Centre bow (CB) design for wave-piercing catamarans (WPCs) is a critical compromise between minimization of slamming and protection against deck diving. To inform the design process, this article ...investigates the slam loads and kinematics during bow entry events in regular head seas for a 112-m WPC with systematic variations to its CB and wet-deck geometry. Model tests using a 2.5-m hydroelastic segmented catamaran considered five different CB configurations, designated as the parent, high, low, long, and short CB. The results indicated that changes in the CB length had little effect on the general kinematic trends obtained for the pitch, heave, and bow vertical displacement at the instant of slamming, but increasing the wet-deck height resulted in an increase in heave (but not pitch) at slamming. Two new design ratios are proposed. The CB immersion depth to arch height ratio showed slamming occurring in the range of 0.3-0.6 depending on the wave encounter frequency and the CB configuration. The CB buoyancy in the encountered waves was estimated by considering both immersion depth and area along the CB in waves through relative motion analyses. It was found that the buoyancy to slam force ratio increased with increasing wet-deck height but not with increasing CB length. This suggests that an optimal CB configuration could be achieved by first modifying the arched cross-structure to reduce the arch filling effect on slamming severity and then maximizing the CB buoyancy to slam force ratio by increasing either the wet-deck height or the CB length.
1. Introduction
An above-water centre bow (CB) for improving seakeeping is a feature of modern wave-piercing catamarans (WPCs) (Soars 1993; Boulton 1998; Fang & Chan 2007; Dubrovsky 2014). Figure 1 shows a 112-m Incat WPC with the CB located between the two demihulls.
There are several important factors to be considered when designing such a central bow. First, the reserve buoyancy offered by the CB is the primary design factor for providing a pitchrestoring moment and eliminating deck diving in the following waves (Davis & Whelan 2007). Second, the CB configuration can influence the slamming loads in WPCs during bow entry in waves (Lavroff et al. 2013). This is due to the complex fluid-structure interaction in the CB area. When the CB enters waves, the water gradually fills the spaces between the CB and demihulls, referred to here as archways, and may result in complete closure of the archways and slamming in excessive pitch conditions. Finally, the frequency of slamming occurrence is, to some extent, related to the CB design as it contributes to lateral jet flow during the CB entry. As a result, slamming may occur in even partial water entrapment below the arch wet-deck cross-structure, which could be the case in small pitch motions (Lavroff & Davis 2015).
Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD ...and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbitnurils (CBn) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system.
In this study we investigated the toxicology, uptake, and bioactivity of two cucurbitnurils (CB5 and CB7) and three CBn-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB7 molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB7 as when given in the unbound form. This result suggests that CB7-bound drug molecules can be released from the container to find their intracellular target.
Our study reveals very low toxicity of five members of the cucurbitnuril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CBn molecular containers as an advanced drug delivery system.
This study aimed to translate movement patterns, technical skills and tactical actions associated with high-intensity efforts into metrics that could potentially be used to construct ...position-specific conditioning drills. A total of 20 individual English Premier League players' high-intensity running profiles were observed multiple times (n = 100) using a computerised tracking system. Data were analysed using a novel high-intensity movement programme across five positions (centre back CB, full-back FB, central midfielder CM, wide midfielder WM and centre forward CF). High-intensity efforts in contact with the ball and the average speed of efforts were greater in WMs than CBs, CMs and CFs (effect sizes ES: 0.9-2.1, P < 0.05). WMs produced more repeated efforts than CBs and CMs (ES: 0.6-1.3, P < 0.05). In possession, WMs executed more tricks post effort than CBs and CMs (ES: 1.2-1.3, P < 0.01). FBs and WMs performed more crosses post effort than other positions (ES: 1.1-2.0, P < 0.01). Out of possession, CFs completed more efforts closing down the opposition (ES: 1.4-5.0, P < 0.01) but less tracking opposition runners than other positions (ES: 1.5-1.8, P < 0.01). CFs performed more arc runs before efforts compared to CBs, FBs and WMs (ES: 0.9-1.4, P < 0.05), however, CBs completed more 0-90° turns compared to FBs, CMs and WMs (ES: 0.9-1.1, P < 0.01). The data demonstrate unique high-intensity trends in and out of possession that could assist practitioners when devising position-specific drills.
•Proposed a DDC block with four cascade branches to cope large morphological differences in gliomas.•Redesigned skip connections to overcome the large contextual gap between encoder-decoder.•Proposed ...a new loss function to handle unequal class distribution in gliomas.•A single convolutional operation is included in the feature encoder and decoder.•CB-D2RNet uses only 6.7 million parameters.
