Κυριακή 19 Νοεμβρίου 2017
Glecaprevir/Pibrentasvir in Patients with HCV Genotype 1 or 4 and Prior Direct-acting Antiviral Treatment Failure
ABSTRACT
Methods: MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and prior virologic failure on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12).
Results: Among 91 patients treated, 87 had GT1 and four had GT4 infection. SVR12 was achieved by 89% (39/44) and 91% (43/47) of patients who received 12 and 16 weeks of G/P, respectively. Virologic relapse occurred in 9% (4/44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Prior treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, while prior treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event was headache (≥10% of patients) and there were no serious adverse events (AEs) assessed as related to study drugs or AEs leading to discontinuation.
Conclusions: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and prior failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors.
Background: Patients with hepatitis C virus (HCV) who have virologic failure after treatment containing an NS5A inhibitor have limited retreatment options. This article is protected by copyright. All rights reserved.
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New insights into diagnosis and therapeutic options for proliferative hepatoblastoma
ABSTRACT
Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo.
In conclusion, the highly proliferating C2A subtype is characterized by TOP2A gene up-regulation and FA pathway activation and HB therapeutic arsenal could include Bortezomib for the treatment of patients with the most aggressive tumors. This article is protected by copyright. All rights reserved.
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Cytoplasmic localization of the cell polarity factor Scribble supports liver tumor formation and tumor cell invasiveness
Abstract
The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison to HCC cells stably expressing wildtype Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype, which were characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L-dependent invasion was mediated by the AP-1 constituents ATF2 and JunB via induction of paracrine-acting secreted protein acidic and cysteine rich (SPARC). Co-expression of ScribP305L and the oncogene c-MYC via hydrodynamic gene delivery in mouse livers promoted tumor formation and increased pAKT, pATF2, and SPARC abundance in comparison to controls. Lastly, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues and the ScribP305L-dependent gene signature was enriched in cancer patients with poor prognosis.
Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination via specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patient groups with higher risk for the development of metastasis. This article is protected by copyright. All rights reserved.
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Development and Validation of a Primary Sclerosing Cholangitis-Specific Patient-Reported Outcomes Instrument: The PSC PRO
ABSTRACT
Background: PSC is a chronic liver disease associated with inflammation and biliary fibrosis that leads to cholangitis, cirrhosis, and impaired quality of life. Our objective was to develop and validate a PSC-specific PRO instrument.
Methods: We developed a 42-item PSC PRO instrument that contains 2 modules (Symptoms and Impact of Symptoms), and conducted external validation. Reliability and validity were evaluated using clinical data and a battery of other validated instruments. Test-retest reliability was assessed in a subgroup of patients who repeated the PSC PRO after the first administration.
Results: 102 PSC subjects (44±13 years, 32% male, 74% employed, 39% cirrhotic, 14% with history of decompensated cirrhosis, 38% history of depression, and 68% with inflammatory bowel disease (IBD) completed PSC PRO and other PRO instruments (SF-36, CLDQ, PBC-40, 5-D Itch). PSC PRO demonstrated excellent internal consistency (Cronbach alphas 0.84-0.94) and discriminant validity (41/42 items had the highest correlations with their own domains). There were good correlations between PSC PRO domains and relevant domains of SF-36, CLDQ, and PBC-40 (R=0.69-0.90; all p<0.0001), but lower (R=0.31-0.60, p<0.001) with 5-D Itch. Construct validity showed that PSC PRO can differentiate patients according to the presence and severity of cirrhosis and history of depression (p<0.05), but not by IBD (p>0.05). Test-retest reliability was assessed in 53 subjects who repeated PSC PRO within a median (IQR) of 37 (27-47) days. There was excellent reliability for most domains with intra-class correlations 0.71-0.88 (all p<0.001).
Conclusions: PSC PRO is a self-administered disease-specific instrument developed according to FDA guidelines. This preliminary validation study suggests good psychometric properties. Further validation of the instrument in larger and more diverse sample of PSC patients is needed. This article is protected by copyright. All rights reserved.
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Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The lowr HDV – 1 study
ABSTRACT
Background and rationale: In a proof-of-concept (POC) study, the oral prenylation inhibitor lonafarnib (LNF) decreased HDV RNA during 4 weeks of treatment. Here we explored optimal LNF regimens. Methods: 15 patients (5 groups; 3 per group) completed dosing as follows: 1) LNF 200 mg BID (12 weeks); 2) LNF 300 mg BID (12 weeks); 3) LNF 100 mg TID (5 weeks); 4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNα) 180 mcg QW (8 weeks); and 5) LNF 100 mg BID + ritonavir (RTV) 100 mg QD (8 weeks). Tolerability and efficacy were assessed. Results: Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy, and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG-IFNα 180 mcg QW. 2/6 patients who received 12 weeks of LNF experienced transient post-treatment ALT increases resulting in HDV RNA negativity and ALT normalization. Conclusions: The CYP3A4 inhibitor RTV allows a lower LNF dose to be used while achieving higher levels of post-absorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV RNA reduction, compared to historical responses with PEG-IFNα alone. 12 weeks of LNF can result in post-treatment HDV RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. This article is protected by copyright. All rights reserved.
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β-Catenin Deficiency in Hepatocytes Aggravates Hepatocarcinogenesis Driven by Oncogenic β-Catenin and MET
ABSTRACT
Both activating and inactivating mutations in ctnnb1, encoding β-catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein we show that deletion of endogenous β-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of β-catenin (CAT) in combination with HGF receptor MET. Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the β-catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and upregulation of pro-tumorigenic cytokines including IL-6 and TGF-β1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in β-catenin-deficient livers, featured by upregulation of Erk, Akt and Wnt/β-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. These data argue that while dominantly activating mutants of β-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment, which may facilitate HCC recurrence following a targeted therapy of the primary tumor. Therefore, an effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and also suppression of the secondary tumor-promoting stromal effects in the liver microenvironment. This article is protected by copyright. All rights reserved.
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Diabetes, Metabolic Comorbidities and Risk of Hepatocellular Carcinoma: Results from Two Prospective Cohort Studies
Abstract
Background: Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk.
Methods: From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986, and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for incident HCC.
Results: Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR 4.59, 95% CI 2.98-7.07), as was an increasing T2D duration (Ptrend<0.001). Compared to non-diabetics, the multivariable HRs for HCC were 2.96 (95% CI 1.57-5.60) for 0 to <2 years; 6.08 (95% CI 2.96-12.50) for 2 to <10 years; and 7.52 (95% CI 3.88-14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, dyslipidemia) was associated with increased HCC risk (Ptrend<0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1-fold increased HCC risk (95% CI 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR 2.04 [95% CI 0.69-6.09], and HR 1.45 [95% CI 0.69-3.07] respectively).
Conclusions: T2D is independently associated with increased risk for HCC, in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. This article is protected by copyright. All rights reserved.
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Hierarchical Multicomponent Inorganic Metamaterials: Intrinsically Driven Self-Assembly at the Nanoscale
Abstract
Increasingly intricate in their composition and structural organization, hierarchical multicomponent metamaterials with nonlinear spatially reconfigurable functionalities challenge the intrinsic constraints of natural materials, revealing tremendous potential for the advancement of biochemistry, nanophotonics, and medicine. Recent breakthroughs in high-resolution nanofabrication utilizing ultranarrow, precisely controlled ion or laser beams have enabled assembly of architectures of unprecedented structural and functional complexity, yet costly, time- and energy-consuming high-resolution sequential techniques do not operate effectively at industry-required scale. Inspired by the fictional Baron Munchausen's fruitless attempt to pull himself up, it is demonstrated that metamaterials can undergo intrinsically driven self-assembly, metaphorically pulling themselves up into existence. These internal drivers hold a key to unlocking the potential of metamaterials and mapping a new direction for the large-area, cost-efficient self-organized fabrication of practical devices. A systematic exploration of these efforts is presently missing, and the driving forces governing the intrinsically driven self-assembly are yet to be fully understood. Here, recent progress in the self-organized formation and self-propelled growth of complex hierarchical multicomponent metamaterials is reviewed, with emphasis on key principles, salient features, and potential limitations of this family of approaches. Special stress is placed on self-assembly driven by plasma, current in liquid, ultrasonic, and similar highly energetic effects, which enable self-directed formation of metamaterials with unique properties and structures.
