traumatic disorders of consciousness

Traumatic brain injury (TBI) is a major risk factor for Alzheimer disease (AD). Although the mechanisms that lead to AD after a TBI are largely unknown, changes in amyloid- (A metabolism and abnormal tau phosphorylation are probably involved. In this study, we evaluated A, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6±176.5days; range 92–578days).

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Announcement

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3. Immunofluorescence characterization of skin nerve misfolded α-synuclein in different synucleinopathies: A confocal study

Intraneural misfolded α-synuclein (syn) characterized different synucleinopathies such as pure autonomic failure (PAF), idiopathic Parkinson disease (IPD) and dementia with Lewy Bodies (DLB). The aim of this study is to characterize by immunofluorescence the skin intraneural α-synuclein (syn) deposits in PAF, IPD and DLB to ascertain conformation-specific differences which may justify a different clinical phenotype.We identified a total of 21 skin intraneural abnormal syn deposits in PAF (3 patients), 22 in IPD (8 patients) and 40 in DLB (7 patients).

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80. Small fiber neuropathy in Amyotrophic Lateral Sclerosis: Contribution of laser-evoked potentials and skin biopsy

Increasing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder, also determining a small fiber neuropathy (SFN) as recognized by skin biopsy studies in distal legs, irrespective of the disease duration. This study aimed at evaluating the performance of a battery of neurophysiological and morphological tests assessing the small fiber loss occurring in ALS.We recruited 10 consecutive ALS patients (5M, age 64.9±7.3, duration of symptoms 29.1±20.7months).

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4. Does small fiber pathology in PD change over time?

Small fiber pathology is part of the clinical picture of PD. Cross-sectional studies have shown no correlation between intraepidermal nerve fiber (IENF) density and patient disease duration and severity. However, it is not known whether IENF density changes over time. We aimed to assess the progression of small fiber pathology in PD patients along the disease course.We assessed epidermal innervation at time 0 and after 1–9years (mean 3.5) in 17 PD patients (M/F=11/6, age=64.4±15.3) leg on punch biopsies.

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42. Functional Tremor: When neurophysiology makes the difference

Functional tremor (FT) still remains a challenge for clinicians; here, we propose a simple and fast test battery for an early diagnosis of FT.We enrolled ten patients with probable FT and compared them with patients with essential tremor (ET) or tremor-dominant Parkinson's Disease (PD). Surface polymyography was bilaterally performed with arms relaxed, with arms outstretched at shoulder level without or with a 500-g mass attached to the wrist ("mass loading"), during voluntary contralateral motor activation and while performing ballistic movements.

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50. Inter hemispheric comparison of PAS-induced cortical plasticity: A pilot study in healthy subjects

Dystonia is considered a "network" disease with an abnormal cortical plasticity induced by by paired-associated-stimulation. In this study, we applied the PAS-TMS paradigm in healthy subjects, with the aim to collect reliable data from both hemispheres in order to put the basis to future application in focal dystonia.We studied 7 healthy subjects (4 females; mean age 32.33±6.79years). We applied electrical stimulatrion of median nerve electrical and MEPs from both abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles (2), following Stefan et al.

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6. Trigeminal neuralgia typical and atypical. A disease or two?

Trigeminal Neuralgia (TN) is a clinical condition characterized by a sudden, usually unilateral, brief, stabbing, recurrent pain with a distribution consistent with one or more divisions of the fifth cranial nerve. In the classical form, the genesis of paroxysmal pain has been attributed to areas of focal demyelination due to vascular compression on the nerve. The 20–50% of patients with TN have an atypical form characterized by the presence of constant pain, often described as burning continuous or sub-continuous, as well as paroxysmal pain.

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7. Cathodal transcranial direct current stimulation reduces seizure frequency and modulates brain functional connectivity with drug-resistant temporal lobe epilepsy: A sham controlled study

Cathodal transcranial direct current stimulation (ctDCS) is a technique able to non-invasively inhibit cortical excitability, which is abnormally increased in epilepsy, but its efficacy in reducing seizures and in modulating epileptic network is still under debate.We evaluated the efficacy of 20-min 1mA ctDCS vs sham-tDCS in reducing seizure frequency and in modulating the functional connectivity (FC) between epileptic focus (EF) and the other cortical areas, in 10 temporal drug-resistant epilepsy (DRE) patients.

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84. Atypical presentation of Guillain-Barré syndrome in childhood: A clinical case

A 31-months old child was admitted with a 4-day history of fever and weakness. The initial neurological examination revealed a meningeal syndrome with neck stiffness, without consciousness impairment. Head CT was normal. Analysis of CSF showed only increased level of proteins. Based on clinical manifestations, an empirical antibiotics and antiviral therapy was started. During the following 48h, a progressive flaccid tetraparesis occurred. An ENG/EMG study was performed to exclude a peripheral involvement that showed decreased CMAP amplitude, partial motor conduction blocks/pseudo-blocks signs in the forearm segment of median and ulnar nerves and absence of F-waves.

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8. Neurophysiological comparison among tonic, high frequency and burst spinal cord simulation: Novel insights into spinal and brain mechanisms of action

Spinal cord Stimulation (SCS) is an effective option for neuropathic pain treatment. New technological developments, as high-frequency (HF) and Theta Burst Stimulation (TBS), have shown promising results, although putative mechanisms of action are still debated.Twenty-five patients with lower back pain were enrolled and underwent LF, HF and TBS. LEPs were recorded by using a Nd:YAG laser: amplitudes and latencies of the main two components (N1, N2/P2) were compared among different experimental conditions.

http://ift.tt/2AAYoEe

36. Bilateral loss of cortical SEPs predict severe MRI lesions in neonatal hypoxic ischemic encephalopathy treated with hypothermia

The introduction of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy call for reevaluation of the prognostic role of SEPs. This study aimed to test the prognostic value of SEPs using as outcome measure MRI severity and patterns of injury.Neonates eligible for hypothermia were recruited from four Italian Centers if they performed SEP and MRI at 4–15days of life. SEPs were scored as: normal (bilaterally recorded/unilaterally absent N20) or altered (bilaterally absent N20). The severity of brain injury was measured using a validated MRI scoring system for acute and sub-acute signal abnormalities.

http://ift.tt/2ytc2br

DAI-1 Receptor Expression in Placenta in Earlyand Late-Onset Preeclampsia

DAI-1 receptor (DNA-dependent activator of IFN-regulatory factors; DLM-1/ZBP-1) is an innate immunity cytoplasmic receptor of the DNA-recognition receptor class of antiviral immunity. DAI-1 expression reflects the severity of the inflammatory response that plays the key role in the pathogenesis of pregnancy complications. We studied DAI-1 receptor expression in the placental villi in early- and late-onset preeclampsia. In case of early-onset preeclampsia DAI-1 staining intensity was lower (p=0.01), and in case of late preeclampsia — significantly higher (p<0.005) than in the reference groups at the corresponding gestational age. There was revealed a correlation between the decrease in DAI-1 receptor expression and the severity of disease progression.

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Egg Case Silk Gene Sequences from Argiope Spiders: Evidence for Multiple Loci and a Loss of Function Between Paralogs

Spiders swath their eggs with silk to protect developing embryos and hatchlings. Egg case silks, like other fibrous spider silks, are primarily composed of proteins called spidroins (spidroin = spider-fibroin). Silks, and thus spidroins, are important throughout the lives of spiders, yet the evolution of spidroin genes has been relatively understudied. Spidroin genes are notoriously difficult to sequence because they are typically very long (10 or more kilobases of coding sequence) and highly repetitive. Here, we investigate the evolution of spider silk genes through long-read sequencing of BAC clones. We demonstrate that the silver garden spider Argiope argentata has multiple egg case spidroin loci with a loss of function at one locus. We also use degenerate PCR primers to search the genomic DNA of congeneric species and find evidence for multiple egg case spidroin loci in other Argiope spiders. Comparative analyses show that these multiple loci are more similar at the nucleotide level within a species than between species. This pattern is consistent with concerted evolution homogenizing gene copies within a genome. More complicated explanations include convergent evolution or recent independent gene duplications within each species.

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Characterization of a novel yeast species Metschnikowia persimmonesis KCTC 12991BP (KIOM G15050 type strain) isolated from a medicinal plant, Korean persimmon calyx (Diospyros kaki Thumb)

The yeast strain Metschnikowia persimmonesis Kang and Choi et al., sp. nov. [type strain KIOM_G15050 = Korean Collection for Type Cultures (KCTC) 12991BP] was isolated from the stalk of native persimmon cultivars...

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Significant increase in cyanide degradation by Bacillus sp. M01 PTCC 1908 with response surface methodology optimization

Cyanide is used in many industries despite its toxicity. Cyanide biodegradation is affordable and eco-friendly. Sampling from cyanide-contaminated areas from the Muteh gold mine and isolation of 24 bacteria we...

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Major Abdominal Trauma

A standardized approach should be used with a patient with abdominal trauma, including primary and secondary surveys, followed by additional diagnostic testing as indicated. Specific factors can make the diagnosis of serious abdominal trauma challenging, particularly in the face of multiple and severe injuries, unknown mechanism of injury, altered mental status, and impending or complete cardiac arrest. Advances in technology in diagnosis and/or treatment with ultrasound, helical computed tomography, and resuscitative endovascular balloon occlusion of the aorta (REBOA) have significantly advanced trauma care, and are still the focus of current and ongoing investigations.

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Amal Mattu

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Reanimating Patients After Traumatic Cardiac Arrest

Resuscitation of traumatic cardiac arrest is typically considered futile. Recent evidence suggests that traumatic cardiac arrest is survivable. In this article key principles in managing traumatic cardiac arrest are discussed, including the importance of rapidly seeking prognostic information, such as signs of life and point-of-care ultrasonography evidence of cardiac contractility, to inform the decision to proceed with resuscitative efforts. In addition, a rationale for deprioritizing chest compressions, steps to quickly reverse dysfunctional ventilation, techniques for temporary control of hemorrhage, and the importance of blood resuscitation are discussed. The best available evidence and the authors' collective experience inform this article.

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Major Trauma Outside a Trauma Center

Care of the critically injured begins well before the patient arrives at a large academic trauma center. It is important to understand the continuum of care from the point of injury in the prehospital environment, through the local hospital and retrieval, until arrival at a trauma center capable of definitive care. This article highlights the important aspects of trauma assessment and management outside of tertiary or quaternary care hospitals. Key elements of each phase of care are reviewed, including management pearls and institutional strategies to facilitate effective and efficient treatment of trauma patients from the point of injury forward.

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Copyright

ELSEVIER

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Airway Management in Trauma

Airway management in the trauma patient presents numerous unique challenges beyond placement of an endotracheal tube and outcomes are dependent on the provider's ability to anticipate difficulty. Airway management strategies for the care of the polytrauma patient are reviewed, with specific considerations for those presenting with traumatic brain injury, suspected c-spine injury, the contaminated airway, the agitated trauma patient, maxillofacial trauma, and the traumatized airway. An approach to airway management that considers the potential anatomic and physiologic challenges in caring for these complicated trauma patients is presented.

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Damage Control: Advances in Trauma Resuscitation

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA

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CME Accreditation Page

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Damage Control: Advances in Trauma Resuscitation

When I began emergency medicine training, trauma care was considered exciting and "sexy" to my colleagues and me. There was excitement with every case, and opportunities to gain experience in procedures abounded. However, as we gained experience in trauma resuscitation, my colleagues and I discovered that trauma care was actually fairly "cookbook." Every patient was managed similarly...the A-B-Cs were employed religiously, with a low threshold for early intubation of any patient that was even mildly sick.

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Acute Management of the Traumatically Injured Pelvis

Severe pelvic trauma is a challenging condition. The pelvis can create multifocal hemorrhage that is not easily compressible nor managed by traditional surgical methods such as tying off a blood vessel or removing an organ. Its treatment often requires reapproximation of bony structures, damage control resuscitation, assessment for associated injuries, and triage of investigations, as well as multimodality hemorrhage control (external fixation, preperitoneal packing, angioembolization, REBOA [resuscitative endovascular balloon occlusion of the aorta]) by multidisciplinary trauma specialists (general surgeons, orthopedic surgeons, endovascular surgeons/interventional radiologists). This article explores this complex clinical problem and provides a practical approach to its management.

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Seismology and Advances in Trauma Resuscitation

The Evolving Science of Trauma Resuscitation

This review summarizes the evolution of trauma resuscitation from a one-size-fits-all approach to one tailored to patient physiology. The most dramatic change is in the management of actively bleeding patients, with a balanced blood product–based resuscitation approach (avoiding crystalloids) and surgery focused on hemorrhage control, not definitive care. When hemostasis has been achieved, definitive resuscitation to restore organ perfusion is initiated. This approach is associated with decreased mortality, reduced duration of stay, improved coagulation profile, and reduced crystalloid/vasopressor use. This article focuses on the tools and methods used for trauma resuscitation in the acute phase of trauma care.

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The Kids Are Alright

The Tragically Hip

Resuscitation Resequenced

Management of Major Vascular Injuries

Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma

Immune checkpoint inhibitors have revolutionized the treatment of advanced stage metastatic melanoma patients, as well as patients with many other solid cancers, yielding long lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed acquired resistance), while others do not respond at all (termed primary resistance). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma and the known mechanisms underlying them involve various components of the cancer immune cycle, and interactions between multiple signalling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma, and detail potential therapeutic strategies to prevent and overcome them.

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PKC epsilon is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia

Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. Experimental Design and Results: We show that RNA interference-mediated inhibition of the serine/threonine kinase PKC-epsilon (PKCe) reduces cell survival in a diverse panel of patient-derived AML samples and significantly delays disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. Utilizing a combination of chemical and genetically-encoded redox sensing probes, we found that PKCe inhibition leads to the induction of multiple reactive oxygen species (ROS) including multiple mitochondrial ROS. We also show that neutralization of mitochondrial ROS with chemical anti-oxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigate the anti-leukemia effects of PKCe inhibition. Similar to PKCe inhibition, direct inhibition of SOD2 also increases mitochondrial ROS and significantly impedes disease progression in vivo. Furthermore, we report that over-expression of PKCe protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCe may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport. Conclusions: This study uncovers a previously unrecognized role for PKC in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.

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RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smokingassociatednon-small cell lung carcinomas sensitive to MEK inhibition.

Purpose: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Experimental Design: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations in RASA1, NF1, or both. Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC which may sensitize to trametinib.

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Highlights in immune response, microbiome and precision medicine in allergic disease and asthma

Milena Sokolowska | Cezmi A. Akdis

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BLU-285 Targets KIT/PDGFRA Conformation and Activating Loop Mutations [Research Watch]

The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.

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Dabrafenib plus Trametinib Is Active in BRAFV600E Anaplastic Thyroid Cancer [Research Watch]

Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV^600E anaplastic thyroid cancers (ATC).

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The DNA Transposase PGBD5 Sensitizes Tumors to Inhibition of DNA Repair [Research Watch]

PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.

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GPX4 Inhibition Selectively Targets Drug-Tolerant Persister Cells [Research Watch]

Targeting GPX4 induces selective cell death of drug-tolerant persister tumor cells by ferroptosis.

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Acalabrutinib Approved for MCL [News in Brief]

Second-generation BTK inhibitor more selective than ibrutinib, may have better safety profile.

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NTZ Increases {beta}-catenin Citrullination to Suppress WNT Signaling [Research Watch]

The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.

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Sclerosing angiomatoid nodular transformation of the spleen in a patient with Maffucci syndrome: a case report and review of literature

Maffucci syndrome is a congenital, non-hereditary mesodermal dysplasia characterized by multiple enchondromas and hemangiomas. The presence of visceral vascular lesions in this syndrome is exceedingly rare.

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Immunohistochemistry with Anti-BRAF V600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAF V600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review

Abstract

The major aim of this study was to evaluate the performance of anti-BRAF V600E (VE1) antibody in colorectal tumors with and without KRAS mutation. KRAS and BRAF are two major oncogenic drivers of colorectal cancer (CRC) that have been frequently described as mutually exclusive, thus the BRAF V600E mutation is not expected to be present in the cases with KRAS mutation. In addition, a review of 25 studies comparing immunohistochemistry (IHC) using the anti-BRAF V600E (VE1) antibody with BRAF V600E molecular testing in 4041 patient samples was included.

One-hundred and twenty cases with/without KRAS or BRAF mutations were acquired. The tissue were immunostained with anti-BRAF V600E (VE1) antibody with OptiView DAB IHC detection kit. The KRAS mutated cases with equivocal immunostaining were further evaluated by Sanger sequencing for BRAF V600E mutation. Thirty cases with BRAF V600E mutation showed unequivocal, diffuse, uniform, positive cytoplasmic staining and 30 cases with wild-type KRAS and BRAF showed negative staining with anti-BRAF V600E (VE1) antibody. Out of 60 cases with KRAS mutation, 56 cases (93.3%) were negative for BRAF V600E mutation by IHC. Four cases showed weak, equivocal, heterogeneous, cytoplasmic staining along with nuclear staining in 25–90% of tumor cells. These cases were confirmed to be negative for BRAF V600E mutation by Sanger sequencing. Overall, IHC with anti-BRAF V600E (VE1) antibody using recommended protocol with OptiView detection is optimal for detection of BRAF V600E mutation in CRC. Our data are consistent with previous reports indicating that KRAS and BRAF V600E mutation are mutually exclusive.

http://ift.tt/2zOo43n

Cramps frequency and severity are correlated with small and large nerve fiber measures in type 1 diabetes

Muscle cramps are defined as sudden sustained and painful contraction of a muscle or muscle group. Muscle cramps are common, with a higher prevalence in the elderly(Abdulla et al. 1999) and in patients with neuropathic conditions,(Katzberg 2015) and are often underreported.(Naylor and Young 1994) The pathogenesis of muscle cramps involves spontaneous discharges of motor nerves, but the exact site of origin of these discharges, and their physiological mechanism remain uncertain.(Layzer 1994) Although the prevailing hypothesis is that muscle cramps originate and are propagated at motor nerves,(Layzer 1994) muscle cramps have also been described in sensory and pure small fiber neuropathies.(Lopate et al.

http://ift.tt/2ji2q0k

Cognitive reserve modulates attention processes in healthy elderly and amnestic mild cognitive impairment: an event-related potential study

Cognitive reserve (CR) is a concept that was proposed to explain susceptibility heterogeneities of different individuals to cognitive impairment while confronting same neural pathology (Barulli et al., 2013). In addition, CR might be associated with lifetime intellectual activities and some other environmental factors including Intelligence Quotient (IQ), education, occupation level and participation in leisure activities, et al (Barulli et al., 2013). There is extensive epidemiological and experimental evidence to support the existence of CR: education, occupation level and participation in leisure activities have been demonstrated to be related to risk for developing dementia (Smith et al., 2010; Stern, 2012; Xu et al., 2015), cognitive impairment while aging (Barulli et al., 2013), and clinical changes in several other neurological and psychiatric disorders (Barnett et al., 2006; Sumowski et al., 2013; Hindle et al., 2014; Nunnari et al., 2014; Mathias et al., 2015).

http://ift.tt/2hqvtym

The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer

The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over-expressed in tumour cells and contributes to cancer aggressiveness. Biliary tract cancer (BTC) is a rare cancer with dismal prognosis due to a lack of effective therapies. Currently, there are no data on the role of G9a in BTC carcinogenesis. We analysed G9a expression in n=68 BTC patient specimens and correlated the data with clinico-pathological and survival data.

http://ift.tt/2zyee4s

Dedifferentiated endometrial carcinomas with neuroendocrine features: a clinicopathologic, immunohistochemical, and molecular genetic study

Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, b-catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression.

http://ift.tt/2hjHpOv

Pathologic and Clinical Characteristics of Early Onset Renal Cell Carcinoma

The majority of RCCs occur within the 7th decade of life, uncommonly arising in adults ≤46years. We reviewed the clinicopathologic features of early-onset renal cell carcinoma (RCC) and evaluated the role of immunohistochemistry (IHC) in potentially identifying diagnoses of newly recognized RCC subtypes that may have been previously misclassified. A retrospective review was performed from 2011–2016 for cases of RCC. Early-onset RCC was defined as ≤46years of age. Clinicopathologic findings and hematoxylin and eosin (H&E) slides were reviewed on early-onset RCC patients.

http://ift.tt/2zxSIgj

Abdominal Fat Pad Excisional Biopsy for the Diagnosis and Typing of Systemic Amyloidosis

