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Παρασκευή 23 Φεβρουαρίου 2018

New-onset refractory status epilepticus (NORSE) and febrile infection–related epilepsy syndrome (FIRES): State of the art and perspectives

Summary

We report the proceedings of the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. To promote awareness of this condition and foster research efforts, we conveyed the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood- and adult-onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine-mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.



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Inspissated cyst fluid in endoscopic ultrasound-guided fine needle aspiration of pancreatic cysts

Background

Inspissated cyst fluid may be identified on pancreatic cyst aspiration cytology. We report on the cytomorphologic characteristics of inspissated cyst fluid on EUS-FNA of pancreatic cysts and correlate this finding with histopathology or multimodal (cytology, cyst fluid analysis, molecular pathology, imaging) classification of cyst type.

Methods

The department archives were searched for pancreatic cyst fine-needle aspiration biopsies that contained dessicated, crystalline or inspissated material on cytologic preparations.

Results

Twenty-eight cases of pancreatic cysts containing inspissated material were identified. The cytomorphology of the inspissated material ranged from fibrillary fan-like structure (54%), ball-like structures (57%), and granular material (43%). When present, the fibrillary inspissated material was associated with neoplastic mucinous cysts in 11/15 (73%) cases, but was also seen in 2 pseudocysts, 1 serous cystadenoma, and 1 cyst of uncertain type (suggestive of mucinous cyst on EUS). The presence of fibrillary inspissated cyst material on cytology had a positive predictive value of 79% and a specificity of 63% for a neoplastic mucinous cyst.

Conclusion

Although not highly specific, the presence of inspissated cyst fluid with fibrillary architecture should be recognized by cytopathologists and interpreted as at least "atypical" given the potential association with neoplastic mucinous cysts of the pancreas.



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Clinical performance of endobronchial ultrasound-guided transbronchial needle aspiration for assessing programmed death ligand-1 expression in nonsmall cell lung cancer

Background

Pembrolizumab was recently approved as a first line agent for metastatic NSCLC in patients with high programmed death-ligand 1 (PD-L1) expression.

Objectives

Since a significant portion of lung cancer is diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA); there is a need for PD-L1 testing in these specimens. However, to date few studies have evaluated performance of cytology specimens from EBUS TBNA for PD-L1 analysis.

Methods

Patients who had a diagnosis of NSCLC and in whom ancillary testing, i.e., next generation sequencing (NGS), anaplastic lymphoma kinase (ALK), and PD-L1 expression was requested between January and May 2017 were reviewed.

Results

Fifty of the 112 patients reviewed had the diagnosis of NSCLC for which ancillary testing was requested. Twelve patients (24%) had squamous cell carcinoma, twenty-seven had adenocarcinoma (54%), five had NSCLC favor adenocarcinoma (10%), two had NSCLC favor squamous cell cancer (4%), and four had NSCLC not otherwise specified (NOS) (8%). Size of the lymph nodes or lesion sampled ranged from 10 to 50 mm. Four (8%) patients had insufficient number of tumor cells in the cell block for any of the ancillary molecular testing. Forty-one (82%) patients had an adequate sample for all three ancillary tests. Satisfactory results for PD-L1 expression for all cases was 86% with 14 (32%) patients having levels of PD-L1 expression >50%.

Conclusion

EBUS TBNA is effective and has a high proportion of satisfactory results for testing PD-L1 expression on tumor cells in addition to NGS and ALK FISH.



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The Australian Managed Entry Scheme: Are We Getting it Right?

Abstract

In 2010, the Australian Government introduced the managed entry scheme (MES) to improve patient access to subsidised drugs on the Pharmaceutical Benefits Scheme and enhance the quality of evidence provided to decision makers. The aim of this paper was to critically review the Australian MES experience. We performed a comprehensive review of publicly available Pharmaceutical Benefits Advisory Committee online documents from January 2010 to July 2017. Relevant information on each MES agreement was systematically extracted, including its rationale, the conditions that guided its implementation and its policy outcomes. We identified 11 drugs where an MES was considered. Most of the identified drugs (75%) were antineoplastic agents and the main uncertainty was the overall survival benefit. More than half of the MES proposals were made by sponsors and most of the schemes were considered after previous rejected/deferred submissions for reimbursement. An MES was not established in 8 of 11 drugs (73%) despite the high evidence uncertainty. Nevertheless, six of these eight drugs were listed after the sponsors reduced their prices. Three MESs were established and implemented by Deeds of Agreement. The three cases were concluded and the required data were submitted within the agreed time frames. The need for feasibility and value of an MES should be carefully considered by stakeholders before embarking on such an agreement. It is essential to engage major stakeholders, including patient representatives, in this process. The conditions governing MESs should be clear, transparent and balanced to address the expectations of various stakeholders.



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Diagnosis of arterial gas embolism in SCUBA diving: modification suggestion of autopsy techniques and experience in eight cases

Abstract

The purpose of this study was to suggest modifications of autopsy techniques in order to improve post-mortem diagnosis of arterial gas embolism (AGE) based on multidisciplinary investigation of SCUBA diving fatalities. Five adult human cadavers from the voluntary donation program of the Human Anatomy Laboratory, and eight judicial autopsied bodies of SCUBA divers from the Forensic Pathology Service were assessed. Before performing any autopsies, we accessed the diving plan and the divers' profiles for each case. We then introduced a new dissection procedure that included identification, isolation, and manipulation of carotid, vertebral and thoracic arterial systems. The dissected vascular structures that allowed optimall isolation of the systemic arterial circulation were identified and ligated. In three of the eight judicial cases, we had a strongly suggestive history of arterial gas embolism following pulmonary barotrauma (PBt/AGE). In these cases, the additional arterial dissection allowed us to clearly diagnose AGE in one of them. The autopsy of the rest of the cases showed other causes of death such as asphyxia by drowning and heart attack. In all cases we were able to reject decompression sickness, and in some of them we showed the presence of artefacts secondary to decomposition and resuscitation maneuvers. These results allow us to suggest a specific autopsy technique divided into four steps, aimed at confirming or excluding some evidence of dysbaric disorders according to a re-enactment of the incident. We have demonstrated the presence of large volumes of intravascular air, which is typical of PBt/AGE.



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Neuronal apoptosis in the brainstem medulla of sudden unexpected death in infancy (SUDI), and the importance of standardized SUDI classification

Abstract

The purpose of this study was to examine the neuronal expression of apoptotic markers in the rostral medulla of a newly characterized dataset of sudden unexpected death in infancy (SUDI), and to determine the impact of diagnostic groupings on these findings and whether they pertain to the intrinsic apoptotic pathway. Immunohistochemical staining was quantified to determine the percentage of neurons positive for active caspase-9 (specific to the intrinsic apoptotic pathway), active caspase-3 (common to the intrinsic and extrinsic apoptotic pathways) and Terminal deoxynucleotidyl transferase mediated dUTP nick-end labelling (TUNEL) (labels DNA fragmentation) in nine nuclei of the rostral medulla. Expression was compared between groups of SUDI infants where the cause of death was initially classified by a forensic pathologist or subsequently after reclassification by an expert panel using the San Diego Criteria. 68 SUDI infants were studied and originally classified as explained SUDI (n = 12), Sudden Infant Death Syndrome (SIDS) (n = 27) and undetermined (n = 29). Reclassification resulted in a decrease in the number of explained SUDI cases to 7 and a decrease in the number of undetermined cases to 4, with a corresponding increase in the number of SIDS cases to 57 (8 SIDS I; 49 SIDS II). The expression of apoptotic markers was similar in explained SUDI and SIDS I infants. However, TUNEL expression was greater in the cuneate (p < 0.001), vestibular (p = 0.01) and hypoglossal (p < 0.001) nuclei and active caspase-3 expression was lower in the arcuate nucleus (p = 0.037) in SIDS II compared to explained Sudden Unexpected Death in Infancy (eSUDI) infants. Compared to SIDS I infants, SIDS II infants had greater TUNEL expression in the dorsal motor nucleus of the vagus (p < 0.01) and greater active caspase-9 expression in the medial and spinal vestibular nuclei (p = <0.01). Changes in apoptotic expression predominated in SIDS II infants. We postulate that these are due to a combination of contributing risk factors including the presence of an upper respiratory tract infection and bed-sharing/co-sleeping. The absence of changes in active caspase-9 expression compared to eSUDI indicates that the intrinsic apoptotic pathway is not upregulated in SIDS.



