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AGA Reading Room 02.02.2017 Comment
HCV Advances Win Lasker Award
Laborious work overcame hurdles
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This Reading Room is a collaboration between MedPage Today® and:
Expert Critique
FROM THE AGA Reading Room
Chioma Ihunnah, MD, MPH Gastroenterology & Hepatology Fellow University of Connecticut Health Center Farmington, CT
The prestigious Albert and Mary Lasker Awards are presented for indelible contributions to mankind through achievements in medicine and science. The 2016 Lasker~Debakey Clinical Medical Research Award was given to Charles Rice, PhD, of Rockefeller University and Ralf Bartenschlager, PhD, of Heidelberg University, for their development of a reliable hepatitis C virus (HCV) replication system, and to Michael Sofia, PhD, of Arbutus Biopharma, who created sofosbuvir (Sovaldi), a nucleotide analog prodrug, which leads to premature termination of HCV replication when incorporated into the growing genetic sequence of the virus.
Hepatitis C affects approximately 130 million to 170 million individuals worldwide. Nearly 80% of patients develop chronic hepatitis, increasing the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. The triumphs in the understanding and treatment of HCV by these scientists have substantial global impact.
Hepatitis C virus, initially identified as non-A, non-B hepatitis, was first isolated in 1989 by Michael Houghton, PhD, a recipient of the 2000 Albert Lasker Clinical Medical Research Award. Soon after HCV was identified, Rice and Bartenschlager began working independently to create systems of efficient intracellular HCV replication. Based upon this foundation, Dr. Sofia and other scientists began to design treatments targeted towards stopping HCV replication. These treatments are called direct-acting antivirals (DAAs). Dr. Sofia created a drug that eradicated the virus at high rates and shortened the HCV treatment length without the use of interferon, which was previously a fundamental component of HCV treatment, yet fraught with dangerous side effects.
These scientists, along with their teams, join the ranks of prior Lasker Award recipients, including Drs. Thomas Starzl and Roy Calne, who received the 2012 Lasker~Debakey Clinical Medical Research Award for the inception of the orthotopic liver transplant and development of immunosuppressive agents to prevent rejection of transplanted organs. Hepatitis C is among the primary indications for liver transplantation in the United States.
Thanks to the laborious dedication of these Lasker Award recipients, the current generation of physicians will have only treated patients in this era of interferon-free regimens. The world is indebted to those committed physicians, scientists, and philanthropists, who work tirelessly towards scientific and medical progress.
Full Critique
Effective interferon-free treatment for hepatitis C (HCV) is regarded as one of the major recent advances in medical science. While this breakthrough may seem to have come quickly -- less than 30 years after the hepatitis C virus (HCV) was first identified -- it was the result of laborious collaborative work that overcame many hurdles.
The 2016 Lasker~Debakey Clinical Medical Research Award, considered to be the most prestigious U.S. science prize, was awarded in September to Charles Rice, PhD, of Rockefeller University and Ralf Bartenschlager, PhD, of Heidelberg University for developing a system to study HCV replication, and to Michael Sofia, PhD, of Arbutus Biopharma for developing the blockbuster drug sofosbuvir (Sovaldi).
"This is an inspired choice to commemorate the medical triumph of the development of the first cure of a chronic viral infection in humans," Raymond Chung, MD, chief of Hepatology at Massachusetts General Hospital in Boston, told MedPage Today.
"These discoveries were critical in building the bridge from virus discovery to curative antiviral cocktails that will prevent and eliminate liver disease and cancer in millions of patients."
More than 3 million people in the U.S. and an estimated 150 million people worldwide have chronic hepatitis C. Over years or decades HCV infection can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure, and it is the most common reason for liver transplantation in the U.S.
In 1989 Michael Houghton, PhD, of Chiron Corp. isolated HCV, a flavivirus responsible for so-called "non-A/non-B hepatitis." He and Harvey Alter, MD, of the National Institutes of Health, who had previously shown that the mystery virus could be transmitted through blood, won the 2000 Lasker Award.
To speed development of drugs for hepatitis C, scientists needed to grow the virus in the laboratory. While they could construct HCV RNA genetic material, standard recombinant techniques did not produce infectious virus that could replicate in cells.
"For years after the original discovery of HCV, one of the most vexing challenges for researchers was the inability to grow the virus in culture to permit study of its lifecycle," Chung explained. "Drs. Rice and Bartenschlager made critical discoveries that enabled the development of a robust model system that successfully overcame this obstacle."
In the late 1990s Rice and his colleagues figured out that sequenced HCV RNA was missing a piece at one end that was necessary for viral replication.
"The first piece of the puzzle was the discovery of a missing part of the virus genome that turned out to be essential," Rice told MedPage Today. "This led to our ability to construct and validate a functional molecular clone of the virus. But while this clone could yield RNA transcripts that were infectious in vivo [in chimpanzees], they failed to replicate in cell culture."
Bartenschlager encountered similar problems getting HCV to replicate in laboratory cells. He and his student Volker Lohmann produced an HCV fragment known as a "replicon" that was missing structural proteins needed to construct whole virus particles, but included the polymerase, protease, and NS5A proteins required for viral replication.
Eventually Bartenschlager and Rice figured out how to manipulate replicons to increase the number of infected cells, finally offering a model that could be used to test drugs that block viral replication in the laboratory.
"It was not until 2005 that a robust system became available to study the entire virus lifecycle," Rice said. "Sometimes real progress takes years and the commitment of many dedicated people. Support of fundamental curiosity-driven research is the pipeline of most transformative discoveries and biomedical advances. Even when these come, there are still major challenges to implementing them on global scale."
Rice continues to work on HCV -- including learning more about how it leads to liver disease and cancer -- as well as studying other viruses such as Zika and how antiviral innate immunity works.
From the Lab to the Clinic
Pharmaceutical companies soon began using the replicon system to test experimental drugs. Initial efforts focused on the HCV protease, based on lessons learned from antiretroviral therapy for HIV. Two early HCV protease inhibitors -- boceprevir (Victrelis) and telaprevir (Incivek) -- improved treatment effectiveness somewhat, but they still had to be used with poorly tolerated interferon and added side effects of their own.
Sofia's team at Pharmasset, a small biotech in Cambridge, Mass., concentrated instead on the HCV polymerase, which is responsible for copying viral RNA. In particular, they looked at nucleoside/nucleotide analogs, defective building blocks of genetic material that bring replication to a halt.
One candidate appeared promising -- well tolerated and able to reduce HCV viral load in the replicon system -- but it was not very stable or bioavailable in the body. Sofia and his colleagues figured out how to modify the drug so it would penetrate the liver.
"First we had to find a molecule that would not only be active against the virus but also safe," Sofia told MedPage Today. "After much investigation we identified a unique nucleoside drug that had these characteristics, but unfortunately it wasn't quite active enough or long-acting enough to be an effective drug."
"The metabolite [we focused on] could not be a real drug because it was very unstable and would never get past the gut and reach the liver," he added. "To solve this problem, we devised a 'prodrug' that acted like a mask and not only made the drug molecule stable, but was also designed so that when it reached the liver it released the desired active drug and trapped it there. Since the drug gets trapped at high concentrations in the liver where it is needed, very little of it goes elsewhere in the body, thus reducing the risk for side effects."
The resulting drug, dubbed PSI-7977, worked well in combination with interferon and ribavirin, but the real goal was interferon-free treatment.
At the 2011 American Association for the Study of Liver Diseases Liver Meeting, researchers reported that an all-oral combination of PSI-7977 plus ribavirin cured 100% of easy-to-treat patients with HCV genotypes 2 and 3. But most harder-to-treat patients with genotype 1 relapsed, suggesting that PSI-7977 would work best in combination with other direct-acting antivirals.
In 2012 Gilead Sciences purchased Pharmasset for $11 billion to obtain the drug, which was named "sofosbuvir" after Sofia.
Pulling the plug on combination studies with other companies, Gilead focused on sofosbuvir plus its own experimental NS5A inhibitor, ledipasvir, which became the blockbuster combination, Harvoni. The combo, which cures more than 90% of genotype 1 patients even without ribavirin, got the FDA nod in 2014. A newer pangenotypic combination of sofosbuvir and velpatasvir -- an NS5A inhibitor that works against all HCV genotypes -- was approved last year.
Sofosbuvir ushered in the era of simple, effective, and well-tolerated therapy for even the hardest-to-treat hepatitis C patients.
"These new treatments are effective for a wide patient population, including those with liver cirrhosis, those co-infected with HIV, patients of all adult age groups and races, and even for patients on liver-transplant lists," Sofia said. "New treatments that include sofosbuvir are very safe, with no or very minimal side effects. This is compared to earlier therapies with cure rates that were relatively low with many difficult-to-manage side effects. Now you take one pill once a day for 8 to 12 weeks and you are cured."
Today the potential of direct-acting antiviral therapy is limited mainly by its high price. Widespread treatment could both reduce the incidence of advanced liver disease and prevent HCV transmission, and current guidelines recommend treatment for nearly everyone with hepatitis C regardless of liver disease severity. But many private insurers, state Medicaid programs, and other payers still deny access due to cost.
"The public outcry about the costs has not escaped the notice of those of us on the Lasker Jury," jury member Harold Varmus, MD, now of Weill Cornell Medical Center, said as he presented the award. "Our job today is to celebrate those who walked a winding scientific trail that led to miraculous drugs and the benefits of using those drugs. At the same time, let us resolve to find the means to provide them to all who can benefit."
With the scientific challenge of hepatitis C treatment essentially solved -- even though the social and economic challenges remain -- Sofia and his team at Arbutus are now working to find a cure for hepatitis B, another chronic liver disease that affects over 350 million individuals worldwide.
"We believe that combining drugs with different mechanisms of action will ultimately be the solution to finding a cure for HBV," Sofia said in an interview. "We are investigating approaches to attack the virus directly and ways to activate the body's immune system to attack the virus. In addition, we are interested in developing agents that can eradicate the reservoir of viral genomic material in the nucleus of liver cells. By bringing these approaches together, we hope to find the magic cocktail for a cure."


