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Τρίτη 16 Μαΐου 2017

Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies

Aims

To investigate the safety of fluoxetine use during pregnancy, and to better understand the relationship between maternal fluoxetine use during the first trimester and congenital malformations in infants.

Methods

PubMed and Web of Science databases were systematically searched from inception to 21 March 2016. Additional studies were identified in a manual search of the reference lists. Two reviewers independently extracted data. A third reviewer checked the data. Estimates were pooled using a random-effects model to calculate the summarized relative ratios (RR) and 95% confidence intervals (CI).

Results

Among 1918 initially identified articles, 16 cohort studies were included. The offspring of pregnant women exposed to fluoxetine during the first trimester had a statistically increased risk of major malformations (RR = 1.18, 95% CI = 1.08−1.29), cardiovascular malformations (RR = 1.36, 95%CI = 1.17−1.59), septal defects (RR = 1.38, 95% CI = 1.19−1.61), and non-septal defects (RR = 1.39, 95% CI = 1.12-1.73) with low heterogeneity in infants. There were no significant observations of other system-specific malformations in the nervous system, eye, urogenital system, digestive system, respiratory system, or musculoskeletal system, respectively. There was no indication of publication bias.

Conclusions

The results of this meta-analysis indicate maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with fluoxetine during pregnancy.



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Peptide-Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite-Mediated Nitration

Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half-life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio-inspired peptide-based NO sensor is developed, which detects NO-derived oxidants, predominately peroxynitrite-mediated nitration of tyrosine residues. It is demonstrated that these peptide-based NO sensors can detect peroxynitrite-mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide-conjugated fluorescent particle immunoassay, peroxynitrite-mediated nitration activity with a detection limit of ≈100 × 10−9m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell-based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.

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Peptide-conjugated fluorescent particles are developed as biosensors to detect nitric oxide (NO) based on 3-nitrotyrosine labelling. The biosensors successfully detect NO release from endothelial cells under shear stress with a sensitivity exceeding that of standard assays. The biosensors provide an integrated measure of NO in the vicinity of the fluorescent particle, thereby allowing spatiotemporal localization of NO production within biological systems.



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Fostering Motivation Could Help Keep Marginalized Girls in School

Education — and girls' education in particular — is often cited as one of the key pathways out of poverty, but in many parts of the world women and girls still face significant barriers that prevent them from attending school. Now, a field study in Malawi reveals psychological factors played an important role in whether girls attended school, even under conditions of extreme poverty and deprivation: Girls were significantly more likely to attend class when they were intrinsically excited about school and learning, even when they struggled with a lack of basic resources at home.

The findings are published in Psychological Science, a journal of the Association for Psychological Science.

"We are prone to think that giving girls a reward for going to school will increase their motivation. Instead, our results indicate that stimulating their intrinsic joy of learning is a stronger predictor of their actual school going behavior, even under conditions of severe poverty," says researcher Marieke van Egmond of the University of Hagen in Germany, lead author on the study.

Even though a significant part of the global population lives under conditions of poverty, empirical psychological research with people living in poverty around the world is rare. Studies like this one are vital to determining whether theories and findings obtained in Western, industrialized settings hold for people who are exposed to very different life circumstances.

"In general, girls really want to go to school, enjoy learning, and go to great lengths to do so. In psychological terms, they are intrinsically motivated," van Egmond explained. "Poverty and social dynamics, however, work against them. Cultural beliefs and attitudes reinforce the idea that girls won't use their education or that they are not smart enough to continue with school. In other words, they don't feel like they belong in school, they don't feel competent and lack power."

To better understand the psychological factors that can help marginalized girls stay in school, van Egmond teamed up with the international development non-profit Theatre for a Change (TfaC) and researchers from One South to conduct a field study. TfaC's program focuses on empowering marginalized girls through school-based girls clubs.

Study participants included 642 girls and young women between the ages of 10 and 22 years old living in rural Malawi, a landlocked country in southeastern Africa that ranks 170 out of 188 on the United Nation's 2016 Human Development Index. Participants were randomly selected from girls attending schools in Theatre for a Change school programs.

Interviews for the study were conducted by a specially trained team of 24 bilingual (English and Chichewa) female interviewers. The interviewers surveyed the girls about their intrinsic and extrinsic motivations for attending school, their health, and how frequently they didn't get enough to eat, didn't have enough clean water, lacked medicine or medical treatment, or lacked any cash income.

The researchers measured school attendance by looking at the number of days that girls had attended school over the month of February 2015.

School attendance was significantly higher among girls who were intrinsically motivated to attend school – those who said they enjoyed school and learning for its own sake – regardless of the level of resource scarcity that the girls were exposed to. Extrinsic motivation – that is, going to school because it is expected or normative — did not predict school attendance.

The results suggest that interventions that target aspects of intrinsic motivation, such as a sense of competence and autonomy, may be as effective as economic approaches in achieving behavioral change, as long as fundamental structural barriers (such as access to pens and paper) are overcome.

"The take home message is that development projects that aim to increase the school attendance of girls in impoverished settings need to not only aim for female empowerment, but for creating environments in which girls feel that they belong and feel able to learn as well," van Egmond says. "This will stimulate the girls' intrinsic motivation to go to school, which is a strong predictor of their actual attendance."

Such interventions could ultimately lead to wide-ranging benefits, as research suggests that attending school provides lifelong health and economic advantages to women and girls, including higher incomes, better health care, and better education for ensuing generations. Yet, according to the UNESCO Institute of Statistics, there are 33 million fewer girls than boys in primary schools worldwide.

Van Egmond and colleagues plan on extending this research to other countries in the sub-Saharan region in order to see if the patterns observed hold in different cultural contexts.   

Co-authors on the research include Andrés Navarrete Berges and Tariq Omarshah of One South and Jennifer Benton of Theatre for a Change.

Theatre for a Change Malawi received funding from the U.K. Department for International Development. The current project was funded within the framework of the Girls Education Challenge (Reference No. 8329).

All materials have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Materials.



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A Single-Molecular AND Gate Operated with Two Orthogonal Switching Mechanisms

Single-molecular electronics is a potential solution to nanoscale electronic devices. While simple functional single-molecule devices such as diodes, switches, and wires are well studied, complex single-molecular systems with multiple functional units are rarely investigated. Here, a single-molecule AND logic gate is constructed from a proton-switchable edge-on gated pyridinoparacyclophane unit with a light-switchable diarylethene unit. The AND gate can be controlled orthogonally by light and protonation and produce desired electrical output at room temperature. The AND gate shows high conductivity when treated with UV light and in the neutral state, and low conductivity when treated either with visible light or acid. A conductance difference of 7.3 is observed for the switching from the highest conducting state to second-highest conducting state and a conductance ratio of 94 is observed between the most and least conducting states. The orthogonality of the two stimuli is further demonstrated by UV–vis, NMR, and density function theory calculations. This is a demonstration of concept of constructing a complex single-molecule electronic device from two coupled functional units.

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A single-molecule AND gate is constructed from two different switching mechanisms, the switch between conjugation to cross-conjugation by light and the shift of conducting orbitals by protonation. The two switches are orthogonal and can be switched reversibly. The switching ratio between the highest and lowest conductance states is 94.



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Potential of UVC germicidal irradiation in suppressing crown rot disease, retaining postharvest quality and antioxidant capacity of Musa AAA “Berangan” during fruit ripening

Abstract

Crown rot caused by fungal pathogen is the most prevalent postharvest disease in banana fruit that results significant economic losses during transportation, storage, and ripening period. Antifungal effects of ultraviolet C (UVC) irradiation at doses varied from 0.01 to 0.30 kJ m−2 were investigated in controlling postharvest crown rot disease, maintenance of fruit quality, and the effects on antioxidant capacity of Berangan banana fruit during ripening days at 25 ± 2°C and 85% RH. Fruits irradiated with 0.30 kJ m−2 exhibited the highest (i.e., 62.51%) reduction in disease severity. However, the application of UVC at all doses caused significant browning damages on fruit peel except the dose of 0.01 kJ m−2. This dose synergistically reduced 46.25% development of postharvest crown and did not give adverse effects on respiration rate, ethylene production, weight loss, firmness, color changes, soluble solids concentration, titratable acidity, and pH in banana as compared to the other treatments and control. Meanwhile, the dose also enhanced a significant higher level of total phenolic content, FRAP, and DPPH values than in control fruits indicating the beneficial impact of UVC in fruit nutritional quality. The results of scanning electron micrographs confirmed that UVC irradiation retarded the losses of wall compartments, thereby maintained the cell wall integrity in the crown tissue of banana fruit. The results suggest that using 0.01 kJ m−2 UVC irradiation dose as postharvest physical treatment, the crown rot disease has potential to be controlled effectively together with maintaining quality and antioxidant of banana fruit.

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UVC irradiation at 0.01 kJ m−2 could be considered as the optimum dose for Berangan banana, which effectively reduced disease severity without causing browning on the fruit peel.



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Cutaneous reflex modulation during obstacle avoidance under conditions of normal and degraded visual input

Abstract

The nervous system integrates visual input regarding obstacles with limb-based sensory feedback to allow an individual to safely negotiate the environment. This latter source can include cutaneous information from the foot, particularly in the event that limb trajectory is not sufficient and there is an unintended collision with the object. However, it is not clear the extent to which cutaneous reflexes are modified based on visual input. In this study, we first determined if phase-dependent modulation of these reflexes is present when stepping over an obstacle during overground walking. We then tested the hypothesis that degrading the quality of visual feedback alters cutaneous reflex amplitude in this task. Subjects walked and stepped over an obstacle—leading with their right foot—while we electrically stimulated the right superficial peroneal nerve at the level of the ankle at different phases. Subjects performed this task with normal vision and with degraded vision. We found that the amplitude of cutaneous reflexes varied based on the phase of stepping over the obstacle in all leg muscles tested. With degraded visual feedback, regardless of phase, we found larger facilitation of cutaneous reflexes in the ipsilateral biceps femoris—a muscle responsible for flexing the knee to avoid the obstacle. Although degrading vision caused minor changes in several other muscles, none of these differences reached the level of significance. Nonetheless, our results suggest that visual feedback plays a role in altering how the nervous system uses other sensory input in a muscle-specific manner to ensure safe obstacle clearance.



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The role of the prefrontal cortex in freezing of gait in Parkinson’s disease: insights from a deep repetitive transcranial magnetic stimulation exploratory study

Abstract

Freezing of Gait (FOG) is one of the most debilitating gait impairments in Parkinson's disease (PD), leading to increased fall risk and reduced health-related quality of life. The utility of parkinsonian medications is often limited in the case of FOG and it frequently becomes dopamine resistant. Recent studies have suggested that pre-frontal cortex (PFC) dysfunction contributes to FOG; however, most previous findings provide only indirect evidence. To better understand the role of the PFC, we aimed to investigate the impact of high frequency, deep, repetitive transcranial magnetic stimulation (drTMS) of the medial PFC on FOG and its mediators. Nine patients with advanced PD participated in a randomized, cross-over exploratory study. We applied drTMS over the medial PFC for 16 weeks, with real and sham conditions; each condition included an intensive (i.e., 3 times a week) phase and a maintenance (once a week) phase. Scores on a FOG-provoking test, the motor part of the Unified Parkinson's Disease Rating Scale, and gait variability significantly improved after real drTMS, but not after the sham condition. Self-report of FOG severity and cognitive scores did not improve. Due to discomfort and pain during treatment, two patients dropped out and the study was halted. These initial findings support the cause-and-effect role of the pre-frontal cortex in FOG among patients with PD. Due to the small sample size, findings should be interpreted cautiously. Further studies are needed to more fully assess the role of the medial PFC in the underlying mechanism of FOG and the possibility of using non-invasive brain stimulation to modify FOG.



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Memory-guided force control in healthy younger and older adults

Abstract

Successful performance of a memory-guided motor task requires participants to store and then recall an accurate representation of the motor goal. Further, participants must monitor motor output to make adjustments in the absence of visual feedback. The goal of this study was to examine memory-guided grip force in healthy younger and older adults and compare it to performance on behavioral tasks of working memory. Previous work demonstrates that healthy adults decrease force output as a function of time when visual feedback is not available. We hypothesized that older adults would decrease force output at a faster rate than younger adults, due to age-related deficits in working memory. Two groups of participants, younger adults (YA: N = 32, mean age 21.5 years) and older adults (OA: N = 33, mean age 69.3 years), completed four 20-s trials of isometric force with their index finger and thumb, equal to 25% of their maximum voluntary contraction. In the full-vision condition, visual feedback was available for the duration of the trial. In the no vision condition, visual feedback was removed for the last 12 s of each trial. Participants were asked to maintain constant force output in the absence of visual feedback. Participants also completed tasks of word recall and recognition and visuospatial working memory. Counter to our predictions, when visual feedback was removed, younger adults decreased force at a faster rate compared to older adults and the rate of decay was not associated with behavioral performance on tests of working memory.



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Free and total plasma concentrations of elvitegravir/cobicistat during pregnancy and postpartum: a case report



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Tumescent anaesthesia: its applications and well tolerated use in the out-of-operating room setting.

Purpose of review: Tumescent anaesthesia is a method of administering dilute local anaesthetic into the subcutaneous tissue. Many anaesthesiologists are unfamiliar with the technique, its applications and potential risks. Recent findings: The maximum safe dose of lidocaine with epinephrine in tumescent anaesthesia for liposuction is probably between 35 and 55 mg/kg. Without liposuction, the maximum dose of lidocaine with epinephrine should be no more than 28 mg/kg. After tumescent infiltration for liposuction, serum lidocaine concentrations peak between 12 and 16 h after injection. When tumescent lidocaine without epinephrine is used for endovenous laser therapy, peak serum lidocaine concentrations are observed much earlier, between 1 and 2 h after injection. Slow administration of more dilute concentrations of local anaesthetic decreases the risk of local anaesthetic systemic toxicity. Summary: Although appealing because of its ability to provide prolonged analgesia, high doses of local anaesthetic are frequently administered using the tumescent technique, and absorption of local anaesthetic from the subcutaneous tissue is variable. When caring for patients having procedures in which tumescent anaesthesia is used, the risk of local anaesthetic toxicity should be acknowledged and lipid emulsion should be available for prompt treatment if needed. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Defining a multimodal signature of remote sports concussions

Abstract

Sports-related concussions lead to persistent anomalies of the brain structure and function that interact with the effects of normal ageing. Although post-mortem investigations have proposed a bio-signature of remote concussions, there is still no clear in vivo signature. In the current study, we characterized white matter integrity in retired athletes with a history of remote concussions by conducting a full-brain, diffusion-based connectivity analysis. Next, we combined MRI diffusion markers with MR spectroscopic, MRI volumetric, neurobehavioral and genetic markers to identify a multidimensional in vivo signature of remote concussions. Machine learning classifiers trained to detect remote concussions using this signature achieved detection accuracies up to 90% (sensitivity: 93%, specificity: 87%). These automated classifiers identified white matter integrity as the hallmark of remote concussions and could provide, following further validation, a preliminary unbiased detection tool to help medical and legal experts rule out concussion history in patients presenting or complaining about late-life abnormal cognitive decline.

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By combining biomarkers from cognitive, genetic, white matter and grey matter assessments, we can develop an objective diagnostic tool for a history of sports concussions. White matter integrity emerges as the hallmark of remote concussions.



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Sedation for advanced procedures in the bronchoscopy suite: proceduralist or anesthesiologist?.

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Purpose of review: This article focuses on the issue of sedation provided either by proceduralists or anesthesiologists for advanced bronchoscopy procedures. The relative merits of both approaches are presented. Current evidence from the literature and guideline recommendations relevant to this topic are reviewed. Recent findings: In general, patient and proceduralist satisfaction as well as patient safety are increased when intravenous sedation is provided for advanced bronchoscopic procedures. However, guidelines by various societies remain vague on defining the appropriate level of care required when providing sedation for these procedures. In addition, targeted depth of sedation varies considerably among practitioners. While in some settings, nonanesthesiologist-administered propofol sedation has been proven safe; nevertheless, its use is controversial, especially in the bronchoscopy suite. Summary: The role of the anesthesiologist in sedation for advanced bronchoscopy remains undefined. When deep sedation for prolonged interventional procedures is needed or when dealing with patients who have multiple comorbidities, an anesthesiologist should be involved. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Safety of deep sedation in the endoscopy suite.

Purpose of review: As the complexity of endoscopic procedures increases, the use of propofol and the desire for deep sedation are becoming more common in the endoscopy suite. This review explores sedation depth, agents used for sedation, recommended monitoring, and adverse event risks that occur during sedation for endoscopy. Recent findings: The sedation provider for endoscopy varies by practice location and with regulatory requirements. As increasingly deep levels of sedation are used in this setting, the need for all providers to have training in the ability to rescue patients from sedation-related side effects is paramount. Propofol has an important role for prolonged and uncomfortable endoscopic interventions and has a strong safety record in the endoscopy suite. Vital signs monitoring is recommended during all endoscopy sedation, and there is emerging interest in advanced monitoring (e.g., capnography, processed electroencephalogram, respiratory monitoring) in this setting. The reported rate of adverse events during endoscopy sedation varies widely; however, advanced age and increasing American Society of Anesthesiologists physical status score are consistently associated with increased risk. Whether anesthesiologist-administered sedation is safer than non-anesthesiologist-administered sedation remains controversial. Summary: This review provides some guidance to providers who administer sedation in the endoscopy suite and is intended to improve the safety of patients. The recommendations are based on best available evidence and expert opinion. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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The role of the anaesthesiologist in air ambulance medicine.

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Purpose of review: The care administered on air ambulances has become increasing complex. This has led to a discussion among experts as to whether air ambulance travel should be manned by physicians. This review provides evidence in support of anaesthesiologists being the physician-leaders in air ambulance medicine, because of their training in advanced airway management, critical care, and resuscitation. Recent findings: Successful prehospital care requires the ability to perform a complex set of advanced diagnostics and interventions. These include airway management, haemorrhage control, pain management, point-of-care diagnostics, complex interfacility transport, and advanced interventions. This skill set closely mirrors the training and expertise of anaesthesiologists. Summary: There are few studies investigating the specific benefit of anaesthesiologists in air ambulance medicine. However, current evidence indicates that their presence does improve patient care and safety. Future studies on this topic should use evidence-based quality indicators and standardized data sets to seek answers to optimal staffing of air ambulance teams. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Perioperative management of antithrombotic therapies.

Purpose of review: Perioperative coagulation management is becoming increasingly frequent in the daily routine of the anesthesiologist and with the plethora of new substances on the market also increasingly complex. The perioperative setting poses unique challenges requiring an individualized evaluation and management of antithrombotic therapy. This review shall summarize the newest developments in this domain. Recent findings: New data in patients with atrial fibrillation have led to a paradigm change in the perioperative management of antithrombotics. The role of bridging therapy has been downgraded in the guidelines, which only foresee bridging in patients with high thromboembolic risk. Furthermore, direct oral anticoagulants are now a cornerstone in antithrombotic therapy, calling for specific perioperative management. The new reversal agents idarucizumab, and potentially in the future andexanet alfa and ciraparantag, will play an increasingly important role in the treatment of major bleeding in this group of patients. Summary: With the new evidence and treatment options available, perioperative coagulation management is experiencing a Renaissance, opening many interesting new doors, but also presenting the clinician with new challenges. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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A preliminary investigation on the utility of temporal features of Force Myography in the two-class problem of grasp vs. no-grasp in the presence of upper-extremity movements

In upper-extremity stroke rehabilitation applications, the potential use of Force Myography (FMG) for detecting grasping is especially relevant, as the presence of grasping may be indicative of functional acti...

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Global Kalman filter approaches to estimate absolute angles of lower limb segments

In this paper we propose the use of global Kalman filters (KFs) to estimate absolute angles of lower limb segments. Standard approaches adopt KFs to improve the performance of inertial sensors based on individ...

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Mouse mammary tumour virus (MMTV) and human breast cancer with neuroendocrine differentiation

Abstract

Background

Mouse mammary tumour viruses (MMTVs) may have a role in a subset of human breast cancers. MMTV positive human breast cancers have similar histological characteristics to neuroendocrine breast cancers and to MMTV positive mouse mammary tumours. The purpose of this study was to investigate the expression of neuroendocrine biomarkers – synaptophysin and chromogranin, to determine if these histological characteristics and biomarker expression were due to the influences of MMTV.

Methods

Immunohistochemistry analyses to identify synaptophysin and chromogranin were conducted on a series of human breast cancers in which (i) MMTV had been previously identified and had similar histological characteristics to MMTV positive mouse mammary tumours and (ii) MMTV positive mouse mammary tumours.

Results

The expression of synaptophysin and chromogranin in MMTV positive mouse mammary tumors were all positive (7 of 7 specimens – 100% positive). The expression of synaptophysin and chromogranin in MMTV positive human breast cancers was much less prevalent (3 of 22 – 14%). There was no expression of synaptophysin and chromogranin in the normal breast tissue control specimens.

Discussion

It is not possible to draw any firm conclusions from these observations. However, despite the small numbers of MMTV positive mouse mammary tumours in this study, the universal expression in these specimens of synaptophysin and chromogranin proteins is striking. This pattern of synaptophysin and chromogranin expression is very different from their expression in MMTV positive human breast cancers. The reason for these differences is not known.

Conclusions

The high prevalence of positive expression of synaptophysin and chromogranin in MMTV positive mouse mammary tumours and low expression of synaptophysin and chromogranin in MMTV positive human breast cancers indicates that MMTV is not usually associated with neuroendocrine human breast cancers.



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Comparative Analysis of Tongue Indices between Patients with and without a Self-Reported Yin Deficiency: A Cross-Sectional Study

We investigated the hypothesis that Yin-deficient patients have a reddened tongue with less coating. We screened 189 participants aged 20 to 49 years, complaining of headache. To classify patients in terms of Yin deficiency, we used two self-reporting Yin-deficiency questionnaires (Yin-Deficiency Questionnaire and Yin-Deficiency Scale) and diagnosis by a doctor. Based on the tests, a total of 33 subjects were assigned to a Yin-deficient group and 33 subjects were assigned to a nondeficient control group. Tongue images were acquired using a computerized tongue diagnostic system, for evaluating tongue indices. The tongue coating percentage and tongue redness were calculated as the mean value of both the whole tongue area (WT ) and the tongue body area (TB ). The tongue coating percentage of the Yin-deficient group (34.79 ± 10.76) was lower than that of the nondeficient group (44.13 ± 14.08). The WT value of the Yin-deficient group (19.39 ± 1.52) was significantly higher than that of the nondeficient group (18.21 ± 2.06). However, the difference in the TB value between the two groups was not significant. In conclusion, we verified that Yin-deficient patients had less tongue coating and tended to have a more reddish tongue than nondeficient patients.

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Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Abstract

Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the CSF and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in MS.

Methods: sNfL levels were measured in healthy controls (HC, n=254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n=142); (2) longitudinal with repeated serum sampling (n=246, median (IQR) follow-up 3.1 (2.0-4.0) years). We assessed their relation to concurrent clinical, imaging and treatment parameters and to future clinical outcomes.

Results: sNfL levels were higher in both MS cohorts than in HC (p<0.001). We found a strong association between CSF NfL and sNfL (β=0.589, p<0.001). Patients with either brain or spinal (43.4 (25.2-65.3) pg/ml) or both brain and spinal gadolinium enhancing lesions (62.5 (42.7-71.4) pg/ml) had higher sNfL than those without (29.6 (20.9-41.8) pg/ml; β=1.461, p=0.005 and β=1.902, p=0.002 respectively). sNfL was independently associated with EDSS assessments (β=1.105, p<0.001) and presence of relapses (β=1.430, p<0.001). sNfL levels were lower under disease modifying treatment (β=0.818, p=0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th and 99th HC based percentiles had higher risk of relapses (97.5th percentile: IRR=1.94, 95%CI=1.21-3.10, p=0.006) and EDSS worsening (97.5th percentile: OR=2.41, 95%CI=1.07-5.42, p=0.034).

Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. This article is protected by copyright. All rights reserved.



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Oxidative Stress-Induced DNA Damage by Manganese Dioxide Nanoparticles in Human Neuronal Cells

Metal nanoparticles have been extensively used in industry as well as in biomedical application. In this work, we have evaluated the toxic potential of manganese dioxide (MnO2) nanoparticles (MNPs) on human neuronal (SH-SY5Y) cells. Cellular toxicity due to MNPs (0, 10, 30, and 60 μg/ml) on the SH-SY5Y cell was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake (NRU) tests. MNPs produced reactive oxygen species (ROS) and declined in mitochondrial membrane potential in the SH-SY5Y cell in dose and duration dependent manner. Moreover, lipid peroxide (LPO), superoxide dismutase (SOD), and catalase (CAT) activities were increased and glutathione was reduced in dose and time dependent manner. A significant upgrade in Hoechst 33342 fluorescence intensity (chromosome condensation) and phosphatidylserine translocation (apoptotic cell) was visualized in cells treated with MNPs for 48 h. On the other hand, caspase-3 activity was increased due to MNPs in SH-SY5Y cells. DNA strand breaks were determined by alkaline single cell gel electrophoresis assay (Comet Assay) and maximum fragmentation of DNA produced due to MNPs (60 μg/ml) for 48 hours. This result provides a basic mechanism of induction of apoptosis and toxicity by MNPs in SH-SY5Y cells.

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Medial sural artery perforator free flap for the reconstruction of leg, foot and ankle defect: an excellent option

Background

The defects over the leg, foot and ankle are best covered with a thin pliable flap. The use of muscle flap for the reconstruction of these defects leaves a grafted, aesthetically inferior result. The medial sural artery perforator (MSAP) free flap gives a thin pliable tissue for the reconstruction with better aesthesis.

Methods

The study design was retrospective case analysis over a period of 2 years. All the patients who underwent flap for leg, foot and ankle defect reconstruction in the form of MSAP free flap were included in the study. The flap characteristics and aesthesis were assessed along with the patient satisfaction. The flap complication and donor site morbidity were also analysed.

Results

A total of seven MSAP free flaps were done for leg, foot and ankle reconstruction. The mean flap size was 14.29 × 6.6 cm and mean pedicle length was 9.71 cm. One flap had venous congestion post-operatively resulting in marginal flap loss. All the flaps had acceptable aesthesis with good patient satisfaction. There was donor site morbidity in two patients, in the form of wound dehiscence.

Conclusion

MSAP free flap is a reliable choice for leg, foot and ankle defect reconstruction.



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Predict pancreatic fistula after pancreaticoduodenectomy: ratio body thickness/main duct

Background

The occurrence of post-operative pancreatic fistula (POPF) after pancreaticoduodenectomy is a challenging issue. The aim was to identify variables on preoperative computed tomography (CT) scan, useful to predict clinically significant POPF (grades B–C) after pancreaticoduodenectomy.

Methods

Patients presented POPF after pancreaticoduodenectomy were included from two tertiary referral centres. B/W ratio was defined by ratio of pancreas body thickness (B) to main pancreatic duct (W). The predictive parameters of POPF on CT scan were assessed with a receiving operator characteristics (ROC) curve and intrinsic characteristics.

Results

Between 2010 and 2013, 186 patients who underwent pancreaticoduodenectomy were included. POPF occurred in 25% of them, and was clinically significant in 13%. After univariate analysis, endocrine tumours (P = 0.03), main pancreatic duct size (P < 0.01) and B/W ratio (P = 0.04) were significantly associated with POPF. ROC curve showed a greater area under curve for B/W ratio (0.68) than for main pancreatic duct size (0.33). A 3.8 threshold displayed 80 and 51% for sensibility and specificity, respectively, and a negative predictive value of 94%. A B/W ratio >3.8 increased the rates of post-operative haemorrhage (odds ratio = 4.3 (1.4–13.2), P = 0.01), and reintervention (odds ratio = 3.4 (1.2–9.6), P = 0.02).

Conclusions

B/W ratio superior to 3.8 assessed on preoperative CT scan may be an easy tool to predict clinically significant POPF after pancreaticoduodenectomy.



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Dermatofibrosarcoma protuberans of the scalp: therapeutic challenges



http://ift.tt/2rp3e3d

Cholecystitis in situs inversus totalis



http://ift.tt/2qPnNsq

Extramedullary leukaemia presenting as cardiac myeloid sarcoma



http://ift.tt/2rp36AG

The Australian laparoscopic radical prostatectomy learning curve

Background

International estimates of the laparoscopic radical prostatectomy (LRP) learning curve extend to as many as 1000 cases, but is unknown for Fellowship-trained Australian surgeons.

Methods

Prospectively collected data from nine Australian surgeons who performed 2943 consecutive LRP cases was retrospectively reviewed. Their combined initial 100 cases (F100, n = 900) were compared to their second 100 cases (S100, n = 782) with two of nine surgeons completing fewer than 200 cases.

Results

The mean age (61.1 versus 61.1 years) and prostate specific antigen (7.4 versus 7.8 ng/mL) were similar between F100 and S100. D'Amico's high-, intermediate- and low-risk cases were 15, 59 and 26% for the F100 versus 20, 59 and 21% for the S100, respectively. Blood transfusions (2.4 versus 0.8%), mean blood loss (413 versus 378 mL), mean operating time (193 versus 163 min) and length of stay (2.7 versus 2.4 days) were all lower in the S100. Histopathology was organ confined (pT2) in 76% of F100 and 71% of S100. Positive surgical margin (PSM) rate was 18.4% in F100 versus 17.5% in the S100 (P = 0.62). F100 and S100 PSM rates by pathological stage were similar with pT2 PSM 12.2 versus 9.5% (P = 0.13), pT3a PSM 34.8 versus 40.5% (P = 0.29) and pT3b PSM 52.9 versus 36.4% (P = 0.14).

Conclusion

There was no significant improvement in PSM rate between F100 and S100 cases. Perioperative outcomes were acceptable in F100 and further improved with experience in S100. Mentoring can minimize the LRP learning curve, and it remains a valid minimally invasive surgical treatment for prostate cancer in Australia even in early practice.



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Mucinous non-neoplastic cyst of the pancreas: is surgical resection avoidable?



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Aortocoronary artery dissection: a partial aortic root remodelling, aortic valve repair and coronary artery bypass



http://ift.tt/2qPfzAG

Modern cardiac surgery: the future of cardiac surgery in Australia

Cardiac surgery is a relatively young specialty and is undergoing many changes presently. The advent of catheter-based technology, minimally invasive surgery and better information regarding the roles of cardiac surgery in the management of common cardiac disease is changing the way we provide services. In Australia, attention must be turned to the way cardiac surgical services are provided to enable delivery of modern procedures. This has implications for the provision of training. We explore the face of modern cardiac surgery and how this may be taken up in Australia.



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Subspecialty approach for the management of acute cholecystitis: an alternative to acute surgical unit model of care

Background

Acute cholecystitis is a common condition. Recent studies have shown an association between creation of an acute surgical unit (ASU) and improved outcomes. This study aimed to evaluate the outcomes of a subspecialty based approach to the management of acute cholecystitis as an alternative to the traditional 'generalist' general surgery approach or the ASU model.

Method

A 6-year retrospective analysis of outcomes in patients admitted under a dedicated upper gastrointestinal service for acute cholecystitis undergoing emergency laparoscopic cholecystectomy.

Results

Seven hundred emergency laparoscopic cholecystectomies were performed over this time. A total of 486 patients were available for analysis. The median time to operation was 2 days and median length of operation was 80 min. A total of 86.9% were performed during daylight hours. Eight cases were converted to open surgery (1.6%). Intra-operative cholangiography was performed in 408 patients. The major complication rate was 8.2%, including retained common bile duct stones (2.3%), sepsis (0.2%), post-operative bleeding (0.4%), readmission (0.6%), bile leak (2.1%), AMI (0.4%), unscheduled return to theatre (0.6%) and pneumonia (0.8%). There were no mortalities and no common bile duct injuries.

Conclusion

Over a time period that encompasses the current publications on the ASU model, a subspecialty model of care has shown consistent results that exceed established benchmarks. Subspecialty management of complex elective pathologies has become the norm in general surgery and this study generates the hypothesis that subspecialty management of patients with complex emergency pathologies should be considered a valid alternative to ASU. Access block to emergency theatres delays treatment and prolongs hospital stay.



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Tail gut cyst: an unusual case



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Patterns of head and neck sarcoma in Australia

Background

Sarcomas affecting the head and neck often require complex management due to the combination of anatomic, aesthetic and oncological considerations. The incidence and patterns of presentation are poorly understood and have not been reviewed in the Australian population.

Method

This study sourced incidence and demographic data from the National Cancer Registry at the Australian Institute of Health and Welfare for the years 1982–2009 (corresponding to 97.3% of the Australian population). All cases of sarcoma, according to ICD-O-3 classification ((International Classification of Diseases for Oncology, 3rd edition), were assessed.

Results

A total of 3911 new cases of sarcoma affecting the head and neck were recorded during the period 1982–2009, including 1383, 2106 and 442 cases arising from skin, soft tissue and bone, respectively. The annual incidence rate of sarcomas affecting the head and neck was 1.59 per 100 000 population. The incidence of head and neck sarcoma rose substantially in older age groups (age 65 years and above) and was most common in male patients (69%). Malignant fibrous histiocytoma (MFH) was the most common pathology. There was an increase in incidence in skin-origin sarcoma in the head and neck, particularly affecting elderly males.

Conclusion

The incidence of head and neck sarcoma in Australia is higher than that reported for an equivalent European population. The increase in MFH arising from the skin in elderly male patients mirrors the patterns of common cutaneous malignancy, particularly melanoma, suggesting that ultraviolet radiation is an epidemiological factor. Management of head and neck sarcoma is complex and best managed in a specialist multidisciplinary environment.



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Derivation and validation of the APPEND score: an acute appendicitis clinical prediction rule

Background

Although many clinical prediction rules (CPRs) for appendicitis exist, none have been developed for a New Zealand population presenting with right iliac fossa (RIF) pain. The aim of this study was to derive and validate an appendicitis CPR for our population.

Method

This is a retrospective review of all patients from December 2010 to February 2012 of at least 15 years of age presenting to the general surgery service with RIF pain. Patient data were divided into derivation and validation groups. Univariate and multiple regression analyses identified significant predictors of appendicitis which were used to construct a CPR. A retrospective validation study was then performed and the CPR was refined accordingly. Finally, the accuracy of the CPR was tested.

Results

The final components of the new CPR, the APPEND score, were Anorexia, migratory Pain, local Peritonism, Elevated C-reactive protein, Neutrophilia and male gender (Dude). This CPR has an area under the receiver operating characteristic curve of 0.84. The CPR can stratify patients into low, intermediate and high-risk groups which may standardize patient care and reduce the negative appendicectomy rate.

Conclusion

A new CPR for predicting appendicitis, in patients presenting with RIF pain, has been derived and validated for use in our population. A prospective study to further evaluate its performance is required.



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Influence of primary site on metastatic distribution and survival in stage IV colorectal cancer

Background

To assess pattern distribution and prognosis of the three anatomical entities of metastatic colorectal cancer, and influence of treatment of metastases on survival.

Methods

Patients presenting with stage IV colorectal cancer (synchronous group), or who developed metastatic recurrence (metachronous group) after initial curative treatment between January 2005 and August 2015 were reviewed. Right sided (cecum to transverse colon), left sided (splenic flexure to sigmoid colon) and rectal cancers were identified. Distribution of metastases were noted as hepatic, lung or peritoneal.

Results

Of 374 patients, 276 were synchronous, 98 were metachronous. Metachronous group had a better 3-year survival (54%, 95% CI: 42–64 versus 33%, 95% CI: 27–39, log rank P = 0.0038). There were equal numbers of right (n = 119), left (n = 115) and rectal cancers (n = 140). Rectal cancers had a higher metastatic recurrence, yet demonstrated better 3-year survival (right colon 45%, 95% CI: 19–67, left colon 49%, 95% CI: 27–68, rectum 59%, 95% CI: 42–72, P = 0.39) due to higher proportions of metachronous patients undergoing treatment for metastases (40 versus 14%). Over half of all organ metastases spread to liver, with equal distribution from all three anatomical groups. Rectal cancers showed highest preponderance for lung metastases.

Conclusion

Rectal cancers have a higher chance of recurring, with a higher metastatic rate to the lung, yet demonstrate better survival outcomes in metastatic colorectal cancer, reflecting the benefit of intervention for metastases.



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Application of Selective Bronchial Intubation versus Neurally Adjusted Ventilatory Assist in the Management of Unilateral Pulmonary Interstitial Emphysema: An Illustrative Case and the Literature Review

AJP Rep 2017; 07: e101-e105
DOI: 10.1055/s-0037-1603322

In the treatment of left-sided pulmonary interstitial emphysema (PIE) in a 23-week neonate, we used two ventilatory strategies: selective bronchial intubation from day 10 to 15 and neurally adjusted ventilatory assist (NAVA) from day 18 to 26. We compared the effects and adverse effects of these two strategies. On selective bronchial intubation, desaturation was frequent. Fentanyl infusion was required. There was an episode of carbon dioxide retention coupled with hypotension. On NAVA, the neonate was clinically stable without the requirement of sedation. On selective bronchial intubation, ventilator setting in terms of mean airway pressure and oxygen requirement was higher, which came down on the first day of NAVA. Radiologically unilateral PIE did not resolve and became localized in the left middle zone of lung field on selective bronchial intubation. Also, the lobar collapse of ipsilateral, as well as contralateral lungs occurred. On NAVA, unilateral PIE resolved. NAVA might be a good option for the management of unilateral PIE.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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



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Impact of MLH1 expression on tumour evolution after curative surgical tumour resection in a murine orthotopic xenograft model for human MSI colon cancer

Abstract

Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumour evolution after curative surgical resection using a xenograft tumour model. Transplantable tumours established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumours were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumour evolution in mice who underwent curative surgical resection and in mice whose tumour was left in situ. Our data indicate that the behaviour of MLH1-deficient CRC is not only governed by mutations arising in genes harbouring microsatellite repeated sequences, but also from their defect in MLH1 per se. This article is protected by copyright. All rights reserved.



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The Extinction of the Surgeon Scientist

No abstract available

http://ift.tt/2qTGQkM

A different inhibitor is required for overcoming entecavir resistance: a comparison of four rescue therapies in a retrospective study

Abstract

Aims

Little clinical data are available regarding reestablishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance.

Methods

A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n=21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n=19), ETV (1.0 mg) monotherapy (n=11) or ETV (0.5 mg) plus TDF combination therapy (n=14). The efficacy and safety of four treatment regimens were compared.

Results

There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2= 0.749, P=0.862) and hepatitis B e antigen-positivity (χ2= 0.099, P=0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37±1.07 log10 IU/mL, -2.16±0.81 log10 IU/mL, -1.17±1.23 log10 IU/mL and -2.49±1.10 log10 IU/mL, respectively (F=4.078, P=0.011). The TDF group and ETV (0.5 mg)+TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg)+ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence.

Conclusions

TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.



http://ift.tt/2pIlib2

Enzyme-mediated formulation of stable elliptical silver nanoparticles tested against clinical pathogens and MDR bacteria and development of antimicrobial surgical thread

Silver nanoparticles (AgNPs) are believed to be emerging tool against various infectious diseases including multi-drug resistant (MDR) bacteria. In the present study, in vitro synthesis of AgNPs was optimized ...

http://ift.tt/2qOT0vR

Surveillance after positive colonoscopy based on adenoma characteristics

Patients with adenomatous polyps are at increased risk for developing colorectal cancer based on the characteristics and number of polyps, but less is known about the individual and combined contribution of these factors. This study aimed to better characterize the risk of advanced adenoma and cancer in patients with positive baseline colonoscopy.

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Erratum to: Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase



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Brain network dynamics in the human articulatory loop



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Fractional amplitude of low-frequency fluctuations is disrupted in Alzheimer’s disease with depression



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Extramural perineural invasion in pT3 and pT4 rectal adenocarcinoma as prognostic factor after preoperative chemoradiotherapy

Perineural invasion (PNI) is widely studied in malignant tumors, and its prognostic significance is well demonstrated in the head and neck and prostate carcinomas, but its significance in rectal cancer is controversial. Most studies have focused on evaluating mural PNI (mPNI); however, extramural PNI (ePNI) may influence the prognosis after rectal cancer resection. We evaluated the prognostic value of ePNI compared with mPNI and with non-PNI, in rectal resections after preoperative chemoradiotherapy in 148 patients with pT3 and pT4 rectal carcinomas.

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The Role of Source Control in Septic Patients

No abstract available

http://ift.tt/2roqhLi

Generalizable Biomarkers in Critical Care: Toward Precision Medicine

imageNo abstract available

http://ift.tt/2qpGDFE

Two Loci Contribute Epistastically to Heterospecific Pollen Rejection, a Postmating Isolating Barrier Between Species

Recognition and rejection of heterospecific male gametes occurs in a broad range of taxa, although the complexity of mechanisms underlying these components of postmating cryptic female choice is poorly understood. In plants, the arena for postmating interactions is the female reproductive tract (pistil), within which heterospecific pollen tube growth can be arrested via active molecular recognition and rejection. Unilateral incompatibility (UI) is one such postmating barrier in which pollen arrest occurs in only one direction of an interspecific cross. We investigated the genetic basis of pistil-side UI between Solanum species, with the specific goal of understanding the role and magnitude of epistasis between UI QTL. Using heterospecific introgression lines (ILs) between Solanum pennellii and S. lycopersicum, we assessed the individual and pairwise effects of three chromosomal regions (ui1.1, ui3.1, and ui12.1) previously associated with interspecific UI among Solanum species. Specifically, we generated double introgression ('pyramided') genotypes that combined ui12.1 with each of ui1.1 and ui3.1, and assessed the strength of UI pollen rejection in the pyramided lines, compared to single introgression genotypes. We found that none of the three QTL individually showed UI rejection phenotypes, but lines combining ui3.1 and ui12.1 showed significant pistil-side pollen rejection. Furthermore, double introgression lines that combined different chromosomal regions overlapping ui3.1 differed significantly in their rate of UI, consistent with at least two genetic factors on chromosome three contributing quantitatively to interspecific pollen rejection. Together, our data indicate that loci on both chromosomes 3 and 12 are jointly required for the expression of UI between S. pennellii and S. lycopersicum, suggesting that coordinated molecular interactions among a relatively few loci underlie the expression of this postmating prezygotic barrier. In addition, in conjunction with previous data, at least one of these loci appears to also contribute to conspecific self-incompatibility, consistent with a partially shared genetic basis between inter- and intraspecific mechanisms of postmating prezygotic female choice.



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Somatosensory Functions in Survivors of Critical Illness

imageObjectives: There is growing evidence for increased levels of pain and reduced health-related quality of life in survivors of critical illness. Recent studies showed marked small nerve fiber pathology in critically ill patients, which may contribute to chronic pain states and reduced physical recovery after ICU discharge. Primary objective of this study was the comparison of somatosensory functions between survivors of critical illness 6 months after ICU discharge and controls. In post hoc analyses, we aimed to identify associations between small fiber deficits, pain, health-related quality of life, and clinical data. Design: Cross-sectional study. Setting: Study in critical illness survivors. Patients: Critical illness survivors (n = 84) and controls (n = 44). Interventions: None. Measurements and Main Results: Somatosensory functions were assessed with validated quantitative sensory testing. Pain and pain-related disability were assessed with the chronic pain grade questionnaire. Health-related quality of life was assessed by means of the Short Form-36. Compared with controls, former patients showed significantly increased thermal detection thresholds and more abnormal values in thermal testing, indicating reduced small fiber functioning. In addition, compared to patients without significant small fiber deficits (n = 46, 54.8%), patients with significant small fiber deficits (n = 38, 45.2%) reported higher average pain intensity, pain-related disability, and reduced physical health-related quality of life in the SF-36. Conclusions: A large portion of former critically ill patients show small fiber deficits which seem to be associated with increased pain and reduced physical health-related quality of life. Screening of somatosensory functions in the (post-) acute setting could possibly help to identify patients at risk of long-term impairments.

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Optimal Cutoff Value for Lung Injury Prediction Score and Potential Confounders for Identifying the Risk of Developing Acute Respiratory Distress Syndrome

No abstract available

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The Septic Shock 3.0 Definition and Trials: A Vasopressin and Septic Shock Trial Experience*

imageObjectives: The Septic Shock 3.0 definition could alter treatment comparisons in randomized controlled trials in septic shock. Our first hypothesis was that the vasopressin versus norepinephrine comparison and 28-day mortality of patients with Septic Shock 3.0 definition (lactate > 2 mmol/L) differ from vasopressin versus norepinephrine and mortality in Vasopressin and Septic Shock Trial. Our second hypothesis was that there are differences in plasma cytokine levels in Vasopressin and Septic Shock Trial for lactate less than or equal to 2 versus greater than 2 mmol/L. Design: Retrospective analysis of randomized controlled trial. Setting: Multicenter ICUs. Methods: We compared vasopressin-to-norepinephrine group 28- and 90-day mortality in Vasopressin and Septic Shock Trial in lactate subgroups. We measured 39 cytokines to compare patients with lactate less than or equal to 2 versus greater than 2 mmol/L. Patients: Patients with septic shock with lactate greater than 2 mmol/L or less than or equal to 2 mmol/L, randomized to vasopressin or norepinephrine. Interventions: Concealed vasopressin (0.03 U/min.) or norepinephrine infusions. Measurements and Main Results: The Septic Shock 3.0 definition would have decreased sample size by about half. The 28- and 90-day mortality rates were 10–12 % higher than the original Vasopressin and Septic Shock Trial mortality. There was a significantly (p = 0.028) lower mortality with vasopressin versus norepinephrine in lactate less than or equal to 2 mmol/L but no difference between treatment groups in lactate greater than 2 mmol/L. Nearly all cytokine levels were significantly higher in patients with lactate greater than 2 versus less than or equal to 2 mmol/L. Conclusions: The Septic Shock 3.0 definition decreased sample size by half and increased 28-day mortality rates by about 10%. Vasopressin lowered mortality versus norepinephrine if lactate was less than or equal to 2 mmol/L. Patients had higher plasma cytokines in lactate greater than 2 versus less than or equal to 2 mmol/L, a brisker cytokine response to infection. The Septic Shock 3.0 definition and our findings have important implications for trial design in septic shock.

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The Association Between Visiting Intensivists and ICU Outcomes*

imageObjectives: We hypothesized that intensivists unfamiliar with an ICU team and the context of that ICU would affect patient outcomes. We examined differences in mortality when ICU patients were admitted under intensivists routinely working in that ICU and compared with those admitted by intensivists familiar with an ICU elsewhere in the same hospital. Design, Settings, and Patients: A 5-year natural experimental crossover study involving patients admitted to four ICUs in a large U.K. teaching hospital. Interventions: During a period of service reconfiguration, intensivists routinely rostered to work in one ICU worked in another of the hospital's four ICUs. "Home" intensivists were those who continued to work in their usual ICU; "visitor" intensivists were those who delivered care in an unfamiliar ICU. Patient data were obtained from electronic patient records to provide analysis on sex, age, admission Sequential Organ Failure Assessment score, date and time of admission, and admission type (elective, transfer, or unplanned). Measurements and Main Results: We analyzed 9,981 admissions to four separate ICUs over a 5-year period. In total, 34.5% of patients were admitted by intensivists working in nonfamiliar surroundings. Visitor intensivists admitted patients with similar age and gender distributions but with greater physiologic derangement (mean Sequential Organ Failure Assessment score, 4.1 ± 2.8 vs 3.9 ± 2.8; p

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The author replies

imageNo abstract available

http://ift.tt/2ro6qv9

Delayed Second Dose Antibiotics for Patients Admitted From the Emergency Department With Sepsis: Prevalence, Risk Factors, and Outcomes*

imageObjective: 1) Determine frequency and magnitude of delays in second antibiotic administration among patients admitted with sepsis; 2) Identify risk factors for these delays; and 3) Exploratory: determine association between delays and patient-centered outcomes (mortality and mechanical ventilation after second dose). Design: Retrospective, consecutive sample sepsis cohort over 10 months. Setting: Single, tertiary, academic medical center. Patients: All patients admitted from the emergency department with sepsis or septic shock (defined: infection, ≥ 2 systemic inflammatory response syndrome criteria, hypoperfusion/organ dysfunction) identified by a prospective quality initiative. Exclusions: less than 18 years old, not receiving initial antibiotics in the emergency department, death before antibiotic redosing, and patient refusing antibiotics. Interventions: We determined first-to-second antibiotic time and delay frequency. We considered delay major for first-to-second dose time greater than or equal to 25% of the recommended interval. Factors of interest were demographics, recommended interval length, comorbidities, clinical presentation, location at second dose, initial resuscitative care, and antimicrobial activity mechanism. Measurements and Main Results: Of 828 sepsis cases, 272 (33%) had delay greater than or equal to 25%. Delay frequency increased dose dependently with shorter recommended interval: 11 (4%) delays for 24-hour intervals (median time, 18.52 hr); 31 (26%) for 12-hour intervals (median, 10.58 hr); 117 (47%) for 8-hour intervals (median, 9.60 hr); and 113 (72%) for 6-hour intervals (median, 9.55 hr). In multivariable regression, interval length significantly predicted major delay (12 hr: odds ratio, 6.98; CI, 2.33–20.89; 8 hr: odds ratio, 23.70; CI, 8.13–69.11; 6 hr: odds ratio, 71.95; CI, 25.13–206.0). Additional independent risk factors were inpatient boarding in the emergency department (odds ratio, 2.67; CI, 1.74–4.09), initial 3-hour sepsis bundle compliance (odds ratio, 1.57; CI, 1.07–2.30), and older age (odds ratio, 1.16 per 10 yr, CI, 1.01–1.34). In the exploratory multivariable analysis, major delay was associated with increased hospital mortality (odds ratio, 1.61; CI, 1.01–2.57) and mechanical ventilation (odds ratio, 2.44; CI, 1.27–4.69). Conclusions: Major second dose delays were common, especially for patients given shorter half-life pharmacotherapies and who boarded in the emergency department. They were paradoxically more frequent for patients receiving compliant initial care. We observed association between major second dose delay and increased mortality, length of stay, and mechanical ventilation requirement.

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Using Clinically Accessible Tools to Measure Sound Levels and Sleep Disruption in the ICU: A Prospective Multicenter Observational Study

imageObjectives: To use clinically accessible tools to determine unit-level and individual patient factors associated with sound levels and sleep disruption in a range of representative ICUs. Design: A cross-sectional, observational study. Setting: Australian and New Zealand ICUs. Patients: All patients 16 years or over occupying an ICU bed on one of two Point Prevalence study days in 2015. Interventions: Ambient sound was measured for 1 minute using an application downloaded to a personal mobile device. Bedside nurses also recorded the total time and number of awakening for each patient overnight. Measurements and Main Results: The study included 539 participants with sound level recorded using an application downloaded to a personal mobile device from 39 ICUs. Maximum and mean sound levels were 78 dB (SD, 9) and 62 dB (SD, 8), respectively. Maximum sound levels were higher in ICUs with a sleep policy or protocol compared with those without maximum sound levels 81 dB (95% CI, 79–83) versus 77 dB (95% CI, 77–78), mean difference 4 dB (95% CI, 0–2), p

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Antibiotic-Associated Apoptotic Enterocolitis in the Absence of a Defined Pathogen: The Role of Intestinal Microbiota Depletion*

imageObjective: Antibiotic therapy is a major risk factor for the development of diarrhea and colitis with varying severity. Often the origin of antibiotic-associated gastrointestinal deterioration remains elusive and no specific infectious agents could be discerned. Patients: We represent three cases of intractable high-volume diarrhea associated with combined antibiotic and steroid therapy in critically ill patients not fitting into established disease entities. Cases presented with severe apoptotic enterocolitis resembling acute intestinal graft-versus-host-disease. Microbiologic workup precluded known enteropathogens, but microbiota analysis revealed a severely depleted gut microbiota with concomitant opportunistic pathogen overgrowth. Interventions: Fecal microbiota transplantation, performed in one patient, was associated with correction of dysbiosis, rapid clinical improvement, and healing of enterocolitis. Conclusions: Our series represents a severe form of antibiotic-associated colitis in critically ill patients signified by microbiota depletion, and reestablishment of a physiologic gastrointestinal microbiota might be beneficial for this condition.

http://ift.tt/2qq8WDD

Increased Early Systemic Inflammation in ICU-Acquired Weakness; A Prospective Observational Cohort Study*

imageObjectives: To investigate whether patients who develop ICU-acquired weakness have a different pattern of systemic inflammatory markers compared with critically ill patients who do not develop ICU-acquired weakness. Design: Prospective observational cohort study. Setting: Mixed medical-surgical ICU of a tertiary care hospital in the Netherlands. Patients: Newly admitted critically ill patients, greater than or equal to 48 hours on mechanical ventilation with a nonneurologic ICU admission diagnosis, were included. Interventions: A panel of systemic inflammatory markers and soluble vascular adhesion molecules were measured in plasma samples of day 0, 2, and 4 after ICU admission. ICU-acquired weakness was diagnosed by manual muscle strength testing as soon as patients were awake and attentive. Measurements and Main Results: Ninety-nine of 204 included patients developed ICU-acquired weakness. Principal component regression analysis, adjusted for confounders, showed that principal component 1, mainly loaded with interleukin-6, interleukin-8, interleukin-10, and fractalkine, was significantly higher in patients who developed ICU-acquired weakness (odds ratio, 1.35 [95% CI, 1.18–1.55]). Partial least squares-discriminant analysis also showed that these markers were the most important discriminative markers. Mixed-effects models of these markers showed that ICU-acquired weakness was associated with an independent 1.5- to two-fold increase in these markers. Conclusions: Systemic inflammation is increased in patients who develop ICU-acquired weakness compared with patients who do not develop ICU-acquired weakness in the first 4 days after ICU admission. This finding is consistent when adjusted for confounders, like disease severity. A group consisting of interleukin-6, interleukin-8, interleukin-10, and fractalkine was identified to be the most important.

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To What Extent Does ABCDEF Bundle Improve Hospital Survival and Reduce Brain Dysfunction of 1,438 Patients With Mechanical Ventilation in Seven California Community Hospitals?

