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Artificial intelligence in cancer therapy.
Science. 2020 02 28;367(6481):982-983
Authors: Ho D
PMID: 32108102 [PubMed - indexed for MEDLINE]]]>
Convolutional Neural Network Can Recognize Drug Resistance of Single Cancer Cells.
Int J Mol Sci. 2020 Apr 30;21(9):
Authors: Yanagisawa K, Toratani M, Asai A, Konno M, Niioka H, Mizushima T, Satoh T, Miyake J, Ogawa K, Vecchione A, Doki Y, Eguchi H, Ishii H
It is known that single or isolated tumor cells enter cancer patients' circulatory systems. These circulating tumor cells (CTCs) are thought to be an effective tool for diagnosing cancer malignancy. However, handling CTC samples and evaluating CTC sequence analysis results are challenging. Recently, the convolutional neural network (CNN) model, a type of deep learning model, has been increasingly adopted for medical image analyses. However, it is controversial whether cell characteristics can be identified at the single-cell level by using machine learning methods. This study intends to verify whether an AI system could classify the sensitivity of anticancer drugs, based on cell morphology during culture. We constructed a CNN based on the VGG16 model that could predict the efficiency of antitumor drugs at the single-cell level. The machine learning revealed that our model could identify the effects of antitumor drugs with ~0.80 accuracies. Our results show that, in the future, realizing precision medicine to identify effective antitumor drugs for individual patients may be possible by extracting CTCs from blood and performing classification by using an AI system.
PMID: 32365822 [PubMed - in process]]]>
The cash didn't amount to a record-breaking total. But it was a welcome uptick from the final quarter of last year, when funding dipped for the first time all year.
Continue to STAT Plus to read the full story…]]>
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Ethics of controlled human infection to address COVID-19.
Science. 2020 05 22;368(6493):832-834
Authors: Shah SK, Miller FG, Darton TC, Duenas D, Emerson C, Lynch HF, Jamrozik E, Jecker NS, Kamuya D, Kapulu M, Kimmelman J, MacKay D, Memoli MJ, Murphy SC, Palacios R, Richie TL, Roestenberg M, Saxena A, Saylor K, Selgelid MJ, Vaswani V, Rid A
PMID: 32381590 [PubMed - indexed for MEDLINE]]]>
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The Twilight Zone season 2 trailer.
It's national Twilight Zone Day (no one knows why), and what better way to mark the occasion than with the official trailer for the second season of Jordan Peele's reboot of The Twilight Zone? We got our first look at still photos a few days ago, and, combined with the trailer, we're optimistic that Peele can pull off another strong season and do this classic science fiction series proud.
(Some spoilers for S1 below.)
Rod Serling created the original Twilight Zone anthology series for CBS in 1959, and it was an instant hit with viewers. Serling was a fan of both pulp fiction and science fiction, and he combined those passions with a strong interest in social commentary on topics such as nuclear war and McCarthyism. And he loved a good twist ending. The series was successfully revived in the 1980s and again (less successfully) in 2002. There was also a 1983 feature film, notorious because star Vic Morrow and two child actors were killed in a freak helicopter accident during filming.
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Documents obtained by CBC News through an access to information request outline a long list of allegations against Canada Border Services Agency officers, covering everything from abuse of authority and criminal association to excessive force and sexual harassment.]]>
Deep learning: shaping the medicine of tomorrow.
Mol Cell Oncol. 2020;7(3):1723462
Authors: Vougas K, Almpanis S, Gorgoulis V
Predicting response to therapy is a major challenge in medicine. Machine learning algorithms are promising tools for assisting this aim. Amongst them, Deep Neural Networks are emerging as the most capable of interrogating across multiple data types. Their further development will lead to sophisticated knowledge extraction, shaping the medicine of tomorrow.
PMID: 32391419 [PubMed]]]>
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The data were only preliminary, and many questions still remain, including the nature of the treatment effect in patients. But for Gilead's chief executive, Daniel O'Day, it was a big moment. O'Day was named as Gilead's CEO in December 2018, and says he is "humbled" by what the company has accomplished.
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Reckless use of a drug can cause devastating side effects, including death, while the unchecked virus, or an unbridled immune response to it, can also be deadly by causing the body's organs to shut down.
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Prediction of drug adverse events using deep learning in pharmaceutical discovery.
Brief Bioinform. 2020 Apr 29;:
Authors: Lee CY, Chen YP
Traditional machine learning methods used to detect the side effects of drugs pose significant challenges as feature engineering processes are labor-intensive, expert-dependent, time-consuming and cost-ineffective. Moreover, these methods only focus on detecting the association between drugs and their side effects or classifying drug-drug interaction. Motivated by technological advancements and the availability of big data, we provide a review on the detection and classification of side effects using deep learning approaches. It is shown that the effective integration of heterogeneous, multidimensional drug data sources, together with the innovative deployment of deep learning approaches, helps reduce or prevent the occurrence of adverse drug reactions (ADRs). Deep learning approaches can also be exploited to find replacements for drugs which have side effects or help to diversify the utilization of drugs through drug repurposing.
PMID: 32349125 [PubMed - as supplied by publisher]]]>
A B.C. judge says a fundamentalist Baptist father who believes homosexuals should be executed shouldn't have any say in the religious upbringing of his children.]]>
Earlier on Wednesday, we reported on some clinical trial data that offered good, if ambiguous, news about treating COVID-19. In the study, participants treated with a drug called remdesivir recovered on average 30 percent quicker than those receiving a placebo. But who owns the drug, how much of it can be made, and what does it cost?
To answer the first question, remdesivir is owned by Gilead Sciences, a US biotechnology company. Gilead got its first patent for the drug in 2017 when the company was originally targeting it as a possible treatment for the Ebola virus. That didn't pan out, but as our earlier article explains, biochemical similarities in how the Ebola and SARS-CoV-2 viruses function led Gilead to see if remdesivir could be repurposed for treating COVID-19. Gilead's patents mean that it has a monopoly on the drug in the United States, so barring government intervention or Gilead licensing the patent to others, it's the only company that can manufacture it until 2037, at which point a generic version could be possible.
To answer the second question, Gilead announced in April that it had ramped up production of remdesivir at its factory in La Verne, California, in January, and by the beginning of April, it had already stockpiled enough to treat 140,000 patients, each over the course of 10 days. The company also said that it plans to produce enough remdesivir to treat 500,000 patients by October and a million patients by the end of 2020. (This explains why there was some outcry in March when it was revealed that Gilead had applied for something called "orphan drug status" for remdesivir, which is supposed to be reserved for rare diseases. Gilead withdrew that application.)
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Amazon is reportedly (and suddenly) enforcing rules limiting employees' internal communication as workers, critical of the company's behavior, become increasingly outspoken and organized.
Internal listservs with more than 500 participants are now required to move to a moderated model where a manager must approve any content before its distribution, according to emails obtained by Recode.
Amazon had almost 800,000 total employees worldwide as of the end of 2019, a number that does not include the recent addition of another 175,000 temporary warehouse and delivery workers the company just hired to handle increased demand due to COVID-19. Of those 800,000, more than 500,000 are in the United States, and at least 275,000 of those are full-time employees.
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There is little doubt about the urgent need for treatment. But premature publication of definitive recommendations based on inappropriate conclusions grounded in scant, hastily-acquired data serve only at best to confuse and at worst mislead at a time when tensions are high and need for help is great. One recent study, "Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open Label Non-randomized Clinical Trial," published in the International Journal of Antimicrobial Agents and receiving attention all the way to the White House, raises such concerns.
In this investigation, 36 adult patients who tested positive were studied over a two-week period at a hospital in Marseille, France. Twenty patients received 200 mg of hydroxychloroquine sulfate three times per day for 10 days while 16 patients served as control subjects. Six of those randomized to the active treatment also received 500 mg of azithromycin on day 1 and then subsequently 250 mg per day for four additional days at the authors' discretion, depending on clinical presentation "to prevent bacterial super-infection."
The results show that at day 6, all of those treated with combination hydroxychloroquine and azithromycin were cured, compared with 57.1% of those receiving hydroxychloroquine only and 12.5% in the control group. The recommendation issued by the authors was thus that "COVID-19 patients be treated with hydroxychloroquine and azithromycin."