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“Defense” type wounds in suicide

Abstract

"Defense" type wounds are sustained when a victim is attempting to ward off an attacker, or a weapon. A 39-year-old woman is reported who was found deceased with incised wounds to the dorsa of both hands that resembled defense wounds. Examination of the flexor surfaces of both wrists, however, revealed horizontal incised wounds typical of self-infliction. Perfusion of the subclavian arteries produced leakage of water from peripheral veins within wounds on both hands and the right wrist. Death was due to exsanguination from incised wounds of the hands and right wrist; manner suicide. This case demonstrates the difficulties that may arise in differentiating self-inflicted from assaultive wounds. On occasion suicidal sharp force injuries may be multiple and in atypical locations. In these circumstances a high index of suspicion for homicide must be maintained.



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Internal patterned injuries in trauma

Abstract

Patterned bruising of the internal organs is unusual. In these cases a cutaneous pattern of bruising is not observed but the underlying tissue may show unusual injuries that may even be recognizable as a tramline pattern. We report the suicide of a 23-year-old man by jumping off a bridge. At autopsy, an unusual finding was "tramline" bruising of the right liver lobe. The "blunt objects" that inflicted the bruising were determined to be the right ribs which were pushed against the liver capsule as a consequence of the extensive thoracic and vertebral trauma after a fall from a height with intermediate impact.



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Double-chambered left ventricle – a “heart within a heart”

Abstract

A 20-year-old previously well man drowned after performing a back-flip off a bridge into a river. At autopsy no significant injuries or organic illness were identified. An unusual incidental finding was a double chambered left ventricle, or so-called "heart within a heart", with the left ventricle subdivided into two separate chambers by a muscular septum. Awareness of this entity in forensic casework is important as this anomaly, despite its dramatic appearance, is not associated with anomalous conduction tracts or arrhythmogenic conditions, and so is usually a completely incidental finding at autopsy.



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Rapid and reliable detection of previous freezing of cerebral tissue by computed tomography and magnetic resonance imaging

Abstract

Due to slowing or even inhibition of postmortem processes, freezing may make an estimation of the time-since-death very difficult. This is also true in previously frozen and subsequently thawed bodies. Knowledge of prior freezing is important, as it may lead to a different assessment of the time since death. Twelve pig heads were frozen at −20 °C, and 6 heads were either kept at room temperature (approximately 20 °C) or in a cooling cell (approximately 5 °C). The frozen brains and cadavers were thawed at either room temperature or in a cooling cell. All specimens underwent repeated CT and MRI scanning until the brains were sampled for histological examination. Two radiologists assessed the images and two pathologists reviewed the histological slides with regard to thawing artifacts and putrefaction. All raters were blinded regarding whether the samples had been frozen, for how long and how they had been thawed. Imaging revealed distinct, tiny bubble-like artifacts only in previously frozen specimens. Histology also revealed artifacts only seen in such cases, namely very distinct, columnar bubbles in the cerebral cortex. All raters successfully identified previously unfrozen brains (100% specificity) and nearly all previously frozen brains. Our results suggest that initial post-mortem imaging can be of enormous importance in everyday forensic practice by identifying possible cases of previous freezing – cases that would therefore warrant closer scrutiny and thus raise caution regarding the time of death.



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Pandora’s box

Abstract

Suitcases or other containers are occasionally involved in forensic investigations. If there is a suspicion that human remains are hidden inside such a container, medico-legal examinations are required. However, these containers are occasionally locked. Forced opening of a locked suitcase or container may cause damage to its contents. Additionally, the safety of the investigator has to be considered as such containers may be booby-trapped or contain other hazardous material. An overview of the contents before opening is desirable in order to avoid the possibility of encountering a Pandora's box. In forensic medicine, an established approach to examine the inside of a body before opening at autopsy is postmortem computed tomography (CT). However, there may be a reluctance to use this approach for suitcases or containers with metallic components because of the assumption that severe metal artifacts will result in inadequate images. In this article, we present a forensic case in which a CT scan of a metallic suitcase was performed in order to examine its contents. Additionally, we performed an experimental scan of a conventional safe in order to determine if CT is able to reveal the contents of such a highly radiopaque storage box.



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A homemade furnace. Influence of occupational skills in a fire-related planned complex suicide

Abstract

The term "planned complex suicide" means the combination of more than one method of suicide, planned to prevent failure of the first method to ensure a fatal outcome. Professional skills and tools are sometimes used to plan and perpetrate the suicide. A case of planned complex suicide of a mechanical engineer working with furnaces in a tube factory is herein reported. The suicide was committed in a rudimental furnace set up in the victim's apartment using his professional skills, by assembling furniture, mattresses, books and flammable liquid present in the house. Three-dimensional models of the crime scene before and after the realization of the "homemade furnace" are proposed. The discussion will focus on the importance of a comprehensive analysis of the professional background of the victim to infer the manner of death for the identification of complex and occupation-related suicides.



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The autopsy and diagnosis of pulmonary thrombo-embolism

Abstract

Pulmonary thrombo-embolism (PTE) is a common cause of death but is frequently undetected by clinicians in spite of advanced diagnostic techniques. The autopsy has traditionally been used to identify the rate of PTE in hospital patients, but the decline in autopsy rates – especially in hospitals – has led to insufficient recent data from which to comment with confidence on the true rate of death from latent PTE. Widespread prophylactic anticoagulation regimens against venous thrombosis may induce complacency amongst clinicians. PTE continues to occur and to kill, and autopsies should be performed more frequently to better estimate the true prevalence of this condition.



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Postmortem radiological case series of acetabular fractures after fatal aviation accidents

Abstract

The purpose of this study was to describe radiological fracture patterns of the acetabulum sustained after fatal small aircraft aviation accidents, aiming at facilitating a better understanding of trauma mechanisms in a forensic setting. Postmortem conventional radiographs or CT scans of 29 victims of 20 small aircraft aviation accidents were analyzed for skeletal acetabular trauma. Among the 29 fatalities (27 males and 2 females, median age 55 years (range: 21–76 years)), 20 victims had pelvic fractures (69%), of which 19 victims (66%) had one or more acetabular fractures. Bilateral acetabular fractures occurred in 11 victims. When considering left and right acetabula in each victim as separate entities, 38 of the 58 acetabula included in this case series exhibited one or more fractures. Both the anterior and posterior acetabular columns were fractured in 28 acetabula. Acetabular fractures were frequently encountered in this series of 29 victims of small fatal aircraft accidents. Fractures of the acetabulum occur from ventrally directed impact (i.e. to the knee) or laterally directed impact (i.e. to the greater trochanter of the femur). Radiological descriptions of the fracture patterns can therefore aid in the forensic analysis of the mechanism of trauma in aviation accidents. Postmortem multi-slice CT scan images are preferrable in the assessment of acetabular fractures.



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Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Abstract

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.

Thumbnail image of graphical abstract

Current evidence about the association between pioglitazone and bladder cancer risk remains inconsistent. This meta-analysis of two randomized controlled trials and 20 observational studies showed that use of pioglitazone might increase risk of bladder cancer. Our findings suggest a close monitoring of bladder cancer in patients with long-term and high-dose exposure to pioglitazone.



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Correction to: Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Clinical Excellence Single Technology Appraisal

Page 41, Column 1, Section 3.1, paragraph 2, 1st sentence which



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A rare case of right pulmonary segmental artery dissection following pacemaker insertion

Description

This paper describes a case of pulmonary segmental artery dissection following pacemaker insertion. The patient was admitted electively and was clinically well prior to admission. The patient had a history of factor V Leiden disease, trifascicular heart block and ischaemic heart disease. The pacemaker was inserted successfully under general anaesthesia.

At day 0 after the operation, the patient was diagnosed with a left leg deep venous thrombosis. Given the high-risk patient factor of developing pulmonary embolism (PE), a CT pulmonary angiogram (CTPA) was performed. No PE was diagnosed; instead, the CTPA discovered a focal dissection flap that originated from the right lower lobe segmental artery, extending into the subsegmental branches craniocaudally for 3 cm (figure 1, figure 2 and figure 3). The CTPA was reviewed by a consultant radiologist. The patient remained asymptomatic. Subsequent discussions with the cardiothoracic surgical team concluded that...



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Severe hypophosphataemia: a rare cause of postoperative muscle weakness

We report a case of severe generalised muscle weakness in a 66-year-old man who underwent revision of left knee arthroplasty. On postoperative day 1, he developed non-focal muscle weakness and shortness of breath which progressed over a 6-hour period. Serum phosphorus level was severely low at 0.5 mg/dL, along with mild degree of hypokalaemia, hypocalcaemia and hypomagnesaemia. His symptoms completely resolved after emergent phosphorus replacement. The authors believe this case is of educational interest to physicians as generalised muscle weakness is an uncommon presentation of severe hypophosphataemia. In a postoperative setting, hypophosphataemia is often multifactorial, thought to result from combination of perioperative catecholamine surge, administration of saline, diuretics, glucose and antacids, poor oral intake and respiratory alkalosis secondary to pain. We report this case to raise awareness among physicians on severe phosphate imbalance as the primary aetiology for acute generalised muscle weakness and respiratory failure, especially after a surgery.



