STORMTOOLS: Coastal Environmental Risk Index (CERI)

One of the challenges facing coastal zone managers and municipal planners is the development of an objective, quantitative assessment of the risk to structures, infrastructure, and public safety that coastal communities face from storm surge in the presence of changing climatic conditions, particularly sea level rise and coastal erosion. Here we use state of the art modeling tool (ADCIRC and STWAVE) to predict storm surge and wave, combined with shoreline change maps (erosion), and damage functions to construct a Coastal Environmental Risk Index (CERI). Access to the state emergency data base (E-911) provides information on structure characteristics and the ability to perform analyses for individual structures. CERI has been designed as an on line Geographic Information System (GIS) based tool, and hence is fully compatible with current flooding maps, including those from FEMA. The basic framework and associated GIS methods can be readily applied to any coastal area. The approach can be used by local and state planners to objectively evaluate different policy options for effectiveness and cost/benefit. In this study, CERI is applied to RI two communities; Charlestown representing a typical coastal barrier system directly exposed to ocean waves and high erosion rates, with predominantly low density single family residences and Warwick located within Narragansett Bay, with more limited wave exposure, lower erosion rates, and higher residential housing density. Results of these applications are highlighted herein

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

Oral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500 μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

open access articleOral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500 μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

Oral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents

Early diastolic filling dynamics in diastolic dysfunction

BACKGROUND: The aim of the study was to determine the relationship between the rate of peak early mitral inflow velocity and the peak early diastolic mitral annular tissue velocities in normal controls and to compare them with subjects with diastolic dysfunction. METHODS: The relationship between early passive diastolic transmitral flow and peak early mitral annular velocity in the normal and in diastolic dysfunction was studied. Two groups comprising 22 normal controls and 25 patients with diastolic dysfunction were studied. RESULTS: Compared with the normal group, those with diastolic dysfunction had a lower E/A ratio (0.7 ± 0.2 vs. 1.9 ± 0.5, p < 0.001), a higher time-velocity integral of the atrial component (11.7 ± 3.2 cm vs. 5.5 ± 2.1 cm, p < 0.0001), a longer isovolumic relaxation time 73 ± 12 ms vs. 94 ± 6 ms, p < 0.01 and a lower rate of acceleration of blood across the mitral valve (549.2 ± 151.9 cm/sec(2 )vs. 871 ± 128.1 cm/sec(2), p < 0.001). They also had a lower mitral annular relaxation velocity (Ea) (6.08 ± 1.6 cm/sec vs 12.8 ± 0.67 cm/sec, p < 0.001), which was positively correlated to the acceleration of early diastolic filling (R = 0.66), p < 0.05. CONCLUSIONS: This investigation provides information on the acceleration of early diastolic filling and its relationship to mitral annular peak tissue velocity (Ea) recorded by Doppler tissue imaging. It supports not only the premise that recoil is an important mechanism for rapid early diastolic filling but also the existence of an early diastolic mechanism in normal

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701