Self-organized formation and self-propelled growth of complex hierarchical multicomponent metamaterials reveal tremendous potential. Recent progress with emphasis on key principles, features, and potential limitations of these materials is reviewed with a special stress placed on self-assembly driven by plasma, current in liquid, ultrasonic, and similar highly energetic effects, which enable self-directed formation of metamaterials with unique properties and structures.
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Influence of Radiation on the Properties and the Stability of Hybrid Perovskites
Abstract
Organic–inorganic perovskites are well suited for optoelectronic applications. In particular, perovskite single and perovskite tandem solar cells with silicon are close to their market entry. Despite their swift rise in efficiency to more than 21%, solar cell lifetimes are way below the needed 25 years. In fact, comparison of the time when the device performance has degraded to 80% of its initial value (T80 lifetime) of numerous solar cells throughout the literature reveals a strongly reduced stability under illumination. Herein, the various detrimental effects are discussed. Most notably, moisture- and heat-related degradation can be mitigated easily by now. Recently, however, several photoinduced degradation mechanisms have been observed. Under illumination, mixed perovskites tend to phase segregate, while, further, oxygen catalyzes deprotonation of the organic cations. Additionally, during illumination photogenerated charge can be trapped in the NH antibonding orbitals causing dissociation of the organic cation. On the other hand, organic–inorganic perovskites exhibit a high radiation hardness that is superior to crystalline silicon. Here, the proposed degradation mechanisms reported in the literature are thoroughly reviewed and the microscopic mechanisms and their implications for solar cells are discussed.
T80 lifetimes of organic–inorganic perovskite solar cells are strongly reduced under illumination. Various degradation mechanisms are therefore discussed throughout the literature. Degradation by moisture or heat is well understood and mitigation possible. Photoinduced phase segregation and photoinduced dissociation of the organic cation, however, remain unsolved. Recent observations enlighten the underlying microscopic mechanisms and may pave the way for stable perovskites.
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Nanomorphology Effects in Semiconductors with Native Ferromagnetism: Hierarchical Europium (II) Oxide Tubes Prepared via a Topotactic Nanostructure Transition
Abstract
Semiconductors with native ferromagnetism barely exist and defined nanostructures are almost unknown. This lack impedes the exploration of a new class of materials characterized by a direct combination of effects on the electronic system caused by quantum confinement effects with magnetism. A good example is EuO for which currently no reliable routes for nanoparticle synthesis can be established. Bottom-up approaches applicable to other oxides fail because of the labile oxidation state +II. Instead of targeting a direct synthesis, the two steps—"structure control" and "chemical transformation"—are separated. The generation of a transitional, hybrid nanophase is followed by its conversion into EuO under full conservation of all morphological features. Hierarchical EuO materials are now accessible in the shape of oriented nanodisks stacked to tubular particles. Magnetically, the coupling of either vortex or onion states has been found. An unexpected temperature dependence is governed by thermally activated transitions between these states.
Access to nanostructures of the ferromagnetic semiconductor Eu(II)O is achieved by a two-step strategy. The synthesis of hierarchical nanotubes of an Eu2O3-organic nanohybrid is followed by conversion to EuO under full conservation of all structural features and shape. Herein, magnetic property correlations are revealed.
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6 Hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c-Fos immunoreactivity throughout the brain
Summary
Objective
Besides seizures, patients with epilepsy are affected by a variety of cognitive and psychiatric comorbidities that further impair their quality of life. The present study provides an in-depth characterization of the behavioral alterations induced by 6 Hz corneal kindling. Furthermore, we correlate these behavioral changes to alterations in c-Fos protein expression throughout the brain following kindling.
Methods
Adolescent male Naval Medical Research Institute (NMRI) mice were kindled via repetitive subconvulsive 6 Hz corneal stimulations until they reached the fully kindled state (defined as 10 consecutive generalized seizures). Afterwards we performed an elaborate battery of behavioral tests and we evaluated c-Fos expression throughout the brain using immunohistochemistry.
Results
Fully kindled mice display an abnormal behavioral phenotype, characterized by basal and amphetamine-induced hyperlocomotion, anhedonia, social withdrawal, and deficits in short- and long-term memory. Moreover, 6 Hz corneal kindling enhances c-Fos immunoreactivity in the visual, parahippocampal, and motor cortices and the limbic system, whereas c-Fos+ cells are decreased in the orbital cortex of fully kindled mice.
Significance
The behavioral outcomes of 6 Hz corneal kindling cluster into 3 main categories: positive symptoms, negative symptoms, and cognitive impairment. These symptoms are accompanied by c-Fos activation in relevant brain regions once the fully kindled state is established. Based on the face validity of this model, we speculate that 6 Hz corneal kindling can be used to model not only pharmacoresistant limbic seizures, but also several neurobehavioral comorbidities that affect patients with epilepsy.
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Access to diagnostic and therapeutic facilities for psychogenic nonepileptic seizures: An international survey by the ILAE PNES Task Force—2nd Revision
Summary
Objective
Studies from a small number of countries suggest that patients with psychogenic nonepileptic seizures (PNES) have limited access to diagnostic and treatment services. The PNES Task Force of the International League Against Epilepsy (ILAE) carried out 2 surveys to explore the diagnosis and treatment of PNES around the world.
Methods
A short survey (8 questions) was sent to all 114 chapters of the ILAE. A longer survey (36 questions) was completed by healthcare professionals who see patients with seizures. Questions were separated into 5 sections: professional role, diagnostic methods, management, etiology, and access to health care.
Results
Responses were received from 63 different countries. The short survey was completed by 48 ILAE chapters, and the long survey by 1098 health professionals from 28 countries. PNES were recognized as a diagnostic and therapeutic problem in all countries. Trauma and mental health issues were most commonly recognized as etiologic factors. There was a clear relationship between income and access to diagnostic tests and expertise. Psychological therapy was most commonly considered the treatment of choice. Although financial difficulties were the most commonly reported problem with service access in low-income countries, in all countries stigma, lack of popular awareness, and lack of information posed challenges.
Significance
This global provider survey demonstrates that PNES are a health problem around the world. Health care for PNES could be improved with better education of healthcare professionals, the development of reliable and simple diagnostic procedures that do not rely on costly tests, and the provision of accessible information.
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Decision-making under risk of gain in young children and mangabey monkeys
Abstract
In contrast to human adults, risk proneness in the gain domain is usually observed in both young children and non-human primates. It is currently unclear what mechanism might be underlying such economic preferences. We investigated decision-making under risk of gain in toddlers and monkeys. The choices of 2.5-year-old children and red-capped mangabeys (Cercocebus torquatus torquatus) were examined in a gambling task for food reward in which participants have to choose between two options, a secure option and a risky option. In contrast to monkeys, toddlers showed a strong preference for the risky option over the safe option. In order to test the hypothesis that risky choices in participants reflect inhibitory control difficulties, toddlers and mangabeys were presented in Experiment 2 with a situation analogous to that used in Experiment 1 except for the fact that the opaque cover under which was placed the secure option was replaced by a transparent cover. In this second experiment, toddlers continued to show a preference for the risky option over the safe option. In contrast, mangabeys showed a preference for the safe option over the risky option in Trial 1 but they shifted their economic preferences in Trial 2. We argue that decision-making strategies under risk of gain in both toddlers and mangabeys (a) do not reflect poor behavioral control and (b) are not reducible to perception-action couplings.
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Development of behavioral responses to thermal challenges
Abstract
Body temperature regulation involves the development of responses to cold and warm challenges. Matching our understanding of the development of body temperature regulation to warm challenges with that of cold challenges will enhance our understanding of the ontogeny of thermoregulation and reveal different adaptive specializations. Warm and cold thermoregulation are important processes, and they include direct thermal effects on offspring, as well as indirect effects on them, such as those imposed by thermally associated alterations of maternal behavior. The present paper is a selective review of the existing literature and a report of some new empirical data, aimed at processes of mammalian development, especially those affecting behavior. We briefly discuss the development of body temperature regulation in rats and mice, and thermal aspects of maternal behavior with emphasis on responses to high temperatures. The new data extend previous analyses of individual and group responses in developing rodents to warm and cool ambient temperatures. This literature not only reveals a variety of adaptive specializations during development, but it points to the earlier appearance in young mammals of abilities to combat heat loss, relative to protections from hyperthermia. These relative developmental delays in compensatory defenses to heating appear to render young mammals especially vulnerable to environmental warming. We describe cascading consequences of warming—effects that illustrate interactions across levels of physiological, neural, and behavioral development.
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Protein deficiency decreases stereotypic behavior frequency and prevalence and activity in the striped mouse Rhabdomys dilectus chakae
Abstract
Diverse motivational triggers, including diet, elicit stereotypic behavior. We investigated whether diets comprised of different protein levels but similar levels of energy were associated with the occurrence of locomotor stereotypies in the striped mouse Rhabdomys dilectus chakae. In a first experiment, 20 stereotypic and 20 non-stereotypic (10 subjects per sex and per group) juvenile (40 days old) subjects were placed on baseline (BP), high (HP) or low protein (LP) diet treatments (120 subjects in total). All subjects initially identified as stereotypic displayed stereotypic behavior in the BP and HP treatments on Days 60–63 and Days 80–83 compared to 35% and 12.5% of LP subjects, respectively. Moreover, LP subjects displayed lower levels of activity and stereotypic behavior than BP and HP subjects. Those identified as non-stereotypic never displayed stereotypy. In a second experiment, 48 individuals, bred and reared on LP and whose parents were stereotypic, were assigned to either HP (13 males, 12 females) or LP (12 males, 11 females) treatments at 50 days of age for 30 days. Stereotypy was three times less likely to occur in the LP than the HP treatment, and activity was greater in LP-HP individuals than LP-LP individuals. In both experiments, LP individuals had the lowest body mass. Striped mice adjusted their behaviors in response to dietary protein levels. Protein deficiency reduced activity and stereotypic behavior and prevalence, possibly related to an energy or neurological deficit.
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ERPs reveal weaker effects of spelling on auditory rhyme decisions in children than in adults
Abstract
A classic finding in psycholinguistics is that orthographic form influences the processing of auditory words. The aim of the present study was to examine how reading experience changes this effect. Specifically, we tested the prediction that top-down visual modulation of spoken word recognition is reduced in children compared to adults, owing to their reduced experience with print. Event-related potentials (ERPs) were measured as 8–10-year-old children and adults made rhyme decisions about spoken word pairs that were either orthographically similar or dissimilar. When orthography did not conflict (e.g., throat-boat), both age groups demonstrated a robust rhyme effect marked by greater N400 to no-rhyme versus rhyme trials. For rhyming trials that differed in orthography (e.g., vote-boat) and non-rhyming trials that shared orthography (e.g., warm-farm), adults showed more interference than children. Differences in orthographic interference suggest an extended developmental schedule for top-down mechanisms in speech recognition.
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In-home salivary melatonin collection: Methodology for children and adolescents
Abstract
In-home salivary collection quality and adherence to a prescribed collection methodology for evaluation of dim light melatonin onset (DLMO) is unknown in children. Primary aims of this study were to 1) describe a novel family centered methodology for in-home salivary collection; 2) determine the acceptance and feasibility of this methodology; 3) measure adherence to collection instructions; and 4) identify patterns between participants' age and quality of samples collected. After receiving instructional handouts from the study team, families utilized in-home salivary melatonin collection. Participants (N = 64) included 39 children (21 female, mean age 9.5 ± 1.61 years) and 25 adolescents (11 female, mean age 15.9 ± 2.12 years) with craniopharyngioma. Participants were 90% adherent to collection schedule, and 89% of the samples collected were of sufficient quantity and quality, with no differences found between age (child vs. adolescent) and melatonin sample quantity and quality. In-home saliva collection provides an acceptable and feasible method to collect salivary melatonin and biomarkers in children and adolescents.
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Annals of Neurology: Volume 82, Number 5, November 2017
ON THE COVER: A 3-dimensional z-stack of images taken with a confocal microscope of synapses (stained green for synaptophysin) being phagocytosed by microglia (stained red for CD68), in the spinal cord of a mouse with knockout of the Abcd1 gene. Mutations in this gene in humans cause adrenoleukodystrophy, one component of which is adrenomyeloneuropathy, in which there is loss of spinal cord synapses.
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Novel technique using a non-tip and short-wire papillotome for biliary cannulation of intradiverticular papilla in patients with Roux-en-Y anastomosis
Abstract
Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) has enabled the endoscopic treatment of pancreatobiliary disease in patients with a surgically altered gastrointestinal anatomy.1-3 However, even though the endoscope can reach the papilla, successful cannulation of the common bile duct may be difficult in the papilla located within a diverticulum because of an insufficient distance from the papilla in the tangential direction. Therefore endoscopic ultrasound-guided biliary drainages have been reported as useful and safety methods.4-5 Herein, we report BE-ERCP using a papillotome for cannulation of the intradiverticular papilla in R-Y anastomosis patients with choledocholithiasis.
This article is protected by copyright. All rights reserved.
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Women and substance use: a qualitative study on sexual and reproductive health of women who use drugs in Delhi, India
Objectives
To explore contextual factors that increase vulnerabilities to negative sexual and reproductive health (SRH) outcomes and possible differences in SRH-related behaviours and the needs of women who use drugs (WUD) through non-injecting and injecting routes.
DesignQualitative study design using semi-structured in-depth interviews.
ParticipantsTwenty women who injected drugs in the past 3 months and 28 women who reported using drugs through non-injecting routes in the past 1 month.
SettingInterviews were conducted at community-based, drop-in centres in Delhi, India.
ResultsStudy findings illustrate that WUD were sexually active and had multiple sex partners including clients of sex work. Transient relationships were reported and many participants engaged in unsafe sex. Factors which affected safe sex behaviours included: gender power imbalance, limited agency for decision-making, lack of accurate information for correct self-risk assessment, and being under the influence of drugs. Despite high awareness, low and inconsistent contraceptive use was reported. Some participants were coerced to conceive while a few others reported their inability to conceive. Violence was a key determinant for SRH outcomes. Perception of certain adverse health outcomes (such as infertility) to be 'common and expected among WUD' influenced access to healthcare. Further, healthcare providers' stigmatising attitudes and lack of women-centric services deterred women from uptake of healthcare services.
ConclusionFindings highlight that SRH-related behaviours and needs of this group are a complex interplay of multiple determinants which need to be addressed at all levels: individual, family, community and institutional. It is imperative to roll out a 'one-stop-shop' for a comprehensive package of health services. Expansion of existing drop-in-centres could be considered for setting-up community-based women-centric services with appropriate linkage to drug dependence treatment and reproductive health services.
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Early-onset group B Streptococcus (EOGBS) infection subsequent to cessation of screening-based intrapartum prophylaxis: findings of an observational study in West London, UK
Objectives
To describe the impact on early-onset group B Streptococcus (EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention.
SettingMaternity services provided by secondary healthcare organisation in North West London.
ParticipantsAll women who gave birth in the healthcare organisation between April 2016 and March 2017. There were no exclusions.
DesignObservational study comparing EOGBS rates in the postscreening period (2016–2017) with prescreening (2009–2013) and screening periods (2014–2015).
MethodsLocal guidelines for risk-based IAP were reintroduced in April 2016. Compliance with guidelines was audited. Gestational age, mode of delivery, maternal demographics and EOGBS rates in three time periods were compared using Poisson regression analysis. EOGBS was defined through GBS being cultured from blood, cerebrospinal fluid or other sterile fluids within 6 days of birth.