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Role Of Conservative Management In Emphysematous Gastritis

Emphysematous gastritis (EG) is a rare disease of the stomach that is caused by gas-forming bacteria, and it can be lethal. There have been <70 reported cases in the English literature of this disease which carries a mortality rate up to 60%. Early recognition and treatment through conservative management have been a popular and successful choice in today's medicine. Studies have shown that surgical intervention does not confer a statistical benefit on mortality in this condition. We present another case of EG in a 33-year-old woman who was successfully managed conservatively.



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Portomesenteric vein thrombosis following laparoscopic sleeve gastrectomy: are underlying haematological disorders the culprit?

Description

A 51-year-old woman with a medical history of hypothyroidism and deep vein thrombosis (DVT) during pregnancy presented to the emergency department 5 days after laparoscopic sleeve gastrectomy (LSG) complaining of worsening abdominal pain and low-grade fevers. A CT scan and upper  gastrointestional series were performed with no evidence of leak or abscess, and the patient was admitted for observation.

On hospital day 2, the patient had worsening abdominal pain and an episode of emesis. An ultrasound revealed a new moderate amount of intraperitoneal-free fluid. A CT scan was repeated which revealed a segmental non-occlusive thrombus in the splenic vein (figure 1) as well as an occlusive thrombus in the superior mesenteric vein near the portosplenic confluence (figure 2).

Figure 1

(A, B) Segmental non-occlusive thrombus (blue arrow) in the splenic vein. 

Figure 2

(A, B) Occlusive...



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First case of acute granulomatous interstitial nephritis with immune reconstitution inflammatory syndrome in a patient with HIV coinfected with disseminated Mycobacterium kansasii

Restoration of immune response by highly active antiretroviral therapy (HAART) effectively improved the overall prognosis of HIV infection. However, 25%–31.7% of patients experience paradoxical worsening of pre-existing infections or unmasking of subclinical infections after starting HAART therapy, which is termed as immune reconstitution inflammatory syndrome (IRIS). Acute granulomatous interstitial nephritis as a consequence of IRIS has never been reported with Mycobacteriumkansasiicoinfection. Here, we describe an HIV/AIDS patient coinfected with disseminated M. kansasii infection, who presented with acute kidney injury 4.5 months after initiation of HAART. The diagnostic workup revealed IRIS was the cause of acute kidney injury. Short-term course of prednisone (1 mg/kg/day) along with antimycobacterial and HAART regimen achieved significant improvement.



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Nail to the heart: no big deal. A rare case of post-traumatic pericarditis

This is a unique case report of a 32-year-old man who presented with pneumatic nail gun injury to his right chest at work. He removed the nail and continued to work through the day. With continued chest pain, he presented to the emergency room and an echocardiogram revealed moderate-size pericardial effusion. He was managed conservatively as he was haemodynamically stable. Serial echocardiograms revealed slow resolution of the effusion over 3 days. At his 3-month follow-up appointment, there was complete resolution of his effusion. This case highlights the importance of obtaining imaging studies in penetrating chest wall injuries and utilisation of medications to prevent expected complications.



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Recurrent postinfectious glomerulonephritis: an unusual evolution compatible with C3 glomerulopathy

Acute endocapillary glomerulonephritis, as its name suggests, is a one-time process, which usually resolves within weeks. However, in a small percentage of patients, the disease becomes chronic. In these cases, a deregulation in the alternative complement pathway, which can be caused by mutations or autoantibodies, has been proposed as a pathophysiological mechanism. As a result, the alternative complement pathway remains active after resolution of infection. We report a patient with two episodes of acute renal failure, both times diagnosed by renal biopsy of acute endocapillary glomerulonephritis, with slow recovery after two episodes of low-serum complement C3, haematuria and proteinuria.



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Stimming behaviour in a 4-year-old girl with autism spectrum disorder

Description

A 4-year-old girl with autism spectrum disorder (ASD) developed a new behaviour of biting hard objects over the previous 6 months. The behaviour has not gotten better over time and she would always explore toys made of hard material (video 1) this way. Fortunately, she has not sustained any injury, choked on or swallowed these objects. She likes hot and spicy foods with textures. Her expressive language has only developed poorly.

Video 1

The child instantly bites and puts hard toys she found in the room into her mouth.

'Stimming' or self-stimulatory behaviours, also known as stereotypic behaviours in ASD, usually come in the form of hand-flapping, body-rocking, pacing or repetition of words. However, chewing or biting non-edible objects is also common. There are a number of possibilities to explain this behaviour. First, stimming acts as a self-regulatory mechanism to help relieve anxiety, anger,...



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Postoperative epidural abscess after spinal anaesthesia for a circumcision necessitated by phimosis

A 70-year-old man was admitted to our hospital for a penile circumcision due to phimosis using continuous dose spinal anaesthesia. On postoperative day 10 he came to the emergency department with a superficial abscess localised at the injection site of the spinal catheter. He was treated with intravenous antibiotics for 10 days, and the superficial abscess was incised and drained. Ten days later, the patient was readmitted to the emergency department with complaints of back pain and fever. A repeat MRI scan of his lumbar sacral area was done and showed epidural abscesses without any compression of the medulla or the myelum. The patient did not have any signs of spinal cord or nerve root compression at that time. He was treated with intravenous antibiotics with resolution of symptoms.



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Incidental presentation of a button battery within a pharyngeal pouch: the first reported case

Description

An 88-year-old woman presented acutely to the ear, nose and throat (ENT) department at a District General Hospital with an unusual foreign body discovered on videofluoroscopy. This investigation had been organised by her general practitioner as the patient was experiencing progressive dysphagia with food regurgitation and weight loss. There was no history of chest or abdominal pain, haemoptysis or known foreign body ingestion. She had a background of polymyalgia rheumatica, ischaemic heart disease, pharyngeal pouch and wore bilateral hearing aids for presbycusis. During videofluoroscopy a circular, radiopaque foreign body was noted within the pharyngeal pouch resembling a button battery (figures 1 and 2). Given these unusual findings, the ENT team was urgently contacted by the speech and language practitioner for further assessment.

Figure 1

Videofluoroscopy image (lateral view) showing a foreign body resembling a button battery within a pharyngeal pouch.



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Attenuated form of type II mucopolysaccharidoses (Hunter syndrome): pitfalls and potential clues in diagnosis

Description

A 7-year-old boy, born of a non-consanguineous union, presented with pain over both hips and progressive difficulty in walking for preceding 2 years. He had normal developmental milestones with satisfactory scholastic performances and his family and perinatal histories were unremarkable. Clinical examination revealed short stature (height SD score (SDS): –2.3; midparental height (MPH) SDS: –1.7) with upper segment (US):lower segment (LS) ratio of 0.97, umbilical hernia, apical pansystolic murmur of mitral regurgitation and waddling gait without corneal opacity or organomegaly (figure 1). Complete blood count, baseline biochemistry and thyroid function tests were normal except presence of azurophilic granules within white blood cells seen in peripheral blood smear (figure 2). Transthoracic echocardiography confirmed moderate mitral regurgitation secondary to prolapsed posterior mitral leaflet leading to coaptation failure. Though the difference between his height centile and MPH centile was not striking, his body proportion was suggestive of short trunk dwarfism (US:LS is normally...



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Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer

Future Oncology, Ahead of Print.


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Dose-response and efficacy of spinal manipulation for care of cervicogenic headache: a dual-center randomized controlled trial

Publication date: Available online 23 February 2018
Source:The Spine Journal
Author(s): Mitchell Haas, Gert Bronfort, Roni Evans, Craig Schulz, Darcy Vavrek, Leslie Takaki, Linda Hanson, Brent Leininger, Moni B. Neradilek
Background ContextThe optimal number of visits for the care of cervicogenic headache (CGH) with spinal manipulative therapy (SMT) is unknown.PurposeTo identify the dose-response relationship between visits for SMT and chronic CGH outcomes; to evaluate the efficacy of SMT by comparison with a light massage control.Study Design/SettingTwo-site, open-label randomized controlled trial.Patient SampleParticipants were 256 adults with chronic CGH.Outcome MeasuresThe primary outcome was days with CGH in the prior 4 weeks evaluated at the 12- and 24-week primary endpoints. Secondary outcomes included CGH days at remaining endpoints, pain intensity, disability, perceived improvement, medication use, and patient satisfaction.MethodsParticipants were randomized to 4 dose levels of chiropractic SMT: 0, 6, 12, or 18 sessions. They were treated 3 times per week for 6 weeks and received a focused light-massage control at sessions when SMT was not assigned. Linear dose effects and comparisons to the no-manipulation control group were evaluated at 6, 12, 24, 39, and 52 weeks. This study was funded by the National Center for Complementary and Integrative Health (R01AT006330) and is registered at ClinicalTrials.gov (NCT01530321). The authors declare no conflicts of interest.ResultsA linear dose-response was observed for all follow-ups, a reduction of approximately 1 CGH day/4 weeks per additional 6 SMT visits (p<.05); a maximal effective dose could not be determined. CGH days/4 weeks were reduced from about 16 to 8 for the highest and most effective dose of 18 SMT visits. Mean differences in CGH days/4 weeks between 18 SMT visits and control were -3.3 (p=.004) and -2.9 (p=.017) at the primary endpoints, and similar in magnitude at the remaining endpoints (p<.05). Differences between other SMT doses and control were smaller in magnitude (p > .05). CGH intensity showed no important improvement nor differed by dose. Other secondary outcomes were generally supportive of the primary.ConclusionThere was a linear dose-response relationship between SMT visits and days with CGH. For the highest and most effective dose of 18 SMT visits, CGH days were reduced by half, and about 3 more days per month than for the light-massage control.