Publication of recommendations based on studies such as this is highly problematic. An investigation with only 20 treated patients (after six dropped out) is significantly underpowered and greatly subject to sample size error. Further, the reason for the addition of azithromycin is poorly described and subject to question. It is one thing to call results promising; it is another to issue definitive treatment recommendations. Hydroxychloroquine exists in limited supply, and poorly grounded recommendations touting effectiveness by health care providers and President Trump only exacerbate this shortfall. This is even more troubling with regard to azithromycin, where overuse may lead to resultant potential shortages of an important antibiotic needed to treat bacterial infection as well as the downstream effect of increasing the number of strains of drug-resistant pathogens. The FDA recently cautioned against the use of hydroxychloroquine because of reports of cardiac arrhythmias and even death in the wake of its unmonitored use.
It is ironic that the authors of this study state, "For ethical reasons and because our first results are so significant and evident we decide to share our findings with the medical community, given the urgent need for an effective drug against SARS-CoV-2 in the current pandemic context." The true ethical responsibility of researchers is to produce and to publish data and subsequent recommendations based on robust methodology and stringent review. Some investigators may be altruistically motivated to rapidly disseminate hopeful conclusions. Nevertheless, the responsibility we hold to our patients and, especially during the pandemic, to society at large depends on good judgment and fiduciary concern rather than on haste to demonstrate beneficial outcomes.
Michael A. Erdek, MD, MA, is an associate professor at Johns Hopkins University School of Medicine and the Berman Institute of Bioethics. Twitter: @MichaelErdek
45% of The Hastings Center's work is supported by individual donors like you. Support our work.
The post Ethical Responsibility in Publishing Research Results on Covid-19 Treatments appeared first on The Hastings Center.]]>
A common ingredient in cough medicines, dextromethorphan, stimulated the growth of SARS-CoV-2 in monkey cells in lab dishes, researchers report April 30 in Nature. Dextromethorphan seems to activate a cellular stress-coping process that is also exploited by the virus for its replication.
"We're not necessarily recommending that everyone stop taking dextromethorphan," said Brian Shoichet of the University of California, San Francisco School of Pharmacy.
This work is only in lab experiments, he noted during a news briefing on April 30. In people, cough suppressants have not been shown to make infections worse. But because the lab results demonstrate "a pro-viral effect, it would be wrong not to highlight it, because it could be detrimental," Shoichet said, noting that more work needs to be done. It's "something to look out for."
Shoichet was part of an international team that mapped interactions between the coronavirus's proteins and proteins found in human and monkey cells. Lung cells produce more of the proteins involved in these viral interactions, the researchers discovered, which may help explain why the virus causes severe disease in the lungs (SN: 4/27/20).
Scientists tested a battery of drugs to see if any could interrupt those interactions and limit the virus's growth. Drugs that have shown some promise in lab experiments involving monkey cells include antipsychotics haloperidol and cloperazine; an anxiety and depression drug called siramesine; antihistamines clemastine and cloperastine; and an experimental drug called zotatifin, now in clinical trials testing its efficacy against cancer.
None has been tried against COVID-19 in people.
The team also found an experimental compound, PB28, that performed better than hydroxychloroquine at inhibiting the virus's growth by interfering with certain protein interactions. Unlike hydroxychloroquine, PB28 doesn't mess with heart rhythm proteins, so may have fewer side effects (SN: 4/21/20). PB28 also hasn't been tested in people.
The hormone progesterone also interfered with the virus's replication, perhaps partially explaining why women are less prone to die from COVID-19 than men (SN: 4/23/20).]]>
Development and validation of a deep neural network model to predict postoperative mortality, acute kidney injury, and reintubation using a single feature set.
NPJ Digit Med. 2020;3:58
Authors: Hofer IS, Lee C, Gabel E, Baldi P, Cannesson M
During the perioperative period patients often suffer complications, including acute kidney injury (AKI), reintubation, and mortality. In order to effectively prevent these complications, high-risk patients must be readily identified. However, most current risk scores are designed to predict a single postoperative complication and often lack specificity on the patient level. In other fields, machine learning (ML) has been shown to successfully create models to predict multiple end points using a single input feature set. We hypothesized that ML can be used to create models to predict postoperative mortality, AKI, reintubation, and a combined outcome using a single set of features available at the end of surgery. A set of 46 features available at the end of surgery, including drug dosing, blood loss, vital signs, and others were extracted. Additionally, six additional features accounting for total intraoperative hypotension were extracted and trialed for different models. A total of 59,981 surgical procedures met inclusion criteria and the deep neural networks (DNN) were trained on 80% of the data, with 20% reserved for testing. The network performances were then compared to ASA Physical Status. In addition to creating separate models for each outcome, a multitask learning model was trialed that used information on all outcomes to predict the likelihood of each outcome individually. The overall rate of the examined complications in this data set was 0.79% for mortality, 22.3% (of 21,676 patients with creatinine values) for AKI, and 1.1% for reintubation. Overall, there was significant overlap between the various model types for each outcome, with no one modeling technique consistently performing the best. However, the best DNN models did beat the ASA score for all outcomes other than mortality. The highest area under the receiver operating characteristic curve (AUC) models were 0.792 (0.775-0.808) for AKI, 0.879 (0.851-0.905) for reintubation, 0.907 (0.872-0.938) for mortality, and 0.874 (0.864-0.866) for any outcome. The ASA score alone achieved AUCs of 0.652 (0.636-0.669) for AKI, 0.787 (0.757-0.818) for reintubation, 0.839 (0.804-0.875) for mortality, and 0.76 (0.748-0.773) for any outcome. Overall, the DNN architecture was able to create models that outperformed the ASA physical status to predict all outcomes based on a single feature set, consisting of objective data available at the end of surgery. No one model architecture consistently performed the best.
PMID: 32352036 [PubMed]]]>
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In silico Design, Virtual Screening and Synthesis of Novel Electrolytic Solvents.
Mol Inform. 2019 10;38(10):e1900014
Authors: Marcou G, Flamme B, Beck G, Chagnes A, Mokshyna O, Horvath D, Varnek A
We report the building, validation and release of QSPR (Quantitative Structure Property Relationship) models aiming to guide the design of new solvents for the next generation of Li-ion batteries. The dataset compiled from the literature included oxidation potentials (Eox ), specific ionic conductivities (κ), melting points (Tm ) and boiling points (Tb ) for 103 electrolytes. Each of the resulting consensus models assembled 9-19 individual Support Vector Machine models built on different sets of ISIDA fragment descriptors.(1) They were implemented in the ISIDA/Predictor software. Developed models were used to screen a virtual library of 9965 esters and sulfones. The most promising compounds prioritized according to theoretically estimated properties were synthesized and experimentally tested.
PMID: 31166649 [PubMed - indexed for MEDLINE]]]>
Hunting for New Drugs with AI.
Nature. 2019 12;576(7787):S49-S53
Authors: Freedman DH
PMID: 31853074 [PubMed - indexed for MEDLINE]]]>
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COVID-19 Drug Discovery Using Intensive Approaches.
Int J Mol Sci. 2020 Apr 18;21(8):
Authors: Asai A, Konno M, Ozaki M, Otsuka C, Vecchione A, Arai T, Kitagawa T, Ofusa K, Yabumoto M, Hirotsu T, Taniguchi M, Eguchi H, Doki Y, Ishii H
Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.
PMID: 32325767 [PubMed - indexed for MEDLINE]]]>
Against pandemic research exceptionalism.
Science. 2020 May 01;368(6490):476-477
Authors: London AJ, Kimmelman J
PMID: 32327600 [PubMed - indexed for MEDLINE]]]>
Read more of this story at Slashdot.]]>
A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study.
Alzheimers Dement (N Y). 2020;6(1):e12013
Authors: Hampel H, Williams C, Etcheto A, Goodsaid F, Parmentier F, Sallantin J, Kaufmann WE, Missling CU, Afshar M
Introduction: The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome-wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2-73), a selective sigma-1 receptor (SIGMAR1) agonist, was studied in a 57-week Phase 2a trial (NCT02244541). The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint.
Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.
Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS-ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS-ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.
Discussion: Confirmatory Phase 2b/3 clinical studies of these patient selection markers are ongoing. This FCA/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.
PMID: 32318621 [PubMed]]]>
A summary of the study results was inadvertently posted to the website of the World Health Organization and seen by STAT on Thursday, but then removed.