text:
Former Israeli General and Ex-State Department Official Clash Over Peace Obstacles
by Rafael Medoff / JNS.org
The late Taylor Force, an American military veteran who was killed in a Palestinian terrorist attack in Tel Aviv in March 2016. Photo: File.
JNS.org – A former Israeli general and an ex-State Department official presented sharply differing views on the obstacles to Middle East peace during a Zionist event in America's capital last week.
Speaking at the American Zionist Movement's national conference on November 15, Brig. Gen. (res.) Yossi Kuperwasser described Palestinian rejection of Israel as the main impediment, while former US Mideast policy adviser Aaron David Miller said both Israel and the Palestinians are to blame.
Kuperwasser said the primary obstacle to peace is "the fact that all Palestinian factions remain committed to the destruction of Israel." He said that despite other religious and political differences they may have, the various Palestinian movements agree that "all of Israel is 'Palestine,' and they do not accept the permanent existence of any kind of Jewish or Zionist state there."
Noting that the theme of the conference was "In the Spirit of Balfour," Kuperwasser said that the Palestinian Arabs and their leaders "to this day reject the basic premise of the Balfour Declaration." November marks the centennial of that British pledge to facilitate the establishment of "the establishment in Palestine of a national home for the Jewish people."
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The Palestinians believe "that the Jews are not a legitimate people, that they never had a genuine connection to the land of Israel at any time in history, and that they had no right to establish a state there in 1948," Kuperwasser said.
Kuperwasser, who formerly headed the research branch of the IDF's military intelligence division, said that "the Palestinians see themselves as victims of British colonialism, American imperialism and Zionism, and as a result they believe that they should not be held to the same standards as others and do not have to play by the rules that the international community expects others to play by."
According to Kuperwasser, "the Palestinians believe, and teach their children, that all forms of struggle, including violence, are legitimate in the war against Israel." They regard "the 'fighting sector' of Palestinian society, those who engage in violence, as heroes who deserve to be rewarded with handsome payments," he said.
Kuperwasser was the author of a recent report, published by the Jerusalem Center for Public Affairs, which documented the Palestinian Authority's (PA) payments to imprisoned terrorists and the families of dead terrorists. The report helped galvanize congressional support for the Taylor Force Act, which was unanimously passed by the House Foreign Affairs Committee last week. The legislation would impose restrictions on US aid to the PA if the payments to terrorists continue.
Miller, by contrast, told the American Zionist Movement conference that Israel and the PA are equally to blame for the fact that peace has not yet been achieved. He said that "both sides lack leaders who will make decisions and who are not prisoners of ideologies." Miller said that he "cannot imagine either Israeli or Palestinian leaders getting up in front of their people and announcing that the conflict is over."
The former State Department official also asserted that "the Israelis and Palestinians don't care as much about [resolving the conflict] as external parties do." He compared their mindset to someone who rents a car but does not really care about it, because it is owned by somebody else.
According to Miller, the other major "missing ingredient" today is "effective US leadership." He praised former President Jimmy Carter as well as former Secretaries of State Henry Kissinger and James Baker as "the only American leaders who understood that you have to use not just honey, but also a fair amount of vinegar" in dealing with Israel.
During the early 1990s, Miller was part of a team of senior advisers to Baker. The aides were widely criticized in the American Jewish community over their treatment of Israel.

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Meeting with the client, exploring the manufacturing process and setting tasks.
During the meeting, the client strikes us with extreme attention to product quality: everything, from the choice of the upper material to design of buttons and quality of the thread is carefully controlled by designers and managers of the company. The core audience of the website will be made of wholesale buyers and outlets' representatives.
The first part of the task: we need to explore the idea of attention to quality on the website. The second part: the website has to be a simple and functional tool for viewing current collections.
This is the first version of the company's website, which means we will be starting from scratch. Looking at the brand's printed catalogs, labels and sketches.
Creating a website map and starting to generate drafts. By the time the website is ready, the 2015–2016 collection will be launched. Taking the first retouched photos from the catalog and putting them on the canvas together with product cards. Deciding to add trivia about manufacturing to break down the rhythm and share information about the production process and quality.
For collection identifiers, coming up with a type structure of a "2015–2016" format where the dash will be replaced by various natural images: flower petals, feathers, colors, etc.
The first drafts start to emerge. We get the idea to show pictures in maximum zoom on product cards in order to highlight the quality of the materials. To make sure the silhouette can still be seen, adding a large switch to change photo angles. All the supplementary information floats freely around the photo as trivia. Following these simple steps we turn a product card into a promo page.
The idea with the card looks fortunate and effective. We get the idea to create an "inverted website" where one of the model cards will become the main page. At the top we'll add the "Entire collection" hyperlink clicking on which will zoom the card out and put it in the collection grid.
The designer starts to write the code and tries the idea in the browser. Coming up with a really rad zoom effect. A magnifier is fixed at the bottom of the screen, an enlarged fragment of an image appears when scrolled through it. On mouse hover, the magnifier gets larger; scrolling further, the viewer sees the material in even more magnification. Combining this block with an additional photo switch to better direct the viewer's attention. Neat!
Assembling ideas into a presentation and demonstrating to the client.
The client likes the ideas and the overall approach. But at the meeting we find out that the client has prepared a new lookbook for the collection and put a lot of time and effort into it. It is the company's first lookbook and their first ideas on brand presentation. Reaching the agreement that the current concept is very functional and lacks an effective presentation of the brand, something that the client has started to develop in the new lookbook.
Taking a break to think and study the lookbook.
The lookbook and client's brand presentation ideas change our task: now apart from being the product catalog and providing information on the quality of items, the website needs to present a brand.
Building on the current ideas and thinking how we can create a bridge between emotional perception of the brand and its "technical specifications." Coming up with a new story with zooming in and out. Creating a façade on the main page: a story about the brand and its values presented in a couple of sentences. Each thesis is illustrated by a picture from the lookbook. On each "level" there is a plus button. When it's clicked, the picture zooms in and another thesis appears, this time about manufacturing and product quality. Now there are two narrative levels and a functional bridge between them: the zooming-in of the photograph.
Continuing to work on design in the browser. Apart from the functional bridge, we want to find a simple visual solution that would underline the core idea. Building on the previous concept with petals and other natural objects, we come up with a way to enhance the appearance of the zoom effect. The images of petals and feathers will float around photographs on the main page. Clicking the plus button will zoom the entire composition to show that petals are made of hundreds of fine threads.
Using the petal image from the classic New Order album cover for the prototype.
Refreshing the visual language as we go, making the style stricter and the product card simpler. Fitting all gallery photos in a scrolling feed.
Presenting the idea to the client. The idea is accepted. An issue arises of the contrast between the brightness of the fragments of the first concept with its facts and petals, and the coldness of the illustrations of the second concept.
Two approaches are born. The first one is based on photorealistic petals and emphasizing the magnification effect with petal textures. The other one relies on illustrations.
After much deliberation, getting the client to approve the photorealistic petal idea. People start thinking about purchasing a coat when it's cold, in autumn or in winter, and we want to make this process a bit warmer.
Launching the development of the website. Starting the simultaneous typesetting of key mock-ups from the concept, development of internal pages and creation of technical graphics.
Calculating the mechanics and zoom coefficients for the main page.
Going to the florist and holding a photo shoot. Choosing plants that blossom in the autumn.
Retouching and assembling into compositions for the main page.
Retouching photos from the lookbook in maximum resolution.
Meanwhile, fabric samples for all products arrive to the studio. Taking photographs and retouching.
Assembling mock-ups of internal pages.
Equalizing backgrounds of all photos in the catalog.
Adding a preloader animation for use with a slow connection.
Polishing the dynamics of page scrolling and animation.
Launching the beta version and fixing bugs.