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Biomechanical evaluation of sacroiliac joint fixation with decortication

Publication date: Available online 23 February 2018
Source:The Spine Journal
Author(s): Yushane C. Shih, Brian P. Beaubien, Qingshan Chen, Jonathan N. Sembrano
Background ContextFusion typically consists of joint preparation, grafting and rigid fixation. Fusion has been successfully used to treat symptomatic disruptions of the SIJ and degenerative sacroiliitis using purpose-specific, threaded implants. The biomechanical performance of these systems is important but has not been studied.PurposeTo compare two techniques for placing primary (12.5mm) and secondary (8.5mm) implants across the SIJ.Study DesignA human cadaveric biomechanical study of sacroiliac joint (SIJ) fixation.MethodsPure moment testing was performed on fourteen human sacroiliac joints in flexion-extension (FE), lateral bending (LB) and axial rotation (AR) with motion measured across the SIJ. Specimens were tested Intact; after Destabilization (cutting the pubic symphysis); after decortication and Implantation of a primary 12.5mm implant at S1 plus an 8.5mm secondary implant at either S1 (S1/S1, n=8) or S2 (S1/S2, n=8); after Cyclic Loading; after removal of the secondary implant. Ranges of motion (ROM) were calculated for each test. Bone density was assessed on CT and correlated with age and ROM. This study was funded by Zyga Technology but was run at an independent biomechanics laboratory.ResultsThe mean ± SD intact ROM was 3.0±1.6 degrees in FE, 1.5±1.0 degrees in LB and 2.0±1.0 in AR. Destabilization significantly increased the ROM by a mean 60-150%. Implantation in-turn significantly decreased ROM by 65-71%, below the intact ROM. Cyclic loading did not impact ROM. Removing the secondary implant increased ROM by 46-88% (nonsignificant). There was no difference between S1/S1 and S1/S2 constructs. Bone density was inversely correlated to age (R=.69) and ROM (R=.36-.58).ConclusionsFixation with two threaded rods significantly reduces SIJ motion even in the presence of joint preparation and after initial loading. The location of the secondary, 8.5mm implant does not affect construct performance. Low bone density significantly affects fixation and should be considered when planning fusion constructs. Findings should be interpreted in the context of ongoing clinical studies.



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Bariatric surgery before elective posterior lumbar fusion is associated with reduced medical complications and infection

Publication date: Available online 23 February 2018
Source:The Spine Journal
Author(s): Deeptee Jain, Sigurd H. Berven, John Carter, Alan L. Zhang, Vedat Deviren
Background contextSeverely obese patients with operative spinal pathology present a challenge to the spine surgeon, given the increased complication risk.PurposeWe aimed to determine the impact of bariatric surgery (BS) on perioperative complications of posterior lumbar fusion.Study DesignThis is a retrospective cohort study.Patient SamplePatients undergoing posterior lumbar fusion surgery in the State Inpatient Databases of New York, Florida, North Carolina, Nebraska, Utah, and California comprised the patient sample.OutcomesThirty-day medical complications, surgical complications (nerve injury, infection, revision), death, readmission, and hospital length of stay (LOS) were the study's outcomes.MethodsWe analyzed 156,517 patients using International Classification of Diseases, Ninth Revision codes. Patients were categorized into three groups: Group 1: history of BS and obesity, Group 2: severe obesity, body mass index (BMI)>40 (severely obese), and Group 3: normal weight, BMI<25 (non-obese). Logistic and linear multivariate regressions were performed to compare complications and LOS, respectively, between BS and severely obese groups and BS and non-obese groups while controlling for confounders. There were no sources of funding for this study.ResultsThere were 590 patients with BS, 5,791 severely obese, and 150,136 non-obese. Comparing BS with severely obese, BS had significantly lower rates of respiratory failure (odds ratio [OR] 0.59, p=.019), urinary tract infection (OR 0.64, p=.031), acute renal failure (OR 0.39, p=.007), overall medical complications (OR 0.59, p<.001), and infection (OR 0.65, p=.025). Bariatric surgery also had significantly lower hospital LOS (B=−0.46, p=.01). Comparing BS with non-obese, there were no significant differences in medical complications; however, BS had significantly higher rates of infection (OR 2.70, p<.001), reoperation (OR 2.05, p=.045), and readmission (OR 1.89, p<.001).ConclusionBariatric surgery before elective posterior lumbar fusion mitigates risk of medical complications and infection. However, these patients still have increased risk of infection, revision surgery, and readmission compared with patients with normal BMI. Surgeons might consider referral for BS for the severely obese patient before undergoing spine surgery.



http://ift.tt/2ESLR12

Genomic-Enabled Prediction Kernel Models with Random Intercepts for Multi-environment Trials

In this study, we compared the prediction accuracy of the main genotypic effect model (MM) without GxE interactions, the multi-environment single variance GxE deviation model (MDs), and the multi-environment environment-specific variance GxE deviation model (MDe) where the random genetic effects of the lines are modeled with the markers (or pedigree). With the objective of further modeling the genetic residual of the lines, we incorporated the random intercepts of the lines (l) and generated another three models. Each of these 6 models were fitted with a linear kernel method (Genomic Best unbiased predictor, GB) and a Gaussian Kernel (GK) method. We compared these 12 model-method combinations with another two multi-environment GxE interactions models with unstructured variance-covariances (MUC) using GB and GK kernels (4 model-method). Thus, we compared the genomic-enabled prediction accuracy of a total of 16 model-method combinations on two maize data sets with positive phenotypic correlations among environments, and on two wheat data sets with complex GxE that includes some negative and close to zero phenotypic correlations among environments. The two models (MDs and MDE with the random intercept of the lines and the GK method) were computationally efficient and gave high prediction accuracy in the two maize data sets. Regarding the more complex GxE wheat data sets, the prediction accuracy of the model-method combination with GxE, MDs and MDe, including the random intercepts of the lines with GK method had important savings in computing time as compared with the GxE interaction multi-environment models with unstructured variance-covariances but with lower genomic prediction accuracy.



http://ift.tt/2CFvkeU

Targeted Long-Read Sequencing of a Locus Under Long-Term Balancing Selection in Capsella

Rapid advances in short-read DNA sequencing technologies have revolutionized population genomic studies, but there are genomic regions where this technology reaches its limits. Limitations mostly arise due to the difficulties in assembly or alignment to genomic regions of high sequence divergence and high repeat content, which are typical characteristics for loci under strong long-term balancing selection. Studying genetic diversity at such loci therefore remains challenging. Here, we investigate the feasibility and error rates associated with targeted long-read sequencing of a locus under balancing selection. For this purpose, we generated bacterial artificial chromosomes (BACs) containing the Brassicaceae S-locus, a region under strong negative frequency-dependent selection which has previously proven difficult to assemble in its entirety using short reads. We sequence S-locus BACs with single-molecule long-read sequencing technology and conduct de novo assembly of these S-locus haplotypes. By comparing repeated assemblies resulting from independent long-read sequencing runs on the same BAC clone we do not detect any structural errors, suggesting that reliable assemblies are generated, but we estimate an indel error rate of 5.7' 10-5. A similar error rate was estimated based on comparison of Illumina short-read sequences and BAC assemblies. Our results show that, until de novo assembly of multiple individuals using long-read sequencing becomes feasible, targeted long-read sequencing of loci under balancing selection is a viable option with low error rates for single nucleotide polymorphisms or structural variation. We further find that short-read sequencing is valuable complement, allowing correction of the relatively high rate of indel errors that result from this approach.



http://ift.tt/2F4ploW

Neural Representations Observed

Abstract

The historical debate on representation in cognitive science and neuroscience construes representations as theoretical posits and discusses the degree to which we have reason to posit them. We reject the premise of that debate. We argue that experimental neuroscientists routinely observe and manipulate neural representations in their laboratory. Therefore, neural representations are as real as neurons, action potentials, or any other well-established entities in our ontology.



http://ift.tt/2ENGpjR

Introducing a New Series: Immunotherapy Facts and Hopes



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FDA Approval: Gemtuzumab ozogamicin for the treatment of adults with newly-diagnosed CD33-positive acute myeloid leukemia

On September 1, 2017, FDA granted approval for gemtuzumab ozogamicin (GO) (Mylotarg; Pfizer, Inc) in combination with daunorubicin and cytarabine (DA) and as a monotherapy for the treatment of adult patients with newly-diagnosed CD33-positive acute myeloid leukemia (AML). GO is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of GO combination treatment was based on a randomized trial of 271 patients with newly-diagnosed AML treated with DA with or without 3 mg/m2 fractionated GO, which resulted in an event-free survival (EFS) of 13.6 months for GO + DA and 8.8 months for DA alone (HR 0.68 [95% CI: 0.51-0.91]). Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with GO + DA. Approval of GO monotherapy was based on a randomized trial of 237 patients with newly-diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with GO versus 3.6 months on best supportive care (HR 0.69, [95% CI 0.53-0.90]). Adverse events were similar on both arms. Post-approval, several studies are required including evaluation of fractionated GO pharmacokinetics, safety of combination GO in the pediatric population, of immunogenicity, and of the effects of GO on platelet function.



http://ift.tt/2sSseEJ

Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium-Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-Cell Lymphoma

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). Experimental Design: Patients were enrolled on three consecutive phase 2 clinical trials. Patients received two doses of rituximab (375 mg/m2 and 1000 mg/m2) during mobilization of stem cells, followed by 1000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.  Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P =0.82). The 5-year overall survival rates were 73%, and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (< vs. > 1 year) after initial induction chemotherapy (P = 0.97).   Conclusions:Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit.



http://ift.tt/2CeIoMk

Administration of Hypoxia-Activated Prodrug Evofosfamide after Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Colorectal Cancer

Purpose: Cancer-initiating cells (C-ICs) have been described in multiple cancer types, including colorectal cancer (CRC). C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities, however recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then targeting hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived CRC xenografts were treated with evofosfamide (Evo), a hypoxia-activated prodrug (HAP), in combination with 5-Fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a non-invasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by Evo not only inhibits tumor growth of xenografts compared to 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, non-invasive FAZA-PET hypoxia imaging was predictive of a tumor's response to Evo. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach.



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Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) help identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP-knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A nuclear factor-kappa B p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.



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Focal Irradiation And Systemic Transforming Growth Factor {beta} Blockade in Metastatic Breast Cancer

PURPOSE: This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.EXPERIMENTAL DESIGN: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum.RESULTS: Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. CONCLUSIONS: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.



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MEK Binding to KSR Promotes Allosteric Activation of BRAF [Research Watch]

KSR–MEK complexes allosterically activate BRAF, which then phosphorylates a second MEK molecule.



http://ift.tt/2BMQCu4

TGF{beta} Promotes Immune Evasion to Limit the Efficacy of Anti-PD-1/PD-L1 [Research Watch]

The TGFβ-activated stroma induces T-cell exclusion to suppress antitumor immunity.



http://ift.tt/2EOv1nT

The Oncolytic Adenovirus DNX-2401 Has Antitumor Activity in Glioblastoma [Research Watch]

In a phase I trial, DNX-2401 is safe and achieves durable responses in patients with recurrent glioma.



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Startups Bring AI to Pathology [News in Brief]

Under development: machine-learning algorithms to help diagnose cancer and identify biomarkers from pathology slides.



http://ift.tt/2oql4Te

The Effects of Vitamin D Supplementation on Biomarkers of Inflammation and Oxidative Stress Among Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Horm Metab Res
DOI: 10.1055/s-0044-101355

The current systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome (PCOS). Cochrane library, Embase, PubMed, and Web of Science database were searched to identify related randomized-controlled articles (RCTs) published up to November 2017. Two researchers assessed study eligibility, extracted data, and evaluated risk of bias of included RCTs, independently. To check heterogeneity Q-test and I2 statistics were used. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary effect size. Seven RCTs were included into our meta-analysis. The findings showed that vitamin D supplementation in women with PCOS significantly decreased high-sensitivity C-reactive protein (hs-CRP) (SMD −1.03; 95% CI, −1.58, −0.49; p <0.001) and malondialdehyde (MDA) (SMD −1.64, 95% CI −2.26 to −1.02, p <0.001), and significantly increased total antioxidant capacity (TAC) levels (SMD 0.86, 95% CI 0.08 to 1.64, p=0.03). Vitamin D supplementation had no significant effect on nitric oxide (NO) (SMD 0.11, 95% CI −0.44 to 0.66, p=0.69) and total glutathione (GSH) levels (SMD 0.54, 95% CI −0.20 to 1.28, p=0.15). Overall, the current meta-analysis demonstrated that vitamin D supplementation to women with PCOS resulted in an improvement in hs-CRP, MDA and TAC, but did not affect NO and GSH levels.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Uro-oncology 2018: new horizons, new treatment options, improved patient outcomes



http://ift.tt/2omcmpc

Targeting angiogenesis in lung cancer

Summary

Angiogenesis inhibition is a promising way to inhibit and eradicate cancer. Many attempts have been made to use this tool for the treatment of lung cancer. Some success has been reported, and antiangiogenic drugs are actively being investigated in combination with other types of anticancer treatments.



http://ift.tt/2BOIRDR

Antiangiogenic therapies in ovarian cancer

Summary

Antiangiogenic compounds were the first active targeted agents implemented in the treatment of ovarian cancer. Bevacizumab and tyrosine kinase inhibitors such as pazopanib, nintedanib and cediranib target the VEGF pathway, while trebananib was developed as an inhibitor of the angiopoietin pathway. All these compounds have been extensively evaluated and, in this review, we provide a structured overview of the randomized trials that have been performed in both primary and relapsed ovarian cancer. From this data, it is evident that antiangiogenic therapy has its place in ovarian cancer. If not during first-line treatment, then at least at some point for the treatment of relapsed disease. In addition, we address and summarize the trials designed to address the remaining issues related to treatment duration, continuation beyond progression and optimal combination. The future clinical development of angiogenesis inhibitors in ovarian cancer indeed looks at combinations with poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors and vascular disrupting agents. Finally, an overview is given of the retrospective translational studies that were performed on the samples of the two pivotal first-line trials GOG(Gynecologic Oncology Group)-218 and ICON(International Collaborative Ovarian Neoplasm study)7, with initial evidence for the predictive value of the BRCA status, some molecular subtypes and histological assessment of microvessel density. If confirmed, these biomarkers could further improve the implementation of antiangiogenic therapy in ovarian cancer.



http://ift.tt/2EOMRXZ

Our differences make us stronger

To improve the quality of hospice and palliative care, the American Academy of Hospice and Palliative Medicine (AAHPM) models inclusion and embraces diverse backgrounds and perspectives of those with whom we work and the patients and families we serve. In 2015, AAHPM initiated a multi-year strategic plan1 to guide efforts to increase the Academy's commitment to diversity and inclusion both within the organization and in the broader field of hospice and palliative medicine. We define diversity as referring to the composition of a group of people from any number of demographic backgrounds, identities (innate and selected), and the collective strength of their experiences, beliefs, values, skills and perspectives.

http://ift.tt/2ChkpfF

Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells

Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells

Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells, Published online: 23 February 2018; doi:10.1038/s41419-018-0374-7

Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells

http://ift.tt/2CgdOlp

Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24

Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24

Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24, Published online: 23 February 2018; doi:10.1038/s41419-018-0274-x

Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24

http://ift.tt/2sWuHOz

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells, Published online: 23 February 2018; doi:10.1038/s41419-018-0377-4

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

http://ift.tt/2sShaHH

Laser evoked potential amplitude and laser-pain rating reduction during high-frequency non-noxious somatosensory stimulation

The inhibition of pain by non-nociceptive cutaneous stimulation represents a well known phenomenon. Daily experience teaches us that rubbing a painful area can reduce pain. The underlying mechanism of the analgesia induced by non-painful somatosensory stimuli has been hypothesized by Melzack and Wall in 1965 (Melzack and Wall, 1965). According to the "gate control theory of pain", it is the balance between the small diameter (C and Aδ) and large diameter (Aβ) fibres at their entrance to the spinal cord to control pain.

