Efficacy and Safety of Direct Oral Anticoagulants (DOACs) Versus Warfarin in Atrial Fibrillation Patients with Prior Stroke: a Systematic Review and Meta-analysis.

BACKGROUND: The purpose of this meta-analysis was to compare efficacy and safety of direct oral anticoagulants (DOACs) to warfarin for secondary stroke prevention among adult patients with atrial fibrillation and prior stroke. METHODS: Major repositories were screened for randomized controlled trials (RCTs), RCT subgroups, and observational studies (OBSs, divided in claims and non-claims). Occurrences of ischemic stroke or transient ischemic attack, systemic embolism, all-cause mortality, intracranial hemorrhage (ICH), and major bleeding were outcomes of interest. Hazard ratios (HRs) and their confidence intervals (95%CIs) were pooled using random-effects models for each study design. Claims studies were analyzed separately from non-claims, while RCT subgroups were grouped with OBSs (non-claims) as the randomization was broken. RESULTS: Of 8647 articles, 20 were included (one RCT, six RCT subgroups, nine claims, and four non-claims). Comparing DOACs to warfarin, pooled HRs (95%CI) were consistently in favor of DOACs although some did not reach statistical significance: for ischemic stroke, 0.84 (0.66-1.07) in claims; 0.90 (0.77-1.06) in non-claims and RCT subgroups; for systemic embolism, 0.77 (0.62-0.96) in claims; 0.86 (0.77-0.96) in non-claims and RCT subgroups; for all-cause mortality, 0.57 (0.33-0.99) in claims; 0.87 (0.79-0.96) in non-claims and RCT subgroups; for ICH, 0.72 (0.39-1.33) in claims; 0.51 (0.38-0.67) in non-claims and RCT subgroups; and for major bleeding, 0.86 (0.71-1.03) in claims; 0.90 (0.76-1.08) for non-claims and RCT subgroups. CONCLUSION: DOACs were associated with better efficacy and safety profiles than warfarin in atrial fibrillation patients with prior stroke, more specifically a lower risk of systemic embolism, all-cause mortality, and ICH.

Extended duration venous thromboembolism prophylaxis with betrixaban for patients re-admitted with venous thromboembolism.

Patients hospitalized for an acute medical illness remain at risk of developing venous thromboembolism (VTE) post-discharge. Betrixaban, an oral direct Factor Xa inhibitor, is approved for extended VTE thromboprophylaxis in acutely ill medical patients. The primary objective of this study was to evaluate patients re-admitted with VTE within 30 days of discharge to determine if they would have been eligible for extended duration VTE prophylaxis during the index admission. We used three different sets of eligibility criteria: the APEX study criteria, the Bevyxxa® (betrixaban) package insert, and Mass General Brigham HealthCare System's Center for Drug Policy Guidelines. A secondary aim was to describe the reasons for ineligibility. Within 30 days of the index hospital admission, 226 patients were re-admitted with new VTE between January 2017 and December 2018. Of these, 134 (59%) were excluded based on pre-defined exclusion criteria. Of the remaining 92, 22 patients (23.9%) were eligible based on the APEX study criteria, 26 patients (28.2%) based on Mass General Brigham HealthCare System's Center for Drug Policy Guidelines, and 92 patients (100%) based on the Bevyxxa® package insert. There were 22 patients (23.9%) who were eligible for VTE prophylaxis with betrixaban based on all three criteria. Appropriate betrixaban use may have prevented some of the VTE events and re-admissions that occurred within 30 days of initial hospital discharge.

Characterization of ß-turns by electronic circular dichroism spectroscopy: a coupled molecular dynamics and time-dependent density functional theory computational study.

Electronic circular dichroism is one of the most used spectroscopic techniques for peptide and protein structural characterization. However, while valuable experimental spectra exist for α-helix, ß-sheet and random coil secondary structures, previous studies showed important discrepancies for ß-turns, limiting their use as a reference for structural studies. In this paper, we simulated circular dichroism spectra for the best-characterized ß-turns in peptides, namely types I, II, I' and II'. In particular, by combining classical molecular dynamics simulations and state-of-the-art quantum time-dependent density functional theory (with the polarizable embedding multiscale model) computations, two common electronic circular dichroism patterns were found for couples of ß-turn types (namely, type I/type II' and type II/type I'), at first for a minimal di-peptide model (Ace-Ala-Ala-NHMe), but also for all sequences tested with non-aromatic residues in the central positions. On the other hand, as expected, aromatic substitution causes important perturbations to the previously found ECD patterns. Finally, by applying suitable approximations, these patterns were subsequently rationalized based on the exciton chirality rule. All these results provide useful predictions and pave the way for a possible experimental characterization of ß-turns based on circular dichroism spectroscopy.