The recent automatic glioma segmentation and localization techniques obtained promising results, but there is much scope for improvement in execution complexity and segmentation efficiency. These methods often fail to pinpoint small and isolated target locations in necrotic and enhancing glioma sub-regions. Moreover, the computational complexity and number of model parameters utilized in these techniques are also high. To address such issues, a Context Bridge-Dense Dilated Residual Net (CB-D2RNet) is proposed in this paper which reflects the five novel contributions. Firstly, a Dense Dilated Convolutional (DDC) block is formed with four cascade branches to cope with large morphological differences in gliomas. Secondly, the skip connections in traditional UNet are redesigned to overcome the large contextual gap between encoder-decoder. Thirdly, a new loss function is proposed that handles unequal class distribution in gliomas and provides a regularization impact. Fourthly, the precise selection of dilation rates is made for each dilated convolutional block in the feature encoder to gather a more receptive view of complex and multiple tumor regions. Lastly, only a single convolutional operation is included in the feature encoder and decoder, unlike other state-of-the-art models. The experiments are conducted on BraTS 2018 and BraTS 2019 benchmarks, demonstrating that the proposed model performs competitively in all three glioma sub-regions. It achieves dice similarity coefficient for the whole tumor, tumor core, and enhancing tumor as 0.982, 0.987, and 0.976, respectively for the BraTS 2018 dataset, whereas 0.983, 0.989, and 0.977 respectively for the BraTS 2019 dataset. Besides this, the model uses only 6.7 million parameters, the lowest among other compared models.
To describe the experience of screening patients with asthma for allergic bronchopulmonary aspergillosis (ABPA) presenting to a chest clinic. The clinical, serologic, radiologic, and treatment ...aspects including outcome of ABPA are also described.
All consecutive patients with asthma presenting to the chest clinic over a period of 2 years were screened with an Aspergillus skin test. Patients who were found to be positive were further investigated for ABPA. Patients were also arbitrarily classified as ABPA-seropositive (ABPA-S), ABPA with central bronchiectasis (ABPA-CB), and ABPA-CB with other radiologic findings (ABPA-CB-ORF) based on the high-resolution CT findings.
Five hundred sixty-four patients were screened using an Aspergillus skin test; 223 patients (39.5%) were found to be positive, and ABPA was diagnosed in 126 patients (27.2%). There were 34 patients (27%) with ABPA-S, 42 patients with ABPA-CB, and 50 patients with ABPA-CB-ORF. Fifty-nine patients (46.8%) had received antitubercular therapy in the past. The vast majority of patients had bronchiectasis at presentation to our hospital. High-attenuation mucous impaction was noted in 21 patients (16.7%). There was no significant difference between the stages of ABPA and the duration of illness, the severity of asthma, and the serologic findings (ie, absolute eosinophil count, IgE levels total and IgE levels for Aspergillus fumigatus). The median duration of follow-up was 13 months (range, 9 to 38 months). All patients went into "remission" at 6 weeks. Twenty-five patients had a "relapse" during the course of their treatment. One hundred nine patients had "complete remission," 17 patients were classified as having "glucocorticoid-dependent ABPA," and 7 patients were classified as having "end-stage ABPA."
There is a high prevalence of ABPA in asthmatic patients presenting at our hospital. The disease entity is still underrecognized in India; the vast majority of patients have bronchiectasis at presentation, and almost half are initially misdiagnosed as having pulmonary tuberculosis. There is a need to redefine the definitions of ABPA and the optimal dose/duration of glucocorticoid therapy. This study reinforces the need for the routine screening of asthmatic patients with an Aspergillus skin test.
Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB
receptor signaling for therapeutic benefits that may avoid the adverse effects associated with ...orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB
negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB
allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB
agonist CP55,940 stimulated calcium mobilization and
SGTP-γ-S binding. Similar to 1, most compounds showed positive cooperativity by increasing
HCP55,940 binding, consistent with the positive allosteric modulator (PAM)-antagonist mechanism. Interestingly, these compounds exhibited differences in ability to increase specific binding of
HCP55,940 and decrease binding of the antagonist
HSR141716. In saturation binding studies, only increases in
HCP55,940 B
, but not K
, were observed, suggesting that these compounds stabilize low affinity receptors into a high affinity state. Among the series, the 2-pyrrolyl analogue (13) exhibited greater potency than 1 in the
SGTP-γ-S binding assay and significantly enhanced the maximum binding level in the
HCP5,5940 binding assay, indicating greater CB
receptor affinity and/or cooperativity.
Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. ...Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (
p
≤ 0.03) and lymphatic invasion (
p
≤ 0.015). In CB high tumor budding was significantly (
p
= 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.