http://ift.tt/2CEleec

Pain-motor Integration and Chronic Pain: One Step Ahead

Pain-motor integration refers to physiological processes responsible for mutual interaction between nociceptive and motor information in the central nervous system. Two separate lines of evidence support the hypothesis that pain-motor integration mechanisms operate in the human cerebral cortex. First, epidural motor cortex stimulation (MCS), as well as non-invasive brain stimulation (NIBS) protocols delivered over the primary motor cortex (M1), can both improve pain in patients with drug-resistant chronic pain.

http://ift.tt/2F0w1EF

Labetalol Hydrochloride Injection by Hospira: Recall - Potential For Cracked Glass At Rim Surface Of Vials

Audience: Pharmacy, Risk Manager, Nursing [Posted 02/23/2018] ISSUE: Hospira is voluntarily recalling 3 lots of Labetalol Hydrochloride Injection, USP, 100 mg/20 mL Vial (NDC 0409-2267-20), and one lot of Labetalol Hydrochloride Injection, USP,...

http://ift.tt/2sLHAec

Intracholecystic papillary neoplasm of the gallbladder protruding into the common bile duct



http://ift.tt/2CFoxBX

Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders

Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only one exploratory randomized control trial and three case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders.

http://ift.tt/2ERUZmB

Real-world Safety and Efficacy of Fluid-filled Dual Intra-gastric Balloon for Weight Loss

Reshape Duo is a saline-filled dual, integrated intra-gastric balloon (IGB) approved by the Food and Drug Administration for weight loss in patients with obesity. In a prospective, randomized trial, obese patients who received the balloon had significantly greater percent excess weight loss (%EWL) compared patients treated with diet and exercise alone. However, there are limited data on the real-world efficacy of the Reshape balloon.

http://ift.tt/2FrMCix

Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data?

Patients with non–dialysis-dependent chronic kidney disease (NDD-CKD) are 10 times more likely to die of cardiovascular (CV) diseases than the general population, and dialysis-dependent patients are at even higher risk. Although traditional CV risk factors are highly prevalent in individuals with CKD, these patients were often excluded from studies targeting modification of these risks. Although treatment of hypertension is beneficial in CKD, the best target blood pressure has not been established.

http://ift.tt/2EMkoOf

Physical Activity in Kidney Transplant Recipients: A Review

Physical activity has known health benefits and is associated with reduced cardiovascular risk in the general population. Relatively few data are available for physical activity in kidney transplant recipients. Compared to the general population, physical activity levels are lower overall in kidney recipients, although somewhat higher compared to the dialysis population. Recipient comorbid condition, psychosocial and socioeconomic factors, and long-term immunosuppression use negatively affect physical activity.

http://ift.tt/2FsbQNO

Management of Heart Failure in Advancing CKD: Core Curriculum 2018

Heart failure and chronic kidney disease have increasing incidence and prevalence owing in part to the aging population and increasing rates of hypertension, diabetes, and other cardiovascular and kidney disease risk factors. The presence of one condition also has a strong influence on the other, leading to greater risks for hospitalization, morbidity, and death, as well as very high health care costs. Despite the frequent coexistence of heart failure and chronic kidney disease, many of the pivotal randomized trials that guide the management of heart failure have excluded patients with more advanced stages of chronic kidney disease.

http://ift.tt/2ESmOLy

How Omics Data Can Be Used in Nephrology

Advances in technology and computing now permit the high-throughput analysis of multiple domains of biological information, including the genome, transcriptome, proteome, and metabolome. These omics approaches, particularly comprehensive analysis of the genome, have catalyzed major discoveries in science and medicine, including in nephrology. However, they also generate large complex data sets that can be difficult to synthesize from a clinical perspective. This article seeks to provide an overview that makes omics technologies relevant to the practicing nephrologist, framing these tools as an extension of how we approach patient care in the clinic.

http://ift.tt/2FrBSRl

Labetalol Hydrochloride Injection by Hospira: Recall - Potential For Cracked Glass At Rim Surface Of Vials

Audience: Pharmacy, Risk Manager, Nursing [Posted 02/23/2018] ISSUE: Hospira is voluntarily recalling 3 lots of Labetalol Hydrochloride Injection, USP, 100 mg/20 mL Vial (NDC 0409-2267-20), and one lot of Labetalol Hydrochloride Injection, USP,...

http://ift.tt/2sLHAec

New Research From Psychological Science

Read about the latest research published in Psychological Science:

Positive Attitude Toward Math Supports Early Academic Success: Behavioral Evidence and Neurocognitive Mechanisms
Lang Chen, Se Ri Bae, Christian Battista, Shaozheng Qin, Tianwen Chen, Tanya M. Evans, and Vinod Menon

Having a positive attitude about learning–including a strong interest in the material and confidence that one can learn it–has been linked with actual learning and academic achievement. In this research, the authors explored the neurocognitive mechanisms underlying this relationship, specifically in the domain of math achievement. A behavioral study of 240 children showed that a more positive attitude toward math (measured using a 12-item survey) correlated with stronger math skills, even after cognitive and affective factors such as IQ, working memory, and math anxiety were taken into account. In an accompanying neuroimaging study, the authors investigated whether this relationship was linked with activity in the affective-motivational system (e.g., amygdala, ventral striatum) or the learning-memory system (e.g., hippocampus, medial temporal lobe). The neuroimaging data revealed that a more positive attitude toward math was associated with greater activation of the hippocampus and more efficient memory retrieval as children solved math problems. The findings suggest that the hippocampus plays a unique role in mediating the association between children's attitude toward math and their math achievement.

Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce: A Swedish National Adoption Study

Jessica E. Salvatore, Sara Larsson Lönn, Jan Sundquist, Kristina Sundquist, and Kenneth S. Kendler
Data show that the adult children of divorced parents are themselves more likely to divorce than are children of continuously married parents. The authors analyzed Swedish national registry data to examine the relative genetic and environmental contributions to the intergenerational transmission of divorce. In an analysis using a classical adoption design, adopted children resembled their biological parents, but not their adoptive parents, in their history of divorce, suggesting that genetic factors primarily accounted for the association. In another analysis, children who lived with their mothers, but not their fathers, resembled both parents in their history of divorce but showed a stronger resemblance to their mothers, a finding that supports the role of genetic factors and indicates additional influence of the rearing environment. These and other findings provide consistent support for the role of genetic factors and inconsistent support for the role of environmental factors in linking divorce across generations. A genetic predisposition for divorce may reflect a variety of individual differences that contribute to marital instability, the authors conclude.

Pathways Into Literacy: The Role of Early Oral Language Abilities and Family Risk for Dyslexia

Sietske van Viersen, Elise H. de Bree, Marjolein Zee, Ben Maassen, Aryan van der Leij, and Peter F. de Jong
Oral language abilities are thought to contribute to reading comprehension through two developmental pathways, one that works through preliteracy and word-decoding skills and another that works through linguistic comprehension. The authors investigated how early language abilities and family risk for dyslexia influence these two pathways, examining data collected from 237 Dutch children starting in kindergarten and continuing through the sixth grade. A structural equation model confirmed two pathways linking early oral language with reading comprehension at age 12. As expected, one pathway was mediated by preliteracy skills (e.g., letter knowledge, phonological awareness, naming speed) and word-decoding skills (e.g., word-reading accuracy and fluency) and another pathway was mediated by language abilities (e.g., vocabulary knowledge). Early verbal and nonverbal intelligence influenced both pathways but predicted reading comprehension only through language abilities. Family risk of dyslexia, on the other hand, appeared to affect reading ability through preliteracy and word-decoding skills. The findings shed light on the developmental pathways that contribute to literacy in later childhood.

Calorie Labeling Promotes Dietary Self-Control by Shifting the Temporal Dynamics of Health- and Taste-Attribute Integration in Overweight Individuals

Seung-Lark Lim, Molly T. Penrod, Oh-Ryeong Ha, Jared M. Bruce, and Amanda S. Bruce

Drawing from research on attention and decision making, the authors hypothesized that people, particularly those who are overweight or obese, may be more likely to choose unhealthy foods when taste attributes are processed faster than health attributes. They used a computer mouse-tracking paradigm to test whether nutritional information might shift these temporal dynamics. Participants indicated whether they would eat various food items, moving the mouse to the "eat" or "not eat" response on screen. Participants' mouse trajectories deviated from a straight line more when they were deciding whether to eat an unhealthy food compared with a healthy food, suggesting that decisions about unhealthy foods required additional cognitive effort. The researchers then used participants' taste and health ratings for the food items to examine how each attribute influenced decision making over time. Individuals who were overweight showed a 230-ms delay in integrating health attributes versus taste attributes relative to individuals who were normal weight or obese; this delay did not occur when calorie information was provided. The results shed light on the temporal dynamics of decisions about food.



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Dengue periodic outbreaks and epidemiological trends in Nepal

Dengue is a global health problem and expansion of its endemics towards new territories in the hilly regions in Nepal is a serious concern. It appeared as a new disease in Nepal in 2004 from Japanese traveler ...