Thromboembolism, Bleeding, and Mortality Incidence of Direct Oral Anticoagulants Versus Warfarin Postbariatric Surgery.

BACKGROUND: There is no randomized controlled trial comparing direct oral anticoagulants (DOACs) and warfarin following bariatric surgery to date. The mortality, thromboembolism, and bleeding risk of DOACs in comparison with warfarin following bariatric surgery remains unclear. We aimed to provide a clinical comparison between DOACs and warfarin for these 3 prespecified outcomes. METHODS: A systematic literature search was performed on November 10, 2019, using PubMed, Embase, clinicaltrial.gov, and Cochrane databases. Studies with adult patients who were on either warfarin or DOACs following bariatric surgery and reported the incidence of thromboembolism, bleeding, or mortality were included. Pooled incidence for these prespecified outcomes and its 95% confidence interval (CI) were calculated for each drug separately using the random-effects model, along with a nonadjusted P value comparing the 2 subgroups. RESULTS: A total of 11 studies (805 patients) were included. Comparing DOACs to warfarin, the following pooled incidences were observed for mortality (DOACs: 3.0%; 95% CI 0.4%-18.6% versus warfarin: 1.5%; 95% CI 0.8%-2.9%; P value comparing the 2 subgroups = .38), thromboembolism (DOACs: 4.9%; 95% CI 1%-21.1% versus warfarin: 1.5%; 95% CI 0.8%-2.9%; P value = .18), and bleeding (DOACs: 3.9%; 95% CI 0.7%-18.2% versus warfarin: 11.3%; 95% CI 5.7%-21.4%; P value = .23). CONCLUSION: The results of our meta-analysis remain hypothesis-generating, providing rationale for future randomized controlled trial design or well-designed comparative observational studies. Currently, it does not support the change in the current recommendation from warfarin to DOACs following bariatric surgery.

Inhibition of PAR-1 Receptor Signaling by Enoxaparin Reduces Cell Proliferation and Migration in A549 Cells.

BACKGROUND/AIM: Low-molecular weight heparins (LMWHs) may possess putative antitumoral properties; however, the underlying mechanism(s) remains elusive. We evaluated the antiproliferative and antimigratory effects of enoxaparin (a LMWH) in lung adenocarcinoma A549 cells, and assessed the possible mechanism involved, and the effect on doxorubicin's efficacy. MATERIALS AND METHODS: Proliferation and migration were evaluated using BrdU and transwell assays, respectively. Immunoblotting was used to measure PAR-1, PAR-2, MMP-2, ERK1/2 and Akt proteins. Apoptosis and cell cycle studies examined the combined effect of enoxaparin and doxorubicin. RESULTS: Enoxaparin inhibited A549 cell proliferation and migration. Following PAR-1 gene knock down, enoxaparin's effect on A549 cell proliferation was diminished compared to scrambled siRNA. Our experiments verified that enoxaparin-mediated down-regulation of MAPK and PI3K, reduced MMP-2 expression and inhibited A549 cell migration. Additionally, enoxaparin increased doxorubicin's efficacy by enhancing apoptosis, while no effect on cell-cycle progression was observed. CONCLUSION: Results suggest that the anticancer activity of enoxaparin in A549 cells was mediated by the interference of two major PAR-1 downstream signaling pathways, MAPK/ERK and PI3K/Akt, which in turn inhibit proliferation and migration. Therefore, enoxaparin may be promising as an adjunct to traditional chemotherapy for lung cancer and warrants further investigation.

Complex Environmental Rearing Enhances Social Salience and Affects Hippocampal Corticotropin Releasing Hormone Receptor Expression in a Sex-Specific Manner.

Methods for understanding the neurocircuitry of ethologically relevant behaviors have advanced substantially; however renovations to standard animal laboratory housing, in the form of enhanced enrichment, have lagged behind. This is despite evidence that environmental enrichment (EE) reduces stress, stereotypy, and promotes healthy species typical behaviors. While many scientists express interest for increased EE as a standard for animal caging systems, there are concerns that its effects on brain, behavior, and cognition are not well characterized. In the present study, male and female Sprague-Dawley rats were housed for six weeks in either EE, Colony Nesting (CN), or Standard Housing (SD) conditions. We show that adolescent exposure to environmental complexity changed the dynamics of social interactions, sensory processing, and underlying basal stress neurocircuitry, in a sex- and enrichment-type-dependent manner. Specifically, EE and CN increased prosocial engagement and the social saliency of male and female rats while the profile of hippocampal Crhr2 expression was affected only in EE males. Hippocampal Crh was associated with anxiety-like behavior in SD males - this did not extend to EE or CN groups, nor to females. Observations such as these are an important consideration for the validity of translational research investigating the neurocircuitry of stress resiliency, and for understanding the mechanisms of psychiatric disorders. Future work must focus on characterizing how individual environmental enhancements (e.g. novelty, social enrichment, physical activity) shape phenotypic differences, how they vary as a function of species, strain and sex, and (if warranted) how to meaningfully implement this knowledge into biomedical research designs.