In this paper a new detection scheme for convective initiation (CI) under day and night conditions is presented. The new algorithm combines the strengths of two existing methods for detecting CI with ...geostationary satellite data. It uses the channels of the Spinning Enhanced Visible and Infrared Imager (SEVIRI) onboard Meteosat Second Generation (MSG). For the new algorithm five infrared (IR) criteria from the Satellite Convection Analysis and Tracking algorithm (SATCAST) and one high-resolution visible channel (HRV) criteria from Cb-TRAM were adapted. This set of criteria aims to identify the typical development of quickly developing convective cells in an early stage. The different criteria include time trends of the 10.8 IR channel, and IR channel differences, as well as their time trends. To provide the trend fields an optical-flow-based method is used: the pyramidal matching algorithm, which is part of Cb-TRAM. The new detection scheme is implemented in Cb-TRAM, and is verified for seven days which comprise different weather situations in central Europe. Contrasted with the original early-stage detection scheme of Cb-TRAM, skill scores are provided. From the comparison against detections of later thunderstorm stages, which are also provided by Cb-TRAM, a decrease in false prior warnings (false alarm ratio) from 91 to 81% is presented, an increase of the critical success index from 7.4 to 12.7%, and a decrease of the BIAS from 320 to 146% for normal scan mode. Similar trends are found for rapid scan mode. Most obvious is the decline of false alarms found for the synoptic class "cold air" masses.
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and ...selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, E max = 98%, CB1 EC50 > 10 μM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, E max = 110%) with excellent pharmacokinetic properties.
Background
Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (cGVHD). However, CB use is rapidly declining because of delayed neutrophil ...recovery, high rates of infections and severe acute GVHD leading to high transplant-related mortality (TRM) and prolonged hospitalization. Several of these complications are related to the low cell number of CB grafts, compromising early engraftment and optimal HLA matching. In order to improve these limitations, we initiated a phase II clinical trial exploiting UM171 expanded CB. This molecule has previously been shown to efficiently expand stem and progenitor cells in 7-day ex vivo cultures. More recent studies have also documented the dominant expanding effect of UM171 on several immuno-modulatory cells, thus profoundly changing graft composition and possibly further reducing relapse and GVHD.
Methods
Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Moreover, the short duration of expansion made the process practical and clinically viable.
Findings
Between 9/16-11/18, 22 adults with a median age of 44 years and high- to very high-risk hematologic malignancies were transplanted with a single UM171 CB. Five pts (23%) had already failed a prior allogeneic transplant and 5 (23%) had refractory/relapsed acute leukemia or aggressive lymphoma. Median co-morbidity index was 2 and 36% of pts had an index ≥3. Because minimal cell dose requirements were lower, we had access to 47% of the CBs in the banks instead of 5% for a 70 kg pt. Consequently, >80% of pts received a ≥6/8 HLA matched CB. UM171 profoundly changed graft composition, including a 600 and 8000-fold increase in dendritic and mast cells, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with pts receiving peripheral blood (PB) or marrow (BM) at same institution and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose and similar to our BM-PB pts. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment as median last day of fever was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts, translating into a shorter duration of admission, similar to that with BM-PB. Median CD4 count was 218/μL and 413/μL at 3 and 12 months, respectively. Cumulative incidences (CI) of grade 2-4 and 3-4 acute GVHD were 60% and 9%, respectively. We observed no steroid refractory acute GVHD, no moderate/severe cGVHD and 91% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM (<5%) and 5 pts (CI 24% at 2 years) had progressive disease. With a median follow-up of 26 months, 2-year progression-free, GVHD-and-relapse-free survival (GRFS), and chronic GRFS were excellent for such a high-risk group at 72%, 62% and 72%, respectively.
Interpretation
A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM and severe GVHD with prompt withdrawal of immunosuppression resulting in excellent GRFS. Hypotheses to explain this could be earlier achievement of 100 neutrophils, protective effect of the immuno-modulatory dendritic cells on mucosal integrity and relapse, and mast cells on gut GVHD, as well as better HLA matching. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of cGVHD and relapse. Encouraged by our observation that several pts with very high-risk disease (e.g. refractory leukemia) remain in CR, we have now embarked on a Canadian and US trial to ascertain if indeed UM171 modified grafts will have a potent antileukemia effect in extremely high-risk disease pts such as those with refractory acute leukemias and high-risk molecular anomalies like p53 mutation and EVI-1 rearrangement.
Display omitted
Cohen:ExCellThera: Consultancy, Equity Ownership, Patents & Royalties: Royalities from sales of UM171, Research Funding. Roy:Celgene: Consultancy, Honoraria, Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria; Sanofi Canada: Research Funding. Delisle:ExCellThera: Patents & Royalties, Research Funding. Bambace:ExCellThera: Patents & Royalties: royalities. Ahmad:ExCellThera: Patents & Royalties. Lachance:ExCellThera: Patents & Royalties. Bernard:ExCellThera: Patents & Royalties. Kiss:ExCellThera: Patents & Royalties. Busque:Paladin: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; ExCellThera: Patents & Royalties; BMS: Consultancy. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve-Rosemont: Patents & Royalties: Author on patent. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Sauvageau:ExCellThera: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
None of the medications listed are approved for this indication.
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