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Duration of acute kidney injury in critically ill patients

Duration of acute kidney injury (AKI) has been recognized a risk factor for adverse outcomes following AKI. We sought to examine the relationship of AKI duration and recurrent AKI with short-term outcomes in c...

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Simulating the Mechanics of Lens Accommodation via a Manual Lens Stretcher

We present an efficient method of studying lens accommodation by using a manual lens stretcher. The protocol mimics physiological accommodation by pulling the zonules connected around the lens capsule, thereby, stretching the lens.

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Can P-glycoprotein and β-tubulin polymorphisms be used as genetic markers of resistance in Dirofilaria immitis from Rio de Janeiro, Brazil?

Dirofilaria immitis, the causative agent of canine heartworm infection, is worldwide the most important filarid to affect domestic dogs. Prevention of this infection is done by macrocyclic lactones, but some repo...

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Lens-free Video Microscopy for the Dynamic and Quantitative Analysis of Adherent Cell Culture

Lens-free video microscopy enables us to monitor cell cultures directly inside the incubator. Here we describe the full protocol used to acquire and analyze a 2.7 day long acquisition of cultured HeLa cells, leading to a dataset of 2.2 x 106 measurements of individual cell morphology and 10584 cell cycle tracks.

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On-Site Molecular Detection of Soil-Borne Phytopathogens Using a Portable Real-Time PCR System

Rapid and accurate detection of plant pathogens on-site, especially soil-borne pathogens, is crucial to prevent further inoculum production and proliferation of plant diseases in the field. The method developed here using a portable real-time PCR detection system enables on-site diagnosis under field conditions.

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Bedside Detection of Overassistance During Pressure Support Ventilation*

No abstract available

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The authors reply

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Continuous Infusion of Low-Dose Iohexol Measures Changing Glomerular Filtration Rate in Critically Ill Patients

imageObjective: Measurement of changing glomerular filtration rate in acute kidney injury remains problematic. We have previously used a continuous infusion of low-dose Iohexol to measure glomerular filtration rate in stable subjects and postulate that changes greater than 10.3% in critically ill patients indicate acute kidney injury. Our objective is to explore the extent to which continuous infusion of low-dose Iohexol can be a measure of changing glomerular filtration rate during acute kidney injury. Design: Clinical observational exploratory study. Setting: Adult ICU. Patients: Three patient groups were recruited: nephrectomy group: predictable onset of acute kidney injury and outcome (n = 10); surgery group: predictable onset of acute kidney injury, unpredictable outcome (n = 11); and acute kidney injury group: unpredictable onset of acute kidney injury and outcome (n = 13). Interventions: Continuous infusion of low-dose Iohexol was administered for 24–80 hours. Plasma (ClP) and renal (ClR) Iohexol clearances were measured at timed intervals. Measurements and Main Results: Kidney Disease: Improved Global Outcomes acute kidney injury criteria were fulfilled in 22 patients (nephrectomy = 5, surgery = 4, and acute kidney injury = 13); continuous infusion of low-dose Iohexol demonstrated acute kidney injury in 29 patients (nephrectomy = 10, surgery = 8, acute kidney injury = 11). Dynamic changes in glomerular filtration rate were tracked in all patients. In the nephrectomy group, ClR decreased by an expected 50% (50.8% ± 11.0%). Agreement between ClP and ClR improved with increasing duration of infusion: bias of ClP versus ClR at 48 hours was –0.1 ± 3.6 mL/min/1.73 m2 (limits of agreement: –7.2 to 7.1 mL/min/1.73 m2). Coefficient of variation of laboratory sample analysis was 2.4%. Conclusions: Continuous infusion of low-dose Iohexol is accurate and precise when measuring glomerular filtration rate and tracks changes in patients with differing risks of acute kidney injury. Continuous infusion of low-dose Iohexol may provide a useful standard against which to test novel biomarkers for the diagnosis of acute kidney injury.

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Kinetics of Urinary Cell Cycle Arrest Markers for Acute Kidney Injury Following Exposure to Potential Renal Insults

imageObjectives: Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure. Design: In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam). Setting: Thirty-five sites in North America and Europe between September 2010 and June 2012. Patients: Seven hundred twenty-three critically ill adult patients admitted to the ICU. Interventions: None. Measurements and Main Results: We compared the urinary [tissue metalloproteinase-2]•[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2–3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2–3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] from the day of exposure to 24–48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7]. Conclusions: Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2–3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast.

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Optimal Cerebral Perfusion Pressure in Centers With Different Treatment Protocols

imageObjectives: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed "optimal cerebral perfusion pressure." Design: Retrospective analysis of prospectively collected data. Setting: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. Patients: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. Interventions: None. Measurements and Main Results: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70 mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70 mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. Conclusions: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment.

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Temporal Trends in Incidence, Sepsis-Related Mortality, and Hospital-Based Acute Care After Sepsis

imageObjectives: A growing number of patients survive sepsis hospitalizations each year and are at high risk for readmission. However, little is known about temporal trends in hospital-based acute care (emergency department treat-and-release visits and hospital readmission) after sepsis. Our primary objective was to measure temporal trends in sepsis survivorship and hospital-based acute care use in sepsis survivors. In addition, because readmissions after pneumonia are subject to penalty under the national readmission reduction program, we examined whether readmission rates declined after sepsis hospitalizations related to pneumonia. Design and Setting: Retrospective, observational cohort study conducted within an academic healthcare system from 2010 to 2015. Patients: We used three validated, claims-based approaches to identify 17,256 sepsis or severe sepsis hospitalizations to examine trends in hospital-based acute care after sepsis. Interventions: None. Measurements and Main Results: From 2010 to 2015, sepsis as a proportion of medical and surgical admissions increased from 3.9% to 9.4%, whereas in-hospital mortality rate for sepsis hospitalizations declined from 24.1% to 14.8%. As a result, the proportion of medical and surgical discharges at-risk for hospital readmission after sepsis increased from 2.7% to 7.8%. Over 6 years, 30-day hospital readmission rates declined modestly, from 26.4% in 2010 to 23.1% in 2015, driven largely by a decline in readmission rates among survivors of nonsevere sepsis, and nonpneumonia sepsis specifically, as the readmission rate of severe sepsis survivors was stable. The modest decline in 30-day readmission rates was offset by an increase in emergency department treat-and-release visits, from 2.8% in 2010 to a peak of 5.4% in 2014. Conclusions: Owing to increasing incidence and declining mortality, the number of sepsis survivors at risk for hospital readmission rose significantly between 2010 and 2015. The 30-day hospital readmission rates for sepsis declined modestly but were offset by a rise in emergency department treat-and-release visits.

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Evaluation of ICU Risk Models Adapted for Use as Continuous Markers of Severity of Illness Throughout the ICU Stay*

imageObjectives: Evaluate the accuracy of different ICU risk models repurposed as continuous markers of severity of illness. Design: Nonintervention cohort study. Setting: eICU Research Institute ICUs using tele-ICU software calculating continuous ICU Discharge Readiness Scores between January 2013 and March 2016. Patients: Five hundred sixty-one thousand four hundred seventy-eight adult ICU patients with an ICU length of stay between 4 hours and 30 days. Interventions: Not available. Measurements and Main Results: Hourly Acute Physiology and Chronic Health Evaluation IV, Sequential Organ Failure Assessment, and Discharge Readiness Scores were calculated beginning hour 4 of the ICU stay. Primary outcome was the area under the receiver operating characteristic curve for the mean score with ICU mortality. Secondary outcomes included area under the receiver operating characteristic curves for ICU mortality with admission, median, maximum and last scores, and for death within 24 hours. The trajectories of each score were visualized by plotting the hourly averages against time in the ICU, stratified by mortality and length of stay. The area under the receiver operating characteristic curves for mean Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores were 0.90 (0.89–0.90), 0.86 (0.86–0.86), and 0.94 (0.94–0.94), respectively. The area under the receiver operating characteristic curves for hourly Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores predicting 24-hour mortality were 0.81 (0.81–0.81), 0.76 (0.76–0.76), and 0.86 (0.86–0.86). Discharge Readiness Scores had a higher area under the receiver operating characteristic curve than both Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment for each metric. Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores increased throughout the first 24 hours in both survivors and nonsurvivors; Discharge Readiness Scores continuously decreased in survivors and temporarily decreased before increasing by hour 36 in nonsurvivors with longer length of stays. Conclusions: Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores all have relatively high discrimination for ICU mortality when used continuously; Discharge Readiness Scores tended to have slightly higher area under the receiver operating characteristic curves for each endpoint. These findings validate the use of these models on a population level for continuous risk adjustment in the ICU, although Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment appear slower to respond to improvements in patient status than Discharge Readiness Scores, and Discharge Readiness Scores may reflect physiologic improvement from interventions, potentially underestimating risk.