Targeted sensory enrichment interventions protect against behavioral and neuroendocrine consequences of early life stress.

Both basic and clinical research support the use of tactile stimulation to rescue several neurobiobehavioral consequences that follow early life stress. Here, using a translational rodent model of the neonatal intensive care unit (NICU), we tested the individual prophylactic potential of a variety of sensory interventions including tactile (brushing pups with a paint brush to mimic maternal licking), auditory (a simulated lactating rat dam heart beat), and olfactory (a series of aroma therapy scents) stimulation. The NICU model was developed to mimic not only the reduced parental contact that sick infants receive (by isolating rat pups from their litters), but also the nosocomial infections and medical manipulations associated with this experience (by utilizing a dual lipopolysaccharide injection schedule). Each of the neurobiobehavioral consequences observed were dissociable between isolation and inflammation, or required a combined presentation ('two hits') of the neonatal stressors. Sprague-Dawley rats exposed to these early life stressors presented with sex-specific disruptions in both separation-induced ultrasonic vocalization (USV) distress calls (males & females) and juvenile social play USVs (males only). All three sensory enhancement interventions were associated with the rescue of potentiated distress calls while olfactory stimulation was protective of social vocalizations. Female rats exposed to early life stress experienced precocious puberty and shifts in the hypothalamic GnRh axis; sensory enrichment counter-acted the advanced pubertal onset. Animals that underwent the NICU protocol also displayed maturational acceleration in terms of the loss of the rooting reflex in addition to hyperalgesia, a reduced preference for a novel conspecific, blunted basal plasma corticosterone and reduced hippocampal glucocorticoid receptor expression. These alterations closely simulated the clinical effects of early life adversity in terms of disruptions in the hypothalamic pituitary "stress" axis, social communication and engagement, tactile system processing, and accelerated maturation. Moreover, sensory enrichment attenuated many of these behavioral and neurophysiological alterations, and even slowed maturation. Overall, this supports the translatability of our novel rodent model and its potential utility in understanding how brain maturation and quality of early life experiences may interact to shape the integrity of stress and sensory system development. Future work must determine the appropriate modalities and parameters (e.g. patterning, timing) for effective sensory enrichment interventions.

Educational and career goals of pharmacy students upon graduation.

OBJECTIVE: To assess the doctor of pharmacy (PharmD) students' desire to obtain additional degrees after graduation. METHODS: During the spring 2011 semester, an anonymous 14-question survey instrument was administered to students across all 6 years of the PharmD program to evaluate their interest in obtaining an additional degree after graduation. Demographic data was also collected and analyzed from this convenience sample. RESULTS: Approximately 34% of the respondents (n=1,239) indicated a desire to seek an additional degree. Of the additional degrees offered in the survey instrument, more than one-third of the students expressed interest in the master of business administration (MBA). Also, 79% of those respondents were willing to take summer courses to achieve a dual or additional degree. CONCLUSION: Pharmacy students are interested in obtaining an additional degree(s) after graduation and are willing to complete summer courses to achieve their career goals.

A new paradigm in health care curriculums: the pharmaceutical and health care business degree.

The rapid growth of the healthcare industry, and the need to operate more efficiently in this environment, has generated an unmet need for competent business professionals with knowledge of the health care sciences. Additionally, student demand for a business curriculum that would satisfy the needs of the health care industry has provided the impetus for the development of the B.S. Pharmaceutical Health Care and Business program (PHCB). The purpose of this paper is to illustrate the evolution of this innovative curriculum within a school of Pharmacy, and to assess student satisfaction with the current PHCB program. To that end, a 19-item online questionnaire was developed and a group of 56 graduates (2007-2009) were surveyed which resulted in a response rate of 80%. The findings of this study indicated there was an overall high level of student satisfaction with this curriculum with an average of 86%, and that the PHCB program may offer potential to prepare graduates for the business and managerial aspects in the pharmaceutical, biotech, medical device, hospital and other allied health care segments.

Brain delivery of proteins by the intranasal route of administration: a comparison of cationic liposomes versus aqueous solution formulations.

The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 microg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with (111)In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the shortest time point, 1 h, for both liposomal and aqueous OVAL. However, the liposomes yielded higher (111)In-OVAL concentrations in brain than (111)In-OVAL in PBS. Moreover, a 2 microg/microL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 microg/microL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders.