Clinical outcomes associated with anti-Xa-monitored enoxaparin for venous thromboembolism prophylaxis.

STUDY OBJECTIVE: The objective of the study was to assess clinical outcomes (composite of any venous thromboembolism [VTE], any bleeding, and mortality) associated with anti-Xa monitoring in the 30 days following enoxaparin initiation for VTE prophylaxis. DESIGN: Retrospective cohort study. SETTING: Hospital within an academic healthcare system. PATIENTS: Propensity score-matched hospitalized adults receiving enoxaparin for VTE prophylaxis. INTERVENTION: Low-molecular-weight heparin anti-Xa monitoring. MEASUREMENTS AND MAIN RESULTS: During the 13-month study period, a total of 6611 patients received enoxaparin for VTE prophylaxis, 301 in the anti-Xa monitored group and 6310 in the unmonitored group (4.6% received monitoring). The mean age was 52.9 years and 52% of patients were male. The mean body mass index was 31 kg/m2 and the mean creatinine clearance was 109 mL/min. Twenty percent of patients had active cancer. The most common indication for enoxaparin prophylaxis was hospitalization for medical illness (52%) followed by nonorthopedic surgery (37%). The adjusted odds ratio for the primary outcome comparing monitored to unmonitored patients was 1.26 (95% confidence interval, 0.75-2.11). None of the between-group differences in the individual components of the composite outcome were statistically significant. CONCLUSIONS: Thirty-day clinical outcomes in patients receiving enoxaparin for VTE prophylaxis were not improved by anti-Xa monitoring. Our results support current evidence-based guideline recommendations against anti-Xa monitoring for patients receiving enoxaparin for VTE prophylaxis.

Trends in antiplatelet strategies 12-months following coronary stent placement in anticoagulated patients.

BACKGROUND: Antithrombotic guidelines for patients undergoing percutaneous coronary interventions (PCIs) and also requiring anticoagulant medications are evolving. This study describes changes to antithrombotic therapy and associated outcomes 12-months following PCI in patients requiring ongoing anticoagulation therapy. METHODS: Records of patients identified from queries of electronic medical records were manually reviewed to verify changes to antithrombotic therapy from discharge to 12-months and at 12-months following PCI, and episodes of major bleeding, clinically relevant non-major bleeding (CRNMB), major adverse cardiovascular or neurological events (MACNE), and all-cause mortality outcomes during an additional 6-months follow-up. RESULTS: Patients (n = 120) receiving anticoagulation therapy at 12-months post PCI were classified into the following groups according to antiplatelet therapy status: no antiplatelet therapy (n = 16), single antiplatelet therapy (SAPT) (n = 85), and dual antiplatelet therapy (DAPT) (n = 19). Between 12- and 18-months following PCI there were 2 major bleeds, 7 CRNMB, 6 MACNE, 2 venous thromboembolisms, and 5 deaths. All but one bleeding episode occurred in the SAPT group. The odds of remaining on DAPT at 12-months were higher in patients who had PCI for acute coronary syndrome (odds ratio [OR] 2.91, 95% confidence interval [CI] 0.96, 8.77), and in those experiencing MACNE in the 12-months following PCI (OR 1.95, 95% CI 0.67, 5.66), but these associations were not statistically significant. CONCLUSION: Most anticoagulated patients were continued on antiplatelet therapy 12-months post PCI. Bleeding was numerically more common in anticoagulated patients continuing SAPT therapy beyond 12 months. There was significant variability in antithrombotic prescribing patterns 12-months post PCI suggesting a potential opportunity for standardizing care in this patient population.

A scoping review of direct oral anticoagulant ambulatory management practices.

Models of care for managing direct oral anticoagulant (DOAC) therapy are evolving. Little is known of what services are provided by anticoagulation managements services (AMS) for DOACs, or what necessitates comprehensive DOAC management and what differentiates it from usual care. The purpose of this scoping review was to describe services, management, or monitoring of DOACs distinct from prescriber-managed or usual care of DOACs. This scoping review reported followed the 2018 Preferred Reporting Items for Systematic Review and Meta-Analyses extension for scoping reviews (PRISMA-ScR). We searched PubMed, CINAHL, and EMBASE from inception to November 2020 to identify articles of interest. No language restriction was applied. Articles were included if they provided a description of DOAC management services, and described longitudinal anticoagulation follow-up that occurred in ambulatory care, community, or outpatient-related settings. Data was extracted from a total of 23 articles. The specific types of DOAC management interventions provided varied across the included studies. Nearly all studies described some form of DOAC therapy appropriateness assessment. Other common interventions included assessments of DOAC therapy compliance, adverse event triage and management, assessment of DOAC dosing appropriateness, periprocedural management of DOAC therapy, educational interventions, and renal function monitoring. A variety of DOAC management interventions were identified, but additional studies are needed to help health systems decide whether specific interventions performed by dedicated services are preferred over the usual care provided by clinicians prescribing DOAC therapy.

Outcomes of isolated distal thrombosis managed with serial compression ultrasonography.

BACKGROUND: Isolated distal deep vein thrombosis (IDDVT) is a common subtype of deep vein thrombosis (DVT). Consensus guidelines provide conflicting recommendations for IDDVT management; some recommend anticoagulant treatment, while others suggest serial compression ultrasonography (CUS) monitoring for patients not at "high risk" of proximal extension. The purpose of this study was to describe outcomes of serial CUS-monitored IDDVT and identify risk factors for proximal thrombus extension or anticoagulant treatment initiation. METHODS: A retrospective descriptive study was conducted using electronic data from University of Utah Health. Adult subjects with objectively confirmed, serial CUS-monitored IDDVT were included. Subjects were followed for 30 days for occurrence of a composite outcome of proximal thrombus extension or anticoagulant treatment initiation. Descriptive statistics were used to summarize characteristics of the study population. Characteristics were compared across outcome groups using inferential statistics. RESULTS: A total of 182 subjects were included, with 53 subjects (29.1%) experiencing the composite outcome. Of these, 12 (22.6%) experienced proximal thrombus extension and 41 (77.4%) initiated anticoagulant treatment. A prior history of venous thromboembolism (VTE) was significantly higher in those who experienced the composite outcome than in those who did not. CONCLUSIONS: Our results suggest that 70% of patients with serial CUS-monitored IDDVT did not experience thrombus extension or require anticoagulant treatment within 30 days of diagnosis, regardless of risk factors for proximal extension. Serial CUS monitoring may be a useful management strategy for IDDVT. A history of VTE may identify patients more likely to experience proximal thrombus extension or require anticoagulation.

Real-world assessment of off-label direct oral anticoagulant dosing for venous thromboembolism.

Preferred anticoagulation therapy for venous thromboembolism (VTE) has shifted from warfarin to direct oral anticoagulants (DOACs). Adherence to DOAC prescribing information is an important quality measure as off-label doses have been associated with increased risk of adverse events (AEs). To identify the prevalence, outcomes, and patient characteristics associated with off-label DOAC dosing during VTE treatment. Patients receiving DOAC for VTE treatment discharged from University of Utah Health (UUH) over a 90-day period were identified. Dosing was classified as "labeled" or "off-label" based on concordance with manufacturer prescribing information. AEs (thromboembolic events, bleeding, death) occurring within 90 days after discharge were identified. Out of 195 patients, 154 (79.0%) received labeled dosing, 31 (15.9%) received off-label dosing, and 10 (5.1%) were indeterminate. Two-thirds of off-label doses were higher than recommended and three-fourths occurred during extended treatment (more than 90 days post-VTE). Off-label dosing rates dropped to 5.6% when 6-month dose reductions were not required. Off-label dosing was associated with apixaban use and extended phase treatment (p < 0.001). No association was found between off-label dosing and age, renal function, prescriber rationale for dose selection, or Thrombosis Clinic referral. AEs were experienced by 18 (11.7%) and 3 (9.7%) patients in the labeled and off-label groups, respectively (p = 0.77). Bleeding events comprised 46.2% of AEs. The rate of off-label DOAC dosing for VTE at UUH was within rates reported in prior studies, occurred primarily with extended-duration apixaban, and did not result in a higher rate of AEs.

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.

Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.

Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.

Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Electroencephalographic changes following direct current deep brain stimulation of auditory cortex: a new model for investigating neuromodulation.

BACKGROUND: Although deep brain (DBS) and transcranial direct current stimulation (tDCS) are used as investigative tools and therapies for a variety of neurological and psychiatric conditions, their mechanisms of action remain poorly understood. Therefore, there is a need for new animal models of neuromodulation. OBJECTIVE: To introduce and validate a direct current DBS (DC-DBS) model that will use the anatomic precision of intracranial electrodes, as used in DBS, to apply direct current, as used in tDCS, over primary auditory cortex (A1) and induce electroencephalographic (EEG) changes. METHODS: Twenty-four mice were assigned to 1 of 2 stimulation groups or a sham group and were implanted with electrodes in A1. Stimulation groups underwent DC-DBS stimulation for 20 minutes at 20 µA. Auditory EEG was recorded before stimulation and at 1 hour, 1 week, and 2 weeks poststimulation. EEG was analyzed for changes in N1 (N100 in humans, N40 in mice) amplitude and latency as well as delta and theta power. RESULTS: DC-DBS led to significant EEG changes (all P values < .05). Among the stimulated animals, there were durable reductions in delta and theta power. There were no differences within the sham group, and neither N40 latencies nor amplitudes changed across time. CONCLUSION: Our results show DC-DBS-induced reductions in slow-wave activity consistent with recent tDCS studies. We propose that this model will provide a means to explore basic mechanisms of neuromodulation and could facilitate future application of DC-DBS in humans.

NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders.

Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials.

Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice.

Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.

NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia.

RATIONALE: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. DESIGN: Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose-response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5-10 Hz) and high (35-80 Hz)-frequencies. RESULTS: High frequency evoked and total power was decreased by MK-801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. CONCLUSIONS: Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia.

Reduced parenteral nutrition requirements following anastomosis of a short residual colonic segment to a short jejunum.

A 22-year-old man suffered an acute small bowel infarct leading to extensive bowel resection, resulting in only 20 cm of jejunum to a jejunostomy, although he also had 50 cm of residual colon with a mucous fistula. The patient was out on long-term home parenteral nutrition (PN) but endured high stomal losses of 5-6 L per day and, despite all conventional measures, required 6.1 L of fluid (including PN) and 555 mmol sodium per day. Although body mass index was maintained, he suffered debilitating malaise and recurrent episodes of catheter-related sepsis and also developed persistently abnormal liver function tests. He was considered a potential intestinal transplant patient, but before taking that step, he opted for reanastomosis of his residual colon to his jejunum, ending in a colostomy. At surgery, only 30 cm of additional bowel lengthening could be achieved, but despite this, the patient's stomal losses reduced to 2.5 L per day, intravenous fluid requirements reduced to 4.1 L per day, and liver function normalized. The patient also gained 7.5 kg despite no change in PN caloric prescription, and his quality of life was dramatically enhanced. The case illustrates that even a small length of colon can grant significant improvements, probably via improvements in small bowel transit and adaptive changes, better sodium and water resorption with decreased hyperaldosteronism, and enhanced energy and nitrogen recovery. Reanastomosis of defunctioned colon should therefore always be considered a management option in short bowel syndrome.