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Phage therapy

Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the Second World War. Bacteriophages, known as phages, are a form of virus that attach to bacterial cells and inject their genome into the cell. The bacteria's production of the viral genome interferes with its ability to function, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against.

Advantages include reduced side effects and reduced risk of the bacterium developing resistance, since bacteriophages are much more specific than antibiotics. They are typically harmless not only to the host organism but also to other beneficial bacteria, such as the gut microbiota, reducing the chances of opportunistic infections. They have a high therapeutic index; that is, phage therapy would be expected to give rise to few side effects, even at higher-than-therapeutic levels. Because phages replicate in vivo (in cells of living organism), a smaller effective dose can be used.

Disadvantages include the difficulty of finding an effective phage for a particular infection; a phage will kill a bacterium only if it matches the specific strain. However, virulent phages can be isolated much more easily than other compounds and natural products. Consequently, phage mixtures ("cocktails") are sometimes used to improve the chances of success. Alternatively, samples taken from recovering patients sometimes contain appropriate phages that can be grown to cure other patients infected with the same strain. Ongoing challenges include the need to increase phage collections from reference phage banks, the development of efficient phage screening methods for the fast identification of the therapeutic phage(s), the establishment of efficient phage therapy strategies to tackle infectious biofilms, the validation of feasible phage production protocols that assure quality and safety of phage preparations, and the guarantee of stability of phage preparations during manufacturing, storage, and transport.

Phages tend to be more successful than antibiotics where there is a biofilm covered by a polysaccharide layer, which antibiotics typically cannot penetrate. Phage therapy can disperse the biofilm generated by antibiotic-resistant bacteria. However, the interactions between phages and biofilms can be complex, with phages developing symbiotic as well as predatory relationships with biofilms.

Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics, particularly in Russia and Georgia. There is also a phage therapy unit in Wrocław, Poland, established in 2005, which continues several-decades-long research by the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, the only such centre in a European Union country. Phages are the subject of renewed clinical attention in Western countries, such as the United States. In 2019, the United States Food and Drug Administration approved the first US clinical trial for intravenous phage therapy.

Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture. If the target host of a phage therapy treatment is not an animal, the term "biocontrol" (as in phage-mediated biocontrol of bacteria) is usually employed, rather than "phage therapy".

History

The discovery of bacteriophages was reported by British bacteriologist Frederick Twort in 1915 and by French microbiologist Felix d'Hérelle in 1917. D'Hérelle said that the phages always appeared in the stools of Shigella dysentery patients shortly before they began to recover. He "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff from pipes, and in the stools of convalescent patients". Phage therapy was immediately recognized by many to be a key way forward for the eradication of pathogenic bacterial infections. A Georgian, George Eliava, was making similar discoveries. He travelled to the Pasteur Institute in Paris, where he met d'Hérelle, and in 1923, he founded the Institute of Bacteriology, which later became known as the George Eliava Institute, in Tbilisi, Georgia, devoted to the development of phage therapy. Phage therapy is used in Russia, Georgia and Poland, and was used prophylactically for a time in the Soviet army, most notably during the Second World War.

In Russia, extensive research and development soon began in this field. In the United States during the 1940s, commercialization of phage therapy was undertaken by Eli Lilly and Company.

While knowledge was being accumulated regarding the biology of phages and how to use phage cocktails correctly, early uses of phage therapy were often unreliable. Since the early 20th century, research into the development of viable therapeutic antibiotics had also been underway, and by 1942, the antibiotic penicillin G had been successfully purified and saw use during the Second World War. The drug proved to be extraordinarily effective in the treatment of injured Allied soldiers whose wounds had become infected. By 1944, large-scale production of penicillin had been made possible, and in 1945, it became publicly available in pharmacies. Due to the drug's success, it was marketed widely in the US and Europe, leading Western scientists to mostly lose interest in further use and study of phage therapy for some time.

Isolated from Western advances in antibiotic production in the 1940s, Russian scientists continued to develop already successful phage therapy to treat the wounds of soldiers in field hospitals. During World War II, the Soviet Union used bacteriophages to treat soldiers infected with various bacterial diseases, such as dysentery and gangrene. Russian researchers continued to develop and to refine their treatments and to publish their research and results. However, due to the scientific barriers of the Cold War, this knowledge was not translated and did not proliferate across the world. A summary of these publications was published in English in 2009 in "A Literature Review of the Practical Application of Bacteriophage Research".

There is an extensive library and research center at the George Eliava Institute in Tbilisi, Georgia. Phage therapy is today a widespread form of treatment in that region.

As a result of the development of antibiotic resistance since the 1950s and an advancement of scientific knowledge, there has been renewed interest worldwide in the ability of phage therapy to eradicate bacterial infections and chronic polymicrobial biofilm (including in industrial situations).

Phages have been investigated as a potential means to eliminate pathogens like Campylobacter in raw food and Listeria in fresh food or to reduce food spoilage bacteria. In agricultural practice, phages have been used to fight pathogens like Campylobacter, Escherichia, and Salmonella in farm animals, Lactococcus and Vibrio pathogens in fish aquaculture, and Erwinia, Xanthomonas, and others in plants of agricultural importance. The oldest use is, however, in human medicine. Phages have been used against diarrheal diseases caused by E. coli, Shigella, or Vibrio and against wound infections caused by facultative pathogens of the skin like staphylococci and streptococci. Recently, the phage therapy approach has been applied to systemic and even intracellular infections, and non-replicating phage and isolated phage enzymes like lysins have been added to the antimicrobial arsenal. However, actual proof for the efficacy of these phage approaches in the field or the hospital is not available.

Some of the interest in the West can be traced back to 1994, when James Soothill demonstrated (in an animal model) that the use of phages could improve the success of skin grafts by reducing the underlying Pseudomonas aeruginosa infection. Recent studies have provided additional support for these findings in the model system.

Although not "phage therapy" in the original sense, the use of phages as delivery mechanisms for traditional antibiotics constitutes another possible therapeutic use. The use of phages to deliver antitumor agents has also been described in preliminary in vitro experiments for cells in tissue culture.

In June 2015, the European Medicines Agency hosted a one-day workshop on the therapeutic use of bacteriophages, and in July 2015, the US National Institutes of Health hosted a two-day workshop titled "Bacteriophage Therapy: An Alternative Strategy to Combat Drug Resistance".

In January 2016, phages were used successfully at Yale University by Benjamin Chan to treat a chronic Pseudomonas aeruginosa infection in ophthalmologist Ali Asghar Khodadoust. This successful treatment of a life-threatening infection sparked a resurgence of interest in phage therapy in the United States.

In 2017, a pair of genetically engineered phages along with one naturally occurring (so-called "phage Muddy") each from among those catalogued by SEA-PHAGES (Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science) at the Howard Hughes Medical Institute by Graham Hatfull and colleagues, was used by microbiologist James Soothill at Great Ormond Street Hospital for Children in London to treat an antibiotic-resistant bacterial (Mycobacterium abscessus) infection in a young woman with cystic fibrosis.

In 2022, two mycobacteriophages were administered intravenously twice daily to a young man with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. Airway cultures for M. abscessus became negative after approximately 100 days of combined phage and antibiotic treatment, and a variety of biomarkers confirmed the therapeutic response. The individual received a bilateral lung transplant after 379 days of treatment, and cultures from the explanted lung tissue confirmed eradication of the bacteria. In a second case, successful treatment of disseminated cutaneous Mycobacterium chelonae was reported with a single phage administered intravenously twice daily in conjunction with antibiotic and surgical management.

Potential benefits

Bacteriophage treatment offers a possible alternative to conventional antibiotic treatments for bacterial infection. It is conceivable that, although bacteria can develop resistance to phages, the resistance might be easier to overcome than resistance to antibiotics. Viruses, just like bacteria, can evolve resistance to different treatments.

Bacteriophages are very specific, targeting only one or a few strains of bacteria. Traditional antibiotics have a more wide-ranging effect, killing both harmful and useful bacteria, such as those facilitating food digestion. The species and strain specificity of bacteriophages makes it unlikely that harmless or useful bacteria will be killed when fighting an infection.

A few research groups in the West are engineering a broader-spectrum phage and also a variety of forms of MRSA treatments, including impregnated wound dressings, preventative treatment for burn victims, and phage-impregnated sutures. Enzybiotics are a new development at Rockefeller University that create enzymes from phages. Purified recombinant phage enzymes can be used as separate antibacterial agents in their own right.

Phage therapy also has the potential to prevent or treat infectious diseases of corals. This could mitigate the global coral decline.

Collection
Phages for therapeutic use can be collected from environmental sources that likely contain high quantities of bacteria and bacteriophages, such as effluent outlets, sewage, or even soil. The samples are taken and applied to bacterial cultures that are to be targeted. If the bacteria die, the phages can be grown in liquid cultures.

Modes of treatment
Phages are "bacterium-specific", and therefore, it is necessary in many cases to take a swab from the patient and culture it prior to treatment. Occasionally, isolation of therapeutic phages can require a few months to complete, but clinics generally keep supplies of phage cocktails for the most common bacterial strains in a geographical area.

Phage cocktails are commonly sold in pharmacies in Eastern European countries, such as Russia and Georgia. The composition of bacteriophagic cocktails has been periodically modified to add phages effective against emerging pathogenic strains.

Phages in practice are applied orally, topically on infected wounds or spread onto surfaces, or during surgical procedures. Injection is rarely used, avoiding any risks of trace chemical contaminants that may be present from the bacteria amplification stage, and recognizing that the immune system naturally fights against viruses introduced into the bloodstream or lymphatic system.

Reviews of phage therapy indicate that more clinical and microbiological research is needed to meet current standards.

Clinical trials
Funding for phage therapy research and clinical trials is generally insufficient and difficult to obtain, since it is a lengthy and complex process to patent bacteriophage products. Due to the specificity of phages, phage therapy would be most effective as a cocktail injection, a modality generally rejected by the US Food and Drug Administration (FDA). Therefore, researchers and observers have predicted that if phage therapy is to gain traction, the FDA must change its regulatory stance on combination drug cocktails. Public awareness and education about phage therapy are generally limited to scientific or independent research rather than mainstream media.

In 2007, phase-1 and 2 clinical trials were completed at the Royal National Throat, Nose and Ear Hospital, London, for Pseudomonas aeruginosa infections (otitis). Phase-1 clinical trials were conducted at the Southwest Regional Wound Care Center of Lubbock, Texas, for a cocktail of phages against P. aeruginosa, Staphylococcus aureus, and Escherichia coli, developed by Intralytix. PhagoBurn, a phase-1 and 2 trial of phage therapy against P. aeruginosa wound infection in France and Belgium in 2015–17, was terminated early due to lack of effectiveness.

Locus Biosciences has created a cocktail of three CRISPR-modified phages. A 2019 study examined its effectiveness against E. coli in the urinary tract, and a phase-1 trial was completed shortly before March 2021. In February 2019, the FDA approved the first clinical trial of intravenously administered phage therapy in the United States.

In July 2020, the FDA approved the first clinical trial of nebulized phage therapy in the United States. This double-blind, placebo-controlled study at Yale University will be focused on treating P. aeruginosa infections in patients with cystic fibrosis.

In February 2020, the FDA approved a clinical trial to evaluate bacteriophage therapy in patients with urinary tract infections. The study started in December 2020 and aims to identify ideal bacteriophage treatment regimens based on improvements in disease control rates.

In February 2021, the FDA approved a clinical trial to evaluate bacteriophage therapy in patients with chronic prosthetic joint infections (PJI). The study was to begin in October 2022 and be conducted by Adaptive Phage Therapeutics, in collaboration with the Mayo Clinic.

Administration
Phages can usually be freeze-dried and turned into pills without materially reducing efficiency. Temperature stability up to 55 °C and shelf lives of 14 months have been shown for some types of phages in pill form. Application in liquid form is possible, stored preferably in refrigerated vials. Oral administration works better when an antacid is included, as this increases the number of phages surviving passage through the stomach. Topical administration often involves application to gauzes that are laid on the area to be treated.

Successful treatments
Phages were used successfully at Yale University by Benjamin Chan to treat a Pseudomonas infection in 2016. Intravenous phage drip therapy was successfully used to treat a patient with multidrug-resistant Acinetobacter baumannii in Thornton Hospital at UC San Diego in 2017. Nebulized phage therapy has been used successfully to treat numerous patients with cystic fibrosis and multidrug-resistant bacteria at Yale University as part of their compassionate use program. In 2019, a Brownsville, Minnesota resident with a longstanding bacterial infection in his knee received a phage treatment at the Mayo Clinic that eliminated the need for amputation of his lower leg. Individualised phage therapy was also successfully used by Robert T. Schooley and others to treat a case of multi-drug-resistant Acinetobacter baumannii in 2015. In 2022, an individually adjusted phage-antibiotic combination as an antimicrobial resistance treatment was demonstrated and described in detail. The scientists called for scaling up the research and for further development of this approach.

Treatment of biofilm infections

Phage therapy is being used to great effect in the treatment of biofilm infections, especially Pseudomonas aeruginosa and Staphylococcus aureus. From 78 recent cases of treatment of biofilm infections, 96% of patients saw clinical improvement using phage therapy, and 52% of patients saw complete symptom relief or a full expungement of the affecting bacteria. Biofilm infections are very challenging to treat with antibiotics. The biofilm matrix and surrounding bacterial membranes can bind to the antibiotics, preventing them from penetrating the biofilm. The matrix may contain enzymes that deactivate antibiotics. Biofilms also have low metabolic activity, which means antibiotics that target growing processes have much lower efficacy. These factors make phage therapy an enticing option for the treatment of such infections, and there are currently two ways to go about such treatment. The first is to isolate the initial bacteria and make a specific treatment phage to target it, while the second way is to use a combination of more general phages. The advantage of the second method is that it can easily be made commercially available for treatment, although there are some concerns that it may be substantially less effective.

Limitations
The high bacterial strain specificity of phage therapy may make it necessary for clinics to make different cocktails for treatment of the same infection or disease, because the bacterial components of such diseases may differ from region to region or even person to person. In addition, this means that "banks" containing many different phages must be kept and regularly updated with new phages.

Further, bacteria can evolve different receptors either before or during treatment. This can prevent phages from completely eradicating them.

The need for banks of phages makes regulatory testing for safety harder and more expensive under current rules in most countries. Such a process would make the large-scale use of phage therapy difficult. Additionally, patent issues (specifically on living organisms) may complicate distribution for pharmaceutical companies wishing to have exclusive rights over their "invention", which would discourage a commercial corporation from investing capital in this.

As has been known for at least thirty years, mycobacteria such as Mycobacterium tuberculosis have specific bacteriophages. No lytic phage has yet been discovered for Clostridium difficile, which is responsible for many nosocomial diseases, but some temperate phages (integrated in the genome, also called lysogenic) are known for this species; this opens encouraging avenues but with additional risks, as discussed below.

The negative public perception of viruses may also play a role in the reluctance to embrace phage therapy.

Development of resistance
One of the major concerns usually associated with phage therapy is the emergence of bacteriophage-insensitive mutants (BIMs) that could hinder the success of this therapy. In fact, several in vitro studies have reported a fast emergence of BIMs within a short period of time after phage treatment. The emergence of BIMs has also been observed in vivo using different animal models, although this usually occurs later than in vitro (reviewed in ). This fast adaptation of bacteria to phage attack is usually caused by mutations on genes encoding phage receptors, which include lipopolysaccharides (LPS), outer membrane proteins, capsules, flagella, and pili, among others. However, some studies suggest that when phage resistance is caused by mutations in phage receptors, this might result in fitness costs to the resistance bacterium, which will ultimately become less virulent. Moreover, it has been shown that the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Therefore, it is conceivable to think that phage therapy that uses phages that exert selection for multidrug-resistant bacteria to become antibiotic-sensitive could potentially reduce the incidence of antibiotic-resistant infections.

Besides the prevention of phage adsorption by loss or modification of bacterial receptors, phage insensitivity can be caused by: (i) prevention of phage DNA entry by superinfection exclusion systems; (ii) degradation of phage DNA by restriction-modification systems or by CRISPR-Cas systems; and (iii) use of abortive infection systems that block phage replication, transcription, or translation, usually in conjunction with suicide of the host cell. Altogether, these mechanisms promote a quick adaptation of bacteria to phage attack and therefore, the emergence of phage-resistant mutants is frequent and unavoidable.

It is still unclear whether the wide use of phages would cause resistance similar to what has been observed for antibiotics. In theory, this is not very likely to occur, since phages are very specific, and therefore, their selective pressure would affect a very narrow group of bacteria. However, we should also consider the fact that many phage resistance systems are mounted on mobile genetic elements, including prophages and plasmids, and thus may spread quite rapidly even without direct selection. Nevertheless, in contrast to antibiotics, phage preparations for therapeutic applications are expected to be developed in a personalized way because of the high specificity of phages. In addition, strategies have been proposed to counter the problem of phage resistance. One of the strategies is the use of phage cocktails with complementary host ranges (different host ranges, which, when combined, result in an overall broader host range) and targeting different bacterial receptors. Another strategy is the combination of phages with other antimicrobials such as antibiotics, disinfectants, or enzymes that could enhance their antibacterial activity. The genetic manipulation of phage genomes can also be a strategy to circumvent phage resistance.

Safety aspects
Bacteriophages are bacterial viruses, evolved to infect bacterial cells. To do that, phages must use characteristic structures at cell surfaces (receptors), and to propagate they need appropriate molecular tools inside the cells. Bacteria are prokaryotes, and their cells differ substantially from eukaryotes, including humans or animals. For this reason, phages meet the major safety requirement: they do not infect treated individuals. Even engineered phages and induced artificial internalization of phages into mammalian cells do not result in phage propagation. Natural transcytosis of unmodified phages, that is, uptake and internal transport to the other side of a cell, which was observed in human epithelial cells, did not result in phage propagation or cell damage. Recently, however, it was reported that filamentous temperate phages of P. aeruginosa can be endocytosed into human and murine leukocytes, resulting in transcription of the phage DNA. In turn, the product RNA triggers maladaptive innate viral pattern-recognition responses and thus inhibits the immune clearance of the bacteria. Whether this also applies to dsDNA phages like Caudovirales has not yet been established; this is an important question to be addressed as it may affect the overall safety of phage therapy.

Due to many experimental treatments in human patients conducted in past decades, and to already existing RCTs (see section: Clinical experience and randomized controlled trials), phage safety can be assessed directly. The first safety trial in healthy human volunteers for a phage was conducted by Bruttin and Brüssow in 2005. They investigated the oral administration of Escherichia coli phage T4 and found no adverse effects of the treatment. Historical record shows that phages are safe, with mild side effects, if any. The most frequent (though still rare) adverse reactions to phage preparations found in patients were symptoms from the digestive tract, local reactions at the site of administration of a phage preparation, superinfections, and a rise in body temperature. Notably, these reactions may have been (i) due to the liberation of endotoxins from bacteria lysed in vivo by the phages, since such effects also can be observed when antibiotics are used, or (ii) caused by bacterial debris that accompanied the phage in cases where unpurified lysates were used.

Bacteriophages must be produced in bacteria that are lysed (i.e., fragmented) during phage propagation. As such, phage lysates contain bacterial debris that may affect the human organism even when the phage itself is harmless. For these and other reasons, purification of bacteriophages is considered important, and phage preparations need to be assessed for their safety as a whole, particularly when phages are to be administered intravenously. This is consistent with general procedures for other drug candidates. In 2015, a group of phage therapy experts summarized the quality and safety requirements for sustainable phage therapy.

Phage effects on the human microbiome also contribute to safety issues in phage therapy. Many phages, especially temperate ones, carry genes that can affect the pathogenicity of the host. Even lambda, a temperate phage of the E. coli K-12 laboratory strain, carries two genes that provide potential virulence benefits to the lysogenic host, one that increases intestinal adherence and the other that confers resistance to complement killing in the blood. For this reason, temperate phages are generally to be avoided as candidates for phage therapy, although in some cases, the lack of lytic phage candidates and emergency conditions may make such considerations moot. Another potential problem is generalized transduction, a term for the ability of some phages to transfer bacterial DNA from one host to another. This occurs because the systems for packaging of the phage DNA into capsids can mistakenly package host DNA instead. Indeed, with some well-characterized phages, up to 5% of the virus particles contain only bacterial DNA. Thus in a typical lysate, the entire genome of the propagating host is present in more than a million copies in every milliliter. For these reasons, it is imperative that any phage to be considered for therapeutic usage should be subjected to thorough genomic analysis and tested for the capacity for generalized transduction.

As antibacterials, phages may also affect the composition of microbiomes, by infecting and killing phage-sensitive strains of bacteria. However, a major advantage of bacteriophages over antibiotics is the high specificity of bacteriophages. This specificity limits antibacterial activity to a sub-species level; typically, a phage kills only selected bacterial strains. For this reason, phages are much less likely (than antibiotics) to disturb the composition of a natural microbiome or to induce dysbiosis. This was demonstrated in experimental studies where microbiome composition was assessed by next-generation sequencing that revealed no important changes correlated with phage treatment in human treatments.

Much of the difficulty in obtaining regulatory approval is proving to be the risks of using a self-replicating entity that has the capability to evolve.

As with antibiotic therapy and other methods of countering bacterial infections, endotoxins are released by the bacteria as they are destroyed within the patient (Jarisch–Herxheimer reaction). This can cause symptoms of fever; in extreme cases, toxic shock (a problem also seen with antibiotics) is possible. Janakiraman Ramachandran argues that this complication can be avoided in those types of infection where this reaction is likely to occur by using genetically engineered bacteriophages that have had their gene responsible for producing endolysin removed. Without this gene, the host bacterium still dies but remains intact, because the lysis is disabled. On the other hand, this modification stops the exponential growth of phages, so one administered phage means at most one dead bacterial cell. Eventually, these dead cells are consumed by the normal house-cleaning duties of the phagocytes, which utilize enzymes to break down the whole bacterium and its contents into harmless proteins, polysaccharides, and lipids.

Temperate (or lysogenic) bacteriophages are not generally used therapeutically, since this group can act as a way for bacteria to exchange DNA. This can help spread antibiotic resistance or even, theoretically, make the bacteria pathogenic, such as in cases of cholera. Carl Merril has claimed that harmless strains of corynebacterium may have been converted into C. diphtheriae that "probably killed a third of all Europeans who came to North America in the seventeenth century". Fortunately, many phages seem to be lytic only with negligible probability of becoming lysogenic.

Regulation and legislation
Approval of phage therapy for use in humans has not been given in Western countries, with a few exceptions. In the United States, Washington and Oregon law allows naturopathic physicians to use any therapy that is legal anywhere in the world on an experimental basis, and in Texas, phages are considered natural substances and can be used in addition to (but not as a replacement for) traditional therapy (they have been used routinely in a wound care clinic in Lubbock since 2006).

In 2013, "the 20th biennial Evergreen International Phage Meeting ... conference drew 170 participants from 35 countries, including leaders of companies and institutes involved with human phage therapies from France, Australia, Georgia, Poland, and the United States."

In France, phage therapy disappeared officially with the withdrawal of the Vidal dictionary (France's official drug directory), in 1978. The last phage preparation, produced by l'Institut du Bactériophage, was an ointment against skin infections. Phage therapy research ceased at about the same time across the country, with the closure of the bacteriophage department at the Pasteur Institute. Some hospital physicians continued to offer phage therapy until the 1990s, when production died out.

On their rediscovery, at the end of the 1990s, phage preparations were classified as medicines, i.e., "medicinal products" in the EU or "drugs" in the US. However, the pharmaceutical legislation that had been implemented since their disappearance from Western medicine was mainly designed to cater for industrially-made pharmaceuticals, devoid of any customization and intended for large-scale distribution, and it was not deemed necessary to provide phage-specific requirements or concessions.

Today's phage therapy products need to comply with the entire battery of medicinal product licensing requirements: manufacturing according to GMP, preclinical studies, phase I, II, and III clinical trials, and marketing authorisation. Technically, industrially produced predefined phage preparations could make it through the conventional pharmaceutical processes, minding some adaptations. However, phage specificity and resistance issues are likely to cause these defined preparations to have a relatively short useful lifespan. The pharmaceutical industry is currently not considering phage therapy products. Yet, a handful of small and medium-sized enterprises have shown interest, with the help of risk capital and/or public funding. Currently, no defined therapeutic phage product has made it to the EU or US markets.

According to some, therapeutic phages should be prepared individually and kept in large phage banks, ready to be used, upon testing for effectiveness against the patient's bacterial pathogen(s). Intermediary or combined (industrially made as well as precision phage preparations) approaches could be appropriate. However, it turns out to be difficult to reconcile classical phage therapy concepts, which are based on the timely adaptation of phage preparations, with current Western pharmaceutical R&D and marketing models. Repeated calls for a specific regulatory framework have not been heeded by European policymakers. A phage therapy framework based on the Biological Master File concept has been proposed as a (European) solution to regulatory issues, but European regulations do not allow for an extension of this concept to biologically active substances such as phages.

Meanwhile, representatives from the medical, academic, and regulatory communities have established some (temporary) national solutions. For instance, phage applications have been performed in Europe under the umbrella of Article 37 (Unproven Interventions in Clinical Practice) of the Helsinki Declaration. To enable the application of phage therapy after Poland had joined the EU in 2004, the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy in Wrocław opened its own Phage Therapy Unit (PTU). Phage therapy performed at the PTU is considered an "experimental treatment", covered by the adapted Act of 5 December 1996 on the Medical Profession (Polish Law Gazette, 2011, No. 277 item 1634) and Article 37 of the Helsinki Declaration. Similarly, in the last few years, a number of phage therapy interventions have been performed in the US under the FDA's emergency Investigational New Drug (eIND) protocol.

Some patients have been treated with phages under the umbrella of "compassionate use", which is a treatment option that allows a physician to use a not-yet-authorized medicine in desperate cases. Under strict conditions, medicines under development can be made available for use in patients for whom no satisfactory authorized therapies are available and who cannot participate in clinical trials. In principle, this approach can only be applied to products for which earlier study results have demonstrated efficacy and safety, but have not yet been approved. Much like Article 37 of the Helsinki Declaration, the compassionate use treatment option can only be applied when the phages are expected to help in life-threatening or chronic and/or seriously debilitating diseases that are not treatable with formally approved products.

In France, ANSM, the French medicine agency, has organized a specific committee—Comité Scientifique Spécialisé Temporaire (CSST)—for phage therapy, which consists of experts in various fields. Their task is to evaluate and guide each phage therapy request that ends up at the ANSM. Phage therapy requests are discussed together with the treating physicians and consensus advice is sent to the ANSM], which then decides whether or not to grant permission. Between 2006 and 2018, fifteen patients were treated in France (eleven recovered) using this pathway.

In Belgium, in 2016 and in response to a number of parliamentary questions, Maggie De Block, the Minister of Social Affairs and Health, acknowledged that it is indeed not evident to treat phages as industrially made drugs, and therefore she proposed to investigate if the magistral preparation pathway could offer a solution. Magistral preparations (compounding pharmacies in the US) are not subjected to certain constraints such as GMP compliance and marketing authorization. As the "magistral preparation framework" was created to allow for adapted patient treatments and/or to use medicines for which there is no commercial interest, it seemed a suitable framework for precision phage therapy concepts. Magistral preparations are medicines prepared in a pharmacy in accordance with a medical prescription for an individual patient. They are made by a pharmacist (or under his/her supervision) from their constituent ingredients, according to the technical and scientific standards of pharmaceutical technology. Phage active pharmaceutical ingredients to be included in magistral preparations must meet the requirements of a monograph, which describes their production and quality control testing. They must be accompanied by a certificate of analysis, issued by a "Belgian Approved Laboratory", which has been granted an accreditation to perform batch-release testing of medicinal products. Since 2019, phages have been delivered in the form of magistral preparations to nominal patients in Belgium.

The first phage therapy case in China can be traced back to 1958, at Shanghai Jiao Tong University School of Medicine. However, many regulations were not yet established back then, and phage therapy soon lost people's interest due to the prevalence of antibiotics, which eventually led to the antimicrobial resistance crisis. This prompted researchers in China as well as the Chinese government to pay attention to phage therapy again, and following the first investigator-initiated trial (IIT) by the Shanghai Institute of Phage in 2019, phage therapy rapidly flourished. Currently, commercial phage therapy applications must go through either one of two pathways. The first is for fixed-ingredient phage products. The second pathway is for personalized phage products, which need to go through IITs. This way, the products are considered restrictive medical technologies.

Animals
Phage therapy has been a relevant mode of treatment in animals for decades. It has been proposed as a method of treating bacterial infections in the veterinary medical field in response to the rampant use of antibiotics. Studies have investigated the application of phage therapy in livestock species as well as companion animals. Brigham Young University has been researching the use of phage therapy to treat American foulbrood in honeybees. Phage therapy is also being investigated for potential applications in aquaculture.

Plants
Phage therapy has been studied for bacterial spot of stonefruit, caused by Xanthomonas pruni (syn. X. campestris pv. pruni, syn. X. arboricola pv. pruni) in prunus species. Some treatments have been very successful.

Cultural impact
The 1925 novel and 1926 Pulitzer Prize winner Arrowsmith by Sinclair Lewis used phage therapy as a plot point.

Greg Bear's 2002 novel Vitals features phage therapy, based on Soviet research, used to transfer genetic material.

The 2012 collection of military history essays about the changing role of women in warfare, Women in War – From Home Front to Front Line includes a chapter featuring phage therapy: "Chapter 17: Women who thawed the Cold War".

Steffanie A. Strathdee's book The Perfect Predator: An Epidemiologist's Journey to Save Her Husband from a Deadly Superbug, co-written with her husband, Thomas Patterson, was published by Hachette Book Group in 2019. It describes Strathdee's ultimately successful attempt to introduce phage therapy as a life-saving treatment for her husband, critically ill with a completely antibiotic-resistant Acinetobacter baumannii infection following severe pancreatitis.

title: Phage therapy


text:
Menace II Society

Menace II Society (pronounced Menace to Society) is a 1993 American teen drama film directed by the Hughes Brothers in their directorial debut. Set in the Watts and Crenshaw neighborhoods of Los Angeles, the film follows the life of Caine Lawson (Tyrin Turner) and his close friends. It gained notoriety for its scenes of violence, profanity, and drug-related content, and also received critical acclaim for the performances of Turner, Jada Pinkett (in her film debut), and Larenz Tate, the direction, and its realistic portrayal of urban violence and powerful underlying messages.

Plot
Kaydee "Caine" Lawson and his best friend Kevin "O-Dog" Anderson enter a liquor store to buy some malt liquor, where a Korean cashier and his wife suspiciously rush them to buy their drinks and leave. As they walk out, the cashier provokingly tells O-Dog "I feel sorry for your mother," leading to deadly consequences for the cashier and his wife as O-Dog kills them both. O-Dog then confiscates the surveillance tape, robs the cashier's wallet and the cash register, and flees with Caine. Caine recounts that his father Tat, a drug dealer, was killed in an unsuccessful drug deal when Caine was 10, and his heroin-addicted mother Karen died of an overdose soon afterwards. This led to his maternal grandparents raising him in the crime-ridden Jordan Downs housing projects.

Following several years of struggling in class, Caine, himself a low-level drug dealer, finally completes high school. On graduation night, Caine and his cousin Harold attend a party, where O-Dog flaunts the surveillance tape to a group of their closest friends, much to Caine's dismay. Later, the cousins are carjacked en route from the party, with Caine suffering a shoulder wound and Harold being murdered. After learning the carjackers' whereabouts, Caine, O-Dog, and their friend A-Wax, an OG, locate and execute them, avenging Harold's death.

Sometime later, Caine visits Ronnie, the girlfriend of his childhood mentor and Tat's business partner Pernell, who is serving life in prison. He bonds with Ronnie’s young son, Anthony, and ensures she has sufficient finances. That night, tasked by their colleague Chauncey, Caine and O-Dog attempt car theft but are arrested. As he is still underage, O-Dog is released with a warning, but Caine is detained as his fingerprints match those on a beer bottle he dropped during the liquor store murders. During an interrogation, a detective tries tricking Caine by changing the questions multiple times, but Caine is soon released due to insufficient evidence. Caine is given advice by his religious grandfather and Sharif's father, a teacher at a local high school to change his ways and warn him about possibly being jailed or killed. Caine's friends Stacy, a teenage father, and Sharif, a devout Muslim, also try to keep Caine out of trouble by convincing Caine to accompany them to Kansas, but fail. Caine, nevertheless, ignores all advice.

Influenced by his late parents’ lifestyle of drugs and crime, Caine purchases and begins cooking a large quantity of crack cocaine, soon becoming a hustler. He also encounters and eventually has sexual intercourse with a local girl named Ilena. One night, he and Sharif are stopped and assaulted by cops, who then dump them in a Hispanic neighborhood. However, the sympathetic Hispanic gang members surprisingly take them to a hospital rather than further assault them as the police anticipated. During his hospitalization, Ronnie invites him to accompany her to her new secretarial job in Atlanta. Initially hesitant, he ultimately agrees. At a party, Caine rescues Ronnie from Chauncey's drunken sexual advances and starts pistol-whipping him, prompting Stacy and Sharif to restrain him. Chauncey retaliates by sending his copy of the surveillance tape to the police, initially unbeknownst to Caine and O-Dog. Ilena phones Caine about her pregnancy, but he denies paternity and rejects her.

Ronnie and Caine visit Pernell in prison, where Caine is gripped by the sight of his incarcerated mentor. Hoping Caine can more positively influence Anthony, Pernell encourages him to relocate to Atlanta. Afterwards, Caine returns home when he is approached by Ilena's cousin outside his house. An exchange of words between the two about Ilena and her pregnancy ensues, resulting in Caine brutally stomping on Ilena's cousin in front of his onlooking neighbors. Caine's grandfather soon comes outside to stop Caine and bring him inside, then firmly tells Caine he no longer wants him in their house and to be out by the evening. Caine then pleas to his grandparents to stay until he leaves for Atlanta, but, because of his trouble-prone nature, they reject his plea and stand firm to kick Caine out. Learning from their friend Doc of Chauncey's betrayal, Caine and O-Dog, now wanted for the liquor store murders, seek refuge at Ronnie's and other friends' houses. O-Dog vows revenge on Chauncey while Ilena's cousin gathers his friends to seek revenge on Caine.

As Caine and Ronnie are preparing to depart, Ilena's cousin and his friends drive by Ronnie's house and engage in a drive-by shootout. During the shootout, Sharif is instantly killed, O-Dog shoots back at the attackers, and Caine gets fatally wounded from shielding Anthony. After the shootout, Stacy and Ronnie emerge from the house, respectively tending to Caine and Anthony. As Caine's life flashes before him, he recalls his grandfather asking him if he cares about being alive, and he realizes in his dying moment that he does, but it's too late.

Cast

 * Tyrin Turner as Kaydee "Caine" Lawson
 * Brandon Hammond as five-year-old Caine
 * Jada Pinkett as Ronnie
 * Larenz Tate as Kevin "O-Dog" Anderson
 * MC Eiht as A-Wax
 * Glenn Plummer as James "Pernell" Richards
 * Clifton Powell as Chauncey
 * Arnold Johnson as Thomas Lawson
 * Pooh-Man as Doc
 * Julian Roy Doster as Anthony
 * Too Short as Lew-Loc
 * Khandi Alexander as Karen Lawson
 * Vonte Sweet as Sharif Butler
 * Bill Duke as Detective
 * Samuel L. Jackson as Tat Lawson
 * Charles S. Dutton as Mr. Butler
 * Saafir as Harold Lawson
 * Ryan Williams as Stacy
 * Reginald Ballard as Clyde

Production
Originally, rapper MC Ren was set to play A-Wax, but later turned down the role when he joined the Nation of Islam in late 1992. MC Eiht replaced MC Ren's role as A-Wax. Rappers Spice 1 and Tupac Shakur were initially set to play Caine and Sharif respectively, but they were later fired, with director Allen Hughes stating that Shakur was causing trouble on the set. Shakur was angry for not being told why Sharif would turn Muslim. When Shakur was cast in the role of Sharif who, as described in the film was "an ex-knucklehead turned Muslim", he did not agree with how the character was written. While many of his rap music contemporaries were portraying roles similar to their gangsta rap personas, Sharif would have required Shakur to portray the character as a stoic & pious Muslim. According to MC Eiht, who played A-Wax in the film:

"My take on it was, everytime we got ready to rehearse, he had an opinion about his character…He wanted them to write in the script WHY he turned Muslim...Show me why I turned Muslim and they wouldn't do it and that's what angered him...You're not just going to give people that ideal that Tupac is just this yeah you know, "preach my brother", fuck that!"

Six months after the firing, Shakur assaulted Hughes, resulting in Shakur being found guilty of assault and battery. Nonetheless, after Tupac's death, Allen Hughes praised the actor, stating "If 'Pac had been in the movie he would've outshined everyone."

Reception
Menace II Society received generally positive reviews from critics. The film has an 85% approval score on Rotten Tomatoes based on 46 reviews, with an average rating of 7.40/10. The consensus reads, "Told with grit and verve by the Hughes brothers in their feature debut, Menace II Society is a gangland epic that breathes with authenticity while steeped in style." Metacritic gave the film a weighted average score of 76 out of 100, based on 19 critics, indicating "generally favorable reviews".

Chicago Reader critic Jonathan Rosenbaum stated, "This is a powerful, convincing, and terrifying look at teenage crime in contemporary Watts." Owen Gleiberman from Entertainment Weekly gave it a positive review, stating, "Menace II Society is bleak, brilliant, and unsparing."

Emanuel Levy gave the film an A, saying it is "The most stunning feature debut in the new African American cinema, even more so than Boyz n the Hood to which the coming of age feature bears thematic resemblance." The film was placed on both Gene Siskel and Roger Ebert's 10 best films of 1993 lists, with Ebert praising "the way the filmmakers tell Caine's story without making him seem either the hero or victim".

However, the film has also received some negative reviews. Geoff Andrew of Time Out stated, "Regrettably, the Hughes Brothers' first feature is a compendium of clichés." Stephen Holden of The New York Times stated, "If Menace II Society is terrific on ambiance, it is considerably less successful in revealing character." At the 1994 MTV Movie Awards, the film was awarded Best Movie, beating out the likes of Philadelphia, Jurassic Park and Schindler's List. At the Independent Spirit Award, The film had nominated an for Best First Feature, but lost to El Mariachi (the first installment in the Robert Rodriguez's Mexico Trilogy).

The film grossed $27.9 million in the United States and Canada but only $1.6 million internationally for a worldwide total of $29.5 million.

Awards and Nomination
1993 Independent Spirit Awards
 * Best First Feature (nominated)
 * Best Cinematography (won) – Rinzler
 * Best Male Lead (nominated) – Turner

 1994 MTV Movie Award
 * Best Movie (won)

Soundtrack
A soundtrack containing hip hop music was released on May 26, 1993, by Jive Records. It peaked at #11 on the Billboard 200 and #1 on the Top R&B/Hip-Hop Albums.

Home media
The director's cut of Menace II Society was released on LaserDisc in January 1994 via The Criterion Collection.

Menace II Society was released on DVD in 1997 by New Line Home Video. The director's cut was released on DVD in 2009. This film was also included in "double feature" and "4 Film Favorites" DVD packages in the 2010s. There is one "double feature" package in DVD Region 1 that includes Juice (released in 2013), and another that includes New Jack City (released in 2016), in addition to Menace II Society. The "4 Film Favorites" DVD package, released in 2013 in Region 1, includes ATL, New Jack City, and Set It Off, in addition to Menace II Society.

In August 2021, Criterion announced that Menace II Society, alongside 5 other films, would be released as a part of its first 4K Ultra HD releases. Criterion indicated each title will be available in a 4K UHD+Blu-ray combo pack including a 4K UHD disc of the feature film as well as the film and special features on the companion Blu-ray. The titles were released in November 2021.

Legacy
In 2013, rapper and record producer Kanye West cited Menace II Society as one of his "most-watched" favorite films on an episode of the Bret Easton Ellis Podcast.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Menace II Society


text:
Talk:List of admission tests to colleges and universities

Why no Italy?

 * Why there's no Italy? 60.250.158.9 (talk) 03:08, 1 June 2016 (UTC)

Is't the TOEIC administered also ? --Jondel 02:08, 27 May 2004 (UTC)

What would y'all think of standardizing the entries as follows, perhaps in a table?
 * Abbreviation (where used) - what the abbreviation stands for; who administers it; what it's used for; what it tests
 * MCAS (Massachusetts, USA) - ???; ???; high school graduation; tests in Math, History, Science, etc.
 * SAT (USA) - formerly Scholastic Aptitude Test; Educational Testing Service (ETS); college admission;  general (verbal and math) and subject tests

--zandperl 22:57, 29 Oct 2004 (UTC)

 * I think this is a good idea as long as the descriptions of "what its used for" can be kept short enough for a table. Angela.

Scope of page
This page is clearly called "...in the United States", yet it contains dozens of entries that have nothing to do with the U.S. I will clean these entries into another article if there are no objections. - Freechild 17:27, 1 June 2007 (UTC)

ATAR
Should the Australian Tertiary Admission Rank be listed here? -- Tea with toast  (話)  06:40, 28 November 2011 (UTC)

India
Why are there two areas for India? Coupon11 (talk) 22:12, 11 April 2016 (UTC)

External links modified
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TOEIC

The Test of English for International Communication (TOEIC) is an international standardized test of English language proficiency for non-native speakers. It is intentionally designed to measure the everyday English skills of people working in an international environment.

There are different forms of the exam: the TOEIC Listening & Reading Test consists of two equally graded tests of comprehension assessment activities totaling a possible 990 score; there are also the TOEIC Speaking and Writing Tests. The TOEIC speaking test is composed of tasks that assess pronunciation, intonation and stress, vocabulary, grammar, cohesion, relevance of content, and completeness of content. The TOEIC Writing test is composed of tasks that assess grammar, relevance of sentences to the pictures, quality and variety of sentences, vocabulary, organization, and whether opinions are supported with reason and/or examples. Both the Speaking and Writing assessments use a score scale of 0–200.

History
The basic idea of the TOEIC test was conceived by Yasuo Kitaoka (北岡靖男), a retired Time magazine staff member who noticed a lack of English communication ability among the Japanese population.

He proposed the idea to the US-based Educational Testing Service (ETS), but the organization rejected him since they preferred to collaborate with nonprofit organizations. He also failed to convince the Ministry of Education, Culture, Sports, Science and Technology, who had already launched STEP Eiken. Instead, Kitaoka found his close friend Yaeji Watanabe (渡辺弥栄司), a retired official from the Ministry of International Trade and Industry, to support him.

Kitaoka and Watanabe later established World Economic Information Services (財団法人世界経済情報サービス) (WEIS), thus enabling Kitaoka to collaborate with ETS. WEIS later established a committee to developed TOEIC. The first TOEIC test was launched in 1979 and taken by 3,000 individuals.

In 1986, a newly created organization, the Institute for International Business Communication (財団法人国際ビジネスコミュニケーション協会) (IIBC), took over the administration of the TOEIC from WEIS. In 2006, ETS released a new version of the TOEIC test.

ETS's major competitors are Cambridge University, which administers the IELTS, FCE, CAE, and CPE, and Trinity College London, which administers the GESE and ISE exams.

TOEIC Listening & Reading Test
The TOEIC Listening & Reading Test lasts two hours; 45 minutes for Listening, and 75 minutes for Reading. It consists of 200 multiple-choice items evenly divided between the listening and reading comprehension section. Each question is worth five points. Each candidate receives independent scores for listening and reading comprehension on a scale from 0 to 495 points. The total score adds up to a scale from 0 to 990 points. The TOEIC certificate exists in five colors, corresponding to the results achieved:
 * orange (0–219)
 * brown (220–469)
 * green (470–729)
 * blue (730–859)
 * gold (860–990)

TOEIC test certificates are optional, unofficial documents that are meant for display only.

2006 redesigned TOEIC tests
A new version of the TOEIC Listening & Reading test was released in 2006. The changes can be summarized as follows:
 * Overall, passages are longer.
 * Part 1 has fewer questions involving photograph descriptions.
 * The Listening Section hires speakers of English from Britain, Australia, New Zealand and North America, and uses an equal distribution of the dialects. However, all the voice actors for the audio sections have lived in the United States for an extended period.
 * Part 6 no longer contains an error-spotting task, criticized as unrealistic in a corporate environment, instead adopting the use of a task wherein the test taker fills in blanks in incomplete sentences.
 * Part 7 contains not only single-passage questions, but also double- and triple-passage questions wherein the test taker reads and compares two or three related passages, such as an e-mail correspondence.

According to a survey conducted in 2006 by the Institute for International Business Communication (財団法人 国際ビジネスコミュニケーション協会), 56.8% of the respondents who took both the older and the revised versions of the TOEIC test in Japan find the latter version more difficult. The lower the score the test taker achieves, the more marked this tendency becomes. As many as 85.6% of those who earned scores ranging from 0 to 395 points find the revised TOEIC test more difficult, while 69.9% of those who earned 400 to 495 points think this way, as do 59.3% of those who earned 500 to 595 points. Among those who achieved 600 to 695 points, 58.9% agreed with these findings; 48.6% of those who scored 700 to 795 points agreed; 47.9% of those who scored 800 to 895 points agreed; and 39.8% of those who scored 900 to 990 points agreed.

2006 also saw the addition of TOEIC Speaking & Writing tests. In 2007 there were additional changes to the TOEIC Reading & Listening test that decreased emphasis on knowledge of grammatical rules.

Test scores in redesigned TOEIC
Scores on the TOEIC Listening and Reading test are determined by the number of correct answers. The number of correct responses on each section is multiplied by five and converted to a scaled score. Three TOEIC Listening and Reading scaled scores are given for each examinee:

 * οne for the Listening Section
 * οne for the Reading Section
 * οne Total Score that consists of the sum of the Listening Section and Reading Section sub-scores.

Each sub-score can range from 0 to 495 points. The Total Score ranges from 0 to 990. There is no negative scoring. The Total Score consists of the sum of the Listening Section and Reading Section sub-scores.

