Appropriateness of small molecule agents for patients with IBD of childbearing age - a RAND/UCLA appropriateness panel.

Background: Many women of childbearing age with inflammatory bowel disease (IBD) require advanced therapies. While biologics are largely low risk during pregnancy, the novel small molecules tofacitinib, filgotinib, upadacitinib and ozanimod (TFUO) have shown concerning teratogenic effects, and decreased fertility in animal studies. Therefore, their use in women of childbearing age needs careful consideration.

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A.

Introduction: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation.

Aim: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec.

Comparative Effectiveness of Valoctocogene Roxaparvovec and Prophylactic Factor VIII Replacement in Severe Hemophilia A.

Introduction: A prospective, non-interventional study (270-902) followed 294 adults with severe hemophilia A (SHA) receiving prophylactic factor VIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase 3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control.

Out of fright, out of mind: impaired memory for information negated during looming threat.

People often need to update representations of information upon discovering them to be incorrect, a process that can be interrupted by competing cognitive demands. Because anxiety and stress can impair cognitive performance, we tested whether looming threat can similarly interfere with the process of updating representations of a statement's truthfulness. On each trial, participants saw a face paired with a personality descriptor.

Failures of executive function when at a height: Negative height-related appraisals are associated with poor executive function during a virtual height stressor.

It is difficult to maintain cognitive functioning in threatening contexts, even when it is imperative to do so. Research indicates that precarious situations can impair subsequent executive functioning, depending on whether they are appraised as threatening. Here, we used virtual reality to place participants at ground level or at a virtual height in order to examine the impact of a threat-related context on concurrent executive function and whether this relationship was modulated by negative appraisals of heights.

Phase II Feasibility Study of a Weight Loss Intervention in Female Breast and Colorectal Cancer Survivors (SWOG S1008).

Objective: This study aimed to test the feasibility of a 12-month weight loss intervention using telephone-based counseling plus community-situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors.

Methods: This multisite cooperative group study enrolled sedentary, female, postmenopausal BC and CRC survivors with BMI ≥ 25 kg/m to receive 12-month fitness center memberships and telephone counseling encouraging 150 min/wk of PA and a 500-kcal/ddecrease in energy intake. Feasibility criteria included accrual, adherence, and retention.

The Ensembl Genome Browser: Strategies for Accessing Eukaryotic Genome Data.

The Ensembl Genome Browser provides a wealth of freely available genomic data that can be accessed for many purposes by genetics, genomics, and molecular biology researchers. Herein we present two protocols for exploring different aspects of these data: a phenotype and its associated variants and genes, and a promoter and the epigenetic marks and protein-binding activity associated with it. These workflows illustrate a subset of the data types available through the Ensembl Browser, and can be considered a springboard for further exploration.

Ensembl 2018.

The Ensembl project has been aggregating, processing, integrating and redistributing genomic datasets since the initial releases of the draft human genome, with the aim of accelerating genomics research through rapid open distribution of public data. Large amounts of raw data are thus transformed into knowledge, which is made available via a multitude of channels, in particular our browser (http://www.ensembl.

Ensembl Genomes 2018: an integrated omics infrastructure for non-vertebrate species.

Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species, complementing the resources for vertebrate genomics developed in the Ensembl project (http://www.

Proactive deprioritization of emotional distractors enhances target perception.

There are many situations in which it is important to focus on a task in the face of emotional distraction. Yet, emotional distractors can impair our ability to report items that appear soon after them, an effect known as emotion-induced blindness (EIB). To what degree does it help to know about emotional distractors ahead of time? Can we deprioritize emotional distractors when forewarned that they will appear? To address this question, we tested whether participants could overcome EIB when forewarned about the nature of an emotional distractor.

Ensembl 2017.

Ensembl (www.ensembl.org) is a database and genome browser for enabling research on vertebrate genomes.

Bringing Home to the Hospital: Development of the Reflection Room and Provider Perspectives.

Background: Alternative locations for children near end of life (EOL) are lacking in the United States with deaths largely occurring within intensive care units (ICUs). The reflection room (RR) was implemented as a relevant space for providing this care in our hospital.

Objective: We hypothesized staff would report a positive experience in providing EOL and/or postmortem (PM) care here and would recommend this to peers.

Medical countermeasures for unwanted CBRN exposures: part II radiological and nuclear threats with review of recent countermeasure patents.

The global threat of a chemical, biological, radiological, or nuclear (CBRN) disaster is an important priority for all government agencies involved in domestic security and public health preparedness. Radiological/nuclear (RN) attacks or accidents have become a larger focus of the United States Food and Drug administration (US FDA) over time because of their increased likeliness. Clinical signs and symptoms of a developing acute radiation syndrome (ARS) are grouped into three sub-syndromes named for the dominant organ system affected, namely the hematopoietic (H-ARS), gastrointestinal (GI-ARS), and neurovascular systems.