No abstract available

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The authors reply

No abstract available

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Ending Life in the ICU: The Vacuity of Sanctity

No abstract available

http://ift.tt/2qpXpEe

Association Between Hospital Case Volume of Sepsis, Adherence to Evidence-Based Processes of Care and Patient Outcomes

imageObjectives: We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence-based processes of care. Design: Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations. Setting: Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals. Subjects: A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization. Interventions: None. Measurements and Main Results: Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1–3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6–2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45–1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70–0.94) but did not strongly mediate case volume-mortality associations (point estimate change ≤ 2%). Conclusions: In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes.

http://ift.tt/2qpFbCU

Impact of Targeted Interventions on Trends in Central Line-Associated Bloodstream Infection: A Single-Center Experience From the Republic of Korea

imageObjective: To assess the impact of targeted interventions on trends in central line-associated bloodstream infection. Design: A before-and-after study between January 2013 and September 2014. Setting: Tertiary hospital in the Republic of Korea. Patients: All patients with central-line catheters in the hospital. Interventions: In September 2013, interventions that targeted central line insertion practices were implemented in 10 ICUs, including compliance monitoring with a central line insertion practices bundle and use of an all-inclusive catheter kit. The impact of targeted interventions on trends in central line-associated bloodstream infection was evaluated by segmented autoregression analysis of an interrupted time series. Measurements and Main Results: The average hospital-wide central line-associated bloodstream infection rates in the baseline and intervention periods were 1.84 and 1.56 per 1,000 catheter-days, respectively. During the baseline period, there was an increase of central line-associated bloodstream infection rate of 0.12 per 1,000 catheter-days per month. In the intervention period, there was a decrease of central line-associated bloodstream infection rate of 0.16 per 1,000 catheter-days per month (change in slope, –0.28; 95% CI, –0.37 to –0.19; p

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Delayed Referral Results in Missed Opportunities for Organ Donation After Circulatory Death

imageObjectives: Rates of organ donation and transplantation have steadily increased in the United States and Canada over the past decade, largely attributable to a notable increase in donation after circulatory death. However, the number of patients awaiting solid organ transplantation continues to remain much higher than the number of organs transplanted each year. The objective of this study was to determine the potential to increase donation rates further by identifying gaps in the well-established donation after circulatory death process in Ontario. Design: Retrospective cohort study. Setting: Provincial organ procurement organization. Patients: Patients who died in designated donation hospitals within the province of Ontario, Canada between April 1, 2013, and March 31, 2015. Interventions: None. Measurements and Main Results: Of 1,407 patient deaths following planned withdrawal of life-sustaining therapy, 54.0% (n = 760) were medically suitable for donation after circulatory death. In 438 cases where next of kin was approached, consent rates reached 47.5%. A total of 119 patients became actual organ donors. Only 66.2% (n = 503) of suitable patients were appropriately referred, resulting in 251 missed potential donors whose next of kin could not be approached regarding organ donation because referral occurred after initiation of withdrawal of life-sustaining therapy or not at all. Conclusions: The number of medically suitable patients who die within 2 hours of planned withdrawal of life-sustaining therapy is nearly six times higher than the number of actual organ donors, with the greatest loss of potential due to delayed referral until at the time of or after planned withdrawal of life-sustaining therapy. Intensive care teams are not meeting their ethical responsibility to recognize impending death and appropriately refer potential organ donors to the local organ procurement organization. In cases where patients had previously registered their consent decision, they were denied a healthcare right.

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Race, Ethnicity, Health Insurance, and Mortality in Older Survivors of Critical Illness

imageObjectives: To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness. Design: A retrospective cohort study. Setting: Two New York City academic medical centers. Patients: A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge. Interventions: None. Measurements and Main Results: We obtained demographic, insurance, and clinical data from electronic health records, determined each patient's neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4–3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76–1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76–1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03–1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10–1.52). Medicaid recipients who were the oldest ICU survivors (> 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction: 0.08, 0.03, and 0.17, respectively). Conclusions: Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance.

http://ift.tt/2qpUsDY

Postoperative Complications and Outcomes Associated With a Transition to 24/7 Intensivist Management of Cardiac Surgery Patients

imageObjectives: Nighttime intensivist staffing does not improve patient outcomes in general ICUs. Few studies have examined the association between dedicated in-house 24/7 intensivist coverage on outcomes in specialized cardiac surgical ICUs. We sought to evaluate the association between 24/7 in-house intensivist-only management of cardiac surgical patients on postoperative complications and health resource utilization. Design: Before-and-after propensity matched cohort study. Setting: Tertiary care cardiac surgical ICU. Patients: Patients greater than 18 years old who underwent cardiac surgery between January 1, 2006, and April 30, 2013 (nighttime resident model), were propensity-matched (1:1) to patients from August 1, 2013, to December 31, 2014 (24/7 in-house intensivist model). Interventions: Cardiac surgical ICU coverage change from a nighttime resident physician coverage model to a 24/7 in-house intensivist staffing model. Measurements and Main Results: The primary outcome of interest was a composite of postoperative major complications. Secondary outcomes included duration of mechanical ventilation, all-cause cardiac surgical ICU readmissions, and surgical postponements attributed to lack of cardiac surgical ICU bed availability. A total of 1,509 patients during the nighttime resident model were matched to 1,509 patients during the intensivist model. The adjusted risk of major complications (26.3% vs 19.3%; odds ratio, 0.73; 95% CI, 0.36–0.85; p

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Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies

Abstract

Purpose of Review

Uveal melanoma is a distinct subset of melanoma with a biology and treatment approach that is unique from that of cutaneous melanoma. Here we will review the current data evaluating immunotherapies in both the adjuvant and metastatic settings in uveal melanoma.

Recent Findings

In the adjuvant setting, interferon demonstrated no survival benefit in uveal melanoma, and studies evaluating immune-based strategies such as vaccine therapy are ongoing. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in uveal melanoma have been evaluated in several small prospective and/or retrospective studies with rare responses and no overall survival benefit demonstrated. Ongoing studies evaluating combination checkpoint inhibition and other antibody-based therapies are ongoing.

Summary

Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited. Clinical trial participation should be prioritized in patients with uveal melanoma.



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(P073) Management of Squamous Cell Carcinoma of the Scalp With Bone Involvement

Squamous cell carcinoma of the scalp (SCC) with bone invasion poses a management challenge. Multimodal therapy, including radiation therapy, is often required. Adequate target coverage can be inferior with older radiation techniques depending on size, depth, and location of bone invasion, but newer RT modalities may be helpful in this regard.

http://ift.tt/2roiMnw

(P075) Thyroid Gland Sparing Radiotherapy in the Management of Head and Neck Cancer: A Single Institution Prospective Approach to Assess Feasibility, Safety, and Response

Hypothyroidism in patients treated with radiotherapy for head and neck cancer is a common event adversely affecting long term quality of life. We initiated a single institution feasibility and safety study focused on thyroid gland sparing intensity modulated radiotherapy (IMRT).

http://ift.tt/2qOSA8A

(P078) Radiotherapy for Parotid Malignancies: Patterns of Care and Impact on Overall Survival

To determine the impact of post-operative radiotherapy (PORT) on the overall survival (OS) of patients with malignancies of the parotid gland.

http://ift.tt/2roo6HF

Delayed Cord Clamping in Newborns Born at Term at Risk for Resuscitation: A Feasibility Randomized Clinical Trial

Infants may benefit if resuscitation could be provided with an intact umbilical cord. Infants identified at risk for resuscitation were randomized to 1- or 5-minute cord clamping. The 5-minute group had greater cerebral oxygenation and blood pressure. Studies are needed to determine whether this translates into improved outcomes.

http://ift.tt/2rde5Qc

Pediatricians, racial disparities, and tackle football

Fishman et al1 report that most pediatricians across the 3 sections of the American Academy of Pediatrics that they surveyed would not allow their own child to participate in tackle football. In contrast, respondents were less likely to consider it appropriate for physicians to counsel against youth participation in full-contact sports. Fishman et al highlight this striking disconnect "between physicians' beliefs and practices regarding their own children vs what they recommend for their patients." They ask whether physicians should disclose their personal attitudes to patients, particularly given evidence that those beliefs strongly influence clinical practice.

http://ift.tt/2rdoyLG

Neurocognitive Outcomes at 10 Years of Age in Extremely Preterm Newborns with Late-Onset Bacteremia

To evaluate the difference in 10-year neurocognitive outcomes between extremely low gestational age newborns without bacteremia and those with suspected or confirmed late-onset bacteremia.

http://ift.tt/2pRSLMh

Lumbar Puncture for All Febrile Infants 29-56 Days Old: A Retrospective Cohort Reassessment Study

To determine the incidence of bacterial meningitis (BM) among all febrile infants 29-56 days old undergoing a lumbar puncture (LP) in the emergency department of a tertiary care children's hospital and the number of low-risk febrile infants with BM to reassess the need for routine LP in these infants.

http://ift.tt/2rd8tp3

The “Candlestick Sign” on Head Ultrasound Imaging

A 1970-g female neonate was born via cesarean delivery, due to spontaneous placental abruption and intrauterine hemorrhage, at 37 weeks of gestation. Her appearance was characterized by microcephaly, low-set ears, nose and frontal bone hypoplasia, and postaxial polydactyly in the right hand. Her occipitofrontal circumference was 28.5 cm (<3 centile) and length 45 cm (<3 centile). Her blood pressure was normal and laboratory diagnostic test results were within normal limits.

http://ift.tt/2rd0M2m

Using Student Reflective Narratives to Teach Professionalism and Systems-Based Practice

Professionalism and systems-based practice are 2 of the 6 core competencies of graduate medical education.1 Although not as explicit in undergraduate medical education, they are also reflected within the Liaison Committee on Medical Education's Standard 7.6: "the development of core professional attitudes" and "… provide coordinated care to patients."2

http://ift.tt/2rcU5xq

Cardiorespiratory Fitness and Muscular Strength as Mediators of the Influence of Fatness on Academic Achievement

To examine the combined association of fatness and physical fitness components (cardiorespiratory fitness [CRF] and muscular strength) with academic achievement, and to determine whether CRF and muscular strength are mediators of the association between fatness and academic achievement in a nationally representative sample of adolescents from Chile.

http://ift.tt/2pSl3WW

Choroidal Coloboma Presenting as Leukocoria

A 10-year-old boy presented for evaluation of a white pupil of the right eye. His medical and ocular history was insignificant. Ocular examination revealed a best-corrected visual acuity of 6/9 in the right eye and 6/9 in the left eye. Intraocular pressure was estimated to be normal (right eye 13 mm Hg, left eye 15 mm Hg). Fundus examination demonstrated the presence of chorioretinal coloboma inferior to the optic disc (Figure) in the right eye. Fundoscopy of the left eye was normal.