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The rapid uptake of Epic's deterioration index is a sign of the challenges imposed by the pandemic: Normally hospitals would take time to test the tool on hundreds of patients, refine the algorithm underlying it, and then adjust care practices to implement it in their clinics.
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'We had a whole bunch of researchers around the world doing different things. All of our research has basically stopped,' says family of toddler with rare genetic condition.]]>
As you know, authorities have been issuing orders requiring people to wear masks if they go out in public. For example, on April 15, New York's governor issued Executive Order 202.17, which says that anyone over the age of two "shall be required to cover their nose and mouth with a mask or cloth face-covering when in a public place and unable to maintain, or when not maintaining, social distance." Similarly, on Wednesday morning, San Francisco started enforcing its order generally requiring face coverings in public. Depending on the jurisdiction, failure to wear a mask in public may be a crime.
One potential problem: wearing a mask in public may also be a crime.
That is the case in New York, where one is guilty of "loitering" if he or she does the following:
Being masked or in any manner disguised by unusual or unnatural attire or facial alteration, loiters, remains or congregates in a public place with other persons so masked or disguised, or knowingly permits or aids persons so masked or disguised to congregate in a public place; except that such conduct is not unlawful when it occurs in connection with a masquerade party or like entertainment if, when such entertainment is held in a city which has promulgated regulations in connection with such affairs, permission is first obtained….
N.Y. Pen. Code § 240.35 (emphasis added). Note that a masquerade-party permit will resolve any concerns, though that may not help here.
In fact, many states and localities have similar anti-disguise laws, most of which date back to the Reconstruction era and were aimed at suppressing the Ku Klux Klan. See Wayne R. Allen, "Klan, Cloth, and Constitution: Anti-Mask Laws and the First Amendment," 25 Ga. L. Rev. 819 (1991). New York's law goes back further, to "legislation enacted in 1845 to thwart armed insurrections by Hudson Valley tenant farmers…." Church of Am. Knights of the Ku Klux Klan v. Kerik, 356 F.3d 197, 203 (2d Cir. 2004). Desperate to avoid evictions during a depression, farmers put on masks and dressed up like Native Americans in order to fight back against the authorities. That also describes the Boston Tea Party, of course, but by 1845 this sort of thing was no longer cool. So the legislature passed a law declaring that anyone caught wearing a disguise in public "and not giving a good account of himself" would be "deemed a vagrant." Id. at 204. This explains why it's still part of the "loitering" statute, presumably.
So, is this constitutional? Well, it depends who you ask. In the Klan case, the district court held that section 240.35 was not constitutional, at least as applied. People could wear masks to a party but not to a Klan rally, so the law discriminated against a particular viewpoint. Disgusting as that viewpoint might be, it was still entitled to protection.
But the Second Circuit reversed. It held, among other things, that the masks themselves weren't sending a message that the pointy hoods didn't already send, which seems like a fair point. Prior cases had established a right to keep membership lists and so forth anonymous, but the court refused to hold that this meant there is a constitutional right to hide your identity while protesting. Ultimately, it held the police hadn't discriminated against the Klan because there was no evidence that any other group had been allowed to protest while wearing masks. So, on its face (no pun intended), the law is constitutional.
In the unlikely event someone were to be prosecuted for wearing a surgical mask due to the pandemic, the First Amendment defense wouldn't be available. A court would probably read an intent requirement into the law, maybe based on the legislative history, or on the word "unlawful" that appears later on. But taken literally, the law makes it illegal to wear a mask "in a public place with other persons so masked" … which is kind of the whole point of wearing one right now.
California's law is more limited, because it applies only to something worn to conceal one's identity for an improper purpose:
It shall be unlawful for any person to wear any mask, false whiskers, or any personal disguise (whether complete or partial) for the purpose of:
One—Evading or escaping discovery, recognition, or identification in the commission of any public offense.
Two—Concealment, flight, or escape, when charged with, arrested for, or convicted of, any public offense. Any person violating any of the provisions of this section shall be deemed guilty of a misdemeanor.
Cal. Pen. Code § 185.
This is one of a surprising number of statutes that has been around, mostly unchanged, since California first codified its laws in 1872, which probably accounts for the inclusion of "false whiskers." I like to imagine that at the time, people were disguising themselves as Ambrose Burnside to rob the stagecoach, sort of like how they wore presidential masks in Point Break more recently. Anyway, given that this law is limited to the wearing of masks, whiskers, or other personal disguises for purposes that are already illegal, it is less problematic than New York's.
On the other hand, "public offense" is a pretty broad category, isn't it? Things like loitering or "disorderly conduct" come to mind, so there is still a potential problem with selective enforcement. And as we have discussed before, anti-face-covering laws may have unintended consequences, or can even be a cover (no pun intended, again) for a form of discrimination. See "Anti-Mask Law Saddens Austrian Shark Mascot" (Oct. 12, 2017).
To me, this is an example (and there are many right now) of the extent to which the fairness of the legal system may turn less on the words we use in a law than on the discretion of those who have the power to enforce it. Considering who some of those people are right now, that is a reason for concern in times like these.
None of this should be taken to mean that I condone the wearing of false whiskers, of course. Anyone caught in false whiskers can go straight into the dungeon, as far as I'm concerned.
DeepScreening: a deep learning-based screening web server for accelerating drug discovery.
Database (Oxford). 2019 01 01;2019:
Authors: Liu Z, Du J, Fang J, Yin Y, Xu G, Xie L
Deep learning contributes significantly to researches in biological sciences and drug discovery. Previous studies suggested that deep learning techniques have shown superior performance to other machine learning algorithms in virtual screening, which is a critical step to accelerate the drug discovery. However, the application of deep learning techniques in drug discovery and chemical biology are hindered due to the data availability, data further processing and lacking of the user-friendly deep learning tools and interface. Therefore, we developed a user-friendly web server with integration of the state of art deep learning algorithm, which utilizes either the public or user-provided dataset to help biologists or chemists perform virtual screening either the chemical probes or drugs for a specific target of interest. With DeepScreening, user could conveniently construct a deep learning model and generate the target-focused de novo libraries. The constructed classification and regression models could be subsequently used for virtual screening against the generated de novo libraries, or diverse chemical libraries in stock. From deep models training to virtual screening, and target focused de novo library generation, all those tasks could be finished with DeepScreening. We believe this deep learning-based web server will benefit to both biologists and chemists for probes or drugs discovery.
PMID: 31608949 [PubMed - indexed for MEDLINE]]]>
Harnessing big 'omics' data and AI for drug discovery in hepatocellular carcinoma.
Nat Rev Gastroenterol Hepatol. 2020 04;17(4):238-251
Authors: Chen B, Garmire L, Calvisi DF, Chua MS, Kelley RK, Chen X
Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer. After nearly a decade with sorafenib as the only approved treatment, multiple new agents have demonstrated efficacy in clinical trials, including the targeted therapies regorafenib, lenvatinib and cabozantinib, the anti-angiogenic antibody ramucirumab, and the immune checkpoint inhibitors nivolumab and pembrolizumab. Although these agents offer new promise to patients with HCC, the optimal choice and sequence of therapies remains unknown and without established biomarkers, and many patients do not respond to treatment. The advances and the decreasing costs of molecular measurement technologies enable profiling of HCC molecular features (such as genome, transcriptome, proteome and metabolome) at different levels, including bulk tissues, animal models and single cells. The release of such data sets to the public enhances the ability to search for information from these legacy studies and provides the opportunity to leverage them to understand HCC mechanisms, rationally develop new therapeutics and identify candidate biomarkers of treatment response. Here, we provide a comprehensive review of public data sets related to HCC and discuss how emerging artificial intelligence methods can be applied to identify new targets and drugs as well as to guide therapeutic choices for improved HCC treatment.
PMID: 31900465 [PubMed - indexed for MEDLINE]]]>
Following the WHO's recommendations, most countries have been implementing widespread testing, contact tracing, isolation, and other social distancing polices to reduce physical interactions between individuals. The United Kingdom, however, has decided to pursue a different and controversial path. For the time being, the U.K. is not mandating strong physical distancing policies or making testing widely available. Instead, it is aiming to create herd immunity. Based on various models with diverse assumptions, the government is planning for 40 million people to become infected. With a 1% mortality rate (the estimated mortality rate in other countries), approximately 400,000 people will die.