text:
Methods and Applications: Development of Cryogenic Disinfectants Using in –18 °C and –40 °C Environments — Worldwide, 2021
Huihui Sun1,&;
Hongyang Duan1,&;
Wei Zhang1;
Chen Liang1;
Luyao Li1;
Yuan Lyu1;
Yanyan Chen1;
Jin Shen1, , ;
Liubo Zhang1, ,
View author affiliation
National Institute of Environment Health, Chinese Center for Disease Control and Prevention, Beijing, China
& Joint first authors.
Corresponding authors: Jin Shen, shenjin@nieh.chinacdc.cn; Liubo Zhang, zhangliubo@nieh.chinacdc.cn
[1] World Health Organization. Coronavirus Disease (COVID-19) dashboard. https://covid19.who.int/. [2021–02–10].https://covid19.who.int/
[2] Han J, Zhang X, He SS, Jia PQ. Can the coronavirus disease be transmitted from food? A review of evidence, risks, policies and knowledge gaps. Environ Chem Lett 2021;19: 5–16. http://npub.ltlogo.top/33024427/.http://npub.ltlogo.top/33024427/
[3] Fisher D, Reilly A, Zheng AKE, Cook A, Anderson D. Seeding of outbreaks of COVID-19 by contaminated fresh and frozen food. bioRxiv 2020. http://dx.doi.org/10.1101/2020.08.17.255166. [2021–03–23].http://dx.doi.org/10.1101/2020.08.17.255166
[4] Chin AWH, Chu JTS, Perera MRA, Hui KPY, Yen HL, Chan MCW, et al. Stability of SARS-CoV-2 in different environmental conditions. Lancet Microbe 2020;1(1):e10. https://pubmed.ncbi.nlm.nih.gov/32835322/.https://pubmed.ncbi.nlm.nih.gov/32835322/
[5] Pang XH, Ren LL, Wu SS, Ma WT, Yang J, Di L, et al. Cold-chain food contamination as the possible origin of COVID-19 resurgence in Beijing. Natl Sci Rev 2020;7(12):1861 − 4. http://dx.doi.org/10.1093/nsr/nwaa264CrossRef
[6] China Daily. The Shanghai 9 confirmed case and the worker's infection can be traced to the source: exposure to an aircraft assembly imported from abroad. https://cnews.chinadaily.com.cn/a/202011/23/WS5fbb52b7a3101e7ce97311be.html. (In Chinese). [2021–03–22].https://cnews.chinadaily.com.cn/a/202011/23/WS5fbb52b7a3101e7ce97311be.html
[7] Ministry of Health of the People's Republic of China. Technical standard for disinfection (2002 version). Beijing: Ministry of Health of the People's Republic of China. 2002. http://book.kongfz.com/3477/2893660662/. (In Chinese). http://book.kongfz.com/3477/2893660662/
[8] National Health Commission of the People's Republic of China. GB/T 38502-2020 Test method for bactericidal effect of disinfectant in laboratory. Beijing: Standards Press of China, 2020. http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=744F030ACEF7928C91AE0CF5C2F306AE. (In Chinese). http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=744F030ACEF7928C91AE0CF5C2F306AE
[9] National Health Commission of the People's Republic of China. GB/T 36758-2018 Hygienic requirements for disinfectants with chlorine. Beijing: Standards Press of China, 2018. http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=CFCB58954F3CA1C01908B0407FF97D8E. (In Chinese). http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=CFCB58954F3CA1C01908B0407FF97D8E
[10] Guo XL, Chen Y, Wang L, Wu XS, Fan JJ, Li F, et al. In vitro inactivation of SARS-CoV-2 by commonly used disinfection products and methods. Sci Rep 2021;11(1):2418. http://npub.ltlogo.top/33510320/.http://npub.ltlogo.top/33510320/
[11] Han L, Liu WR, Ao XF. Observation on impact of antifreeze on chlorine dioxide's disinfection efficacy. Port Health Control 2009;14(4):20–2. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2009&filename=KAWS200904014&v=JjHocTDu6izPQNpTfOHfX%25mmd2FRDCB7nc6h4Q9wTABredPysqO5JldhzK%25mmd2BrayQZFtKlZ. (In Chinese). https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2009&filename=KAWS200904014&v=JjHocTDu6izPQNpTfOHfX%25mmd2FRDCB7nc6h4Q9wTABredPysqO5JldhzK%25mmd2BrayQZFtKlZ
[12] Xu L, Wang LY, Li J, Yu MB, Chen GY, Han LL. Preliminary study on the effect of a chlorine-containing disinfectant on microorganism disinfection in low temperature environment. In: Proceedings of the 30th Annual Conference of the Chinese Chemical Society. Dalian: Chinese Chemical Society. 2016; p. 1. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CPFD&dbname=CPFDLAST2017&filename=ZGHY201607045054&v=S0BTfXkAmQ9x4Gwcq1tteh6%25mmd2F1twO0IwGQk3GsbcvCjRsrfUzCNTbrgPKK%25mmd2BgFg4vYTToM%25mmd2BHIMefw%3d. (In Chinese). https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CPFD&dbname=CPFDLAST2017&filename=ZGHY201607045054&v=S0BTfXkAmQ9x4Gwcq1tteh6%25mmd2F1twO0IwGQk3GsbcvCjRsrfUzCNTbrgPKK%25mmd2BgFg4vYTToM%25mmd2BHIMefw%3d
[13] Harrison AG, Li T, Wang PH. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol 2020;41(12):1100–15. http://npub.ltlogo.top/33132005/.http://npub.ltlogo.top/33132005/
[14] Deng FR. Factors affecting the disinfection effect of chemical disinfectants. Chin J Clin 2001;29(2):15–6. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2001&filename=ZLYS200102012&v=WRcAlwNxMNYifoMQR2U%25mmd2BHQ%25mmd2F68FPYV0f%25mmd2FXc7un2B5qzii1zY1skejSbXpC1i9xtkx. (In Chinese). https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2001&filename=ZLYS200102012&v=WRcAlwNxMNYifoMQR2U%25mmd2BHQ%25mmd2F68FPYV0f%25mmd2FXc7un2B5qzii1zY1skejSbXpC1i9xtkx
TABLE 1. Neutralizer identification test on Staphylococcus aureus.
Group –18 °C Cryogenic disinfectant –40 °C Cryogenic disinfectant
Average colony forming units of
each group (CFU/tablet) Error rate between groups (%) Average colony forming units of
each group (CFU/tablet) Error rate between groups (%)
1 407 4.2 542 4.23
Note: Group 1: soak the carrier tablet in 5.0 mL neutralizing agent for 10 minutes; Group 2: soak the carrier tablet in 5.0 mL of neutralization products for 10 minutes; Group 3: soak the carrier tablet in 5.0 mL tryptone saline solution (TPS) dilution for 10 minutes; Group 4: 1 mL of TPS diluent, 1 mL of neutralizing agent and the same culture medium as that of the first three groups was added and placed into sterile plates.The neutralizer of –18 °C Cryogenic disinfectant was 0.03 mol/L PBS containing 0.3% sodium thiosulfate, 0.1% lecithin and 1% tween-80 while 0.03 mol/L PBS containing 0.5% sodium thiosulfate, 0.5% lecithin and 2% tween-80 was for –40 °C Cryogenic disinfectant.
TABLE 2. Killing effect of disinfectant of –18 °C/–40 °C disinfectant on Staphylococcus aureus and Escherichia coli.
Bacteria Available chlorine (mg/L) Logarithm of the mean colony number of the positive control group Average killing log of bacteria at different times of disinfection
2.5/5 min 5/10 min 7.5/15 min
Staphylococcus aureus 2,919/4,869 6.18/6.07 5.81/3.91 5.88/4.12 6.18/4.10
Escherichia coli 2,919/4,869 6.36/6.36 5.23/4.78 5.23/5.14 6.18/5.39
TABLE 3. The disinfection effect of –18 °C/–40 °C cryogenic disinfectant on Staphylococcus aureus/Escherichia coli on outer surface of the cartons.
Sample number Carrier position Colony forming units of test group (CFU/tablet) Killing log value Sample number Carrier position Colony forming units of test group (CFU/tablet) Killing log value
1 Top side of carton 1 (265, 0)/(10, 25) >3.00 16 Right side of carton 3 (10, 0)/(20, 5) >3.00
2 Bottom side of carton 1 (235, 15)/(615, 0) >3.00 17 Front side of carton 3 (5, 10)/(30, 0) >3.00
3 Left side of carton 1 (15, 0)/(10, 15) >3.00 18 Back side of carton 3 (0, 0)/(5, 0) >3.00
4 Right side of carton 1 (15, 0)/(10, 0) >3.00 19 Top side of carton 4 (0, 15)/(65, 0) >3.00
5 Front side of carton 1 (5, 10)/(50, 30) >3.00 20 Bottom side of carton 4 (425, 65)/(60, 950) >3.00
6 Back side of carton 1 (0, 5)/(0, 0) >3.00 21 Left side of carton 4 (0, 0)/(5, 0) >3.00
7 Top side of carton 2 (0, 15)/(480, 45) >3.00 22 Right side of carton 4 (10, 0)/(0, 0) >3.00
8 Bottom side of carton 2 (10, 50)/(515, 20) >3.00 23 Front side of carton 4 (5, 0)/(10, 0) >3.00
9 Left side of carton 2 (145, 0)/(5, 0) >3.00 24 Back side of carton 4 (10, 0)/(0, 0) >3.00
10 Right side of carton 2 (5, 0)/(5, 25) >3.00 25 Top side of carton 5 (0, 0)/(5, 5) >3.00
11 Front side of carton 2 (0, 10)/(5, 55) >3.00 26 Bottom side of carton 5 (15, 40)/(210, 5) >3.00
12 Back side of carton 2 (0, 20)/(5, 0) >3.00 27 Left side of carton 5 (50, 0)/(0, 5) >3.00
13 Top side of carton 3 (5, 0)/(10, 10) >3.00 28 Right side of carton 5 (5, 0)/(0, 15) >3.00
14 Bottom side of carton 3 (100, 5)/(0, 10) >3.00 29 Front side of carton 5 (0, 0)/(10, 0) >3.00
15 Left side of carton 3 (0, 0)/(10, 0) >3.00 30 Back side of carton 5 (230, 0)/(0, 0) >3.00
Note: Positive control bacteria count of Staphylococcus aureus and Escherichia coli: 4.26×106 CFU/tablet (9.0×105–6.6×106 CFU/tablet), 1.91×106 CFU/tablet (3.15×105–9.15×106 CFU/tablet).
TABLE 4. The disinfection effect of –18 °C/–40 °C cryogenic disinfectant on Staphylococcus aureus/Escherichia coli in –18 °C/–40 °C storage.
Sample number Colony forming units of test group (CFU/tablet) Killing log value Sample number Colony forming units of test group (CFU/tablet) Killing log value
1 (0, 0)/(30, 5) >3.00 16 (5, 0)/(0, 5) >3.00
2 (0, 0)/(0, 0) >3.00 17 (0, 0)/(20, 10) >3.00
3 (0, 0)/(5, 0) >3.00 18 (0, 0)/(0, 0) >3.00
4 (0, 0)/(0, 65) >3.00 19 (0, 0)/(0, 0) >3.00
5 (0, 0)/(10, 5) >3.00 20 (0, 0)/(0, 70) >3.00
8 (0, 0)/(0, 0) >3.00 23 (0, 0)/(15, 135) >3.00
9 (0, 0)/(0, 0) >3.00 24 (0, 0)/(5, 115) >3.00
10 (0, 0)/(0, 0) >3.00 25 (0, 0)/(20, 10) >3.00
11 (0, 0)/(0, 15) >3.00 26 (0, 0)/(10, 100) >3.00
12 (0, 0)/(5, 0) >3.00 27 (0, 0)/(20, 0) >3.00
14 (0, 0)/(5, 0) >3.00 29 (0, 0)/(20, 340) >3.00
15 (0, 0)/(0, 0) >3.00 30 (0, 0)/(0, 170) >3.00
Note; Positive control bacteria count of Staphylococcus aureus and Escherichia coli: 4.26×106 CFU/tablet (9.0×105–6.6×106 CFU/tablet), 1.91×106 CFU/tablet (3.15×105–9.15×106 CFU/tablet).
Development of Cryogenic Disinfectants Using in –18 °C and –40 °C Environments — Worldwide, 2021
1. National Institute of Environment Health, Chinese Center for Disease Control and Prevention, Beijing, China
Corresponding authors:
Jin Shen, shenjin@nieh.chinacdc.cn;
Liubo Zhang, zhangliubo@nieh.chinacdc.cn
Introduction: Since the outbreak of coronavirus disease 2019 (COVID-19) in Beijing Xinfadi Wholesale Market, a series of COVID-19 outbreaks has indicated the threat of transmission due to outer surfaces of objects under low temperatures. Therefore, 2 kinds of chlorine-containing disinfectants for −18 °C and −40 °C were developed in order to solve the problem of low temperature disinfection.
Methods: The properties of two cryogenic disinfectants were evaluated by low-temperature test. Staphylococcus aureus and Escherichia coli were used as two indicator microorganisms to evaluate the effects of the two cryogenic disinfectants in the laboratory and field tests according to Technical Specifications for Disinfection (2002 version) and Test method for bactericidal effect of disinfectants in laboratory (GB/T 38502-2020).
Results: Two disinfectants could remain in the liquid state at −18 °C or −40 °C in 72 hours without crystallization and precipitation, and the average log values of microbial reduction before and after disinfection (the average killing log value) both on Staphylococcus aureus and Escherichia coli were >3 in the laboratory and field tests.
Discussion: The results showed that these two disinfectants remained functional at low temperature to disinfect the packaging of imported cold chain food and surrounding packaging to prevent transmission of COVID-19 from material to people.
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, there have been more than 10 million confirmed cases and 2,320,497 deaths (1). According to the current understanding of COVID-19 virus, the virus can be transmitted by air droplets and aerosols or through deposit on the surfaces of inanimate objects and subsequent contact with those objects (2). A previous study showed that COVID-19 virus survived for 21 days on refrigerated (4 °C) and frozen (–20 °C and –80 °C) salmon and chicken (3) but was inactivated after 5 min at 70 °C (4), indicating that cold temperature extended the survival time of the virus on surfaces.
COVID-19 virus was detected on a cutting board used for processing imported salmon in a food contamination incident that occurred on June 12, 2020 in Xinfadi Agricultural Produce Wholesale Market in Beijing (5), and subsequent outbreaks occurred in Xinjiang and Shanghai (6). These incidents demonstrated that COVID-19 virus could survive on the surface of objects in cold environments for long times and could cause cluster outbreaks.
The temperature of Xinjiang, Inner Mongolia, and other places in China has dropped below –20 °C in 2020 winter, as it has in Russia, Canada, and some northern regions of the United States. Temperature is an important factor affecting the effectiveness of disinfection as low temperature will make microbicidal efficiency decrease and there are no appropriate disinfection measures available for use at such cold temperatures. Therefore, the prevention and control of COVID-19 virus in these regions has become more difficult.
In this study, 2 chlorine-containing cryogenic disinfectant were developed to kill Staphylococcus aureus and Escherichia coli at –18 °C and –40 °C, and these effects were verified.
Bacterial Strains, Bacterial Carriers, and media
Staphylococcus aureus and Escherichia coli bacteria were cultured on Tryptone soy agar (TSA) medium; Tryptone soy broth (TSB) medium was used to dilute the bacteria cultured overnight to the required concentration; 10 μL of fresh Staphylococcus aureus and Escherichia coli were applied to cloth carriers, which were left at room temperature to dry and dropped to –18 °C or –40 °C before disinfection.
Formula Determination
Calcium chloride, ethanol, and ethylene glycol were chosen as antifreeze agents. Sodium dichloroisocyanurate was selected as the main active ingredient, combined with the optimum proportion of antifreeze to assess the killing effect of microorganisms under low temperatures.
Icing Test
For this test, 5 mL disinfectant was added to 90 mm glass petri dishes, and 20 mL disinfectant was added to 50 mL centrifuge tubes; the objects were then placed in the –18 °C or –40 °C environment and observed at different timepoints.
Laboratory Bactericidal Experiment
Before each bactericidal experiment, the available chlorine concentration of the disinfectant was measured using the iodometric method described in the Technical Specifications for Disinfection (2002 version)(7).
For neutralizer identification test, it was divided into 4 groups according to the Test method for bactericidal effect of disinfectant in laboratory (GB/T 38502-2020) (8) to evaluate whether the neutralizing agent, neutralizing product, and diluent affected the bacterial tablet.
For carrier quantitative germicidal test, the effect of the disinfectant on Staphylococcus aureus and Escherichia coli was evaluated according to the Technical Specifications for Disinfection (2002 edition). The infected bacterial carriers were immersed into the disinfectant (5.0 mL per carrier tablet) and positive control bacterial carriers into the diluent. The experiment was repeated three times.
Cartons (58 cm × 38 cm × 34 cm) were selected as simulating container to evaluate the disinfection to the outer packaging of refrigerated articles. One piece of Staphylococcus aureus carrier and one piece of Escherichia coli carrier were fixed on each of the six sides of the carton. Then, the cartons were immediately placed in a high-speed micron spray sterilizer for six-sided disinfection until each carrier was soaked after the bacteria carriers reached –18 °C or –40 °C.
To test cold storage disinfection, a total of 10 Staphylococcus aureus carriers and 10 Escherichia coli carriers placed on each plate were evenly placed in the front, back, left, right, and middle of the –18 °C or –40 °C cold storages. A disinfectant sprayer equipped with the low-temperature disinfectant was used to spray and disinfect the cold storage, and the spraying volume is about 200–300 mL/m2.
In field tests, the temperatures of the carriers were verified to reach –18 °C or –40 °C before disinfection and 3 samples for each bacterium were put into cold storage together with the experimental group but not sterilized as the positive control group.
Another 10 minutes after the carriers were completely soaked were allowed, and the bacterial carriers were placed in 10 mL neutralizer solutions while the positive control bacteria carriers were placed in 10 mL diluent. The colonies were then counted. The test was repeated three times.
Physical Property Tests
In this study, the disinfectant remained liquid without crystallization or precipitation in cold storage times of 72 h.
When evaluating the bactericidal effect of –18 °C disinfectant, the mean available chlorine concentration prepared in the laboratory tests was 2,919 mg/L (2,872–2,943 mg/L) while in field tests was 2,795 mg/L (2,765–2,819 mg/L). The available chlorine concentrations of –40 °C disinfectant before the 3 sets of laboratory experiments were 4,892 mg/L, 4,875 mg/L, and 4,839 mg/L, while those for field tests were 5,283 mg/L, 5,141 mg/L, and 5,247 mg/L.
For the two cryogenic disinfectants, two types of neutralizers could effectively neutralize the effect of the disinfectant remaining on the surface of bacteria in diluent on Staphylococcus aureus, and neither the neutralizer nor the neutralizing product had any adverse effect on Staphylococcus aureus or the medium (Table 1).
Based on neutralizer identification test, we carried out bactericidal experiments with the disinfectants. The average killing log values of the 2 disinfectants against Staphylococcus aureus and Escherichia coli were >3.00 at –18 °C and –40 °C, demonstrating the qualified effects of the disinfectants (Table 2).
There were 1 sample of Staphylococcus aureus and 1 sample of Escherichia coli on each side of each carton, and a total of 60 samples were collected at –18 °C or –40 °C. After the carton was sterilized by a high-speed micron spray sterilizer, the killing log values of Staphylococcus aureus and Escherichia coli on the carrier were all >3.00, demonstrating a qualified disinfection effect.
The killing log values of 30 Staphylococcus aureus tablets and 30 Escherichia coli tablets were all >3.00 after sterilizing the –18 °C or –40 °C storages with a sprayer (the dosage of disinfectant was 200–300 mL/m2), also meeting the requirements for qualified disinfectants (Tables 3–4).
Formulation of Disinfectant
With a combination of freezing tests, laboratory experiments and field tests, we obtained two disinfectants, the disinfectant for –18 °C contained 25% calcium chloride, 9.5% ethanol, and 3,000 mg/L sodium dichloroisocyanurate, while 30% calcium chloride, 9.5% ethanol, 9.9% ethylene glycol, 5,000 mg/L sodium dichloroisocyanurate, and 0.09% benzalkonium chloride were used in the –40 °C disinfectant.
In this study, chemical disinfectants were applied to determine effectiveness at low temperatures. Disinfectants with chlorine were considered suitable for disinfecting general object surfaces, food and drinking utensils, fabrics, fruits, vegetables, and water, etc., in public places and families (9). COVID-19 virus can be inactivated in 0.5 min at room temperature at an available chlorine level of 250 mg/L (10). Considering economic costs and convenience of application, sodium dichloroisocyanurate (available chlorine) was selected as the representative chlorine-containing disinfectant, and a small amount of benzalkonium chloride was added to synergize the disinfection effect in the –40 °C cryogenic disinfectant.
The formulation contained antifreeze agents including calcium chloride, ethanol, and glycol. Industrial calcium chloride aqueous solution was widely used in all kinds of equipment and environments that require a reduced freezing point. However, the saturation point of calcium chloride decreases with decreasing temperature, and calcium chloride is corrosive (8). Therefore, ethanol and ethylene glycol were also added as antifreeze agents. Ethanol has a antifreeze effect in chlorine dioxide compounds at –20 °C (11). Methanol and ethylene glycol have also been reported as antifreeze compounds facilitating the disinfection effect of chlorine-containing disinfectants at 0°C and –20 °C (12). Considering its toxicity and price, methanol was not selected for this formula.
The COVID-19 virus is lipophilic and an enveloped virus (13), and it is generally believed to be more sensitive to chemical disinfection factors than Staphylococcus aureus and other bacteria (14). So, staphylococcus aureus and Escherichia coli were considered indicators to evaluate the disinfection effect. The cryogenic disinfectant developed in this study solved the problem of freezing and effectiveness of chemical disinfectants at low temperatures, which meant that the cryogenic disinfectants could be used for disinfection of COVID-19 virus. This study provided a new method for solving the technical problems of the disinfection of cold chain food packaging or environments, outdoor environments, and cold winter items.
This study was subject to some limitations. First, since the stability of this disinfectant has not been studied, it should be created for use immediately. Second, because there was no evaluation method for the metal corrosion of disinfectants at low temperatures, the metal corrosion test at low temperature has not been conducted for these two disinfectants.
Further studies are needed to adjust the formulation without affecting the effectiveness of disinfection to enhance stability for better application. This disinfectant should be used only when the effectiveness of disinfection reaches qualifying levels. Strict personal protection measures should be carried out in the process of disinfectant configuration and onsite disinfection because of the bleachability, corrosiveness, and skin irritation of the disinfectant as it is a chlorine-based disinfectant.
Acknowledgment: HaiYunYiJianPan-Health Technology Co., Ltd and Beijing Capital Agribusiness Group.
[1] World Health Organization. Coronavirus Disease (COVID-19) dashboard. https://covid19.who.int/. [2021–02–10].
[2] Han J, Zhang X, He SS, Jia PQ. Can the coronavirus disease be transmitted from food? A review of evidence, risks, policies and knowledge gaps. Environ Chem Lett 2021;19: 5–16. http://npub.ltlogo.top/33024427/.
[3] Fisher D, Reilly A, Zheng AKE, Cook A, Anderson D. Seeding of outbreaks of COVID-19 by contaminated fresh and frozen food. bioRxiv 2020. http://dx.doi.org/10.1101/2020.08.17.255166. [2021–03–23].
[4] Chin AWH, Chu JTS, Perera MRA, Hui KPY, Yen HL, Chan MCW, et al. Stability of SARS-CoV-2 in different environmental conditions. Lancet Microbe 2020;1(1):e10. https://pubmed.ncbi.nlm.nih.gov/32835322/.
[5] Pang XH, Ren LL, Wu SS, Ma WT, Yang J, Di L, et al. Cold-chain food contamination as the possible origin of COVID-19 resurgence in Beijing. Natl Sci Rev 2020;7(12):1861 − 4. http://dx.doi.org/10.1093/nsr/nwaa264.
[6] China Daily. The Shanghai 9 confirmed case and the worker's infection can be traced to the source: exposure to an aircraft assembly imported from abroad. https://cnews.chinadaily.com.cn/a/202011/23/WS5fbb52b7a3101e7ce97311be.html. (In Chinese). [2021–03–22].
[7] Ministry of Health of the People's Republic of China. Technical standard for disinfection (2002 version). Beijing: Ministry of Health of the People's Republic of China. 2002. http://book.kongfz.com/3477/2893660662/. (In Chinese).
[8] National Health Commission of the People's Republic of China. GB/T 38502-2020 Test method for bactericidal effect of disinfectant in laboratory. Beijing: Standards Press of China, 2020. http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=744F030ACEF7928C91AE0CF5C2F306AE. (In Chinese).
[9] National Health Commission of the People's Republic of China. GB/T 36758-2018 Hygienic requirements for disinfectants with chlorine. Beijing: Standards Press of China, 2018. http://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=CFCB58954F3CA1C01908B0407FF97D8E. (In Chinese).
[10] Guo XL, Chen Y, Wang L, Wu XS, Fan JJ, Li F, et al. In vitro inactivation of SARS-CoV-2 by commonly used disinfection products and methods. Sci Rep 2021;11(1):2418. http://npub.ltlogo.top/33510320/.
[11] Han L, Liu WR, Ao XF. Observation on impact of antifreeze on chlorine dioxide's disinfection efficacy. Port Health Control 2009;14(4):20–2. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2009&filename=KAWS200904014&v=JjHocTDu6izPQNpTfOHfX%25mmd2FRDCB7nc6h4Q9wTABredPysqO5JldhzK%25mmd2BrayQZFtKlZ. (In Chinese).
[12] Xu L, Wang LY, Li J, Yu MB, Chen GY, Han LL. Preliminary study on the effect of a chlorine-containing disinfectant on microorganism disinfection in low temperature environment. In: Proceedings of the 30th Annual Conference of the Chinese Chemical Society. Dalian: Chinese Chemical Society. 2016; p. 1. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CPFD&dbname=CPFDLAST2017&filename=ZGHY201607045054&v=S0BTfXkAmQ9x4Gwcq1tteh6%25mmd2F1twO0IwGQk3GsbcvCjRsrfUzCNTbrgPKK%25mmd2BgFg4vYTToM%25mmd2BHIMefw%3d. (In Chinese).
[13] Harrison AG, Li T, Wang PH. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol 2020;41(12):1100–15. http://npub.ltlogo.top/33132005/.
[14] Deng FR. Factors affecting the disinfection effect of chemical disinfectants. Chin J Clin 2001;29(2):15–6. https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2001&filename=ZLYS200102012&v=WRcAlwNxMNYifoMQR2U%25mmd2BHQ%25mmd2F68FPYV0f%25mmd2FXc7un2B5qzii1zY1skejSbXpC1i9xtkx. (In Chinese).