In the past, the diagnosis and typing of amyloidosis often required an invasive biopsy of an internal organ, such as the heart or kidneys. Abdominal fat pad excisional biopsy (FPEB) offers a less invasive approach, but the sensitivity of this technique has been unclear. To determine the sensitivity of FPEB for immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, we performed a retrospective clinicopathologic analysis of 97 patients who had undergone FPEB, of which 16 were positive for amyloid.

http://ift.tt/2hj41P4

Piperacillin–tazobactam as alternative to carbapenems for ICU patients

Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteria...

http://ift.tt/2yqqWih

Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD

Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown.

http://ift.tt/2i4q7G5

Associations Between Weight Loss, Kidney Function Decline, and Risk of ESRD in the Chronic Kidney Disease in Children (CKiD) Cohort Study

Anorexia and malnutrition are associated with poor outcomes in children with chronic kidney disease (CKD).

http://ift.tt/2AuqIHB

An Interview Study of Patient and Caregiver Perspectives on Advance Care Planning in ESRD

Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, it can be an emotionally charged process for patients with kidney disease and their caregivers. This study aimed to describe the perspectives and attitudes of patients with end-stage renal disease (ESRD) and their caregivers toward ACP.

http://ift.tt/2i1vIg6

High Prevalence of Barrett’s Esophagus and Esophageal Squamous Cell Carcinoma after Repair of Esophageal Atresia

Esophageal atresia is rare, but improved surgical and intensive care techniques have increased rates of survival in children, so there are now many adults with this disorder. Many patients with esophageal atresia develop gastroesophageal reflux (GER), raising concerns about increased risk of Barrett's esophagus (BE; prevalence of 1.3%–1.6% in general population) and esophageal carcinoma. We assessed the prevalence of BE and esophageal carcinoma in this population.

http://ift.tt/2yr1mtG

When should screening stop for elderly individuals at average and increased risk for colorectal cancer?

http://ift.tt/2AzhwTl

Comparative Efficacy of Colonoscope Distal Attachment Devices in Increasing Rates of Adenoma Detection: A Network Meta-analysis

Several add-on devices have been developed to increase rates of colon adenoma detection (ADR). We assessed their overall and comparative efficacy, and estimated absolute magnitude of benefit through a network meta-analysis.

http://ift.tt/2ypB3nF

Characteristics and Progression of Preclinical Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic disease usually diagnosed after the appearance of gastrointestinal symptoms. Little is known about IBD progression during its early and even preclinical phases. We aimed to determine the number of new incidental diagnoses of IBD in an older population, and evaluate disease progression from its early stages.

http://ift.tt/2ABKcv2

When should patients undergo genetic testing for hereditary colon cancer syndromes?

http://ift.tt/2ypB379

Cold endoscopic mucosal resection of large sessile serrated polyps at colonoscopy (with video)

The optimal technique for the resection of sessile serrated polyps (SSPs) is unknown, with established limitations and risks with conventional polypectomy. Although cold snare polypectomy is safe, the efficacy of piecemeal resection for large lesions is untested. In this study, we evaluate the safety and efficacy of cold endoscopic mucosal resection (EMR) for large SSPs.

http://ift.tt/2AzhieX

Force Spectroscopy with 9-μs Resolution and Sub-pN Stability by Tailoring AFM Cantilever Geometry

Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) is a powerful yet accessible means to characterize the unfolding/refolding dynamics of individual molecules and resolve closely spaced, transiently occupied folding intermediates. On a modern commercial AFM, these applications and others are now limited by the mechanical properties of the cantilever. Specifically, AFM-based SMFS data quality is degraded by a commercial cantilever's limited combination of temporal resolution, force precision, and force stability.

http://ift.tt/2yOEwAr

A National Description of Treatment among United States Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

To characterize lifetime and current rates of attention-deficit/hyperactivity disorder (ADHD) treatments among US children and adolescents with current ADHD and describe the association of these treatments with demographic and clinical factors.

http://ift.tt/2yOpPgN

Bilirubin Albumin Binding and Unbound Unconjugated Hyperbilirubinemia in Premature Infants

To evaluate the associations between unbound bilirubin (UB) and total serum bilirubin (TSB), bilirubin:albumin molar ratio (BAMR), and bilirubin albumin binding affinity (Ka) as a function of gestational age (GA) in infants born at 24-33 weeks GA.

http://ift.tt/2mhU4qL

Force Spectroscopy with 9-μs Resolution and Sub-pN Stability by Tailoring AFM Cantilever Geometry

Artificial neural networks to predict future bone mineral density and bone loss rate in Japanese postmenopausal women

Predictions of the future bone mineral density and bone loss rate are important to tailor medicine for women with osteoporosis, because of the possible presence of personal risk factors affecting the severity ...

http://ift.tt/2yQ5AiY

Virological response, HIV-1 drug resistance mutations and genetic diversity among patients on first-line antiretroviral therapy in N’Djamena, Chad: findings from a cross-sectional study

The national antiretroviral therapy in the Republic of Chad provides free of charge antiretroviral regimens and therapeutic monitoring for patients receiving antiretroviral therapy nationwide. For a successful...

http://ift.tt/2mb2nV0

Temperature Variability in a Modern Targeted Temperature Management Trial

Objectives: The Eurotherm3235 trial showed that therapeutic hypothermia was deleterious in patients with raised intracranial pressure following traumatic brain injury. We sought to ascertain if increased temperature variability within the first 48 hours, or for 7 days post randomization, were modifiable risk factors associated with poorer outcome. Design: Eurotherm3235 was a multicenter randomized controlled trial. Patients were randomized to receive either therapeutic hypothermia in addition to standard care or the later only. Mean moving range (mr) was used to stratify subjects into tertiles by the variability present in their core temperature within the first 48 hours post randomization and within 7 days post randomization. The primary outcome measure was a collapsed Glasgow Outcome Scale-Extended at 6 months post randomization. The temperature variability effect was estimated with ordinal logistic regression adjusted for baseline covariates and treatment effect. Setting: Forty-seven critical care units in 18 countries. Patients: Patients enrolled in the Eurotherm3235 trial to either therapeutic hypothermia or control treatments only. Measurements and Main Results: Three hundred eighty-six patients were included in our study. High level of temperature variability during the first 48 hours was associated with poorer collapsed Glasgow Outcome Scale-Extended. This effect remained statistically significant when only the control arm of the study was analyzed. No statistically significant effect was seen within the first 48 hours in the hypothermia group or within 7 days in either group. Conclusions: When targeting normothermia, temperature variability may be a statistically significant variable in an ordinal analysis adjusted for baseline covariates. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Current Controlled Trials number: ISRCTN34555414 Supported, in part, by The University of Edinburgh and NHS Lothian. Dr. Rodriguez's institution received funding from the National Institute for Health Research Health Technology Assessment, and she received funding from the University of Edinburgh. The remaining authors have disclosed that they do not have any potential conflicts of interest. This research was performed at The University of Edinburgh and NHS Lothian. For information regarding this article, E-mail: p.andrews@ed.ac.uk Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2yrtpcw