It is classic and brutal utilitarian ethical calculation: creating herd immunity will potentially save lives in the long term and conserve other socially valuable goods which are greater than the costs of implementing socially disruptive policies and resource investments now to prevent as many deaths as possible of the 1% to 5% who are most vulnerable. The greatest risk is to older people and those with chronic diseases and conditions– and probably the most socially disadvantaged.
The U.K. government's lack of transparency about the epidemiological models and reasoning behind the policies, and default to utilitarian calculations shows that past two decades of public health/global health ethics scholarship has had little impact. Of particular concern, at a time when hundreds of thousands of citizens' lives are at stake, the British leadership is reverting to what Bernard Williams scathingly described as "Government House Utilitarianism." That is, some of the great advocates of utilitarianism argued that secrecy may be necessary to achieve a utilitarian conclusion, as the uneducated might not understand the ambiguity or complexity, much less find it palatable.
Over the past four decades, I and other philosophers have argued that the distribution of health and disease reflects the way we organize our societies, and how we relate to each other. Living together allows us to create goods that help us pursue our life plans. And living together also exposes us to burdens, and harms. Public health ethics is not primarily or foremostly about the conflict between the interests of the few versus the greater good. It is about how we organize our society, how we relate to one another, to ensure that every individual is able to pursue a good life. From this perspective, the people who are currently infected with COVID-19, as well as older people and those with serious health conditions, are not the few whose rights need to be balanced against the greater good. Each of those individuals are equal members our society whose abilities to live good lives are at risk. If there are decisions to be made about whose lives are to be saved first, or what other socially valued goods need to be protected, justice demands that there be public deliberation, or as philosophers call it, the "publicity requirement."
Indeed, this talk of ethics and public deliberation during a pandemic may seem superfluous to those who admire how the Chinese government acted boldly, and with unprecedented scale. It pursued actions for the greater good, and apparently gave a gift to the world by slowing infections down by weeks. But outbreaks and their progression into epidemics and pandemics reflect the way we organize our social institutions and relate to each other. There is much work here for those courageous enough to show how social inequities and injustice produced the outbreak and the way it is progressing.
But more presently, our jobs now as health ethicists throughout the world is to help support national and global responses to think harder and better. Everyone is a global ethicist now.
Sridhar Venkatapuram is an associate professor of global health and philosophy at King's College London. He is on Twitter: @sridhartweet
For additional information and ethics resources on the Coronavirus, please visit our Ethics Resources page:
The post COVID-19 and the Global Ethics Freefall appeared first on The Hastings Center.]]>
In its own guidance on COVID-19-related crowdfunding, GoFundMe suggests starting campaigns to help with living expenses for people without sick leave from work, provide low-income people with food and water supplies, and pay for testing and treatment for people who may be infected but lack adequate medical insurance. News stories are proliferating about crowdfunding campaigns aimed at helping affected groups, including professional athletes starting campaigns for employees impacted by the suspension of sports leagues and musicians starting campaigns for out-of-work road crews. GoFundMe has set up a page highlighting a slate of coronavirus-related campaigns, targeting people suddenly unemployed due to physical distancing efforts and food banks in hard hit communities.
On social media, many individuals are appealing for help for themselves and their loved ones. These campaigns have been joined by a range of celebrities seeking to use their visibility to encourage giving by their fans and followers. One of the most prominent, a campaign to raise money to pay for personal protective equipment for frontline responders, has raised $4.7 million of their $10 million dollar goal. In other cases, more modest and localized needs like a food kitchen in Philadelphia have received support.
Supporting the needs of those affected by the COVID-19 pandemic, through crowdfunding or other means, is a praiseworthy act of solidarity with the most vulnerable among us. However, there are two important respects in which we should view these actions as a deeply imperfect means of addressing systemic rot rather than simply an example of people coming together to meet one another's needs.
First, while crowdfunding can help vulnerable people harmed by the coronavirus and other emergencies, it doesn't do so in a fair or highly effective way. Campaigns by professional athletes to help stadium staff put out of work by the cancelation of sporting events are a good example of this. While these employees often work in precarious positions with few benefits and for a minimum wage, they are only being helped in this instance by the happenstance of being associated with prominent and charismatic benefactors. Helping precariously employed and poorly compensated workers in this way leaves out the restaurant workers, janitors, and daycare employees who are also in need but lack the good luck to work in proximity to the wealthy and famous. Thus, crowdfunding can take the form of distribution according to popularity rather than need.
Second, these campaigns do nothing to address the failures of our institutions to meet our basic needs. Crowdfunding is a Band-Aid solution that can help to staunch the bleeding of some individuals in an emergency but does nothing to address the root causes of these needs. This is a point that GoFundMe's former CEO, Rob Solomon, noted when he suggested that crowdfunding "shouldn't be the solution to a complex set of systemic problems. They should be solved by the government working properly, and by health care companies working with their constituents." With GoFundMe's very large and active role in the COVID-19 pandemic, notably, GoFundMe is seemingly beginning to view itself as part of the solution to gaps in the social safety net along with government aid. In a recent interview, GoFundMe's current CEO, Tim Cadogan, stated that "We are by no means the only solution. We all hope that there's going to be some more government aid. But we have a role and, you know, it's sort of our duty to do everything we possibly can to use our platform." Noting the limitations of crowdfunding as a solution to these problems is important, but in itself this simply leaves us to repeat a pattern of giving without addressing why this giving is needed in the first place.
President Trump and other leaders have called the COVID-19 pandemic an "unforeseen problem." This is to some extent true given the rapidity of the virus's spread and ubiquity of global restrictions on movement instituted in response. But pandemics are not new, and this is likely not the last one we will see this century. And we will continue to see other disasters, both natural and human-caused, ranging form earthquakes and forest fires to the consequences of climate change.
The recently passed pandemic aid bill in the U.S. includes a one-time direct financial benefit based on income, temporary extension of unemployment benefits, temporary relief of student loan payments, and emergency aid to hospitals, universities, and small businesses. These are helpful and important steps to address the impacts of the pandemic. However, as with crowdfunding campaigns, they largely take the form of addressing symptoms of a weak and inadequate social support system rather than enhancing the system itself.
Systemic failures to protect the most vulnerable among us are also not new and they are revealed again and again. By all means, donate to a crowdfunding initiative or other charitable group to help those most impacted by the coronavirus. If you choose to do so, try to do so fairly by helping those with the quietest voices and least visibility – donations to local food pantries are one fair way of doing so. But we should also use our voices and votes to advocate for systemic changes to make crowdfunding less necessary when the next emergency rolls around. Universal insurance coverage, permanently expanded paid sick leave, affordable child care, and other social supports won't prevent pandemics from happening. However, they can lessen their harms for everyone and not just the fortunate few able to catch the public's attention.
Jeremy Snyder is a professor of health sciences at Simon Fraser University. Twitter: @jeremycsnyder
For additional information and ethics resources on the Coronavirus, please visit our COVID-19 Ethics Resources page:
The post Crowdfunding for Covid-Related Needs: Unfair and Inadequate appeared first on The Hastings Center.]]>
But instead of hoping for attention, now I find myself dreading the use of my work. Over a decade ago, I helped develop guidelines for the ethical allocation of scarce resources during a public health emergency, such as a pandemic. My colleagues and I carefully considered various scenarios, with different numbers and proportions of people affected and different clinical needs and imagined how, in conditions of scarcity, resources might be fairly distributed. We based these guidelines on a robust ethical foundation and we made sure that the policies and procedures did not give doctors and nurses caring for patients "the terrible task of improvising decisions about whom to treat or making these decisions in isolation," but instead, honored and protected the ethical obligations of clinicians to care for and advocate for patients. Instead of asking doctors to decide who gets what resources, we thought that these decisions would be best handled by those not directly caring for the patients, by people with expertise in medicine, nursing, and ethics. We also strongly emphasized the need not to make existing health disparities worse.
Phew. Like most medical centers, ours expects a surge of patients. If I am called to inpatient service, I am grateful that, if the surge overwhelms our resources, I won't be asked to decide which of my patients to save. So, I am glad for my work–and the work of many others– that provide guidelines for making those terrible decisions. Really, though, I hope and pray no one, here or elsewhere, will need to call on those guidelines. Please, please let them sit on a shelf or in an archived folder until they need to be updated for preparedness' sake.