THE POTENTIATION OF THE RADIOPROTECTIVE EFFICACY OF TWO MEDICAL COUNTERMEASURES, GAMMA-TOCOTRIENOL AND AMIFOSTINE, BY A COMBINATION PROPHYLACTIC MODALITY.

This study was designed to evaluate the possible potentiation of survival protection afforded by relatively low-dose amifostine prophylaxis against total body irradiation in combination with a protective, less toxic agent, gamma-tocotrienol (GT3). Mice were administered amifostine and/or GT3, then exposed to 9.2 Gy Co γ-irradiation and monitored for survival for 30 days.

Progenitor Cell Mobilization by Gamma-tocotrienol: A Promising Radiation Countermeasure.

This article reviews studies of progenitor mobilization with gamma-tocotrienol (GT3), a tocol under advanced development as a radiation countermeasure for acute radiation syndrome (ARS). GT3 protects mice against high doses of ionizing radiation and induces high levels of granulocyte colony-stimulating factor (G-CSF). GT3-induced G-CSF in conjunction with AMD3100 (a chemokine receptor antagonist clinically used to improve the yield of mobilized progenitors) mobilizes progenitors; these mobilized progenitors mitigate injury when infused to mice exposed to acute, high-dose ionizing radiation.

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates.

The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model.

Use of biomarkers for assessing radiation injury and efficacy of countermeasures.

Several candidate drugs for acute radiation syndrome (ARS) have been identified that have low toxicity and significant radioprotective and radiomitigative efficacy. Inasmuch as exposing healthy human volunteers to injurious levels of radiation is unethical, development and approval of new radiation countermeasures for ARS are therefore presently based on animal studies and Phase I safety study in healthy volunteers. The Animal Efficacy Rule, which underlies the Food and Drug Administration approval pathway, requires a sound understanding of the mechanisms of injury, drug efficacy, and efficacy biomarkers.

Baseline Depressive Symptoms, Completion of Study Assessments, and Behavior Change in a Long-Term Dietary Intervention Among Breast Cancer Survivors.

Background: Depressive symptoms can lower adherence and change in dietary studies. Behavioral activation may reduce these effects.

Purpose: This study aims to assess relationships among depressive symptoms on adherence and dietary change in the Women's Healthy Eating and Living (WHEL) Study

Methods: Secondary analyses from the WHEL Study, which achieved major dietary change in breast cancer survivors (N = 2817), were conducted.

Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice.

Purpose: A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production.

Materials And Methods: Female B6D2F(1)/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound.

Animal models for acute radiation syndrome drug discovery.

Introduction: Although significant scientific advances have been made over the past six decades in developing safe, nontoxic and effective radiation/medical countermeasures (MCMs) for acute radiation syndrome (ARS), no drug has been approved by the US FDA. The availability of adequate animal models is a prime requisite under the criteria established by the FDA 'animal rule' for the development of novel MCMs for ARS and the discovery of biomarkers for radiation exposure.

Areas Covered: This article reviews the developments of MCMs to combat ARS, with particular reference to the various animal models (rodents: mouse and rat; canine: beagle; minipigs and nonhuman primates [NHPs]) utilized for the in-depth evaluation.

Progenitors mobilized by gamma-tocotrienol as an effective radiation countermeasure.

The purpose of this study was to elucidate the role of gamma-tocotrienol (GT3)-mobilized progenitors in mitigating damage to mice exposed to a supralethal dose of cobalt-60 gamma-radiation. CD2F1 mice were transfused 24 h post-irradiation with whole blood or isolated peripheral blood mononuclear cells (PBMC) from donors that had received GT3 72 h prior to blood collection and recipient mice were monitored for 30 days. To understand the role of GT3-induced granulocyte colony-stimulating factor (G-CSF) in mobilizing progenitors, donor mice were administered a neutralizing antibody specific to G-CSF or its isotype before blood collection.

Biologics as countermeasures for acute radiation syndrome: where are we now?

Despite significant scientific advances toward the development of a safe, nontoxic and effective radiation countermeasure for acute radiation syndrome (ARS) over the past six decades, no drug has been approved by the US FDA. Several biologics are currently under development as radiation countermeasures for ARS, of which three have received FDA Investigational New Drug (IND) status for clinical investigation. Presently, two of these agents, entolimod (CBLB502) and HemaMax (recombinant human IL-12) are progressing with large animal studies and clinical trials.

Radiation countermeasure agents: an update (2011-2014).

Introduction: Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government.

Area Covered: This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures.

Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): a review.

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event.

Tocols induce G-CSF and mobilise progenitors that mitigate radiation injury.

Tocols induce high levels of granulocyte-colony-stimulating factor (G-CSF). G-CSF mobilises progenitors that allow mice that have been severely immunocompromised by exposure to acute, high-dose ionising irradiation to recover and to survive. The neutralisation of G-CSF abrogates the radioprotective efficacy of tocols.