Renal Decapsulation Prevents Intrinsic Renal Compartment Syndrome in Ischemia-Reperfusion–Induced Acute Kidney Injury: A Physiologic Approach

Objectives: Acute kidney injury is a serious complication with unacceptably high mortality that lacks of specific curative treatment. Therapies focusing on the hydraulic behavior have shown promising results in preventing structural and functional renal impairment, but the underlying mechanisms remain understudied. Our goal is to assess the effects of renal decapsulation on regional hemodynamics, oxygenation, and perfusion in an ischemic acute kidney injury experimental model. Methods: In piglets, intra renal pressure, renal tissue oxygen pressure, and dysoxia markers were measured in an ischemia-reperfusion group with intact kidney, an ischemia-reperfusion group where the kidney capsule was removed, and in a sham group. Results: Decapsulated kidneys displayed an effective reduction of intra renal pressure, an increment of renal tissue oxygen pressure, and a better performance in the regional delivery, consumption, and extraction of oxygen after reperfusion, resulting in a marked attenuation of acute kidney injury progression due to reduced structural damage and improved renal function. Conclusions: Our results strongly suggest that renal decapsulation prevents the onset of an intrinsic renal compartment syndrome after ischemic acute kidney injury. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Drs. Cruces, Salas, and F. Lillo received support for article research from the Sociedad Chilena de Pediatria. The remaining authors have disclosed that they do not have any potential conflicts of interest. Supported, in part, by the Fondecyt Regular number 1160631 grant of the Fondo Nacional de Desarrollo Científico y Tecnológico, the Proyecto en Ciencias Biomédicas y Clínicas 2015 Universidad Andrés Bello (DI-749-15/CB), and by funding from the Sociedad Chilena de Pediatría 2012001 Grant. For information regarding this article, E-mail: dhurtado@ing.puc.cl Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2zxzOUX

Osmotic Shifts, Cerebral Edema, and Neurologic Deterioration in Severe Hepatic Encephalopathy

Objectives: We sought to determine the effect of acute electrolyte and osmolar shifts on brain volume and neurologic function in patients with liver failure and severe hepatic encephalopathy. Design: Retrospective analysis of brain CT scans and clinical data. Setting: Tertiary care hospital ICUs. Patients: Patients with acute or acute-on-chronic liver failure and severe hepatic encephalopathy. Interventions: Clinically indicated CT scans and serum laboratory studies. Measurements and Main Results: Change in intracranial cerebrospinal fluid volume between sequential CT scans was measured as a biomarker of acute brain volume change. Corresponding changes in serum osmolality, chemistry measurements, and Glasgow Coma Scale were determined. Associations with cerebrospinal fluid volume change and Glasgow Coma Scale change for initial volume change assessments were identified by Spearman's correlations (rs) and regression models. Consistency of associations with repeated assessments was evaluated using generalized estimating equations. Forty patients were included. Median baseline osmolality was elevated (310 mOsm/Kg [296–321 mOsm/Kg]) whereas sodium was normal (137 mEq/L [134–142 mEq/L]). Median initial osmolality change was 9 mOsm/kg (5–17 mOsm/kg). Neuroimaging consistent with increased brain volume occurred in 27 initial assessments (68%). Cerebrospinal fluid volume change was more strongly correlated with osmolality (r = 0.70; p = 4 × 10–7) than sodium (r = 0.28; p = 0.08) change. Osmolality change was independently associated with Glasgow Coma Scale change (p = 1 × 10–5) and cerebrospinal fluid volume change (p = 2.7 × 10–5) in initial assessments and in generalized estimating equations using all 103 available assessments. Conclusions: Acute decline in osmolality was associated with brain swelling and neurologic deterioration in severe hepatic encephalopathy. Minimizing osmolality decline may avoid neurologic deterioration. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Dr. Liotta contributed to study conception and design; data acquisition, analysis, and interpretation; drafted the article and revised it critically for important intellectual content; approved the final article draft; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Liotta had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Liotta takes responsibility for the integrity of the work as a whole. Dr. Romanova contributed to data acquisition and analysis, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Lizza contributed to data acquisition, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Rasmussen-Torvik contributed to study design; data analysis and interpretation; revised the article critically for important intellectual content; approved the final article draft; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Rasmussen-Torvik also provided statistical consultation and review. Dr. Kim contributed to data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Francis contributed to data acquisition, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Sangha contributed to data acquisition, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Carroll contributed to study design, data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Drs. Ganger, Ladner, and Prabhakaran contributed to study conception, data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Naidech and Maas contributed to study conception and design, data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Paparello contributed to data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Sorond contributed to study conception, data interpretation, critically revised the article for important intellectual content, approved the final article draft, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Supported, in part, by the National Institutes of Health's National Center for Advancing Translational Sciences, Grant Number KL2TR001424, and the National Institutes of Health, Grant Number L30 NS098427 and by departmental funding from the Ken & Ruth Davee Department of Neurology in the Northwestern University Feinberg School of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Liotta, Rasmussen-Torvik, Sorond, and Maas received support for article research from the National Institutes of Health (NIH). Dr. Liotta is supported by a KL2 career development grant awarded through the Northwestern University Clinical and Translational Sciences Institute. Dr. Liotta's institution received funding from NIH's National Center for Advancing Translational Sciences and the NIH's National Center for Advancing Translational Sciences, Grant Number KL2TR001424; he received funding from the NIH, Northwestern University, and NIH Grant Number L30 NS098427; and he disclosed that his institution received grant support from Placement of AoRTic TraNscathetER Valves II Trial (Edwards Lifesciences), TranScatheter Aortic Valve RepLacement System U.S. Feasibility Trial (Direct Flow Medical), and SAGE-547 Clinical Trial (SAGE therapeutics) for his work on those clinical trials. Dr. Ganger received funding from Abbvie, Gilead, and Merck. Dr. Naidech's institution received funding from the Agency for Healthcare Research and Quality, K18 HS023437. Dr. Maas' institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: eric.liotta@northwestern.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis

Objectives: A recent post hoc analysis suggested that driving pressure may be more important than traditional ventilatory variables in determining outcome in mechanically ventilated patients with acute respiratory distress syndrome. We conducted a systematic review and meta-analysis to summarize the risk of mortality for higher versus lower driving pressure. Data Sources: MEDLINE, EMBASE, PubMed, CINAHL, and Cochrane CENTRAL from inception to February 10, 2017. Study Selection: Studies including mechanically ventilated adult patients with acute respiratory distress syndrome, reporting driving pressure and mortality. Data Extraction: Seven studies including five secondary analysis of previous randomized controlled trials and two observational studies (6,062 patients) were eligible for study. All studies were judged as having a low risk of bias. Median (interquartile range) driving pressure between higher and lower driving pressure groups was 15 cm H2O (14–16 cm H2O). Median (interquartile range) mortality of all included studies was 34% (32–38%). Data Synthesis: In the meta-analyses of four studies (3,252 patients), higher driving pressure was associated with a significantly higher mortality (pooled risk ratio, 1.44; 95% [CI], 1.11–1.88; I2 = 85%). A sensitivity analysis restricted to the three studies with similar driving pressure cutoffs (13–15 cm H2O) demonstrated similar results (pooled risk ratio, 1.28; 95% CI, 1.14–1.43; I2 = 0%). Conclusions: Our study confirmed an association between higher driving pressure and higher mortality in mechanically ventilated patients with acute respiratory distress syndrome. These findings suggest a possible range of driving pressure to be evaluated in clinical trials. Future research is needed to ascertain the benefit of ventilatory strategies targeting driving pressure in patients with acute respiratory distress syndrome. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Drs. Aoyama and Fan conceived this article. Drs. Aoyama, Pettenuzzo, Englesakis, and Fan performed the systematic review. Drs. Aoyama, Aoyama, and Pinto performed the analysis on the result of the literature search, and Drs. Pettenuzzo, Aoyama, Pinto, and Fan provided input on the interpretation. Drs. Aoyama and Aoyama wrote the initial draft of the article, and Drs. Pettenuzzo, Pinto, Englesakis, and Fan helped draft the final version, which was approved by all authors. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: eddy.fan@uhn.ca Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2youW2R

Transplantation of Hepatocyte Growth Factor–Modified Dental Pulp Stem Cells Prevents Bone Loss in the Early Phase of Ovariectomy-Induced Osteoporosis

Human Gene Therapy , Vol. 0, No. 0.

http://ift.tt/2AzPs20

Systemic SMAD7 Gene Therapy Increases Striated Muscle Mass and Enhances Exercise Capacity in a Dose-Dependent Manner

Human Gene Therapy , Vol. 0, No. 0.

http://ift.tt/2ys792d

Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles

The objective of this study was to evaluate in vitro lipid-lowering drug effects in modulating the morphology of cholesterol particles. Comparison of lipid-lowering drugs revealed variations in their effect in modulating the morphological features of cholesterol particles.

http://ift.tt/2zxcvwi

Bright light therapy improves cancer-related fatigue in cancer survivors: a randomized controlled trial

Abstract

Purpose

Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue.

Methods

This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life.

Results

A total of 81 participants were randomly assigned to receive BWL (n = 42) or DRL (n = 39). Analyses revealed a group-by-time interaction for fatigue (p = .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group d = .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (p's < .01).

Conclusions

BWL was associated with greater improvements in fatigue and both groups displayed improvements on secondary psychosocial outcomes.

Implications for cancer survivors

These findings, along with previous reports of light therapy for CRF, support the use of this intervention to improve fatigue in cancer survivors.

http://ift.tt/2zy3FfJ

Effectiveness of intrapartum antibiotic prophylaxis for early-onset group B Streptococcal infection: An integrative review

Publication date: Available online 10 November 2017
Source:Women and Birth
Author(s): Kathryn Braye, John Ferguson, Deborah Davis, Christine Catling, Amy Monk, Maralyn Foureur
BackgroundIn some countries, up to 30% of women are exposed to intrapartum antibiotic prophylaxis for prevention of early-onset group B Streptococcal infection. Intrapartum antibiotic prophylaxis aims to reduce the risk of neonatal morbidity and mortality from this infection. The intervention may adversely affect non-pathogenic bacteria which are passed to the newborn during birth and are considered important in optimising health. Since many women are offered intrapartum antibiotic prophylaxis, effectiveness and implications of this intervention need to be established. This review considers clinical trials and observational studies analysing the effectiveness of intrapartum antibiotic prophylaxis.MethodsAn integrative literature review was conducted. One systematic review, three clinical trials and five observational studies were identified for appraisal.FindingsRandomised controlled trials found intrapartum antibiotic prophylaxis effective but all retrieved randomised clinical trials had significant methodological flaws. High quality observational studies reported high rates of effectiveness but revealed less than optimal adherence to screening and administration of the prophylaxis. Scant consideration was given to short term risks, and long-term consequences were not addressed.DiscussionStudies found intrapartum antibiotic prophylaxis to be effective. However, evidence was not robust and screening and prophylaxis have limitations. Emerging evidence links intrapartum antibiotic prophylaxis to adverse short and longer-term neonatal outcomes.ConclusionOur review found high quality evidence of the effectiveness of intrapartum antibiotic prophylaxis was limited. Lack of consideration of potential risks of the intervention was evident. Women should be enabled to make informed decisions about GBS management. More research needs to be done in this area.

http://ift.tt/2jiBfTb

The Authors’ Reply

No abstract available

http://ift.tt/2hioP9v

Should persistent hepatitis E virus replication in transplant patients be tolerated?

No abstract available

http://ift.tt/2zytkaj

Developing A Risk Score to Predict Long-Term Adverse Outcomes After Kidney Transplantation

No abstract available

http://ift.tt/2hjwCDT

Chronic airway fibrosis in orthotopic mouse lung transplantation models - an experimental reappraisal?

No abstract available

http://ift.tt/2zxNlO4

The Authors’ Reply

No abstract available

http://ift.tt/2hiYLLl

The natural history of idiopathic scoliosis during growth: a meta-analysis

Objective To provide a meta-analysis of current literature concerning the natural history of idiopathic scoliosis during growth. Design A comprehensive search of MEDLINE, EMBASE, and SCOPUS databases was conducted up to November 2016. Eligible works were prospective or retrospective studies that enrolled patients with infantile (IIS), juvenile (JIS), or adolescent idiopathic scoliosis (AIS), followed up without any treatment from the time of detection. A meta-analysis for proportion was performed. The studies were grouped per diagnosis: IIS, JIS, and AIS. Results Of the 1797 citations screened, we assessed 61 full-text articles and included 13 of these (2301 participants). Three studies included IIS patients (347 participants), five studies included a mixed population of JIS and AIS (1330 participants), and five studies included AIS patients only (624 participants). The random pooled estimated progression rate was 49% (95% CI: 1–97%) for IIS; 49% in a mixed group of patients affected by JIS or AIS (95% CI: 19–79%), and 42% in AIS (95% CI: 11–73%). Conclusions During growth, idiopathic scoliosis tends to progress in a high percentage of cases. The progression rate varies according to the age at diagnosis, with infantile scoliosis being the most unpredictable. There are many confounders, such as age, Risser sign and baseline Cobb angles that were not consistent among studies, making the data very heterogeneous. Address correspondence to: Francesca Di Felice, ISICO (Italian Scientific Spine Institute), Via Bellarmino 13/1, Milan, 20141 +393492682688 ORCID iD 0000-0002-9553-4499 Funding Source: No funding was secured for this study. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Conflict of Interest: The authors have no conflicts of interest to disclose. Previous presentation at scientific meetings: SOSORT 2017 Lyon, ISSLS 2017 Athens. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Graduate Medical Education Funding & Curriculum in PM&R: A Survey of Physical Medicine & Rehabilitation Department Chairs