I'm scared, though. Scared of seeing patients die because of lack of resources, of having to be honest about a patient's clinical picture with the decision-makers, and tell patients and the ones who love them about their prognosis, their priority for care, and, sometimes, their death. Scared that some of those patients might be colleagues, neighbors, or friends. For decades I have taught students and residents how to communicate in difficult situations like patient requests for unnecessary services or planning for the end of life. I dread having to employ those skills to explain that we can't provide necessary care because of this pandemic, or to ask if they might be willing to refuse intensive care to save resources for someone else.
Of course, I am scared of other things (#anticipatoryanxiety). I am scared that my lack of recent experience with inpatient medicine could hurt someone, even as I recognize that, during extreme scarcity, I might be better than the alternative.
I'm not terribly scared of getting sick since psychological defense mechanisms convince me that I may be immune, or at least likely to recover from Covid-19. I am however, like most health care workers, scared I could give this to someone I love.
Please don't use my work on resource allocation during a pandemic; please don't need to use it.
Susan Dorr Goold, MD, is a professor of internal medicine and health management policy at the University of Michigan and a Hastings Center fellow. Twitter: @susangoold
45% of The Hastings Center's work is supported by individual donors like you. Support our work.
The post Please Don't (Need to) Use My Work appeared first on The Hastings Center.]]>
"White fragility" is the term educator Robin DiAngelo coined to describe such behavior. This avoidance of dealing with race and racism stems in part, she says, from whites not understanding themselves as raced, not owning up to being the dominant racial group in the United States and to having racial privilege. White fragility is not new to bioethics, but it is highly visible now.
The inequitable racial landscape of the United States is hardly deniable. The effects of racism on health status and on access to health care are well documented. Comprehensive race/ethnicity data relevant to Covid-19 will likely affirm inequitable patterns in exposure, testing, and treatment, patterns that are already being observed by practitioners in some facilities and officials in some states.
Other bioethicists have been clear, at least in professional circles, that social inequities including structural racism do in fact shape crisis standards of care, that ostensibly "objective" measures of the likelihood of short and long term survivability depend at least in part on comorbidities that disproportionately affect people of color. And they acknowledge that such criteria will have life-threatening consequences when ventilators are scarce. To do otherwise would be to deny the very presence of racism in health care and medicine.
Last week I watched "Edge of the City," a 1957 film starring Sidney Poitier, John Cassavetes, and Ruby Dee. At the movie's end, white man after white man denies witnessing their white boss's racist murder of a black co-worker. Denial of this man's death was a denial of his life as well as a denial of the racism that led to his death. This interpersonal racism has a corollary in structural racism, which also kills.
What to do about structural racism in health care is a critical conversation that requires white people, as members of the dominant racial group, to sit with the uncomfortable reality that we have benefited from a racial hierarchy that has harmed others. It requires us to acknowledge that structural racism is present in health care, health policy, and public health; to understand that the intent of policymakers is less important than the effects of their policies. And to trust that those most affected by structural racism have crucial knowledge about effective strategies to reduce and end it. To begin that conversation, bioethicists must, at the least, stop denying that structural racism exists in health care policy and that it can kill.
Charlene Galarneau is a senior lecturer in the Department of Global Health and Social Medicine at Harvard Medical School's Center for Bioethics and associate professor Emerita at Wellesley College's Department of Women's and Gender Studies.
The post Structural Racism, White Fragility, and Ventilator Rationing Policies appeared first on The Hastings Center.]]>
Artificial intelligence and machine learning to fight COVID-19.
Physiol Genomics. 2020 04 01;52(4):200-202
Authors: Alimadadi A, Aryal S, Manandhar I, Munroe PB, Joe B, Cheng X
PMID: 32216577 [PubMed - indexed for MEDLINE]]]>
Proportion of Patients in Phase 1 Oncology Trials Receiving Treatments that are Ultimately Approved.
J Natl Cancer Inst. 2020 Apr 01;:
Authors: Zhang SX, Fergusson D, Kimmelman J
BACKGROUND: Phase 1 oncology trials are often regarded as a therapeutic option for patients. However, such claims have relied on surrogate measures of benefit, such as objective response.
METHODS: Using a systematic search of publications, we assessed the therapeutic value of phase 1 cancer trial participation by determining the probability that patients will receive active doses of treatments that eventually receive FDA approval or an NCCN guideline recommendation for their indication. ClinicalTrials.gov, Pubmed, ASCO reports, NCCN Guidelines and Drugs@FDA were searched between May 1, 2018 and July 31, 2018. All statistical tests were two-sided.
RESULTS: 1000 phase 1 oncology trials initiated between 2005 and 2010 and enrolling 32,582 patients were randomly sampled from 3229 eligible trials on ClinicalTrials.gov. A total of 386 (1.2%) patients received a treatment that was approved by the U.S. Food and Drug Administration for their malignancy at a dose delivered in the trial; including NCCN guideline recommendations, the number and proportion are 1168 (3.6%). Meta regression showed a statistically significantly greater proportion of patients receiving a drug that was ultimately FDA approved in biomarker trials (rate ratio = 4.49, 95%CI = 1.53 to 13.23, p = 0.006) and single-indication trials (rate ratio = 3.32, [1.21 - 9.15], p = 0.02; proportions were significantly lower for combination vs. monotherapy trials (rate ratio = 0.09, [0.01 - 0.68], p = 0.02).
CONCLUSIONS: One in 83 patients in phase 1 cancer trials received a treatment that was approved for their indication at the doses received. Given published estimates of serious adverse event rates of 10-19%, this represents low therapeutic value for phase 1 trial participation.
PMID: 32239146 [PubMed - as supplied by publisher]]]>
The RCMP in Nova Scotia knew it had a murderous gunman on the loose Saturday night but failed to warn local residents about the threat to their safety through the provincial emergency alert system.]]>
Read more of this story at Slashdot.]]>
Read more of this story at Slashdot.]]>
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Read more of this story at Slashdot.]]>
Scientists are beginning to fear that the rush to understand the coronavirus and find ways to treat COVID-19, the illness it causes, is leading to an erosion of traditional safeguards against bad science.]]>


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The high quality polyamide fabric gives good coverage and support and works throughout the year. The much-loved flat wide waistband with inner draw cord gives superb comfort and security, and the elasticated hem stops the leg length from riding up. Mesh is used behind the knee to add extra breathability and reflective trim keeps you safe when light levels are low. This design features flattering seam lines and a stretch pocket on one thigh, in addition to the zip secure pocket at the centre back. Our product testers have commented that they love having two pockets for carrying different items and many like carrying their phone in this thigh pocket.


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2020-05-26 Cranberries – Sunday
Intro: B A G then again A and G with the same pattern; E|-2-----------------------0-----------------------3-----------------------| B|-4-4---4-----4-----4---4-2-2---2-----2-----2---2-3-3---3-----3-----3---3-| G|-4---4---4-----4-----4---2---2---2-----2-----2---0---0---0-----0-----0---| D|-4---------4-----4-------2---------2-----2-------0---------0-----0-------| A|-2-----------------------0-----------------------2-----------------------| E|-2-----------------------------------------------3-----------------------| F C E|-----------------------------------------------------------------| B|---1---1---1---1---1---1---1---1---1---1---1---1---1---1---1---1-| G|-----2---2---2---2---2---2---2-------0---0---0---0---0---0---0---| D|-3-------------------------------2-------------------------------| A|-----------------------------------------------------------------| E|-----------------------------------------------------------------| Verse1: Keep strumming F and C like in the Intro 4 times; then only strum F once 2nd guitar plays these riffs: D|-3--2-3--2-3-2--- and -2-3-2-3--2-3--2-3-2---| A|---------------3- ---------------------3-| Verse2;3: F c (x4) 2nd guitar strums F once at the start of verse 2 Bridge: F E Am E (x3) Am 2nd guitar plays this riff over the E : D|-3--2-------------| A|-------5--3--2--3-| Verse4,5,6: F C (x4) Outro: F E Am E(x4) 2nd guitar plays this riff over the first 4 E 's: D|-3--2-------------| A|-------5--3--2--3-| Here are the lyrics with the parts of the song: Intro VERSE1: Oh, Do you know, Riff#1 Where to go, where to go? Something on your mind, Riff#2 Riff#1 Wanna leave me behind, wanna leave me behind. VERSE2: You're spinning me around, My feet are off the ground. I dunno where I stand. Do you have to hold my hand? You mystify me, you mystify me, you mystify me... VERSE3: Oh, when he walked into the room, It happened oh so soon. I didn't want to know. Does he really have to go? You mystify me, you mystify me, you mystify me... BRIDGЕ VERSE4: And I couldn't find the words, To say, "I love you." And he couldn't find the time, To say, "I need you." It wouldn't come out right. It wouldn't come out right. Just came out all wrong. VERSE5: You're spinning me around, My feet are off the ground. I dunno where I stand. Do you have to hold my hand? You mystify me, you mystify me, you mystify me... VERSE6: Oh, Do you know, Where to go, where to go? Something on your mind, Wanna leave me behind, wanna leave me behind. Outro


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Showing 52 care companions
Gretchen F.
