Summary
Derangement of the coagulation system is a common phenomenon in critically ill patients, who may present with severe bleeding and/or conditions associated with a prothrombotic state. ...Monitoring of this coagulopathy can be performed with conventional coagulation assays; however, point‐of‐care tests have become increasingly attractive, because not only do they yield a more rapid result than clinical laboratory testing, but they may also provide a more complete picture of the condition of the hemostatic system. There are many potential areas of study and applications of point‐of‐care hemostatic testing in critical care, including patients who present with massive blood loss, patients with a hypercoagulable state (such as in disseminated intravascular coagulation), and monitoring of antiplatelet treatment for acute arterial thrombosis, mostly acute coronary syndromes. However, the limitations of near‐patient hemostatic testing has not been fully appreciated, and are discussed here. The currently available evidence indicates that point‐of‐care tests may be applied to guide appropriate blood product transfusion and the use of hemostatic agents to correct the hemostatic defect or to ameliorate antithrombotic treatment. Disappointingly, however, only in cardiac surgery is there adequate evidence to show that application of near‐patient thromboelastography leads to an improvement in clinically relevant outcomes, such as reductions in bleeding‐related morbidity and mortality, and cost‐effectiveness. More research is required to validate the utility and cost‐effectiveness of near‐patient hemostatic testing in other areas, especially in traumatic bleeding and postpartum hemorrhage.
Summary
The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC ...scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 × 109/l transfusion of platelets should be considered. In non‐bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co‐existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half‐life and reversibility. Weight adjusted doses (e.g. 10 μ/kg/h) may be used without the intention of prolonging the APTT ratio to 1·5–2·5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non‐bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 μg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 × 109/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half‐life ≈20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).
Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support ...practitioners in decisions about pharmacological interventions for overweight and obesity.
A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice.
The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap.
In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.
BACKGROUND AND PURPOSE—Cerebral microbleeds (petechial hemorrhages) are a well-known consequence of cerebral amyloid angiopathy and chronic hypertension among other causes. We report 12 patients with ...a clinically and radiologically distinct microbleed phenomenon in the cerebral white matter.
METHODS—These patients were assessed at the University Health Network (Toronto, Canada) between 2004 and 2014.
RESULTS—Median age was 40 years (range, 27–63 years), and 7 out of 12 patients were women. All patients had brain magnetic resonance imaging during or immediately after an intensive care unit admission. All patients had respiratory failure, 11 out of 12 received mechanical ventilation, and 3 out of 12 received extracorporeal life support. Magnetic resonance imaging in all 12 patients showed extensive microbleeds, diffusely involving the juxtacortical white matter and corpus callosum but sparing the cortex, deep and periventricular white matter, basal ganglia, and thalami. Several patients also had internal capsule or posterior fossa involvement.
CONCLUSIONS—We have described a distinct microbleed phenomenon in the cerebral white matter of patients with critical illness. The specific cause of the microbleeds is unclear, but the pathogenesis may involve hypoxemia as the microbleeds are similar to those described with high-altitude exposure.
Amblyopia is a developmental abnormality that results from physiological alterations in the visual cortex and impairs form vision. It is a consequence of abnormal binocular visual experience during ...the “sensitive period” early in life. While amblyopia can often be reversed when treated early, conventional treatment is generally not undertaken in older children and adults. A number of studies over the last twelve years or so suggest that Perceptual Learning (PL) may provide an important new method for treating amblyopia.
The aim of this mini-review is to provide a critical review and “meta-analysis” of perceptual learning in adults and children with amblyopia, with a view to extracting principles that might make PL more effective and efficient. Specifically we evaluate:
1).
What factors influence the outcome of perceptual learning?
2).
Specificity and generalization – two sides of the coin.
3).
Do the improvements last?
4).
How does PL improve visual function?
5).
Should PL be part of the treatment armamentarium?
A review of the extant studies makes it clear that practicing a visual task results in a long-lasting improvement in performance in an amblyopic eye. The improvement is generally strongest for the trained eye, task, stimulus and orientation, but appears to have a broader spatial frequency bandwidth than in normal vision. Importantly, practicing on a variety of different tasks and stimuli seems to transfer to improved visual acuity. Perceptual learning operates via a reduction of internal neural noise and/or through more efficient use of the stimulus information by retuning the weighting of the information. The success of PL raises the question of whether it should become a standard part of the armamentarium for the clinical treatment of amblyopia, and suggests several important principles for effective perceptual learning in amblyopia.
We report catalytic, enantioselective intramolecular hydroacylation of N-vinylindole-2-carboxaldehydes. These hydroacylation reactions occur in the presence of a readily accessible rhodium catalyst ...and form chiral, non-racemic 2,3-dihydro-1H-pyrrolo1,2-aindol-1-ones in high yields with excellent enantioselectivities.
Stereopsis, the perception of depth based on the disparity of the images projected to the retinas of the two eyes, is an important process in our three-dimensional world; however, 3–5% of the ...population is stereoblind or has seriously impaired stereovision. Here we provide evidence for the recovery of stereopsis through perceptual learning, the repetitive practice of a demanding visual task, in human adults long deprived of normal binocular vision. We used a training paradigm that combines monocular cues that were correlated perfectly with the disparity cues. Following perceptual learning (thousands of trials) with stereoscopic gratings, five adults who initially were stereoblind or stereoanomalous showed substantial recovery of stereopsis, both on psychophysical tests with stimuli that contained no monocular cues and on clinical testing. They reported that depth "popped out" in daily life, and enjoyed 3D movies for the first time. After training, stereo tests with dynamic random-dot stereograms and band-pass noise revealed the properties of the recovered stereopsis: It has reduced resolution and precision, although it is based on perceiving depth by detecting binocular disparity. We conclude that some human adults deprived of normal binocular vision can recover stereopsis at least partially.
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine ...non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.
•High TMB correlates with efficacy of PD-1 plus CTLA-4 blockade in NSCLC•TMB and PD-L1 are independent variables•In multivariate analysis, TMB associated most strongly with efficacy
Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.
This work summarizes the results of our studies devoted to Mg ions mobility in Chevrel phases (CPs), M
x
Mo
6
T
8
(M – metal, T = S, Se) and presents our vision of the problem of multivalent ions’ ...diffusion in intercalation compounds. A simplified analysis of the main factors, which affect the activation energy barriers, as well as experimental data of Mg ions insertion into different hosts, show that low Mg ions mobility in common transition metal oxides or sulfides cannot be explained only by strong ionic interactions, but it is rather caused by a hard redistribution of the bivalent cations charge in inorganic materials. In contrast to these hosts, CPs allow for a high mobility of multivalent cations, because their unusual crystal structure with octahedral Mo
6
-clusters enables a fast and efficient attainment of local electro-neutrality upon insertion of cations of high charge density. Analysis of diffusion pathways based on the detailed structural determinations sheds light on important aspects of the electrochemical behavior of CPs, such as partial Mg ions trapping in the course of reversible Mg insertion and the ways to avoid it.
PDF