Abstract This national survey highlights graduate medical education funding sources for PM&R residency programs as well as: perceived funding stability; alignment of the current funding and educational model; the need of further education in post-acute care settings; and the practice of contemporary PM&R graduates as perceived by PM&R department/division chairs. About half of the reported PM&R residency positions appear to be funded by Centers of Medicare and Medicaid Services (CMS); over 40% of PM&R chairs believe their residency program is undersized and nearly a quarter feel at risk for losing positions. A total of 30% of respondents report PM&R resident experiences in home health, 15% in long-term acute care, and 52.5% in a skilled nursing facility/subacute rehabilitation facility. In programs that do not offer these experiences, a majority of chairs feel this training should be included. In addition, study results suggest that a majority of PM&R graduates work in an outpatient setting. Based on the results that chairs strongly feel the need for resident education in post-acute care settings and that a majority of graduates go on to practice in outpatient settings, there is a potential discordance for our current CMS GME funding model being linked to the acute care setting. Author Disclosures: All authors state no competing interests, funding, grants or equipment provided for the project from any source; nor financial benefits to the authors. There are no previous presentations or submissions of this research. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Contralateral involvement of congenital muscular torticollis and clavicular fracture

ABSTRACT Congenital muscular torticollis (CMT) is known to concur with some conditions such as developmental dysplasia of the hip or brachial plexus injury, which gives us some insights for pathogenesis of CMT. While clavicular fracture is the most common fracture in newborns, little is known about concurrence of CMT and clavicular fracture. Our clinical experience led us to realize that concurrence of CMT and clavicular fracture tended to occur on the contralateral side for each other rather than the ipsilateral side. This study aimed to verify contralateral concurrence of CMT and clavicular fracture. This is a retrospective cohort study in a tertiary hospital, including 996 subjects with CMT. Concurrent clavicular fracture was found in 20 of 996 subjects with CMT, with the concurrence rate being 2.01%. CMT and clavicular fracture occurred on the contralateral side for each other in 18 subjects (90%) rather than the ipsilateral side. This contralateral concurrence between side of CMT and clavicular fracture was significant (P=0.001), with an odds ratio of 81 (P=0.0032). CMT and clavicular fracture seem to occur significantly more on the contralateral side for each other. Underlying mechanism for consistent contralateral concurrence needs to be verified in the near future. Correspondence: All correspondence and requests for reprints should be addressed to: Shin-Young Yim, MD, PhD, The Center for Torticollis, Department of Physical Medicine and Rehabilitation, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea. Tel: +82-31-219-5284, Fax: +82-31-219-5209. E-mail address: syyim@ajou.ac.kr Author Disclosures: No conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. No funding or grants or equipment provided for the project from any source have been reported by the authors. Funding/Support: This work was supported by the grants through the National Research Foundation of Korea (NRF) funded by the Ministry Science, ICT and Future Planning, Republic of Korea (2016R1A2B1010654). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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No MERS-CoV but positive influenza viruses in returning Hajj pilgrims, China, 2013–2015

There is global health concern that the mass movement of pilgrims to and from Mecca annually could contribute to the international spread of Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In China, a...

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Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation

This protocol describes the use of centrifugal elutriation to separate primary acute lymphoblastic leukemia cells into different cell cycle phases.

http://ift.tt/2zxRDFk

Synthesis of Core-shell Lanthanide-doped Upconversion Nanocrystals for Cellular Applications

A protocol is presented for the synthesis of core-shell lanthanide-doped upconversion nanocrystals (UCNs) and their cellular applications for channel protein regulation upon near-infrared (NIR) light illumination.

http://ift.tt/2iJoKMc

Correlative Super-resolution and Electron Microscopy to Resolve Protein Localization in Zebrafish Retina

This protocol describes the necessary steps to obtain subcellular protein localization results on zebrafish retina by correlating super-resolution light microscopy and scanning electron microscopy images.

http://ift.tt/2zxHGWg

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

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Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors

Abstract

Background

While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context.

Methods

In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models.

Results

Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively.

Conclusions

In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population.

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Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter “real life” study

Abstract

Background

To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.

Methods

A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic.

Results

We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4–2100). The median exposure to AA was 10 months (range 1–35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline.

Conclusions

The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline.

Trial registration

The study was retrospectively registered at ISRCTN as DOI:10.1186/ISRCTN 52513758 in date April the 30th 2016.

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The preoperative neutrophil to lymphocyte ratio is a superior indicator of prognosis compared with other inflammatory biomarkers in resectable colorectal cancer

Abstract

Background

Growing evidence has indicated that some inflammatory markers, including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), can be used as indicators in the prognosis of colorectal cancer (CRC). However, there is controversy concerning what is the best predictor of prognosis in CRC.

Methods

A cohort of 1744 CRC patients in our institution was analyzed retrospectively. Harrell's concordance index (c-index) and Bayesian information criterion (BIC) were used to determine the optimal cut-off values of inflammatory markers and compare their predictive capacity. The association of inflammatory markers with overall survival (OS) and cancer-specific survival (CSS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model.

Results

The multivariate analysis indicated that among these inflammatory markers, NLR (< 2.0 vs. ≥ 2.0) was the only independent prognostic factor for poor OS [hazard ratio (HR) = 0.758, 95% confidence intervals (CI) = 0.598–0.960, P = 0.021)] and CSS (HR = 0.738, 95% CI = 0.573–0.950, P = 0.018). Among these inflammatory markers, the c-index and BIC value for NLR were maximum and minimum for OS, respectively. In addition, the c-index was higher and the BIC value was smaller in TNM staging combined with NLR compared with the values obtained in TNM staging alone.

Conclusion

NLR is a superior indicator of prognosis compared with LMR, PLR, and PNI in CRC patients, and NLR may serve as an additional indicator based on the current tumor staging system.

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YRNA expression predicts survival in bladder cancer patients

Abstract

Background

Non-coding RNAs play an important role in human carcinogenesis. YRNAs (Ro-associated Y), a novel class of non-coding RNAs, have been identified as biomarker in various malignancies, but remain to be studied in urinary bladder cancer (BCA) patients.

Methods

The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival BCA (urothelial carcinoma, n = 88) and normal urothelial bladder (n = 30) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for overall and cancer-specific survival were analysed.

Results

All YRNAs were significantly downregulated in BCA tissue. A low expression of RNY1, RNY3 and RNY4 was associated with muscle-invasive BCA, lymph node metastases and advanced grade. Furthermore, expression of RNY1 and RNY3 was predictive for BCA patients' overall (also RNY4) and cancer-specific survival as estimated using Kaplan-Meier and univariate (but not multivariate) Cox regression analyses. RNY1, RNY3 and RNY4 show good discriminative ability between tumor and normal tissue, as well as between muscle-invasive and non-muscle-invasive urothelial carcinoma.

Conclusions

The expression of YRNAs is altered in BCA and associated with poor prognosis. Possible diagnostic role of YRNAs should be investigated in further studies.