http://ift.tt/2pSiS5E

Hemocytometric Measures Predict the Efficacy of Oral Rehydration for Children with Postural Tachycardia Syndrome

To explore whether hemocytometric measures could be qualified predictors for the effect of oral rehydration salts (ORS) in children with postural tachycardia syndrome (POTS).

http://ift.tt/2pSfQhS

Preparing pathology for precision medicine: challenges and opportunities



http://ift.tt/2qpWiV9

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status

Abstract

Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses' Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features. 120,813 participants were followed for 26 or 32 years and 1528 rectal and colon cancer cases with available tumor pathological data were documented. The association between BMI and colorectal cancer risk significantly differed depending on the presence or absence of poorly-differentiated foci (Pheterogeneity = 0.006). Higher BMI was associated with a higher risk of colorectal carcinoma without poorly-differentiated foci (≥30.0 vs. 18.5–22.4 kg/m2: multivariable-adjusted hazard ratio, 1.87; 95% confidence interval, 1.49–2.34; Ptrend < 0.001), but not with risk of carcinoma with poorly-differentiated foci (Ptrend = 0.56). This differential association appeared to be consistent in strata of tumor microsatellite instability or FASN expression status, although the statistical power was limited. The association between BMI and colorectal carcinoma risk did not significantly differ by overall tumor differentiation, mucinous differentiation, or signet ring cell component (Pheterogeneity > 0.03, with the adjusted α of 0.01). High BMI was associated with risk of colorectal cancer subtype containing no poorly-differentiated focus. Our findings suggest that carcinogenic influence of excess energy balance might be stronger for tumors that retain better intestinal differentiation throughout the tumor areas.



http://ift.tt/2pR9Jue

Mindfulness-based stress reduction for people with multiple sclerosis – a feasibility randomised controlled trial

Multiple sclerosis (MS) is a stressful condition. Mental health comorbidity is common. Stress can increase the risk of depression, reduce quality of life (QOL), and possibly exacerbate disease activity in MS. ...

http://ift.tt/2ro29aW

Short review San Antonio 2016

Summary

The San Antonio Breast Cancer Symposium 2016 featured all areas in the treatment of breast cancer. However, the meeting again showed that surgery remains the major column in the treatment of breast cancer. Various areas of development in the surgical management of breast cancer received significant attention in 2016 – sentinel lymph node (SLN) biopsy after neoadjuvant chemotherapy, radiotherapy after breast reconstruction and imaging strategies for the surgical treatment of breast cancer. In this short overview the most interesting presentations from the meeting are presented.



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American Society of Hematology 2016 annual meeting

Summary

For heterogeneous myelodysplastic syndromes (MDS), patient management is still a challenge. Despite the progress achieved in recent years, there is need for improvement at least for specific situations such as failure of hypomethylating agents or in patients with thrombocytopenia or with anemia failing erythropoiesis stimulating agents. This review covers studies for MDS presented at the American Society of Hematology (ASH) 2016 annual meeting. New treatment approaches, for which results from phase 1/2 studies were reported, will now move into phase 3 and hopefully into clinical practice in the future. Choosing the right agent and individualizing treatment will be the next challenges.



http://ift.tt/2rokhlN

Clinical utility of risk models to refer patients with adnexal masses to specialized oncology care: multicenter external validation using decision curve analysis

OBJECTIVES: To evaluate the utility of pre-operative diagnostic models for ovarian cancer based on ultrasound and/or biomarkers for referring patients to specialized oncology care. The investigated models were RMI, ROMA, and three models from the International Ovarian Tumor Analysis (IOTA) group (LR2, ADNEX, and the Simple Rules risk score, SRRisks). <p>DESIGN: A secondary analysis of prospectively collected data from two cross-sectional cohort studies performed to externally validate diagnostic models.</p> <p>PARTICIPANTS: A total of 2763 patients (2403 in dataset 1 and 360 in dataset 2) from 18 centers (11 oncology centers and 7 non-oncology hospitals) in 6 countries.</p> <p>MAIN OUTCOME MEASURE: Excised tissue was histologically classified as benign or malignant. The clinical utility of the pre-operative diagnostic models was assessed with Net Benefit (NB) at a range of risk thresholds (5% to 50% risk of malignancy) to refer patients to specialized oncology care. We visualized results with decision curves and generated bootstrap confidence intervals.</p> <p>RESULTS: The prevalence of malignancy was 41% in dataset 1 and 40% in dataset 2. For thresholds up to 10%-15%, RMI and ROMA had a lower NB than referring all patients. SRRisks and ADNEX demonstrated the highest NB. At a threshold of 20%, the NBs of ADNEX, SRrisks and RMI were 0.348, 0.350, and 0.270, respectively. Results by menopausal status and type of center (oncology versus non-oncology) were similar.</p> <p>CONCLUSIONS: All tested IOTA methods, especially ADNEX and SRRisks, are clinically more useful than RMI and ROMA to select patients with adnexal masses for specialized oncology care.



http://ift.tt/2qP1gvE

Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma

Purpose: Disruption of PD-L1/cytotoxic T-cell PD-1 signalling by immune-checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD1 therapies in melanoma patients, particularly early during treatment, and correlate them with treatment response<br /><br />Experimental Design: Forty-six tumor biopsies from 23 unresectable AJCC Stage III/IV melanoma patients receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n=21), within two months of commencing treatment (EDT, n=20) and on disease progression after previous response (PROG, n=5). Thirteen patients responded (defined as CR, PR or durable SD by RECIST/irRC criteria), ten didn't respond. <br /><br />Results: PRE intra-tumoral and peri-tumoral PD-1+ T-cells density were 7-fold (p=0.006) and 5-fold higher (p=0.011), respectively in responders compared with non-responders and correlated with degree of radiologic tumor response (r=-0.729, p=0.001 and r=-0.725, p=0.001, respectively). PRE PD-L1 expression on tumor and macrophages wasn't significantly different between the patient groups but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders vs. non-responders (p=0.025 and p=0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intra-tumoral CD8+ lymphocytes (p=0.046) and intratumoral CD68+ macrophages (p=0.046).<br /><br />Conclusions: Higher PRE PD-1+ T-cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies, and may allow better selection of patients most likely to benefit from anti-PD1 therapies and warrants further evaluation.



http://ift.tt/2rdgmuR

In vivo hemin conditioning targets the vascular and immunological compartments and restrains prostate tumor development

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study we assessed how hemin, a pharmacological inducer of Heme Oxygenase-1 (HO-1), impacts upon prostate cancer (PCa) development in an in vivo conditioning model. <p>Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used PCa patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.</p> <p>Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histological analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated HUVEC exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1 conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neo-vascularization in an in vivo Matrigel plug assay. Additionally, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo. A significant systemic increase in CD8+ T-cell frequency was observed in pre-conditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of PCa patient-derived xenografts and PCa patient samples with mild HO-1 and low Gal-1 expression levels.</p> Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response.



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Feasibility and diagnostic performance of dual-tracer-guided sentinel lymph node biopsy in cT1-2N0M0 gastric cancer: a systematic review and meta-analysis of diagnostic studies

Abstract

Background

Dual-tracer-guided sentinel lymph node (SLN) biopsy may provide a promising diagnostic tool to assess accurately the status of lymph node metastasis in the surgical operation and assure the oncologic safety of the function or stomach preserving surgery. The diagnostic performance of this technology in recent studies varied. Thus, we conducted this meta-analysis.

Methods

This systematic review and meta-analysis was registered at the PROSPERO. Eligible studies were searched in the PubMed, EMBASE, Web of Knowledge, and Cochrane Library databases. A random-effect model was used to pool the data. Summary receiver operator characteristic curves, analysis for publication bias, meta-regression, and subgroup analysis were also performed.

Results

The pooled SLN identification rate and sensitivity were 0.97 and 0.89. 99mTc-human serum albumin with indocyanine green (ICG), 99mTc-antimony sulfur colloid with ICG, performing SLN biopsy ≥15 min after dye injection, an SLN ≥5, the basin dissection, laparoscopic surgery, in studies conducted in Japan and studies published after 2012, were associated with higher sensitivity. CT1 stage, performing SLN biopsy ≥15 min after dye injection, in studies conducted in Japan and studies published after 2012, were related with a higher identification rate.

Conclusions

Dual tracer is promising in SLN biopsy in gastric cancer, and the clinical application of SLN biopsy should be limited to the patients of cT1N0M0 gastric cancer. The combination of 99mTc-human serum albumin and ICG as well as the combination of 99mTc-antimony sulfur colloid and ICG may be the optimal tracer combination. However, it seems not justified to put this technique into routine clinical application recently. Some factors that might enhance diagnostic value are identified.



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Mechanisms and strategies of papillomavirus replication

Journal Name: Biological Chemistry
Issue: Ahead of print


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The multi-morbid old brain



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p62/SQSTM1 cooperates with hyperactive mTORC1 to regulate glutathione production, maintain mitochondrial integrity and promote tumorigenesis

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate which accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes TSC1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/- and Tsc2f/f Ksp-CreERT2+ mice crossed to p62-/- mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1 and Srxn1 which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial ROS and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of glutathione biosynthesis by buthionine sulfoximine (BSO). Our findings show how p62 helps maintain intracellular pools of glutathione needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors.

http://ift.tt/2qpnumT