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- 57 years old
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Hello. I love cats. I was a volunteer and foster care family for animal haven before it became spca. I have taken care of neighbors cats when they are gone. Other then that, I have not done this...
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I have spent a lifetime in service to my community. Following my service in the US. Navy, I spent twenty five years in the death care industry, I have previously been engaged teaching at the Kansas...
Kristin Y.
- 10 years paid experience
- 46 years old
- Kansas City, KS
- 19 miles
I am a mother of 3. I was a care giver for my mother with MS for 10 years or more. I helped with wound care, positioning, feeding tube care and anything else that needed to be done to ensure her...
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I became a caregiver because I love help people young or elderly. I would always find myself helping my aunt with a daughter who is disabled or helping my grandma with her elderly father. Growing up I...
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My job as a paraprofessional is that of Special Education Para Educator III. My purpose/s of assisting in the supervision, care and instruction of special needs students in the regular classroom,...
Adriauna M.
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Adriauna moye 21 years old The past 2 years I've been working as a certified nurse assistant through the Kansas city kansas area. I also enjoy house keeping work,
Yvonne H.
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I am an occupational therapist and was working8 yrs in a hospital for eldery. I provided care and therapy there and loved working with "granma" and "granddad" I also worked 5yrs with people with...
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I am a undergraduate social welfare student at the University of Kansas who has a passion for spending time with special needs individuals. I have been a part of Best Buddies for 3. 5 years now and...
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My name is Stacey I'm 51 single live near downtown OP area. I work as a dental assistant Mon-Thursday and looking to pick up some hours. If your interested I can provide references and background...
Blake P.
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Hello! My name is Blake, and I am a female Doctor of Physical Therapy Student in Kansas City. I have experience caring for a woman with multiple sclerosis and a boy with a rare genetic disease....
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I love care-giving! I have experience working with folks with disabilities in a group home setting and working with children at camp
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Im 26 mom of two flexible scheduling worked as a medical assistant in geriatrics for 5 years and I have early child hood development degree working with kindergartners for 5 years im presuing my...
Molly B.
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I have 13+ years of experience working with individuals with developmental disabilities and autism. Roles have included Para, RBT, Residential Grouphome Manager of 3 homes, foster parent,...
Dina Jade R.
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My experience has been mainly with children of all ages for over 20 years. Some have had challenges that I had to work with and overcome. I have also worked with intellectually disabled people some...
Tiffany H.
- 8 years paid experience
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- Kansas City, KS
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I have worked in the field of I/DD (intellectual and developmental disabilities for the past 20 years. I have worked with children through senior adults. I have provided respite care for adults and...


text:
Item description
a Clip for a scarf 10024. Insert: cabochon square 17х22 mm Qty: 1 pieces product: clip for shawls. Product type: decoration on the shoulders and chest. Metal: jewelry alloy based on brass. Coating: all natural coating with silver of 999 tests (9 to 12 µm), gold 875 samples (0.45 µm), rhodium (0.2 microns).
coating Material: Silver plated, 999, from 9 to 12 µm
product Material: Alloy based on brass
Country of origin: Russia
item Size with packaging: 75 mm 55 mm
shelf Life: indefinite
Warranty: 6 months


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These Tiny Homes Will Inspire You To Think Small
While perhaps most people still dream of owning a mansion one day, a growing number of people are choosing to go small instead. The tiny house trend is appealing for many reasons and not only because of the low price tag. While a large house may afford you a life of luxury, these people are realizing that the greatest luxury is being able to live a peaceful, quiet life in nature. Check out some of the most charming tiny homes below!
Winter In Style
We can totally imagine curling up by the fireplace in this humble abode.
Cute And Compact
Good things really do come in small packages.
Cabin Fever
We're really loving this woodsy vibe.
Home On The Go
Have caravan, will travel.
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Yummy Desserts That Are Bound To Delight
Let's be honest, who doesn't love filling the house with the smell of freshly baked cakes and goodies? We really can't think of anyone. Whether you're hosting guests for dinner or just want to bake a special surprise for your kids, there are several dessert recipes that are simply bound to impress. Here are some timeless […]


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Blockchain isn't very a cool geek-talk anymore! Bitcoin modernised the way many of us found stock markets, ledgers, funds transfers together with transactions. The beauty in all virtual values is that virtually each a person of them tries in order to handle a challenge. Plus this is when our gold coin of interest instructions Nexty – comes in action. During the write-up, this similarity of the Nexty platform will likely be compared having Nano – XRB to be able to gain a better knowing of this specific platform.
In very simple terms, Nexty program is frequency since a good transaction system that will eliminate the principle of financial transaction fee although making sure super swift transfers to help its customers. Apart from this, the exchanges are ultra easy for the reason that transactions don't require this miners to carry out verification as in often the case of some other digital currencies such as Bitcoin etc.
However, as every the white paper launched by creators of Nexty, the primary usage of Nexty is meant for recently established e-commerce corporations to aid generate public funding. Since there are no transaction, ultra quick transfer (2 seconds! And that is pretty much real time) plus confirmation fee, typically the fundraising will turn out to be trouble considerably less. The coin can be operatively targeting the ecommerce stores because that is going to cultivate a great eco-system wherever these shops will end up being accepting NTY coins coming from shoppers.
The strategy behind NTY is producing on a daily basis online trades some sort of smooth experience. The team right behind NTY comprises of Blockchain coders and established marketers.
bridgewater zip code of the team members have ten to be able to 12 several years of experience entirely stack development and advertising and marketing.
Many of you might fight of which Nano – Recently called Railblocks, XRB instructions has already been performing the exact same functions because NTY. The XRB lieu is a new bit exclusive because that uses its proprietary block-lattice files structures. Due in order to this, each Nano bank account has it is very own blockchain which reduces dormancy intended for fast transfer. In addition to this, often the XRB is electric power and even resource efficient plus will not need high end GRAPHICS system for transaction execution. However, Nano doesn't come with a smart-contract ability. Smart deals are intended to end up being interchanging triggers for any crypto foreign money. These contracts help interchanging funds, real estate, stocks or any perceptible or maybe non touchable enterprise of a financial price. The smart contracts as well overthrow the need intended for brokers while taking our crypto to advantage swapping properly. Apart from this kind of a person difference, NTV and even XRB (Nano) are whole lot more as well as less identical. A further major capability of the Nexty platform is definitely its the usage within present ecommerce purposes such as Joomla cms. As per the developers of NTY, the integration can take 3-4 time max.
Around order to achieve the requirement – supply stability of the NTY, the software comes with a built-in smart staking program. This specific program offers bonuses and even credits on buying, offering and holding Nexty. The program is intended for traders and daily users as the same time.


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Baga Retreat House OverviewRanked 11 of 18 sightseeing in Miramar
The Baga Retreat House is located on Baga Hill, around 22.2 km away from Miramar. This beach is believed to have been established in 1951 by Fr. Adrian Le Tellier SJ, a Belgian Jesuit. This house is dedicated to St. Francis Xavier.
The surrounding areas of the house are famous for trekking and can be reached by climbing up to the Baga Hill. A lush green hill is the major attraction of this place that lies near the entrance.
Planning Miramar trip?
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Written by
Joe Martin
September 18, 2008 | 10:51
Tags: #half-life
Companies: #google #steam #valve
Want to comment? Please log in.
