Single center evaluation on the use of conditionally ordered low molecular weight heparins in malignant hematology patients with venous thromboembolism.

BACKGROUND: Cancer and cancer-related treatments are significant independent risk factors for malignant hematology (MH) patients in developing venous thromboembolism (VTE). Treatment of VTE in MH patients at the Princess Margaret Cancer Centre is predominantly initiated with low molecular weight heparin (LMWH) in accordance with guidelines. While guidelines recommend against LMWH use in patients with thrombocytopenia, prescribers may order LMWH conditionally based on platelet values. Currently, there is a lack of consistent practice with variation in both the use of conditional orders as well as the threshold of platelet values for conditional orders. The objectives of the study were to (a) describe the use of conditionally ordered LMWH based on platelet values; (b) determine its safety by measuring administration concordance with conditional orders and bleeding event rates during inpatient admission; and (c) determine its efficacy by measuring the rate of worsening VTE or recurrence during inpatient admission. METHODS: Electronic records of MH inpatients admitted between January 2017 and December 2019 and who were administered at least one dose of an LMWH for the treatment of VTE were screened. RESULTS: One hundred and eight patients were screened to obtain 50 eligible patients with a median age of 59 years (SD = ±18.8 years). The most frequent MH diagnosis was acute lymphoblastic leukemia (30%). Sixty percent (n = 30) of patients received conditional orders. Out of 571 administrations, 543 (95%) were administered concordantly (Χ2(1) = 472, p < 0.0001). In this group of patients, 8 patients had either documented bleeding or experienced a drop in hemoglobin >10 g/L within a 72 h time frame. No patients experienced a recurrent VTE during inpatient treatment (for up to 40 days post-admission). CONCLUSIONS: It appears that conditionally ordered LMWH can be concordantly administered and is safe and effective in the treatment of VTE in MH patients experiencing thrombocytopenia. There were no reports of worsening or new VTE in our small sample.

Does the sensorimotor system minimize prediction error or select the most likely prediction during object lifting?

The human sensorimotor system is routinely capable of making accurate predictions about an object's weight, which allows for energetically efficient lifts and prevents objects from being dropped. Often, however, poor predictions arise when the weight of an object can vary and sensory cues about object weight are sparse (e.g., picking up an opaque water bottle). The question arises, what strategies does the sensorimotor system use to make weight predictions when one is dealing with an object whose weight may vary? For example, does the sensorimotor system use a strategy that minimizes prediction error (minimal squared error) or one that selects the weight that is most likely to be correct (maximum a posteriori)? In this study we dissociated the predictions of these two strategies by having participants lift an object whose weight varied according to a skewed probability distribution. We found, using a small range of weight uncertainty, that four indexes of sensorimotor prediction (grip force rate, grip force, load force rate, and load force) were consistent with a feedforward strategy that minimizes the square of prediction errors. These findings match research in the visuomotor system, suggesting parallels in underlying processes. We interpret our findings within a Bayesian framework and discuss the potential benefits of using a minimal squared error strategy. NEW & NOTEWORTHY: Using a novel experimental model of object lifting, we tested whether the sensorimotor system models the weight of objects by minimizing lifting errors or by selecting the statistically most likely weight. We found that the sensorimotor system minimizes the square of prediction errors for object lifting. This parallels the results of studies that investigated visually guided reaching, suggesting an overlap in the underlying mechanisms between tasks that involve different sensory systems.

Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice.

We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr-/-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/-xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.