An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2␣, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action.

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Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are pointof-care viscoelastic devices that use whole blood samples to assess coagulation and fibrinolysis. These devices have been studied extensively in cardiac surgery, but there is limited robust evidence supporting its use in obstetrics. The hesitancy toward its routine use in obstetrics may be due to the current lack of randomized controlled trials and large observational studies. The study aims to systematically review studies that investigated TEG/ROTEM use in pregnancy or peripartum, and to provide recommendations for future studies to fill current research gaps. We performed a systematic review of studies on viscoelastic testing in obstetrics. Included studies were original research, used TEG or ROTEM during pregnancy or peripartum, and published in English. Ninety-three studies, spanning 31 years from 1989 to 2020 and with a total of 32,817 participants, were included. Sixty-two (66.7%) of the studies used TEG and 31 (33.3%) used ROTEM. To date, there are a total of two randomized controlled trials on TEG/ROTEM use in obstetrics. ROTEM may be used to guide transfusion therapy for postpartum hemorrhage. TEG and ROTEM can detect the hypercoagulable changes associated with pregnancy. Variability between study protocols and results suggests the need for future large prospective high-quality studies with standardized protocols to investigate the utility of TEG/ROTEM in assessing risk for thrombosis and hemorrhage as well as in guiding prophylaxis and treatment in obstetric patients. This review identifies the gaps and provides concrete recommendations for future studies to fill those gaps.

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Hereditary variant transthyretin amyloidosis (ATTRv) is a rare genetic defect that affects about 5000–10,000 people worldwide, causing amyloidosis secondary to misfolding of mutant transthyretin (TTR) protein fibrils. TTR mutations can cause protein deposits in many extracellular regions of organs, but those deposits in cardiac and axonal cells are the primary cause of this clinical syndrome. Treatment options are limited, but new drugs are being developed. Patisiran, a novel drug, is a liposomal siRNA against TTR that specifically targets this protein, reducing the accumulation of TTR in tissues, with subsequent improvement in both neuropathy and cardiac function. Patisiran is likely to serve as a prototype for the development of further intelligent drug solutions for use in targeted therapy. In this review we summarize the evidence currently available on the treatment of polyneuropathy in people with ATTRv with patisiran. We review the evidence on its efficacy, safety, and indications of use, citing novel and seminal papers on these subjects.