Multi-disciplinary full-text database, with more than 8,500 full-text periodicals, including more than 7,300 peer-reviewed journals. In addition to full text, this database offers indexing and abstracts for more than 12,500 journals and a total of more than 13,200 publications.
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Acadoodle is an online resource that boasts a large selection of video tutorials which can be viewed individually, or as part of a tested course.
There are approximately 19,272 in-depth, detailed Canadian association profiles in Associations Canada 2018, which include the association's various chapters and branch locations. In addition, this resource lists 902 foreign associations — those not headquartered in Canada, but have a Canadian presence, either physically or otherwise.


text:
American Security Project » About » Our Staff & Fellows » ASP's Adjunct Fellows » Adin Dobkin
Adin Dobkin
Adjunct Fellow
Expertise: American Competitiveness, Military Capabilities, Governance
Adin Dobkin is a national security and defense technology analyst with a with a background in communications and government affairs. He currently splits his time between Capitol Hill and acting as the Communications Director of the Military Writers Guild, a coalition of military officers, DOD civilians, analysts, and writers dedicated towards the field of arms.
Dobkin previously served as the Government and Media Affairs Officer of ASP. In his role, he briefed key members of government bodies, coordinated ASP's efforts with nationally-recognized media outlets, and developed the political strategy behind ASP's research efforts.
His work on military strategy, national security, and space policy has been featured by the Hill, the Atlantic Council, the Bridge, and others. He is a member of the Center for International Maritime Security, the Military Writers Guild, and the National Press Club.
Follow Adin on Twitter @AdinDobkin
Cyber Escalation: A Military Planner's Blank Slate
ASP's Smith on CCTV America
BGen Cheney Discusses U.S. Space Program on BBC Newsnight
American Security Quarterly - August 2014
Gen Shelton "There's no substitute to global-ready space capabilities"
Posted on: Jul 22, 2014
By: Nicole Franiok
Key Reads Iran says it's now enriching uranium at levels higher than before nuclear deal Alex Ward / Vox The announcement is mainly a message to Western Europeans, an Iranian audience, and maybe Trump. Eleven US Troops Were Injured in Jan. 8 Iran Missile Strike Kevin Baron / Defense One... All News
Posted by Nicole Franiok


text:
Beltré, Mauer Among First-Year Eligible Players for Baseball Hall of Fame in 2024
Adrian Beltré and Joe Mauer highlight the group of player begin Baseball Hall of Fame eligibility in 2024
By Noah Trister • Published January 25, 2023
Scott Rolen is headed to the Hall of Fame. Next year, make way for another star third baseman.
Adrián Beltré highlights the first-time eligibles for 2024. While Rolen's election Tuesday capped an impressive six-year rise in his vote total, Beltré has a good chance to go in on the first ballot. Although he was never an MVP, he finished his career with 3,166 hits, 477 home runs and five Gold Gloves, remaining productive all the way through his final season at age 39.
Joe Mauer, Chase Utley, David Wright, José Bautista and Matt Holliday are also expected to make their debuts on the ballot next year. Mauer is the only catcher to win three batting titles and was the American League MVP in 2009.
It was no surprise that several players made big jumps in the voting this year. Barry Bonds, Roger Clemens and Curt Schilling — all of whom received majority support but fell short of the 75% threshold for induction — weren't on the ballot anymore. Since there's a 10-player maximum for each voter, when candidates like that are no longer an option, others can benefit.
Get New England news, weather forecasts and entertainment stories to your inbox. Sign up for NECN newsletters.
Rolen improved from 63.2% to 76.3%, Todd Helton from 52.0% to 72.2% and Billy Wagner from 51.0% to 68.1%. Andruw Jones went from 41.1% to 58.1%.
The presence of Beltré, Mauer and Utley, however, could make it harder for other players to gain ground next year. Helton still has five more years on the ballot and Jones has four. Wagner, however, has only two more chances.
"Helton's going to be pulling something like three-quarters of the vote, and Beltré might be the first guy to threaten a hundred percent since (Derek) Jeter and Mariano (Rivera), and then there's certainly going to be a lot of Mauer and Utley support, I'd think," said Ryan Thibodaux, who runs the online Hall of Fame ballot tracker that allows fans to follow the voting process as it unfolds each year.
Patriots, Red Sox, Bruins, Celtics and more
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"Is Wagner able to get that final 7% in one shot, or does it take him until his 10th ballot? I think that's going to be really interesting to watch next year."
DECENT START
Next year also seems like a significant one for Carlos Beltrán, who received the support of 46.5% of the voters in his debut on the ballot. That type of first-year performance normally bodes very well for a candidate, but Beltrán's total was probably hurt by his role in the Houston Astros' cheating scandal.
"I made a bit of a joke in our Slack of our tracker team, that we should have, this entire time, been tracking who either said explicitly or sort of hinted that they were giving like a one-year punishment," Thibodaux said. "I can only kind of anecdotally say that I think there are a significant number of voters who are planning to vote for him next year who didn't vote for him this year."
Bonds and Clemens, dogged by performance-enhancing drug accusations, seemed to hit a ceiling in the vote after a while. If Beltrán is treated in a similar fashion he could be in trouble, but if voters indeed are only planning to penalize him for one year, that should be evident in 2024.
Gary Sheffield received 55.0% of the vote, and next year is his last on the ballot. He needs to pull off a repeat of Larry Walker's final-year surge.
Walker was at 54.6% in 2019. Then he made it to 75% the following year in his last chance.
But Jack Morris received 67.7% in his second-to-last year and never did get voted in by the Baseball Writers' Association of America. He was later elected by the Modern Era committee. That puts the jump Sheffield needs in perspective.
"That is going to be a really tough leap for him," Thibodaux said.
MLBBaseball Hall of fame
Body Found on Marblehead Beach, Authorities Say


text:
require 'spec_helper'

require 'prime'

# Summation of primes
# Problem 10
#
# The sum of the primes below 10 is 2 + 3 + 5 + 7 = 17.
# Find the sum of all the primes below two million.

describe Problems::Ten do
  before :all do
    @elapsed_time_ruby_build_in_solution = Benchmark.realtime do
      @ruby_build_in_solution = 0
      Prime.each(2_000_000){|prime_number| @ruby_build_in_solution += prime_number}
    end
  end

  describe '.solve' do
    it 'should return sum of all primes below 2 million' do
      expect(Problems::Ten.solve).to eq 142_913_828_922
    end

    it 'should return same sum as ruby build in solution' do
      expect(Problems::Ten.solve).to eq @ruby_build_in_solution
    end

    it 'should be faster than ruby build in solution' do
      pending('Ruby build in solution is 7 times faster')
      elapsed_time = Benchmark.realtime {Problems::Ten.solve}

      expect(elapsed_time < @elapsed_time_ruby_build_in_solution).to be_true
    end
  end

  describe '.prime?' do
    it 'should return false for 1' do
      expect(Problems::Ten.prime?(1)).to be_false
    end

    it 'should return true for 2' do
      expect(Problems::Ten.prime?(2)).to be_true
    end

    it 'should return true for 17' do
      expect(Problems::Ten.prime?(17)).to be_true
    end

    it 'should return false for 21' do
      expect(Problems::Ten.prime?(21)).to be_false
    end
  end
end

redpajama_set_name: RedPajamaGithub


Multinational human resources company, providing tax advisory services on the buy side, including tax due diligence of target companies, deal structuring, 2009.
Construction company, support in appealing a tax assessment act on administrative and court level, court representation, 2008.
Multinational retail company, complex advice on VAT, corporate income tax, local taxes and fees for an asset deal, 2008.
Bulgarian investment company, advice on restructuring the activities from a tax point of view, including coordination of the completion of process, 2008.
EU telecommunication service company, assistance in the application of a double tax treaty, 2007.
Multinational telecommunication company, providing tax advisory services on the buy side, including tax due diligence of several target companies, 2007.
German-owned company, providing legal representation in court regarding the appeal of a tax assessment act, 2007.
International store chain, tax due diligence of target companies, 2007.
Taxacta OOD is a firm established by experts with extensive experience in tax advisory. We have participated as advisors in a number of transactions related to acquisition of companies or assets. Our job relates to provision of tax advice to Bulgarian and international clients in relation to their activities in Bulgaria.