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Virucidal efficacy of peracetic acid for instrument disinfection

Various peracetic-acid (PAA)-based products for processing flexible endoscopes on the market are often based on a two-component system including a cleaning step before the addition of PAA as disinfectant. The ...

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Book Review—Diagnostic pathology: thoracic, 2nd edition

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Firearms and suicide: Finding the right words

Abstract

As emergency physicians, we're used to asking patients about sensitive topics. We overcame discomfort by practicing questions like "Do you have sex with men, women or both?" until the words flowed smoothly. In lectures, I urge providers to counsel suicidal patients about firearm access, given that reducing lethal means access can save lives.^1,2 But early on, I didn't know how to talk about firearms without offending my patients.

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Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial

Abstract

Objective

We evaluated the efficacy of topical application of the injectable form of tranexamic acid (TXA) compared with anterior nasal packing (ANP) for the treatment of epistaxis in patients taking antiplatelet drugs (Aspirin, Clopidegrol or both) who presented to the emergency department (ED).

Methods

A randomized, parallel group clinical trial was conducted at 2 EDs. A total of 124 participants were randomized to receive topical TXA (500 mg in 5 ml) or ANP, 62 patients per group. The primary outcome was the proportion of patients in each group whose bleeding had stopped at 10 minutes. Secondary outcomes were the re-bleeding rate at 24 hours and one week, ED length of stay (LOS), and patient satisfaction.

Results

Within 10 minutes of treatment, bleeding was stopped in 73% of the patients in the TXAgroup, compared with 29% in the ANP group (difference 44%, 95% confidence interval, 26%-57%; p<.001). Additionally, re-bleeding was reported in 5% and 10% of patients during the first 24 hours in the TXA and the ANP groups, respectively. At 1 week, 5% of patients in the TXA group and 21% of patients in the ANP group had experienced recurrent bleeding (p=.007). Patients in the TXA group reported higher satisfaction scores [(median (IQR), 9 (8-9.25)] compared with the anterior nasal packing group [median (IQR), 4 (3-5)] (p<.001). Discharge from the ED in <2 hours was achieved in 97% of patients in the TXA group vs. 13% in the ANP group (p<.001). There were no adverse events reported in either group.

Conclusions

In our study population, epistaxis treatment with topical application of TXA resulted in faster bleeding cessation, less re-bleeding at 1week, shorter ED LOS, and higher patient satisfaction as compared with ANP.

http://ift.tt/2ArSvII

Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

Abstract

Background

To determine the potential role of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).

Methods

One hundred twenty-nine patients (pts) with ⁶⁸Ga-PSMA PET/CT were retrospectively analysed. Potentially influencing factors (androgen deprivation therapy, amount of ⁶⁸Ga-PSMA-HBED-CC, PSA doubling time ≤/> 10 months, PSA before PET/CT, T−/N-category and Gleason score) were evaluated by logistic regression analysis. The detection rate of PSMA PET/CT was compared to contrast enhanced CT and its impact on RT management analysed.

Results

One hundred twenty-nine patients (pts) (20 at initial diagnosis, 49 with PSA relapse and 60 with PSA persistence after radical prostatectomy) received PSMA PET/CT prior to RT. The majority of pts. (71.3%) had PET-positive findings (55.1% of pts. with PSA recurrence, 75% of pts. with PSA persistence and 100% of newly diagnosed pts). Median PSA before PET/CT in pts. with pathological findings (n = 92) was 1.90 ng/ml and without (n = 37) 0.30 ng/ml. PSA level at time of PET/CT was the only factor associated with PET-positivity. In pts. with a PSA ≤ 0.2 ng/ml, the detection rate of any lesion was 33.3%, with a PSA of 0.21–0.5 ng/ml 41.2% and with a PSA of 0.51–1.0 ng/ml 69.2%, respectively. Regarding the anatomic distribution of lesions, 42.2% and 14.7% of pts. with relapse or persistence had pelvic lymph node and distant metastases. In pts. at initial diagnosis the detection rate of pelvic lymph nodes and distant metastases was 20% and 10%. ⁶⁸Ga-PSMA PET/CT had a high detection rate of PCa recurrence outside the prostatic fossa in pts. being considered for salvage RT (22.4% PET-positive pelvic lymph nodes and 4.1% distant metastases). Compared to CT, PSMA PET/CT had a significantly higher sensitivity in diagnosing rates of local recurrence/primary tumour (10.1% vs. 38%), lymph nodes (15.5% vs. 38.8%) and distant metastases (5.4% vs. 14.0%). This resulted in a modification of RT treatment in 56.6% of pts.

Conclusions

The detection of PCa is strongly associated with PSA level at time of ⁶⁸Ga-PSMA PET/CT. PSMA PET/CT differentiates between local, regional and distant metastatic disease with implications for disease management. PSMA PET/CT allows for tumour detection in post-prostatectomy pts. with PSA ≤ 0.5 ng/ml considered for salvage RT.

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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

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Issue Information

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Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis

Abstract

Background

Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review.

Methods

Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis.

Results

Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13–2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93–1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12–2.55), with no effect seen when restricted to studies which adjusted for key covariates.

Conclusion

A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

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MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Abstract

Background

Melanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells.

Methods

TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide.

Results

Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR-195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti-proliferative agent, with potential impact in sensitization of melanoma cell death.

Conclusions

This study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells.

http://ift.tt/2zxvCod

miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.

Methods

We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.

Results

The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = −0.28, P = 3.88 × 10⁻³). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.

Conclusions

Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

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Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients

Abstract

Background

The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position.

Methods

Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996–2008) and late groups (2009–2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed.

Results

The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001).

Conclusions

Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes.

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Contrast-enhanced ultrasound of small cell carcinoma in urinary bladder: a case report and review of literature

Abstract

Background

Small cell carcinoma of the urinary bladder (SCCB) is a relatively rare malignant bladder tumor, and few reports have investigated the microvasculature of SCCB imaged using contrast-enhanced ultrasound (CEUS).

Case presentation

A 63-year-old female was admitted to our hospital after experiencing painless gross hematuria for one week. The gray-scale ultrasound (US) demonstrated a 4.8 × 3.4 × 3.6-cm³ hypoechoic mass in the apex of the urinary bladder with a wide base and an irregular surface; the mass did not move with changes in body position. Color Doppler flow imaging (CDFI) showed rich blood flow in the mass. CEUS with low mechanical index (MI) of 0.06 confirmed a highly enhanced 5.0 × 3.3 × 3.8 cm³ mass within the bladder at the apex wall. The time-intensity curves (TICs) showed a wash-in time of 10 s, a time to peak (TTP) of 33 s, a signal intensity (SI) of 62.7% and a wash-out time > 60 s. Finally, the transurethral resection of the bladder tumor (TURBT) was performed, and the pathological examination proved the diagnosis of SCCB.

Conclusion

CEUS can provide valuable information related to the rich microvasculature of SCCB, which may be helpful in its diagnosis.

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Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Παρασκευή 10 Νοεμβρίου 2017

Abstract

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Implications for cancer survivors

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Trial registration

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