Valve has said it is more profitable per employee than either Google or Apple.
Valve have definitively explained why they aren't interested in making PlayStation 3 games and why other studios will always handle their ports.
"Human error" is blamed for a glitch at Google that saw the site warning users that the entire internet could "harm your computer" for half an hour on Saturday.
July 1 2020 | 17:34
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Small bathroom floor plans with both tub and shower blueprint view napoleon master bath. 14 multifunctional bathroom designs with laundry space laundry bathroom combo, laundry room. Laundry room building a country house house plans # 508 2 case study. Parankewich manor walkout level generation suite laundry mud room laundry room layouts.
|April 1, 2020
|Bathroom floor plan laundry room design ideas


text: It was lovely to be back at Moor Hall Hotel & Spa today providing the daytime entertainment for Sian & Grant's wedding. The happy couple kindly invited me to play for their reception and I loved playing a variety of music on the hotel's Bechstein grand whilst the newly-weds enjoyed their drinks and mingled with their family and friends. Many congratulations to the new Mr & Mrs Lowe and thank you for all your kind appreciation.


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Croft Port, 1945
Vintage Port - Oporto Bottled
Level in neck | Unlabelled | Damaged capsule
Bottle size: 75cl
* excludes delivery (free standard UK delivery on orders over £100)
The Croft 1945 Vintage Port has a much deeper colour than the '42 as one would expect. Quite limpid for a 62-year old with a lovely, elegant nose of ginger, leather, figs, almond and black cherries in the background. Very refined with a sedate feel to it. The palate is just sublime with perfect acidity, rich and decadent for Croft and in a sense, riper than the '35 thanks to the Indian summer? Powerful, spicy and almost decadent towards the finish with wild honey, heather, fig, raisin and liquorice. Very long – this '45 flirts with perfection. A gorgeous '45 port.
Rich red cherries on the nose. So rich and alcoholic. Extraordinary fruit. Total velvet. The greatest Croft ever made. Voluptuous. So sweet one tends to think it is Graham, but it is its own 'man' and a truly stunning Port. Another bottle had a lightish brown appearance. Very fruity, smoky bouquet - very Croft. Lovely sweet prunes and glorious walnuts. One senses the power behind it. On the palate, it starts on a fruity note and then the power, backbone and structure hit you. Long and lingering. Strength and elegance - a great achievement. Serena Sutcliffe, MW
Unlabelled - Level in Neck - capsule chipped
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Wine Legends by Decanter magazine: Graham's Vintage Port 1945.
Tasting Notes
Graham's 1945 is consistently, …


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Results 1 - 24 (of 24)
'You Only Live Twice' (released through United Artists). Six original photographs for 'Cinema 66' magazine.
n.d. [25th August 1966]. Six original black and white photographs of Sean Connery as James Bond, taken on location in Japan during the filming of Ian Fleming's You Only Live Twice. Three photos capture a relaxed Connery in full Japanese costume, in between takes. The other three photos were taken..... More
"Quantum of Solace" (released through United Artists/Columbia Pictures). Advance Production Notes for the film.
Eon Productions Limited, 2008. SIGNED COPY. Extensive Press notes issued just before release of the James Bond film "Quantum of Solace" [Based on an original story written by Neal Purvis and Robert Wade, using characters created by Ian Fleming]. 46 pages, stapled. With a synopsis, notes on locations, biographies of..... More
James Bond. The Paradise Plot. Original Comic Strip artwork, signed by the Illustrator.
Copyright, Glidrose 1981-2. A three-strip panel, being board number 256 drawn in pen and ink on artboard, with pasteover sections of text. Twice SIGNED by John McLusky, firstlly beneath central illustration and again, to revese side, together with adoodled '007' motif, below his 6-linehand-written description. In a simple matt black..... More
Chitty Chitty Bang Bang. The Magical Car. Illustrated by John Burningham.
London: Jonathan Cape and Queen Anne Press, 2014. [Children's illustrated] LIMITED EDITION. In three volumes, complete. Octavo (25 x 17cm), pp.48; pp.48; pp.48. Publisher's white hardcovers in glossy pictorial dust-wrappers, the three volumes are presented in a racing green slip-case. A facsimile of the first edition of Ian Fleming's famous..... More
Complete Paperback First Editions of Ian Fleming's James Bond Novels. Comprising: Casino Royale, Live and Let Die, Moonraker, Diamonds Are Forever, From Russia With Love, Dr. No, Goldfinger, For Your Eyes Only (short stories inc. From A View To A Kill, Quantum of Solace), Thunderball, The Spy Who loved Me, On Her Majesty's Secret Service, You Only Live Twice, The Man with the Golden Gun, Octopussy and The Living Daylights (short stories).
London: Pan Books, 1955-1967. [Spy fiction] All paperback First Editions. Fourteen volumes, octavo (18 x 12 x 19cm). Publisher's illustrated softcovers. Live and Let Die being the 'thick' paper variant. All UK printings [Live and Let Die, Dr No, For Your Eyes Only, OHMSS (60c), You Only Live Twice and..... More
Complete Set of First Editions of Ian Fleming's James Bond Novels The Works comprise: Casino Royale, Live and Let Die, Moonraker, Diamonds Are Forever, From Russia With Love, Dr. No, Goldfinger, For Your Eyes Only (short stories containing From A View To A Kill and Quantum of Solace), Thunderball, The Spy Who loved Me, On Her Majesties Secret Service, You Only Live Twice, The Man with the Golden Gun, Octopussy and The Living Daylights.
London: Jonathan Cape, 1953-1966. FIRST IMPRESSIONS, with a leaf SIGNED BY IAN FLEMING included in the first title. 14 volumes. Octavo. Beautifully bound in full deep red oasis morocco with gilt raised bands and gilt titles to spines, '007 device blocked in gilt to upper, gilt edges, black endpapers. Internally..... More
Dr. No.
London: Jonathan Cape, 1958. [James Bond] FIRST EDITION. Octavo (20 x 14cm), pp.256. Publisher's black cloth-effect paper over boards, silver titles to spine, in pictorial dust wrapper designed by Pat Marriott. Second state binding, with the 'Dancing Lady' design to the upper. Edges a little dusty/spotted else a fine copy..... More
For Your Eyes Only.
London: Foyles' Book Club, n.d. [1961]. UK BOOK CLUB EDITION. ASSOCIATION COPY, INSCRIBED BY THE AUTHOR. Octavo, pp.192. Publisher's green cloth in pictorial dust-wrapper illustrated by Cuthill. With presentation note to the flyleaf 'The sixth will have / to wait. / x / Ian. (underlined). A fine copy in a...... More
The Man With the Golden Gun.
London: Jonathan Cape, 1965. FIRST ISSUE, SECOND STATE, BINDING B. Octavo (19 x 13cm), pp.221; [1]. Publisher's dark grey cloth-effect paper over boards with bronze lettering to the spine, plain covers, patterned green endpapers. In the original pictorial dust-jacket illustrated by Richard Chopping, priced at 18s. price-clipped. Small mark to..... More
London: Jonathan Cape, 1955. FIRST IMPRESSION, FIRST PRINTING, BINDING A (Fabroleen material). This version with 'shoot' correctly printed to page 10. Octavo, pp.256. Publisher's black cloth-effect paper over boards, titled in silver, in 'flame' design dust-wrapper by Kenneth Lewis. Presented in a custom made leather-spined clamshell case. Both book and..... More
London: Jonathan Cape, 1961. [Spy thriller] FIRST EDITION. Octavo (19 x 13cm), pp.254. Publisher's cloth-effect paper over boards with embossed skeleton hand design to upper board, gilt titles to spine. In dust-wrapper illustrated by Richard Chopping. A very lightly used copy with a splash to top edge, jacket with a...... More
You Only Live Twice. (a James Bond novel).
London: Jonathan Cape, 1964 [actually issued late 1963]. UNCORRECTED PROOF copy of the first edition. In printed green wrappers and the pictorial dust-jacket, stamped 'Proof Only' etc. on inside front flap, with minor variations to the blurb on rear flap over the published version. An attractive copy, preserved in an..... More
For Your Eyes Only (James Bond short stories).
London: Jonathan Cape, 1960. [Espionage] FIRST EDITION, Binding B. Octavo (19 x 13cm), pp.252. Publisher's black cloth-effect paper over boards, blocked in silver to spine, pictorial dust-wrapper priced at 15s. Book is fine, jacket with a few light marks, very light wear to crown, decent red colouring to spine. Remains..... More
The Spy Who Loved Me.
New York, NY: The Viking Press, 1962. [Espionage novel] FIRST US EDITION. Octavo (21 x 14cm), pp.211; [5], blank. Publisher's salmon-coloured cloth blocked in brown to spine, brown endpapers, tinted top edge, pictorial jacket illustrated by Richard Chopping. A lovely fine copy in like, price-clipped jacket. A particularly fresh example..... More
[MOVIE POSTER] For Your Eyes Only.
Litho in USA, 1981. [Film promotion] U.S. one-sheet poster for the 1981 United Artists film starring Roger Moore as Ian Fleming's James Bond, produced by Albert R. Broccoli's Eon Productions. 'Legs' style Artwork by Bill Gold. Approximate dimensions 27 x 40 inches. Rolled. Creased to lower margin with a couple..... More
[MOVIE POSTER] From Russia With Love.
Litho in USA, 1964. [Film promotion] U.S. style 'A' one-sheet poster for the 1964 United Artists film starring Sean Connery as Ian Fleming's James Bond, produced by Harry Salzman and Albert R. Broccoli's Eon Productions. Design by David Chasman. Approximate dimensions 27 x 40 inches. Folded. National Screen Service stamp..... More
[MOVIE POSTER] Moonraker.
Litho in USA, 1979. [Film promotion] U.S. Review-style one-sheet poster for the 1979 United Artists film starring Roger Moore as Ian Fleming's James Bond, produced by Albert R. Broccoli's Eon Productions. Approximate dimensions 27 x 40 inches. Folded. Fine condition (Poster Grade 'A'). Will be despatched rolled, in a substantial..... More
"Live and Let Die" (Released through United Artists)
England 1973. ORIGINAL SHOOTING SCRIPT WITH FINE ASSOCIATION. A complete production-used script by Tom Mankiewicz and directed by Guy Hamilton, Eon Productions Ltd, October 2nd 1972. 120pp mimeographed typescript, orig embossed green covers, copy of Victor Joseph Heutschy (died 2011) film and TV publicist with his name in ballpoint at..... More
Zur Chirurgie des Herzens und des Herzbeutels, in 'Archiv fur Klinische Chirurgie'.
Berlin: Verlag von August Hirshwald 1907. Pp.904. Original printed wrappers. Prof. Dr. Rehn's treatise appears on pp.723-778. A fine copy, in a folding protective case with gilt-titled orange leather label to spine and gilt crest to upper (some wear to box). This is an account of the first successful suture..... More
The James Bond Dossier.
London: Jonathan Cape, 1965. [Reference critique] FIRST EDITION. Octavo (24 x 16cm), pp.159; [1]. Publisher's black cloth-effect paper over boards with gilt titles to spine in pictorial dust-wrapper, based on the familiar 'trompe l'oeil' designs which decorated the Ian Fleming first editions. Priced at 16s. to flap. A near fine..... More
London, BCA by arrangement with Hodder and Stoughton. 1995. True first hardback EDITION, issued several months before the Hodder edition. Octavo (24 x 16cm), pp.218. Publisher's black cloth in pictorial dust-wrapper. Minor toning to page edges. A fine copy of a scarce Gardner 007 novelisation. The author's second film novel..... More
SilverFin (Young James Bond series).
London: Puffin Books, 2011. [Children's adventure novel] The SECOND LIMITED EDITION, No.32 of 1000 copies, SIGNED by the author. Publisher's illustrated hardcovers with 'glow-in -the-dark' feature, in transparent perspex slipcase. A very fine/as new copy, in the original clear wrap with printed limitation label affixed, foam support, in an outer..... More
The Life of Ian Fleming. Creator of James Bond.
London: Jonathan Cape, 1966. UNCORRECTED PROOF COPY. Large octavo (24 x 16cm). pp.346, with pp.16 photographic plates. Publisher's patterned green softcovers. Prelims spotted, spine wrinkled, some toning to edges and extremities, joints rubbed. Very good, in a custom-made quarter green morocco clamshell box. Scarce in this format. The proof features..... More
The James Bond Girls. With an Introduction by Cubby Broccoli.
London: Boxtree, 1999. [Bond Film reference] REVISED EDITION, SIGNED BY THE AUTHOR. Quarto (29 x 23cm), pp.130; [2]. Illustrated throughout with colour and black and white photographs. Publisher's black cloth with silver titles to spine. With the red pictorial dust-jacket. Autographed by Graham Rye in black ink to title page..... More
Results 1 - 24 (of 24)


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Is Ukraine the Bait for a New Cold War?
The prolonged political, social and economic crisis in Ukraine tests the nerves, diplomatic skills and the capacity for international leadership in the United States, the European Union and Russia. The political balance is up in the air while the most powerful players look for solutions before the destabilization of the country deepens even more.
The U.S. European allies were angered by the outburst of the Secretary of State for European Affairs, Victoria Nuland, who this week left no doubt of how little she thought about EU partners. She revealed in a telephone call how much involvement the Americans have in the current conflict between the Ukrainian government and the opposition parties. Nuland said "fuck the EU" while criticizing Brussels policy towards Ukraine. The outburst happened during a private conversation with the U.S. ambassador to Kiev. Nuland had to apologize, but not before causing the condemnation of German Chancellor Angela Merkel.
After nearly three months of having mobilized its diplomatic teams, even during Christmas, neither the EU nor the U.S. have found the key to overcoming the confrontation between the regime of President Viktor Yanukovych, and protesters calling for his removal. During the telephone conversation both American officials made it clear that the United States is determined to support the Ukranian opposition in an effort to kick out President Yanukovych.
"U.S. and EU value the situation in the same way in Ukraine. Namely, it is necessary to resolve the conflict peacefully through a round table, although they may have differences in methods on how to help, "says Irina Gerashchenko, deputy of the UDAR group and member of the European Integration of the Verkhovna Rada of Kiev.
Gerashchenko refuses to comment on the content of the conversation in which Nuland asserted that her choice to head the government would be Arseniy Yatseniuk and not Vitali Klitschko. "The Ukrainian security services are in such an unfortunate situation that it is possible for foreign secret services to act in our country."
The Russian spies have become the prime suspects of the filtration that unmasked the real American intentions. Russian President Vladimir Putin made ??his career in the KGB and then the Federal Security Service ( FSS ) and Russian political circles attribute the spread of incriminating documents to the Russian secret service. Its actions include the video that brought down the Prosecutor General of Russia in the nineties when he was about to organize an investigation into the family of former president Boris Yeltsin.
The revelation of Nuland's dialog with the American ambassador would be a new cause for 'war', which adds up to the case of the former intelligence analyst, Edward Snowden, who is currently asyled in Russia.
On her last trip to Kiev, EU representative Catherine Ashton, found Yanukovych was indifferent to the theoretically open prospect of having Ukraine's partnership agreement with the EU fail, the media reported.
In this political game, both Americans and Europeans have relied on the leaders of parliamentary opposition groups, who are not exactly trustworthy because the protests have their own dynamics and protesters their own claims.
Western envoys well known to Klitschko, leader of UDAR, Arseniy Yatseniuk, the head of the parliamentary group of Yulia Timoshenko and Oleg Tiagnibok a nationalist from the Freedom Party. European diplomats who in November strove to " keep alive " the flame of Euromaidán to press for Ukraine's integration into Europe, are now trying to identify groups of protesters, in a critical situation, to play a moderating role and deterr radicals willing to die if Yanukovych is taken from power.
The current president "will not yield power and, moreover, his figure is necessary for the East of Ukraine to remain stable" say, in private, European diplomats who are very involved in finding a solution to the conflict in Ukraine.
His message, also private, is that the U.S. and Russia should maintain their involvement in the search for a solution. This would require forming a basis of trust among these big players who are experiencing divergent paths. Moscow presents the protests in Ukraine as a phenomenon of fascist ideology permeated in society and accuses Western countries of fanning the protests with anti-Russian intentions. The Ukrainian opposition politicians have turned their back to Moscow, saying that the Kremlin meddles in the affairs of their country and helps to destabilize it.