Primary outcomeEOGBS rates/1000 live births in prescreening, screening and postscreening periods
ResultsIncremental changes in maternity population were observed throughout the study period (2009 onwards), in particular the ethnic profile of mothers. Of the 5033 live births in postscreening period, 9 babies developed EOGBS infection. Only one of the mothers of affected babies had a risk factor indicating use of IAP. Comparison of postscreening period with screening period showed a fivefold increase in EOGBS rates after adjustment for ethnicity (1.79 vs 0.33/1000 live births; risk ratio =5.67, p=0.009). There was no significant difference between prescreening and postscreening periods with rates of infection reverting to their prescreening level.
ConclusionsThis study provides further evidence of efficacy of screening-based IAP compared with risk-based IAP in prevention of EOGBS in newborns in an area of high incidence.
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Direct medical costs of motorcycle crashes in Ontario [Research]
BACKGROUND:
There is no reliable estimate of costs incurred by motorcycle crashes. Our objective was to calculate the direct costs of all publicly funded medical care provided to individuals after motorcycle crashes compared with automobile crashes.
METHODS:We conducted a population-based, matched cohort study of adults in Ontario who presented to hospital because of a motorcycle or automobile crash from 2007 through 2013. For each case, we identified 1 control absent a motor vehicle crash during the study period. Direct costs for each case and control were estimated in 2013 Canadian dollars from the payer perspective using methodology that links health care use to individuals over time. We calculated costs attributable to motorcycle and automobile crashes within 2 years using a difference-in-differences approach.
RESULTS:We identified 26 831 patients injured in motorcycle crashes and 281 826 injured in automobile crashes. Mean costs attributable to motorcycle and automobile crashes were $5825 and $2995, respectively (p < 0.001). The rate of injury was triple for motorcycle crashes compared with automobile crashes (2194 injured annually/100 000 registered motorcycles v. 718 injured annually/100 000 registered automobiles; incidence rate ratio [IRR] 3.1, 95% confidence interval [CI] 2.8 to 3.3, p < 0.001). Severe injuries, defined as those with an Abbreviated Injury Scale ≥ 3, were 10 times greater (125 severe injuries annually/100 000 registered motorcycles v. 12 severe injuries annually/100 000 registered automobiles; IRR 10.4, 95% CI 8.3 to 13.1, p < 0.001).
INTERPRETATION:Considering both the attributable cost and higher rate of injury, we found that each registered motorcycle in Ontario costs the public health care system 6 times the amount of each registered automobile. Medical costs may provide an additional incentive to improve motorcycle safety.
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Course and predictors of post-traumatic stress disorder in a cohort of psychologically distressed patients with cancer: A 4-year follow-up study
BACKGROUND
Scant evidence exists on the long-term course of cancer-related post-traumatic stress disorder (PTSD). This is among the few studies worldwide, and the first in the South-East Asian region, to prospectively evaluate PTSD in patients with cancer using gold-standard clinical interviews. The objective of the study was to assess the course and predictors of PTSD in adult patients with cancer in a South-East Asian population.
METHODS
A prospective, longitudinal study was conducted in a cohort of 469 consecutively recruited patients (aged ≥18 years) with various cancer types within 1 month of diagnosis at a single oncology referral center. Only patients who had significant psychological distress (Hospital Anxiety and Depression Scale total cutoff score ≥16) underwent the PTSD module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (SCID) at at 6-months follow-up. All patients completed the SCID at the 4-year follow-up assessment regardless of their initial Hospital Anxiety and Depression Scale score.
RESULTS
In an analysis combining patients who had both full and subsyndromal PTSD, there was a 21.7% incidence of PTSD at the 6-month follow-up assessment (n = 44 of 203 SCID-interviewed patients), with rates dropping to 6.1% at the 4-year follow-up assessment (n = 15 of 245 SCID-interviewed patients). Patients with breast cancer (compared with those who had other types of cancer) were 3.68 times less likely to develop PTSD at 6-months, but not at 4-years follow-up.
CONCLUSIONS
The overall rates of PTSD decreased with time, but one-third of patients (34.1%) who were initially diagnosed had persistent or worsening PTSD 4 years later. There is a need for early identification of this subset of patients who have cancer with PTSD to design risk-targeted interventions. Cancer 2017. © 2017 American Cancer Society.
http://ift.tt/2hEf3OY
Oxidative stress does not influence local sweat rate during high intensity exercise
Abstract
Nitric oxide (NO)-dependent sweating is diminished during high but not moderate intensity exercise. We evaluated whether this impairment stems from increased oxidative stress during high intensity exercise. On two separate days, 11 young (24 ± 4 years) males cycled in the heat (35°C) at a moderate (500 W; 52 ± 6%VO2peak) or high (700 W; 71 ± 5%VO2peak) rate of metabolic heat production. Each session included two 30-min exercise bouts separated by a 20-min recovery. Local sweat rate was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with: (1) lactated Ringer's solution (Control), (2) 10 mm ascorbate (Ascorbate; non-selective antioxidant), (3) 10 mm NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor), or (4) 10 mm Ascorbate + 10 mm L-NAME (Ascorbate + L-NAME). During moderate exercise, sweat rate was attenuated at the L-NAME and Ascorbate + L-NAME sites (both ∼1.0 mg·min−1·cm−2, all P < 0.05) but not at the Ascorbate site (∼1.1 mg·min−1·cm−2, both P ≥ 0.28) in comparison to the Control site (∼1.1 mg·min−1·cm−2). However, no differences were observed between treatment sites (∼1.4 mg·min−1·cm−2; P = 0.75) during high intensity exercise. We conclude that diminished NO-dependent sweating during intense exercise occurs independent of oxidative stress.
This article is protected by copyright. All rights reserved
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End-of-treatment positron emission tomography after uniform first-line therapy of B cell posttransplant lymphoproliferative disorder identifies patients at low risk of relapse in the prospective German PTLD registry
Background Fluorine-18 fluorodeoxyglucose (18F-FDG) - positron-emission tomography (PET) is a recommended standard in the staging and response assessment of 18F-FDG-avid lymphoma. Posttransplant lymphoproliferative disorder (PTLD) can be detected by 18F-FDG-PET at diagnosis with high sensitivity and specificity. However, the role of response assessment by end of treatment (EOT)-PET has only been addressed in small case series. Methods We performed a retrospective, multi-center study of 37 patients with CD20-positive posttransplant lymphoproliferative disorder (PTLD) after solid organ transplantation (SOT) treated with uniform, up-to-date first-line protocols in the prospective German PTLD registry who had received EOT-18F-FDG-PET between 2006 and 2014. Median follow-up was 5.0 years. Any nonphysiological 18F-FDG uptake (Deauville score greater 2) was interpreted as PET-positive. Results By computed tomography (CT) final staging, 18 out of 37 patients had a complete response (CR), 18 had a partial response and 1 patient had stable disease. EOT PET was negative in 24/37 patients and positive in 13/37. The positive predictive value of EOT PET for PTLD relapse was 38% and the negative predictive value 92%. Time to progression (TTP) and progression-free-survival (PFS) were significantly longer in the PET negative group (p=0.019 and p=0.013). In the 18 patients in a partial response by CT staging, we noted highly significant differences in overall survival (p=0.001), TTP (p=0.007), and PFS (p
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http://ift.tt/2B4zjlt
Lung transplantation as a therapeutic option in acute respiratory distress syndrome
Background Lung transplantation (LTPL) is considered as a salvage therapeutic option in patients with end-stage lung disease. However, there is a lack of sufficient data on the use of LTPL in patients with acute respiratory distress syndrome (ARDS). While there are few case reports on lung transplant for ARDS, no case series exist up to date. The aim of this study was to evaluate the clinical outcomes of patients with ARDS in accordance with the LTPL status. Methods Patients who had severe ARDS (PaO2/FiO2 ratio ≤ 100 mmHg with positive end expiratory pressure ≥ 5 cmH2O) and were listed for LTPL with no underlying end-stage lung disease were included in this single-center retrospective study. Demographic and clinical data of the patients were collected and analyzed. Results Fourteen patients were listed for LTPL due to severe ARDS. All patients received mechanical ventilation, and 12 (86%) patients underwent extracorporeal membrane oxygenation. Of the nine patients who underwent LTPL, eight (89%) survived, whereas only one patient (20%) out of those who did not receive LTPL survived. The median survival time of the patients who underwent LTPL was 1996 days (interquartile range (IQR), 872–2239), compared with 49 days (IQR, 872–2239) in patients who did not undergo LTPL. The median survival time after LTPL was 64 months (IQR, 28–72). The three-year survival rate of the recipients was 78%. Conclusions LTPL may be considered as a therapeutic option in a select group of patients with severe ARDS. However, the irreversibility of the patient's lung status should be considered. Correspondence to: Seung-Il Park, M.D.: Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, E-mail: sipark@amc.seoul.kr, Sang-Bum Hong, M.D.: Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, E-mail:sbhong@amc.seoul.kr Seung-Il Park, M.D. and Sang-Bum Hong, M.D. equally contributed to this study. Contributions: Conception and design: SH, SP, TS; Acquisition, analysis and interpretation: YC, SL, SC, HK, YK, DK, KD, IC; Drafting the manuscript for important intellectual content: YC, SH, SP, TS. Conflicts of interest: The authors declare no conflicts of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2yXUvIr