As a global leader in casualty insurance, Chubb understands the business of protection. More and more life sciences companies are conducting clinical trials in South Africa and around the world. Chubb understands the complexity of this environment and specialises in underwriting this coverage, examining consent forms and clinical trials agreements to better understand the risk of each client.


Rosa cespuglio Ibrido Tea/Romantica, a portamento vigoroso/eretto, ben ramificato e senza spine o quasi. Fogliame sm/lucido, grande, verde scuro. Fiori grandi, a gambo lungo, rosa veneziano, singoli. Fragranza intensa, di agrumi. Rustica e resistente malattie. Rifiorente. Adatta x fiori da espozione e taglio. H.100cm L.60cm.
In my alkaline clay, own-root Frederic Mistral is hardy and vigorous in zone 5a. The size is 3' x 5', very wide, needs room. Paul in CT, zone 5b, informed me that Frederic Mistral needs protection during spring frosts - this explains why Fred flowers so late. Fred needs full-sun and plenty of water for best flowering.
5a ! Interesting, thanks for sharing.
Frederic Mistral is terrific! Good substance and form on long stems, and strongly scented. Grows like it's on steroids.
frederic mistral seems to be hardier as it is commonly thought of because mine passed this hard winter without any damages, while other ht´s and floribundas like julia´s rose, just joey, cynthia brooke, amber queen, papa meilland, oklahoma and even paul´s lemon pillar died back to the ground.


text:
Home Betting Tips Merson: Difficult games for Liverpool and Man Utd
Merson: Difficult games for Liverpool and Man Utd
Sky Sports pundit Paul Merson has given his predictions of the matches in the Premier League on Sunday.
Merson expects difficult games for both Liverpool and Manchester United.
Manchester United travel to Brighton and Merson does not believe it will be an easy game for the visitors.
He told Sky Sports: "Brighton were probably the most disappointing team of the opening weekend if you look at the result and the way they played. But they lift their game against teams like Man Utd.
"This is a difficult game but, if they go out to win, I'll go for United."
Merson expects a similar outcome of the game between Crystal Palace and Liverpool.
He told Sky Sports: "What a game! This is a good game, Selhurst Park is a hard place to go, Palace won at Fulham but Liverpool were irresistible against West Ham.
"This is a big game for Liverpool, Man City will have already won and you've got to win these games if you're going to win the Premier League. I think this is a difficult game for them but I'll just go with Liverpool."
Merson's predictions for the Premier League matches on Sunday:
Brighton v Manchester United 1-2
Crystal Palace v Liverpool 1-2
Burnley v Watford 1-0


Daily newspaper from Weatherford, Texas that includes local, state and national news along with advertising.
four pages : ill. ; page 20 x 14 in. Digitized from 35 mm. microfilm.
Creator: Unknown. October 9, 1914.
This newspaper is part of the collection entitled: Texas Digital Newspaper Program and one other and was provided by UNT Libraries to The Portal to Texas History, a digital repository hosted by the UNT Libraries. It has been viewed 12 times . More information about this issue can be viewed below.
four pages : ill. ; page 20 x 14 in.
Folio reads, "Official Organ of the City."
Parker County (Tex.) -- Newspapers.
These issues depict content from the Weekly Herald from Weatherford in Parker County. The weekly paper began publishing in 1900, providing the residents of Parker County with news and advertising for over two decades.
Oct. 30, 2015, 3:27 p.m.
The Daily Herald (Weatherford, Tex.), Vol. 15, No. 231, Ed. 1 Friday, October 9, 1914, newspaper, October 9, 1914; Weatherford, Texas. (https://texashistory.unt.edu/ark:/67531/metapth644671/: accessed April 21, 2019), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu; .


276 What is certificate pinning?
262 How do I see the commit differences between branches in git?
122 How do I display line numbers in Emacs (not in the mode line)?
105 How do I use su to execute the rest of the bash script as that user?
85 What's the difference between the build and create methods in FactoryGirl?
29 Why doesn't apache2 respect my envvars file?
27 How do I configure Emacs to use 'ispell' on Mac OS X?


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To Redoute's Choice & Zarkava, a colt
Champion unbeaten mare Zarkava safely foaled a colt by champion sire Redoute's Choice on Monday morning at the Aga Khan's Haras de Bonneval in France.
The colt is described by Georges Rimaud, manager of the Aga Khan Studs in France as "a very elegant foal that is correct and strong."
Zarkava (Zamindar-Zarkasha by Kahyasi) whose seven victories included five at Group 1 level, will now visit the unbeaten champion Frankel.
Redoute's Choice is covering a second high-class book of mares at Haras de Bonneval, among them 18 Aga Khan mares. They include the dams of Group winner Valyra & Bayrir, a sister to Classic sire Azamour, and the Group 1 winners Rosanara, Shalanaya, Daryakana & Mandesha.
Redoute's Choice is enjoying a splendid season in Australia with progeny earnings of almost $6 million and seven stakeswinners headed by the sprinting sensation Lankan Rupee, winner of the Oakleigh Plate G1 & last Saturday's Newmarket H. G1.
Thirty-four yearlings by Redoute's Choice will be offered at next month's Inglis Australian Easter Sale, among them 6 colts & 3 fillies in the Arrowfield draft.
Tags: Aga Khan, Arrowfield, Georges Rimaud, Haras de Bonneval, Redoute's Choice, stallions


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(PDF DOWNLOAD) The Tao of Pooh by Benjamin Hoff
5.00 Avg rating—1 Votes
Publisher: Egmont Books, Limited
Genres: Classic Books for Children, Mind, Body, Spirit: Thought & Practice, Popular Philosophy, Oriental & Indian Philosophy
Authors: Benjamin Hoff
Tags: Classic Books for Children, Mind, Body, Spirit: Thought & Practice, Popular Philosophy, Free Download, PDF Download, Oriental & Indian Philosophy
Physical Form: Book
Size: Huge
Type: Digital
The Tao of Pooh. The how of Pooh? The Tao of who? The Tao of Pooh!
Winnie-the-Pooh has a certain Way about him, a way of doing things which has made him the world's most beloved bear, and Pooh's Way, as Benjamin Hoff brilliantly demonstrates, seems strangely close to the ancient Chinese principles of Taoism.
While Eeyore frets... and Piglet hesitates... and Owl pontificates... Pooh just is.
The Tao of Pooh is a philosophical study of Winnie-the-Pooh that demonstrates that the ancient wisdom of the Tao courses its way through this delightful book in a most mysterious way.
© 2020 d-pdf.com.


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Filtered by Building Technologies, Catalysis, Fossil Energy, Microbiome Science, National Security, Nuclear Energy, and Radiation Measurement
Agile BioFoundry
PNNL evaluates bacterial, fungi, and algae strains as part of a four-step process to streamline and standardize biomanufacturing processing.
FEMP's operations and maintenance (O&M) resources offer federal agencies technology- and management-focused guidance to improve energy and water efficiency and ensure safer and more reliable operations.
Biodefense Policy Landscape Analysis
The Biodefense Policy Landscape Analysis Tool (B-PLAT), captures and presents a slew of information about U.S. efforts to protect its citizens and others around the world from diverse threats.
Chemical Catalysis for Bioenergy Consortium
PNNL provides tools and expertise to bring faster, cost-effective catalysts to industry that can be produced at a large scale.
Clean Energy and Transactive Campus
PNNL's pioneering CETC project with regional universities demonstrates transactive controls among multiple commercial buildings and devices for energy efficiency and grid reliability.
Co-Optimization of Fuels & Engines
PNNL and their collaborators are investigating combinations of fuels to boost vehicle efficiency, performance, and affordability.
PNNL is a leader in the integration of aberration-corrected electron microscopy, in-situ techniques, and atom probe tomography to address challenges in nuclear materials, environmental remediation, energy storage, and national security.
The Institute for Integrated Catalysis (IIC) at Pacific Northwest National Laboratory explores and develops the chemistry and technology of catalyzed processes that enable a carbon-neutral future.
NNSA Graduate Fellowship Program
Northwest Regional Technology Center
(-) Building Technologies
(-) Catalysis
(-) Fossil Energy
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The physicians of the Center for Joint Preservation and Replacement are elected members of the highest ranking body of the orthopedic profession, the American Academy of Orthopedic Surgeons. They have extensive postgraduate training, are board certified, hold numerous academic appointments and have a combined experience that exceeds 75 years in the treatment of all types of joint degenerative disease and arthritis.
As leaders in their field, these physicians are recognized for their academic contributions to orthopedic surgery. The Center for Joint Preservation and Replacement team includes a highly skilled and dedicated group of nurses, OR staff, nurse practitioners, physician assistants, social workers, physical therapists, rehabilitation physicians, pain management specialists, fellows and residents.
The physicians of the Center for Joint Preservation and Replacement pride themselves on treating every patient like a member of their own family. They are enthusiastic about spending time educating patients and their families so they can be actively involved and informed in making medical and surgical decisions. Our goal is for patients to understand how to preserve their own joints, cartilage and tissues so they can avoid potential deterioration in the future. Each physician is committed to serving their patients with dedication, energy, kindness and empathy.
Ronald E. Delanois, M.D., is a board-certified, fellowship-trained orthopedic surgeon who brings more than 20 years of experience with complex hip, knee and shoulder reconstructive surgery to the Rubin Institute for Advanced Orthopedics. His emphasis is on the diagnostic, arthroscopic and joint-preserving procedures affecting these joints.
Barry J. Waldman, M.D., serves as co-director of the Center for Joint Preservation and Replacement at Sinai Hospital. He works to develop innovative techniques in the surgical treatment of arthritis and perioperative care.
James Nace, D.O., M.P.T., F.A.O.A.O., is a board-certified, fellowship-trained orthopedic surgeon specializing in hip, knee and shoulder joint preservation and reconstruction. He is proficient in the most modern nonoperative and operative treatments such as minimally invasive surgery, arthroscopy, primary and revision hip, knee, shoulder replacement surgery, and general orthopedic care including fractures and sprains.
Robert M. Peroutka, M.D., is a board-certified, fellowship-trained orthopedic surgeon who brings more than 28 years of experience to the Rubin Institute of Advanced Orthopedics. He specializes in adult hip and knee joint preservation and reconstruction.