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Validation of a Novel Molecular Host Response Assay to Diagnose Infection in Hospitalized Patients Admitted to the ICU With Acute Respiratory Failure

imageObjectives: Discrimination between infectious and noninfectious causes of acute respiratory failure is difficult in patients admitted to the ICU after a period of hospitalization. Using a novel biomarker test (SeptiCyte LAB), we aimed to distinguish between infection and inflammation in this population. Design: Nested cohort study. Setting: Two tertiary mixed ICUs in the Netherlands. Patients: Hospitalized patients with acute respiratory failure requiring mechanical ventilation upon ICU admission from 2011 to 2013. Patients having an established infection diagnosis or an evidently noninfectious reason for intubation were excluded. Interventions: None. Measurement and Main Results: Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (higher bands indicating higher infection probability) and compared with the infection plausibility as rated by post hoc assessment using strict definitions. Of 467 included patients, 373 (80%) were treated for a suspected infection at admission. Infection plausibility was classified as ruled out, undetermined, or confirmed in 135 (29%), 135 (29%), and 197 (42%) patients, respectively. Test results correlated with infection plausibility (Spearman's rho 0.332; p

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Effects of Propofol on Cellular Bioenergetics in Human Skeletal Muscle Cells

imageObjectives: Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells. Design: In vitro study on human skeletal muscle cells. Settings: University research laboratories. Subjects: Patients undergoing hip surgery and healthy volunteers. Interventions: Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1–10 μg/mL propofol for 96 hours. Measurements and Main Results: Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-14C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II–IV. Although cell survival and basal oxygen consumption rate were only affected by 10 μg/mL of propofol, concentrations as low as 1 μg/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated. Conclusions: Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria.

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Update of a Systematic Review of Autoresuscitation After Cardiac Arrest

imageObjectives: There has been a growth in publications focusing on the phenomena of autoresuscitation in recent years. In 2010, we systematically reviewed the medical literature with the primary objective of summarizing the evidence on the timing of autoresuscitation. Healthcare professionals have continued to voice concerns regarding the potential for autoresuscitation. With this in mind, the objective of this brief report is to update the results of our original review of autoresuscitation. Data Sources: We applied the same search strategy described in our original article to update our findings to include articles published from January 2009 to September 2016. Study Selection and Data Extraction: We screened an additional 1,859 citations, after duplicates were removed, and then assessed 46 full-text articles for eligibility, from which 15 studies were included for data extraction. Data Synthesis: During the time period of this review, there have been 1) 10 additional adult and three pediatric case reports of autoresuscitation in patients after cessation of cardiopulmonary resuscitation; in those cases with continuous monitoring and confirmation of circulation, the longest events are reported to be 10 and 2 minutes, respectively for adults and children; 2) six adults (4%, total n = 162) with autoresuscitation events reported from two observational studies and one chart review of patients undergoing withdrawal of life-sustaining therapy; the longest time reported to be 89 seconds with electrocardiogram and invasive arterial blood pressure monitoring and 3 minutes with electrocardiogram monitoring only; 3) 12 pediatric patients studied with vital sign monitoring during withdrawal of life-sustaining therapy without any reports of autoresuscitation. Conclusions: Although case reports of autoresuscitation are hampered by variability in observation and monitoring techniques, autoresuscitation has now been reported in adults and children, and there appears to be a distinction in timing between failed cardiopulmonary resuscitation and withdrawal of life-sustaining therapy. Although additional prospective studies are required to clarify the frequency and predisposing factors associated with this phenomenon, clinical decision-making regarding patient management under uncertainty is required nonetheless. Both adult and pediatric healthcare professionals should be aware of the possibility of autoresuscitation and monitor their patients accordingly before diagnosing death.

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Initial Antifungal Strategy Reduces Mortality in Critically Ill Patients With Candidemia: A Propensity Score–Adjusted Analysis of a Multicenter Study*

imageObjective: The objective of this study was to evaluate the impact of the empirical therapy with fluconazole or an echinocandin on 30- and 90-day mortality in critically ill patients with candidemia. The outcome of patients in whom the empirical echinocandin was deescalated to fluconazole was also assessed. Design: Retrospective, observational multicenter study. Setting: Medical and surgical ICUs in nine Spanish hospitals. Patients: Adult patients (≥ 18 yr) with an episode of Candida bloodstream infection during ICU admission from January 2011 to April 2016. Interventions: Patient characteristics, infection-related variables, therapeutic interventions, and metastatic complications were reviewed. A propensity score–adjusted multivariable analysis was performed to identify the risk factors significantly associated with 30-day and 90-day mortality. Measurements and Main Results: A total of 294 patients were diagnosed of candidemia in the participant ICUs. Sixty patients were excluded (other antifungals in the primary therapy or the patient died without empirical antifungal therapy). The study group comprised 115 patients who received fluconazole (30-day mortality, 37.4%) and 119 patients treated empirically with an echinocandin (30-day mortality, 31.9%). The use of an echinocandin in the empirical therapy was a protective factor for 30-day (odds ratio, 0.32; 95% CI, 0.16–0.66; p = 0.002) and 90-day mortality (odds ratio, 0.50; 95% CI, 0.27–0.93; p = 0.014) in the propensity score– adjusted multivariable analysis. Deescalation of the empirical echinocandin to fluconazole was not associated with a higher mortality or the occurrence of long-term complications. Conclusions: Empirical use of an echinocandin in critically ill patients with documented candidemia reduces mortality at 30 and 90 days significantly. Deescalation of the empirical echinocandin to fluconazole is safe and effective in fluconazole-susceptible infections.

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The Association of ICU Acuity With Outcomes of Patients at Low Risk of Dying

imageObjective: Many ICU patients do not require critical care interventions. Whether aggressive care environments increase risks to low-acuity patients is unknown. We evaluated whether ICU acuity was associated with outcomes of low mortality-risk patients. We hypothesized that admission to high-acuity ICUs would be associated with worse outcomes. This hypothesis was based on two possibilities: 1) high-acuity ICUs may have a culture of aggressive therapy that could lead to potentially avoidable complications and 2) high-acuity ICUs may focus attention toward the many sicker patients and away from the fewer low-risk patients. Design: Retrospective cohort study. Setting: Three hundred twenty-two ICUs in 199 hospitals in the Philips eICU database between 2010 and 2015. Patients: Adult ICU patients at low risk of dying, defined as an Acute Physiology and Chronic Health Evaluation-IVa–predicted mortality of 3% or less. Exposure: ICU acuity, defined as the mean Acute Physiology and Chronic Health Evaluation IVa score of all admitted patients in a calendar year, stratified into quartiles. Measurements and Main Results: We used generalized estimating equations to test whether ICU acuity is independently associated with a primary outcome of ICU length of stay and secondary outcomes of hospital length of stay, hospital mortality, and discharge destination. The study included 381,997 low-risk patients. Mean ICU and hospital length of stay were 1.8 ± 2.1 and 5.2 ± 5.0 days, respectively. Mean Acute Physiology and Chronic Health Evaluation IVa–predicted hospital mortality was 1.6% ± 0.8%; actual hospital mortality was 0.7%. In adjusted analyses, admission to low-acuity ICUs was associated with worse outcomes compared with higher-acuity ICUs. Specifically, compared with the highest-acuity quartile, ICU length of stay in low-acuity ICUs was increased by 0.24 days; in medium-acuity ICUs by 0.16 days; and in high-acuity ICUs by 0.09 days (all p

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Severity of Illness Scores May Misclassify Critically Ill Obese Patients*

imageObjective: Severity of illness scores rest on the assumption that patients have normal physiologic values at baseline and that patients with similar severity of illness scores have the same degree of deviation from their usual state. Prior studies have reported differences in baseline physiology, including laboratory markers, between obese and normal weight individuals, but these differences have not been analyzed in the ICU. We compared deviation from baseline of pertinent ICU laboratory test results between obese and normal weight patients, adjusted for the severity of illness. Design: Retrospective cohort study in a large ICU database. Setting: Tertiary teaching hospital. Patients: Obese and normal weight patients who had laboratory results documented between 3 days and 1 year prior to hospital admission. Interventions: None. Measurements and Main Results: Seven hundred sixty-nine normal weight patients were compared with 1,258 obese patients. After adjusting for the severity of illness score, age, comorbidity index, baseline laboratory result, and ICU type, the following deviations were found to be statistically significant: WBC 0.80 (95% CI, 0.27–1.33) × 109/L; p = 0.003; log (blood urea nitrogen) 0.01 (95% CI, 0.00–0.02); p = 0.014; log (creatinine) 0.03 (95% CI, 0.02–0.05), p

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