Incidence and Risk Factors of Intracranial Hemorrhage in Liver Transplant Recipients
Background Intracranial hemorrhage after liver transplantation is an infrequently reported complication but one which can have devastating consequences. Methods We performed a retrospective cross-sectional analysis of all liver transplants performed between January 2010 and June 2015 at a single high-volume institution using a prospectively maintained electronic database and query of the electronic medical record. Cases of intracranial hemorrhage were adjudicated as either spontaneous intraparenchymal (IPH) or extra-axial (EAH) hemorrhages. Patients with confirmed intracranial hemorrhage were compared with all other liver transplant recipients. Risk factors were identified by univariate analysis and logistic regression models for IPH and EAH. Results Thirty-one (5.2%) of 595 liver transplant recipients developed an intracranial hemorrhage within 12 months of transplantation, 15 IPH and 16 EAH. The majority of intracranial hemorrhages were diagnosed within 1 month of transplantation. Eight (26%) intracranial hemorrhage patients died during hospitalization. Fourteen (45%) intracranial hemorrhage patients died within 1 year of transplantation and 1-year mortality was greater than in patients without intracranial hemorrhage (11.2%, p
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http://ift.tt/2B41fWT
Lung Isolation in the Patient With a Difficult Airway
One-lung ventilation is routinely used to facilitate exposure for thoracic surgical procedures and can be achieved via several lung isolation techniques. The optimal method for lung isolation depends on a number of factors that include (1) the indication for lung isolation, (2) anatomic features of the upper and lower airway, (3) availability of equipment and devices, and (4) the anesthesiologist's proficiency and preferences. Though double-lumen endobronchial tubes (DLTs) are most commonly utilized to achieve lung isolation, the use of endobronchial blockers offer advantages in patients with challenging airway anatomy. Anesthesiologists should be familiar with existing alternatives to the DLT for lung isolation and alternative techniques for DLT placement in the patient with a difficult airway. Newer technologies such as videolaryngoscopy with or without adjunctive fiberoptic bronchoscopy may facilitate intubation and lung isolation in difficult airway management. Accepted for publication October 3, 2017. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Randal S. Blank, MD, PhD, Department of Anesthesiology, Thoracic Anesthesia, University of Virginia Health System, PO Box 800710-0710, Charlottesville, VA 22908. Address e-mail to rsb8p@virginia.edu. © 2017 International Anesthesia Research Society
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http://ift.tt/2AU7MCm
Ultrasound-Assisted Versus Fluoroscopic-Guided Lumbar Sympathetic Ganglion Block: A Prospective and Randomized Study
BACKGROUND: Fluoroscopy (FL)-guided lumbar sympathetic ganglion block (LSGB) is widely performed to diagnose and manage various diseases associated with sympathetically maintained pain. Recently, numerous ultrasound (US)-assisted procedures in pain medicine have been attempted, showing an advantage of low radiation exposure. This randomized, prospective trial compared the procedural outcomes and complications between FL-guided and US-assisted LSGBs. METHODS: Fifty LSGBs were randomly divided into 2 groups: FL-guided (FL group) or US-assisted (US group) LSGB group. Both groups received FL-guided or US-assisted LSGB with 10 mL of 0.25% levobupivacaine. The primary end point was the total procedure time. Secondary outcomes were success rate, imaging time, onset time (based on temperature rise), dosage of radiation exposure, other procedure-related outcomes, and complications. RESULTS: Total procedure time and success rate were not statistically different between the 2 groups, whereas imaging time of the US group was longer than that of the FL group (P = .012). The onset time was faster in the US group (P = .019), and bone touching during the procedure was less frequent in the US group (P = .001). Moreover, radiation exposure was significantly lower in the US group than in the FL group (P
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http://ift.tt/2ixNA2r
Perioperative Noninvasive Blood Pressure Monitoring
The most commonly monitored variable for perioperative hemodynamic management is blood pressure. Several indirect noninvasive blood pressure monitoring techniques have been developed over the last century, including intermittent techniques such as auscultation (Riva-Rocci and Korotkoff) and oscillometry (Marey) and continuous techniques. With the introduction of automated noninvasive blood pressure devices in the 1970s, the oscillometric technique quickly became and remains the standard for automated, intermittent blood pressure measurement. It tends to estimate more extreme high and low blood pressures closer to normal than what invasive measurements indicate. The accuracy of the oscillometric maximum amplitude algorithm for estimating mean arterial pressure is affected by multiple factors, including the cuff size and shape, the shape of the arterial compliance curve and arterial pressure pulse, and pulse pressure itself. Additionally, the technique typically assumes a consistent arterial compliance and arterial pressure pulse, thus changes in arterial compliance and arrhythmias that lead to variation in the pressure pulse can affect accuracy. Volume clamping, based on the Penaz principle, and arterial tonometry provide continuous tracking of the arterial pressure pulse. The ubiquitous use of blood pressure monitoring is in contrast with the lack of evidence for optimal perioperative blood pressure targets. Accepted for publication September 27, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Kai Kuck, PhD, Department of Anesthesiology, University of Utah Medical School, 30 N 1900 E Room 3c444, Salt Lake City, UT 84132. Address e-mail to kai.kuck@hsc.utah.edu. © 2017 International Anesthesia Research Society
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http://ift.tt/2AUor8N
Two-Year Follow-Up Survey: Views of US Anesthesiologists About Health Care Costs and Future Practice Roles
Anesthesiologists' perspectives on US health care finance reform are increasingly germane to recent policy reforms. The aim of this follow-up survey was to examine how anesthesiologists' views of health care costs and future practice roles have changed since 2014. Six thousand randomly chosen active members of the American Society of Anesthesiologists were again surveyed and were also asked several new questions regarding specialties and perioperative management. Results showed an increase in self-reported understanding of the perioperative surgical home. Government, insurance companies, and pharmaceutical companies saw an increase in perceived "major responsibility" for cost reduction. Respondents vastly preferred that patient care under the perioperative surgical home be multidisciplinary. Accepted for publication September 1, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Joseph B. Rinehart, MD, Department of Anesthesiology & Perioperative Care, University of California, Irvine, 101 The City Dr S, Orange, CA 92868. Address e-mail to jrinehar@uci.edu. © 2017 International Anesthesia Research Society
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http://ift.tt/2iyywlp
Reducing Maternal Mortality in Papua New Guinea: Contextualizing Access to Safe Surgery and Anesthesia
Papua New Guinea has one of the world's highest maternal mortality rates with approximately 215 women dying per 100,000 live births. The sustainable development goals outline key priority areas for achieving a reduction in maternal mortality including a focus on universal health coverage with safe surgery and anesthesia for all pregnant women. This narrative review addresses the issue of reducing maternal mortality in Papua New Guinea by contextualizing the need for safe obstetric surgery and anesthesia within a structure of enabling environments at key times in a woman's life. The 3 pillars of enabling environments are as follows: a stable humanitarian government; a safe, secure, and clean environment; and a strong health system. Key times, and their associated specific issues, in a woman's life include prepregnancy, antenatal, birth and the postpartum period, childhood, adolescence and young womanhood, and the postchildbearing years. Accepted for publication September 8, 2017. Funding: None. The author declares no conflicts of interest. This review was undertaken as part of work completed by Associate Professor Dennis at the University of Sydney as part of the completion of her Master of International Public Health. Reprints will not be available from the author. Address correspondence to Alicia T. Dennis, MBBS, PhD, MIPH, PGDipEcho, FANZCA, Department of Anaesthesia, The Royal Women's Hospital, The University of Melbourne, Locked Bag 300, Corner Grattan St & Flemington Rd, Parkville, Victoria 3052, Australia. Address e-mail to alicia.dennis@thewomens.org.au. © 2017 International Anesthesia Research Society