The Senior Resident Magistrate Court in Mzuzu has jailed Nelson Nyirenda to four years imprisonment with hard labour after convicting him on three counts of using, illegal possession and production of counterfeits bank notes.
Police arrested Nyirenda on August 14, 2011 at Msongwe Township in Mzuzu after he knowingly used a fake MK500 note to buy mobile phone airtime worthy MK200.
Nyirenda was also found with fake MK4, 000 in MK500 notes.
On November 4, 2011, the court convicted Nyirenda on using Counterfeit Bank notes contrary to section 23 (2) (b) of the Reserve Bank of Malawi Act, Illegal possession of Counterfeit Bank notes and making Counterfeit Bank notes both contrary to section 374 (a) of the penal code.
The court sentenced Nyirenda to four years on each count but the sentences will run concurrently, which means Nyirenda will serve a total of fours only.
Reserve bank of Malawi Counsel Thabo Chakaka Nyirenda told the court that there were rampant cases of similar nature in Lilongwe and other areas.
In his judgement Magistrate Kondwani Banda agreed with both the prosecution and Counsel for the Reserve Bank of Malawi that the use of fake money has detrimental effect on the economy.
"They tend to affect commodity prices negatively," he noted.
Banda quashed Nyirenda's plea for leniency citing family obligations saying family obligations would have deterred him from committing the crime in the first place.
"Obviously as a court we will be failing in our duty if we ignore the interest of society for justice is more of public property. Further more if we grant a non custodial sentence, then society will wonder as to who is left to protect it," he said.
And in case of Shauzi Banda who was arrested at Tutlas Supermarket in Mzuzu in September2011 after she knowingly use two MK500 notes to buy a tray of eggs and a loaf of Bread, the court found that the State contradicted itself in presenting its evidence.
Banda was charged with two counts of using Counterfeit Bank notes contrary to section 23 (2) (b) of the Reserve Bank of Malawi Act, Illegal possession of Counterfeit Bank notes contrary to section 374 (a) of the penal code.
But Reserve Bank of Malawi Counsel Thabo Chakaka Nyirenda was not amused with acquittal.


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teenFish#7: Big Choices and Tin Foil Ladies in LET IT SNOW
Welcome to teenFish, a podcast series that lets teenagers speak about media that matters to them in their own voice. Hosted by Daniel Collins (Infinity Warm-Up), teenFish airs every month and invites local youth to engage the truth and lies of the shows and films that excite them.
When a snowstorm hits a small midwestern town on Christmas Eve, a group of high school students are brought together and find the lines between their friendships and love lives blurring together. This month, Daniel and Jacob talk about listening to unexpected sources and making big life choices.
You can also stream the episode above on podomatic, Alexa (via Stitcher), or Spotify! Or, you can download the ep on Apple Podcasts or Google Play!
Filed Under: Film, Netflix, teenFish Tagged With: John Green, Let It Snow, Netflix, teenFish
TFIOS: Seeking Love – Apply Within #TBT
February 9, 2017 by Steve Norton Leave a Comment
"Maybe she wasn't loved widely but she was loved deeply… and isn't that more than most of us get?" – Augustus Waters (The Fault in Our Stars)
It's hard to find love at the movies.
Well, to be fair, it's not hard to find what they think love is. Most films seem to have some kind of romance in the story, usually because someone feels like their life is meaningless without it. Then, as the movie goes on, that person finally finds that special someone to meet their needs and they realize what it means to be happy.
But then there's a film like The Fault in Our Stars.
The Fault in our Stars tells us the story of Hazel Grace Lancaster, a 17-year-old girl who is suffering from life-threatening cancer in her lungs. While her family loves and cares for her, she feels very much alone and lost, feeling that life is something that happens to other people. Eventually, she decides to join a support group for cancer patients (in the 'literal heart of Jesus') and it's here that she meets Augustus Waters, a charismatic young cancer patient who quickly becomes enamoured with her. As their relationship grows, the young couple quickly learns the realities of genuine love in the face of life and death.
Now, on the surface, the story sounds like a lot of other romance flicks.
A timid woman who's inexperienced at love is drawn to the charisma of a bad boy with a heart of gold. On that level, you could insert pretty much any set of characters and churn out pretty much any film, ranging from The Spectacular Now to the Twilight series to (arguably) Fifty Shades of Grey. In movies like these, 'love' usually takes the form of making someone happy with either romance or sex.
Once you've got that, everything else is fine. Cue the music and fade to black.
Even though it falls into some of these traps along the way, Fault shows us that love is something else entirely. From the very beginning of the film, Hazel wants us to know that what we've been sold about love and pain simply isn't true. "I believe we have a choice in this world about how we tell sad stories," she says, "On the one hand, you can sugar coat it, like they do in romance novels or movies. Nothing is too mixed up that can't be corrected with an apology or a Peter Gabriel song… It's just not the truth."
That cuts to the heart of it fairly quickly, doesn't it?
Still, in this movie, 'finding love' isn't the end goal. While most relationship flicks want us to believe that romance is the thing we're missing, Fault wants us to understand that love is far more complicated than getting promises and flowers. In fact, the film shows that the mark of real love comes when we're willing to stand by one another when we're at our worst.
(By the way, here come the spoilers…)
The love between Hazel and Augustus is rooted in genuine commitment to one another, even in the face of death. As Augustus' cancer slowly spreads and his health gets worse, Hazel doesn't run away. She demonstrates real love by her commitment to him in his worst moments of anger, fear, and sickness. She doesn't stay with Augustus because she feels guilty and she doesn't run when things get hard. In fact, she's even thankful that she's had the experience. "Some infinities are bigger than other infinities. I cannot tell you how thankful I am for our little infinity," she says.
If that isn't the best onscreen depiction of 1 Corinthians 13 you've ever seen, I don't know what is.
Hazel's love for Augustus isn't some 'teen crush' (or vice versa). Instead, it's rooted in a deep commitment to help the other person become the best version of themselves emotionally and spiritually. To quote the Bible, their love "bears all things, believes all things, hopes all things [and] endures all things." While love is certainly a basic need, too often we're told that it's about us.
Our feelings.
Our wants.
In Fault though, love is shown to be more about what we can give to the other person than what we take ourselves. While the film doesn't seem to fully draw the lines to Christian faith—even though much of it takes place in 'the literal heart of Jesus'—it very clearly depicts what genuine Biblical love is all about.
So, let's not settle for less.
Filed Under: #tbt, Editorial Tagged With: infinity, John Green, Love, okay, relationship, romance, tfios, The Fault In Our Stars, Valentine's Day


Why not shop local, support your local farm mamas, and gift your family with the joy of some farm time with chickens, pigs, goats and horses!
We have some amazing jams made by Veggie Wrangler Terri, who keeps her horses with us and uses some of our growing space here at the farm. They are pepper jams made with Laughing Buck Farm peppers: Sweet red pepper, spicy cranberry pepper, and roasted poblano. They would make a nice addition to a holiday cheese spread. They are $6 a jar-- send me an email to coordinate pickup.
Two NEW flavors: Cranberry Pepper Jam (medium) and Fire-Roasted Poblano & Sweet Yellow Pepper Jam (No heat). These flavors also available in Sugar-Free jams made with Organic Stevia.
December, 2015: We are all out of soap at this time but stay tuned for availability.
We have a beautiful cider press that includes a crusher and press that we will use with you. Set up a time to bring your apples to the farm and we will show you how to make cider. We ask that in return you share some of the cider with us as a barter. Email laughingbuckfarm at gmail dot com to arrange a time to come by.
Raised right here on a diet of garden thinnings, windfall apples, goats-milk whey, and kitchen leftovers. Email or check the Laughing Buck Farm Facebook page for current availability.
Sorry, our hens have slowed down and we do not have any eggs available at this time.
Email or message me on the Laughing Buck Farm Facebook page.
*apples, *peaches, *plums, *strawberries... and more!


When you are running a company, it is certain that you will be producing a lot of new information, not only from the work you are doing, but from your workers as well. To be able to manage these well, you will need some kind of system that, aside from making your job easier, will also guard these confidential information. A human resource information software system or HRIS system is one way that a lot of companies use to manage everything easily and become even more productive. Having this system in your company could aid the human resource team to become more organized and practice being practical in the workplace. Since this converts all the information digitally, you use of paper will definitely decrease. Now, isn't this method eco-friendly, too? There are a lot more benefits that you can get from having good cloud HR software. Human resource information is really important since these all involve the core of your company, your employees. It is only fair that you treat all the information involving them with utmost confidence. Having this kind of attitude towards your employees will make them feel confident and secure. This in turn makes them more productive and will become happy at work. This is why it is very important to maintain your credibility as a good employer so that your workforce will also have confidence in you.
With the cloud HR software, you can track down to which path your work-related decisions are taking you.
By having a clearer view of what is presently happening in your company, you can also predict what could happen in the future. One important thing that you could monitor through this is the cash flow of the company. Through the cloud HR software, you can monitor and justify some of the HR-related expenses that the company has incurred over a period of time.
Some HR-related expenses that can be monitored through this system are the training costs of newly-hired employees, and the benefits given to the employees and their reported dependents. From the termination costs, you can also pull out an evaluation of how the HR handles employee concerns. If this is high, you can try to see the reason behind why the employees are leaving. By finding out what these reasons are, you can implement changes that could improve your company. Attendance can also be monitored here. Since being frequently absent or tardy could decrease the company's productivity, it is important that you have a system wherein you can easily observe if there is an abuse of the company's system. By having employees who have good attendance, you increase your company's chances of increased revenue.


A big mistake many addiction rehab centers make is to treat addiction as if it occurs in a vacuum. Addiction, however, is usually more of a symptom of something deeper than it is the root of the problem. The layered and complex nature of these problems is why Phoenix Rising utilized trauma informed care. We attempt to address the underlying issues of your struggle, and teach you how to heal yourself from there.
When dealing with the distress of trauma and addiction, things can seem overwhelming. We are here to show you that it is conquerable and understandable. At Phoenix Rising, we are here to give you the hope and support you need.
There is a reason trauma informed care for substance abuse is becoming more popular as of late. People are recognizing that trauma is not only usually connected to addiction, but perhaps its source. The realization that addiction is usually a symptom is the foundation of trauma informed care.
Our team is comprised of experts who understand the psychology of trauma therapy. In fact, many of our staff members have been exactly where you are right now. As a result, we understand your struggle. We also understand that every person's journey is unique. The result of these traits is that we possess a level of compassion and expertise that is almost unrivaled.
Whether the root of your emotional distress is clean-cut or not, we encourage you to heal through holistic methods. This means that while we have experts on mental health present, we do not offer medication-assisted treatment. We do not want to replace one chemical dependency with another or offer you artificial relief. Our goal is to help you find balance and to take the lessons you learn with us into the real world.
We have a number of trauma informed care treatment methods to help this. Firstly, there is our large array of clinical addiction counseling services. We offer individual psychotherapy, which includes psychodrama, group and family therapy, cognitive behavioral therapy, and dialectical behavior therapy. In addition to these more standard options, we also offer art therapy, music therapy, and equine therapy.
We also want to support you on your quest for spiritual health. Mindful meditation can be an invaluable tool in mental health. It helps you learn to be present in the moment and free of the anxieties of the past or the future. We also teach yoga and general physical fitness with the use of our in-house gym.
The power of trauma informed care does not lie in any one of these things individually. When combined, these substance abuse treatment services are more than the sum of their parts. To restate our purpose, the key here is balance. Through balance you can learn to maintain your health, self-control, accountability, and mindfulness.
Coming to our Phoenix Rising addiction treatment center doesn't just mean you will treat and manage your addiction. It means that you will begin to heal as a person, from top to bottom. We believe this is the only way to create sustainable change.
To learn more about trauma informed care or trauma therapy in general, contact us at 855.232.8211. Don't wait! We are here to help you begin your journey to recovery today.


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The Grangefield Academy
Find out how The Grangefield Academy rates compared to other secondary schools in Stockton-on-Tees with our school ratings
Teesside Live
Rank 976/3,166
Here The Grangefield Academy, Oxbridge Avenue, Stockton-on-Tees, TS18 4LE, is put into focus to show its scores in relation to other schools in the area.
Oxbridge Avenue, Stockton-on-Tees, TS18 4LE
The open date and status above indicates when The Grangefield Academy opened or when it changed to its most recent incarnation, with a number of schools converting to academies in recent years. Where schools have changed type recently, data for previous years covering their previous incarnation is included below as well.
What type of school is The Grangefield Academy and what are the admission criteria?
976 (out of 3,166) 1,465 (out of 3,031) 2,696 (out of 3,088)
Yes - -
How The Grangefield Academy scores in terms of stars for each indicator.
In its most recent inspection, Ofsted has given The Grangefield Academy an overall rating of Good.
How does The Grangefield Academy perform on each of the areas inspected by Ofsted? A blank table indicates no recent inspections and as of September 2012, a score of 3 changed from indicating Satisfactory to Requires Improvement.
How have pupils at The Grangefield Academy done in their GCSEs and how does it compare to Local Authority and national averages?
In 2018 the average Attainment 8 score per pupil at The Grangefield Academy was 49.5.
In 2018, 23% of pupils at The Grangefield Academy had entries in all EBacc subject areas and 22% achieved the EBacc, with a standard pass in English and Maths, while 15% achieved it with a strong pass in those subjects.
In 2017, the most recent results available, 74% of pupils at The Grangefield Academy gained at least 5 A* to C or 9-4 grade GCSES including English and Maths at 9 to 4. Nationally 60.1% of pupils achieved this.
How does The Grangefield Academy do when it comes to GCSE results in just English and Maths and what percentage of pupils pass those at A* to C or 9 to 4 grades?
How have pupils at The Grangefield Academy done in terms of their Progress 8 score for each element?
What were the Progress 8 scores for different groups of pupils at The Grangefield Academy?
0.57 Significantly above average
0.8 Significantly above average
What is the pupil:teacher ratio at The Grangefield Academy and how does it compare to the national average?
SUPP 8 5
What is the total school spend per pupil The Grangefield Academy compared to the local and national average? (school is in blue)
How much does The Grangefield Academy spend per pupil on teachers and educational support staff and how does this compare to the average spending across the Local Authority?
GuisboroughMountain biker rescued and air ambulance called in busy Sunday shift for mountain rescue team
The team was called out three times after a number of accidents
Pubs & BarsLandlord clears up why central Middlesbrough pub has temporarily closed
A sign was put up on the door outside to inform customers
SedgefieldPopular hotel closed temporarily after police incident where guest got 'annoyed with himself'Sedgefield hotel forced to close temporarily after windows smashed in flare-up


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Components and code samples to use in development of applications that interact with Excel. These Excel solutions have been built to be utilized for the development of applications that interact remotely with the Excel application and include coding tools, code samples, ActiveX and other programming specific components. Excel solutions provide the means to communicating to and from as well as within the Excel application to facilitate sharing of data between applications and platforms and the generation of Excel based content from remote services.
VBA Coding Tools enable coding faster for Microsoft Excel, Access, Word, Outlook and other Office applications. With Code-VBA coding tools are added to your Visual Basic development environment to create better VBA code faster.
The Excel Reporting export component for Delphi is a powerful band-oriented generator of template based reports in Excel.
Scramble VBA Code for Excel is designed to protect VBA code and intellectual property by scrambling and encrypting the VBA code.
C++ Library for Excel is available for Mac, Linux and Windows to read and write native Excel files from applications.
.NET Components for Excel provide a managed code Excel file manipulation engine as well as Excel and PDF report generation for .NET & .NET Compact Frameworks.
The Java Library for Excel is a component for Java development environments allowing to create and modify Excel spreadsheets.


The laser light is monochromatic means colored. Thus laser light is monochromatic light means that laser light is only a single color light.
The monochromaticity is the major characteristic of laser making it different from ordinary light. To prove the monocromaticity of laser light, we can use prism. The glass separate wave lengths by bending each wavelength at different angle. When we pass the standard white color (which consist of all colors) through prism then it break white color in to component colors with gradual bending from short wavelength to long wavelength, as shown in Figure 1.
Now on other hand if we pass beam of laser light through the prism then beam is only changed in direction but it is not separated into different colors, as show in Figure 2.
Another important characteristic of laser is that laser light does not spread out or diverge, but it stays together in a beam.
We know that when light travels then it tends to spread out this spreading of light is called divergence and the angle at which the light spreads is called angle of divergence, denoted by phi (ɸ).
Divergence is more in ordinary light as compared to ordinary light. Therefore the angle of divergence will be greater in ordinary light case while will be lesser in laser light case.
Usually a laser generates a beam of less than one mille radian (0.001 rad). This means that a beam from the laser will spread to less than one foot diameter circle at a distance of 1000 feet from the laser. When a laser beam is sent through special optical devices then its divergence can be reduced even further. Due to divergence characteristic the major application of laser light is measuring the long distances such as distance between earth and moon can be measured by using laser light.
If we sent a laser beam through telescope from earth to moon then when it reaches to moon, it covers approximately 2.5 miles diameter circle. Now what will be the divergence angle?
Divergence angle = ɸ = 1.25 miles / 250000 miles = Radius of beam / distance covered.
The 3rd important characteristic of laser light that makes it unique is the coherence. Coherence means that the light waves are in phase. Laser light is much more coherent than ordinary light. It is impossible to detect this property with our eyes and therefore its important is some time over lacked.
The incoherent waves have no relationship to each other. They don't start at the same point in time and space, nor do they have same wavelength, as shown in Figure 3.
If two waves are not perfectly monochromatic means not of identical wavelengths, then they will not remain coherent, as illustrated.
If the wave is moving w.r.t each other even though they have identical wave lengths. They cannot remain coherent, as illustrated.
Note: - The laser as good as it is cannot perfectly coherent, monochromatic and have no divergence.


GRAND PRAIRIE – Trinity 161 Distribution Center, 3100 North Hwy. 161, is completed. The property sits at the intersection of Trinity Blvd. and SH 161.
The new distribution center features 266,000 sf of spec warehouse space along SH 161.
The building is constructed with tilt-up construction, with tan coating and decorative reveals.
It's designed for smaller tenants, 20K to 60K SF, as well as the larger users. With a depth of 210 feet, the building is just right for small and large users.
Check out DFW Industrial Research for updated quarterly data.


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Home Sports JB's Sports Blog Iowa's Keegan Murray Named Big Ten MBB Player of the Week
JB's Sports Blog
Iowa's Keegan Murray Named Big Ten MBB Player of the Week
Iowa Hawkeyes forward Keegan Murray (15) during a photo shoot at Carver-Hawkeye Arena in Iowa City, IA on Monday, September 13, 2021. (Stephen Mally/hawkeyesports.com)
IOWA CITY, Iowa — University of Iowa men's basketball sophomore Keegan Murray has been named Big Ten Player of the Week, it was announced Monday by the Big Ten Conference Office.
Murray has earned the Big Ten weekly honor three times (Nov. 22; Dec. 20; Jan. 3) this season, including twice in the past three weeks.
Murray (6-foot-8, 225 pounds) posted game bests in points (29), rebounds (10), and blocks (3), while also dishing out three assists in Iowa's 92-71 win over Western Illinois on Dec. 29, in Iowa City. The native of Cedar Rapids, Iowa, registered his third double-double of the season and shot a blistering 65 percent from the field, making 13-of-20 attempts.
Murray, who is tops in the country in points per game (23.7), has netted 25+ points six times this season.
Iowa (10-3, 0-2) faces Maryland (8-4, 0-1) tonight at 8:07 p.m. (CT) on Mediacom Court at Carver-Hawkeye Arena in Iowa City. Tickets are available for purchase at hawkeyesports.com/tickets.
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Explorers Ink First Contract of 2022
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