http://ift.tt/2AU7L1g
http://ift.tt/2AU7L1g
Alkalinized Lidocaine Preloaded Endotracheal Tube Cuffs Reduce Emergence Cough After Brief Surgery: A Prospective Randomized Trial
BACKGROUND: Alkalinized lidocaine in the endotracheal tube (ETT) cuff decreases the incidence of cough and throat pain on emergence after surgery lasting more than 2 hours. However, alkalinized lidocaine needs 60–120 minutes to cross the ETT cuff membrane; therefore, its usefulness in shorter duration surgery is unknown. This prospective double-blind randomized controlled trial tested the hypothesis that alkalinized lidocaine would reduce the incidence of emergence cough after surgeries lasting 90 minutes before intubation with either 2 mL of 2% lidocaine and 8 mL of 8.4% bicarbonate (group AL) or 10 mL of normal saline (group S). Cuffs were emptied immediately before intubation. After intubation, either 2 mL of 2% lidocaine (AL) or 2 mL of saline (S) were injected into the cuff. Additional 8.4% bicarbonate (AL) or saline (S) was injected into the cuff until there was no air leak. Anesthesia was maintained using desflurane, rocuronium, and either fentanyl or sufentanil to maintain vital signs within 20% of baseline values. Opioids administered in prophylaxis of extubation cough were proscribed. A standardized "no touch" emergence technique was used. A blinded assessor noted any cough above 0.2 minimum alveolar concentration (MAC) of expired desflurane. At 0.2 MAC, once every 30 seconds, the patient was instructed to open his eyes and extubation occurred once a directed response was noted. RESULTS: A total of 213 patients were randomized and 100 patients in each group completed the experimental protocol. The incidence of extubation cough in group AL was 12%, significantly lower (1-sided P = .045) than the 22% incidence in group S. The 1-tailed risk ratio for cough in group AL was 0.55 (0–0.94, P = .045). Total amount of opioids administered (P = .194), ETT cuff preloading times (P = .259), and extubation times (P = .331) were not significantly different between groups. The average duration of surgery was 59 ± 28 minutes in group AL and 52 ± 29 minutes in group S (P = .057). CONCLUSIONS: Alkalinized lidocaine in the ETT cuff significantly decreased general anesthesia emergence cough after surgeries with an average duration of slightly
http://ift.tt/2iyyvhl
http://ift.tt/2iyyvhl
The Science of Local Anesthesia: Basic Research, Clinical Application, and Future Directions
Local anesthetics have been used clinically for more than a century, but new insights into their mechanisms of action and their interaction with biological systems continue to surprise researchers and clinicians alike. Next to their classic action on voltage-gated sodium channels, local anesthetics interact with calcium, potassium, and hyperpolarization-gated ion channels, ligand-gated channels, and G protein–coupled receptors. They activate numerous downstream pathways in neurons, and affect the structure and function of many types of membranes. Local anesthetics must traverse several tissue barriers to reach their site of action on neuronal membranes. In particular, the perineurium is a major rate-limiting step. Allergy to local anesthetics is rare, while the variation in individual patient's response to local anesthetics is probably larger than previously assumed. Several adjuncts are available to prolong sensory block, but these typically also prolong motor block. The 2 main research avenues being followed to improve action of local anesthetics are to prolong duration of block, by slow-release formulations and on-demand release, and to develop compounds and combinations that elicit a nociception-selective blockade. Accepted for publication October 16, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Markus W. Hollmann, MD, PhD, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Address e-mail to m.w.hollmann@amc.uva.nl. © 2017 International Anesthesia Research Society
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http://ift.tt/2AU7J9E
Improvement of the Elevated Tryptase Criterion to Discriminate IgE- From Non–IgE-Mediated Allergic Reactions
BACKGROUND: Differentiating between immunoglobulin E (IgE)-dependent and IgE-independent hypersensitivity reactions may improve the etiologic orientation and clinical management of patients with allergic reactions in the anesthesia setting. Serum tryptase levels may be useful to discriminate the immune mechanism of allergic reactions, but the diagnostic accuracy and optimal cutpoint remain unclear. We aimed to compare the diagnostic accuracy of tryptase during reaction (TDR) alone and the TDR/basal tryptase (TDR/BT) ratio for discriminating IgE- from non–IgE-mediated allergic reactions, and to estimate the best cut point for these indicators. METHODS: We included 111 patients (45% men; aged 3–99 years) who had experienced an allergic reaction, even though the allergic reaction could be nonanaphylactic. Allergy tests were performed to classify the reaction as an IgE- or non–IgE-mediated one. The area under the curve (AUC) of the receiver operating characteristic analysis was performed to estimate the discriminative ability of TDR and TDR/BT ratio. RESULTS: An IgE-mediated reaction was diagnosed in 49.5% of patients, of whom 56% met anaphylaxis criteria. The median (quartiles) TDR for the IgE-mediated reactions was 8.0 (4.9–19.6) and 5.1 (3.5–8.1) for the non–IgE-mediated (P = .022). The median (quartiles) TDR/BT ratio was 2.7 (1.7–4.5) in IgE-mediated and 1.1 (1.0–1.6) in non–IgE-mediated reactions (P
http://ift.tt/2ixNuI7
http://ift.tt/2ixNuI7
Effects of Increasing Airway Pressures on the Pressure of the Endotracheal Tube Cuff During Pelvic Laparoscopic Surgery
BACKGROUND: Tracheal tube cuff pressures exceeding the perfusion pressures of the tracheal mucosa have been associated with complications such as sore throat, tracheal mucosa ulcers, tracheal rupture, and subglottic stenosis. Despite appropriate inflation, many factors can increase the tracheal cuff pressure during mechanical ventilation. This prospective observational cohort study was designed to test the hypothesis that during a clinical model of decreasing respiratory compliance, the pressure within the endotracheal tube cuff will rise in direct relationship to increases in the airway pressures. METHODS: Twenty-eight adult obese patients (BMI ≥30 kg/m2) scheduled for elective laparoscopic gynecologic procedures were enrolled. All patients received general anesthesia utilizing endotracheal tubes with low-pressure high-volume cuffs. After baseline adjustment of the cuff pressure to 25 cm H2O, the airway pressures and endotracheal cuff pressures were continuously measured using pressure transducers connected to the anesthesia circuit and cuff pilot, respectively. Data on cuff and airway pressures, mechanical ventilation parameters, intraabdominal pressures, and degree of surgical table inclination were collected throughout the anesthetic procedure. General linear regression models with fixed and random effects were fit to assess the effect of increases in airway pressures on cuff pressure, after adjusting for covariates and the clustered structure of the data. RESULTS: The mean (standard deviation) age and body mass index were 42.2 (8.8) years and 37.7 (5.1) kg/m2, respectively. After tracheal intubation, the cuffs were overinflated (ie, intracuff pressures >30 cm H2O) in 89% of patients. The cuff pressures significantly changed after concomitant variations in the airway pressures from a mean (standard error) value of 29.6 (1.30) cm H2O before peritoneal insufflations, to 35.6 (0.68) cm H2O after peritoneal insufflation, and to 27.8 (0.79) cm H2O after peritoneal deflation (P
http://ift.tt/2iyyrOD
http://ift.tt/2iyyrOD
Epidural Space Identification With Loss of Resistance Technique for Epidural Analgesia During Labor: A Randomized Controlled Study Using Air or Saline—New Arguments for an Old Controversy
BACKGROUND: The best technique to identify the epidural space for labor analgesia is still unclear despite the publication of various randomized controlled studies and meta-analyses. Our aim was to assess the superiority of the saline loss of resistance (SLOR) technique over the air loss of resistance (ALOR) technique with respect to the quality of the block. METHODS: Consenting parturients admitted to our obstetric suite for spontaneous or induced labor were randomized to receive epidural analgesia using either the ALOR or SLOR technique. Our primary outcome was to compare the impact of the SLOR and ALOR technique on pain score improvement measured 30 minutes after administration of epidural block. Our secondary outcomes included the density of motor blockade and analgesic efficacy measured at 30 minutes. Primary and secondary outcomes were compared using the Student t test and Mann-Whitney U test. Statistical significance was set at P
http://ift.tt/2AVcP5v
http://ift.tt/2AVcP5v
Patients initial steps to cancer diagnosis in Denmark, England and Sweden: what can a qualitative, cross-country comparison of narrative interviews tell us about potentially modifiable factors?
Objectives
To illuminate patterns observed in International Cancer Benchmarking Programme studies by extending understanding of the various influences on presentation and referral with cancer symptoms.
DesignCross-country comparison of Denmark, England and Sweden with qualitative analysis of in-depth interview accounts of the prediagnostic process in lung or bowel cancer.
Participants155 women and men, aged between 35 and 86 years old, diagnosed with lung or bowel cancer in 6 months before interview.
SettingParticipants recruited through primary and secondary care, social media and word of mouth. Interviews collected by social scientists or nurse researchers during 2015, mainly in participants' homes.
ResultsParticipants reported difficulties in interpreting diffuse bodily sensations and symptoms and deciding when to consult. There were examples of swift referrals by primary care professionals in all three countries. In all countries, participants described difficulty deciding if and when to consult, highlighting concerns about access to general practitioner appointments and overstretched primary care services, although this appears less prominent in the Swedish data. It was not unusual for there to be more than one consultation before referral and we noted two distinct patterns of repeated consultation: (1) situations where the participant left the primary care consultation with a plan of action about what should happen next; (2) participants were unclear about under which conditions to return to the doctors. This second pattern sometimes extended over many weeks during which patients described uncertainty, and sometimes frustration, about if and when they should return and whether there were any other feasible investigations. The latter pattern appeared more evident in the interviews in England and Denmark than Sweden.
ConclusionWe suggest that if clear action plans, as part of safety netting, were routinely used in primary care consultations then uncertainty, false reassurance and the inefficiency and distress of multiple consultations could be reduced.
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Establishment of an Extracellular Acidic pH Culture System
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Surgical Training for the Implantation of Neocortical Microelectrode Arrays Using a Formaldehyde-fixed Human Cadaver Model
We designed a procedure in which a formaldehyde-fixed human cadaver is used to assist neurosurgeons in training for the implantation of microelectrode arrays into the neocortex of the human brain.
http://ift.tt/2zOkCp3
Impaired permeability and antimicrobial barriers in type 2 diabetes skin are linked to increased serum levels of advanced glycation end-product
Abstract
Background
The incidence of type 2 diabetes mellitus (DM) has been increasing rapidly, and the disease has become a serious sociomedical problem. Many skin problems, such as xerosis, pruritus, skin infections, and delayed wound healing, that might be related to chronic impairment of skin barrier function decrease the quality of life in DM patients. However, the status of the permeability and antimicrobial barrier of the skin in DM remains unknown.
Objective
This study aimed to elucidate skin barrier impairment in type 2 DM patients and its patho-mechanisms using classic animal models of type 2 DM.
Methods
Functional studies of the skin barrier and an analysis of stratum corneum (SC) lipids were compared between type 2 DM patients and age- and sex-matched non-diabetes controls. Also, functional studies on the skin barrier, epidermal lipid analyses, and electron microscopy and bio-molecular studies were performed using type 2 DM animal models, db/db and ob/ob mice.
Results
Type 2 DM patients presented with epidermal barrier impairments, including SC hydration, which was influenced by blood glucose control (HbA1c level). In the lipid analysis of SC, ceramides, fatty acids, and cholesterol were significantly decreased in type 2 DM patients compared with controls. Type 2 DM murine models presented with severe hyperglycemia, impairment of skin barrier homeostasis, decreases in epidermal proliferation and epidermal lipid synthesis, decreases in lamellar body (LB) and epidermal anti-microbial peptides (AMPs), an increase in receptors for advanced glycation end-product (AGE) in the epidermis, and an increase in serum AGE.
Conclusion
Impairment of the skin barrier was observed in type 2 DM, which results in part from a decrease in epidermal proliferation. Serum AGE and its epidermal receptors were increased in type 2 diabetic mice which display impaired skin barrier parameters such as epidermal lipid synthesis, LB production, epidermal AMP, and SC lipids.
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Modulation of Immune Function in Rats Using Oligosaccharides Extracted from Palm Kernel Cake
To investigate the prebiotic and immunomodulatory effects of PKC extract (OligoPKC) a total of 24 male rats were randomly assigned to three treatment groups receiving basal diet (control), basal diet containing 0.5% OligoPKC, or basal diet containing 1% OligoPKC for four weeks. We found that OligoPKC had no significant effect on the tested growth parameters. However, it increased the size of the total and beneficial bacterial populations while reducing pathogen populations. OligoPKC increased the concentration of immunoglobulins in the serum and cecal contents of rats. It also enhanced the antioxidant capacity of the liver while reducing lipid peroxidation in liver tissue. OligoPKC affected the expression of genes involved in immune system function in the intestine. Therefore, OligoPKC could be considered a potential mannan-based prebiotic for humans and animals due to its beneficial effects on the health and well-being of the model rats.
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ASCT2 defined by enzyme-mediated activation of radical sources enhances malignancy of GD2-plus small cell lung cancer
Abstract
Ganglioside GD2 is specifically expressed in small cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we performed enzyme-mediated activation of radical sources combined with mass spectrometry in GD2 positive (+) SCLC cells. Consequently, we identified ASC amino-acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid-enriched microdomain/rafts in GD2(+) SCLC cells, and co-localized with GD2 in proximity ligation assay and immunocytostaining, and bound with GD2 in immuneoprecipitation/TLC-immunostaining. Malignant phenotypes of GD2(+) SCLC cells were enhanced via glutamine uptake, and were suppressed by L-γ-glutamyl-p-nitroanilide, a specific inhibitor of ASCT2, via reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in GEM/rafts in GD2(+) SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of mTORC1 signaling axis.
This article is protected by copyright. All rights reserved.
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Detection of CTCs in cervical cancer using a conditionally replicative adenovirus targeting telomerase-positive cells
Abstract
Circulating tumor cells (CTCs) are newly discovered biomarkers of cancers. Although many systems detect CTCs, a gold standard has not yet been established. We analyzed CTCs in uterine cervical cancer patients using an advanced version of conditionally replicative adenovirus targeting telomerase-positive cells, which was enabled to infect coxsackievirus-adenovirus receptor-negative cells and to reduce false-positive signals in myeloid cells. Blood samples from cervical cancer patients were hemolyzed and infected with the virus and then labeled with fluorescent anti-CD45 and anti-pan cytokeratin antibodies. GFP (+)/CD45 (−) cells were isolated and subjected to whole-genome amplification followed by polymerase chain reaction analysis of human papillomavirus (HPV) DNA. CTCs were detected in 6 of 23 patients with cervical cancers (26.0%). The expression of CTCs did not correlate with the stage of cancer or other clinicopathological factors. In 5 of the 6 CTC-positive cases, the same subtype of HPV DNA as that of the corresponding primary lesion was detected, indicating that the CTCs originated from HPV-infected cancer cells. These CTCs were all negative for cytokeratins. The CTCs detected by our system were genetically confirmed. CTCs derived from uterine cervical cancers had lost epithelial characteristics, indicating that epithelial marker-dependent systems do not have the capacity to detect these cells in cervical cancer patients.
This article is protected by copyright. All rights reserved.
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Clinical significance of disease-specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma
Abstract
Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. On the other hand, mutational analyses using cell-free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell-free DNA from PCNSL patients, we performed droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in consecutive 14 PCNSL patients from whom paired tumor-derived DNA and cell-free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor-derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell-free DNAs evaluated by ddPCR (14/14) and TDS (13/14), MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell-free DNAs was traced in five patients; unexpectedly, the mutations disappeared after the chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell-free DNA and could be used as non-invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.
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The Prognostic Value of HRAS mRNA Expression in Cutaneous Melanoma
This study aimed to investigate the prognostic value of HRAS mRNA expression in cutaneous melanoma. Cutaneous melanoma is an aggressive cancer with an increasing incidence. Few studies have focused on the transcriptional level of RAS isoforms (KRAS, NRAS, and HRAS) in cutaneous melanoma. To gain further insight into RAS isoforms at transcriptional level, we obtained the cutaneous melanoma data from cBioPortal and investigated the RAS mRNA expression levels in different stages of melanoma and evaluated their correlation with clinical characteristics and patients' survival. Furthermore, we retrieved and analyzed the coexpression data and performed pathway enrichment analysis. Totally, 452 cutaneous melanoma cases were included in this study. We found that lower HRAS expression level was associated with longer patient survival. 206 genes that negatively correlated with HRAS expression were positively correlated with KRAS and NRAS expression. In contrast, no gene that positively correlated with HRAS expression was positively correlated with KRAS and NRAS expression. In conclusion, our data showed that transcriptional regulation was different for the three RAS isoforms in cutaneous melanoma. This study highlighted the prognostic value of HRAS mRNA expression and revealed that HRAS greatly differs from KRAS and NRAS at the transcriptional level.
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Influence of Restorative Materials on Color of Implant-Supported Single Crowns in Esthetic Zone: A Spectrophotometric Evaluation
Restorations of 98 implant-supported single crowns in anterior maxillary area were divided into 5 groups: zirconia abutment, titanium abutment, and gold/gold hue abutment with zirconia coping, respectively, and titanium abutment with metal coping as well as gold/gold hue abutment with metal coping. A reflectance spectrophotometer was used to evaluate the color difference between the implant crowns and contralateral/neighboring teeth, as well as the color difference between the peri-implant soft tissue and the natural marginal mucosa. The mucosal discoloration score was used for subjective evaluation of the esthetic outcome of soft tissue around implant-supported single crowns in the anterior zone, and the crown color match score was used for subjective evaluation of the esthetic outcome of implant-supported restoration. ANOVA analysis was used to compare the differences among groups and Spearman correlation was used to test the relationships. A gold/gold hue abutment with zirconia coping was the best choice for an esthetic crown and the all-ceramic combination was the best for peri-implant soft tissue. Significant correlation was found between the spectrophotometric color difference of peri-implant soft tissue and mucosal discoloration score, while no significant correlation was found between the total spectrophotometric color difference of implant crown and crown color match score.
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Area PEc Neurons Use a Multiphasic Pattern of Activity to Signal the Spatial Properties of Optic Flow
The cortical representation of visual perception requires the integration of several-signal processing distributed across many cortical areas, but the neural substrates of such perception are largely unknown. The type of firing pattern exhibited by single neurons is an important indicator of dynamic circuitry within or across cortical areas. Neurons in area PEc are involved in the spatial mapping of the visual field; thus, we sought to analyze the firing pattern of activity of PEc optic flow neurons to shed some light on the cortical processing of visual signals. We quantified the firing activity of 152 optic flow neurons using a spline interpolation function, which allowed determining onset, end, and latency of each neuronal response. We found that many PEc neurons showed multiphasic activity, which is strictly related to the position of the eye and to the position of the focus of expansion (FOE) of the flow field. PEc neurons showed a multiphasic activity comprised of excitatory phases interspersed with inhibitory pauses. This phasic pattern seems to be a very efficient way to signal the spatial location of visual stimuli, given that the same neuron sends different firing patterns according to a specific combination of FOE/eye position.
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A Novel Methicillin-Resistant Staphylococcus aureus t11469 and a Poultry Endemic Strain t002 (ST5) Are Present in Chicken in Ebonyi State, Nigeria
Background. The changing epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) from a hospital-associated pathogen to an organism commonly found in the community and in livestock reflects an organism well-equipped to survive in diverse environments and adjust to different environmental conditions including antimicrobial use. Methods. We investigated the molecular epidemiology of S. aureus and MRSA in poultry in Ebonyi State, Nigeria. Samples were collected from 1800 birds on 9 different farms within the state. Positive isolates were tested for antibiotic susceptibility and molecular typing. Results. Prevalence in birds was 13.7% (247/1800). MRSA prevalence in poultry was 0.8%. The prevalence of MRSA in broilers and layers was 1.2% and 0.4%, respectively. All tested isolates were susceptible to vancomycin. Molecular analysis of the isolates revealed 3 spa types: t002, t084, and a novel spa type, t11469. The novel spa type t11469 belonged to sequence type ST5. Conclusion. The detection of t002 in chicken suggests the presence of livestock-associated MRSA in poultry in Ebonyi State. The detection of the new spa type t11469 in poultry that has not been characterised to ascertain its pathogenic potential remains a cause for concern, especially as some were found to carry PVL genes, a putative virulence factor in staphylococcal infection.
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Preparation of P3HB4HB/(Gelatin + PVA) Composite Scaffolds by Coaxial Electrospinning and Its Biocompatibility Evaluation
This study was conducted to prepare coaxial electrospun scaffolds of P3HB4HB/(gelatin + PVA) with various concentration ratios with P3HB4HB as the core solution and gelatin + PVA mixture as the shell solution; the mass ratios of gelatin and PVA in each 10 mL shell mixture were 0.6 g : 0.2 g (Group A), 0.4 g : 0.4 g (Group B), and 0.2 g : 0.6 g (Group C). The results showed that the pore size, porosity, and cell proliferation rate of Group C were better than those of Groups A and B. The ascending order of the tensile strength and modulus of elasticity was Group A Group B > Group A. The osteogenic and chondrogenic-specific staining showed that Group C was stronger than Groups A and B. This study demonstrates that when the mass ratio of gelatin : PVA was 0.2 g : 0.6 g, a P3HB4HB/(gelatin + PVA) composite scaffold with a core-shell structure can be prepared, and the scaffold has good biocompatibility that it may be an ideal scaffold for tissue engineering.
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Biomechanical Effects of Posterior Condylar Offset and Posterior Tibial Slope on Quadriceps Force and Joint Contact Forces in Posterior-Stabilized Total Knee Arthroplasty
This study aimed to determine the biomechanical effect of the posterior condylar offset (PCO) and posterior tibial slope (PTS) in posterior-stabilized (PS) fixed-bearing total knee arthroplasty (TKA). We developed ±1, ±2, and ±3 mm PCO models in the posterior direction and −3°, 0°, 3°, and 6° PTS models using a previously validated FE model. The influence of changes in the PCO and PTS on the biomechanical effects under deep-knee-bend loading was investigated. The contact stress on the PE insert increased by 14% and decreased by 7% on average as the PCO increased and decreased, respectively, compared to the neutral position. In addition, the contact stress on post in PE insert increased by 18% on average as PTS increased from −3° to 6°. However, the contact stress on the patellar button decreased by 11% on average as PTS increased from −3° to 6° in all different PCO cases. The quadriceps force decreased by 14% as PTS increased from −3° to 6° in all PCO models. The same trend was found in patellar tendon force. Changes in PCO had adverse biomechanical effects whereas PTS increase had positive biomechanical effects. However, excessive PTS should be avoided to prevent knee instability and subsequent failure.
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Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer
New England Journal of Medicine, Ahead of Print.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