2016 updated TOEIC L&R tests
In 2016, a new version of the TOEIC test was released in Japan and South Korea, including new types of questions. The updated TOEIC test became available worldwide in 2018.

Some of the changes to the test are as follows:

Listening:
 * Number of photograph and question response questions decreased, number of conversation questions increased instead
 * 3 or more speakers in some conversations
 * Shorter turns and more exchanges in some conversations
 * Colloquial phases (e.g., "gonna") and incomplete sentences/fragments (e.g., "Yes, in a minute") in conversations
 * New question types include:
 * Identifying information using a graphic (a table, graph, etc.)
 * Understanding the implied meaning of speakers within a conversation

Reading:
 * Number of incomplete sentence filling questions decreased
 * Addition of long text completion (fill-in-the-blank) questions
 * New question type to test the understanding of three related passages
 * Text messages, instant messages, or online chat conversations with multiple speakers

Despite these changes, the update to the test came with no change to score scale, test difficulty, number of items, or test length, according to ETS.

TOEIC Speaking & Writing Test
The TOEIC Speaking & Writing Tests were introduced in 2006. Test takers receive separate scores for each of the two tests, or they can take the Speaking test without taking the Writing test and vice versa. The Speaking test assesses pronunciation, intonation and stress, vocabulary, grammar, cohesion, relevance of content, and completeness of content; while the Writing test assesses grammar, relevance of sentences to the pictures, quality and variety of sentences, vocabulary, organization, and whether the opinion is supported with reason and/or examples. The tests are designed to reflect actual English usage in the workplace, though they do not require any knowledge of specialized business terms. The TOEIC Speaking Test takes approximately 20 minutes to complete; the TOEIC Writing Test lasts approximately 60 minutes. Each test has a score range between 0–200, with test takers grouped into eight proficiency levels for Speaking and nine proficiency levels for Writing.

Test accommodations
Below are the types of accommodations commonly given:

 * extended testing time
 * additional rest breaks
 * reader
 * scribe
 * recorder to mark answers
 * headphones
 * alternate test formats, e.g. Braille, enlarged print
 * alternate response formats, e.g. computer for writing section
 * wheelchair access

TOEIC Bridge Test
ETS also administers another version of the TOEIC test called the TOEIC Bridge. The TOEIC Bridge test targets beginning and intermediate learners and consists of 100 multiple-choice questions, requiring about one hour of testing time.

Chile
The TOEIC Bridge was used in Chile as part of the 2010 SIMCE test.

Europe
In France, some grandes écoles require a TOEIC score of at least 785 for a diploma. This policy has been criticized, as it makes state-awarded diplomas dependent on a private institution, despite the fact that it was not the private institution that set the 785 mark but a recommendation from the Commission des titres d'ingénieur indicating a B2+ level on the Common European Framework of Reference for Languages. Students who fail to achieve a 785 score may validate their diplomas by other means in most schools. Some institutions delay awarding diplomas for one year after the end of studies in such cases.

In Greece, the TOEIC is accepted by ASEP, the organization responsible for hiring new employees to work for the government. It is administered by the Hellenic American Union and offered weekly in most major cities in Greece.

Japan
The Institute for International Business Communication (財団法人国際ビジネスコミュニケーション協会) administers the TOEIC test in Japan, where nearly 2.4 million people (as of 2014 ) take the test; 1.3M for institutional program (IP) and 1.1M for secure program (SP).

There are two ways to take the TOEIC test properly. One is called the TOEIC SP Test (Secure Program Test; 公開テスト), in which one can take the test individually or in a group on specified dates at a test center specified by the TOEIC Steering Committee. The other is the TOEIC Institutional Program (IP) Test (団体特別受験制度), in which an organization can choose the date and administer the test at its convenience in accordance with the TOEIC Steering Committee. The TOEIC SP Test was renewed in May 2006, followed by the TOEIC IP Test in April 2007 in line so that it would be with the SP Test.

More and more companies use TOEIC scores for personnel assessment instead of the homegrown STEP Eiken test organized by the Society for Testing English Proficiency (STEP) (日本英語検定協会主催実用英語技能検定試験「英検」). The TOEIC Speaking Test/Writing Test started on January 21, 2007, in addition to the TOEIC SP Test and the TOEIC IP Test.

Scandal
The Institute for International Business Communication (IIBC), the non-profit organization that administers the TOEIC in Japan, was the subject of a scandal in 2009.

In May and June 2009, articles in the Japanese weekly magazine FRIDAY accused the IIBC's 92-year-old chairman Yaeji Watanabe of nepotism when he appointed his girlfriend's son to the position of chairman of the IIBC board of directors. To force the appointment, half of the volunteers serving on the board were driven out by Watanabe. The magazine article also questioned why Watanabe only showed up for work about one day a week.

In his defense, Watanabe claimed that he held a ceremonial title and was chairman in name only. As a result, Watanabe claimed that he had little to do with the decision to appoint his girlfriend's son to the position. The magazine article concluded by asking why someone who is chairman in name only and works only one day a week should receive an annual salary in excess of 25 million yen (approximately US$300,000).

In August 2009, the online version of the English-language newspaper The Japan Times published a two-part series examining the TOEIC's origins and early history as well as the use of test-taker fees by the IIBC on the internet. The August 18 article examined the questionable uses of test fees, including a fivefold increase in utility expenses in one year, 13 million spent annually on research about adapting to Chinese culture, sponsorship of poetry readings by the Chinese Poetry Recitation Association, and membership fees to join the Beautiful Aging Association, for which Watanabe happened to be chairman.

The article also questioned the relationship between the IIBC and its for-profit partner International Communications School with which it shared office space. International Communications School is responsible for selling the TOEIC Institutional Program Test given by companies and schools; publishes IIBC-approved TOEIC preparation textbooks; and administers the TOEIC Japanese language website. One of International Communications School's subsidiaries is E-Communications, which administers the TOEIC's online application system and provides online TOEIC study materials.

In 2009, Watanabe suddenly resigned from the IIBC, leaving his girlfriend's son in charge of the non-profit. Watanabe received a 25 million yen retirement payment.

The IIBC lowered the price of the TOEIC Secure Program Test from 6,615 yen to 5,985 yen starting with the September 13, 2009 test. The price had to be lowered due to pressure from the Ministry of Trade, which instructed the IIBC to reduce the profits being generated by the test.

In July 2010, the Tokyo Tax Bureau announced that International Communications School, IIBC's for-profit partner, hid 100 million yen in income and had to pay 30 million yen in back taxes and fines.

South Korea
Historically, the International Communication Foundation, a subsidiary of the language education company YBM Sisa (currently YBM Inc.), administered TOEIC tests in Korea from 1982 to 2006. Its role as administrator was transferred to the Korea TOEIC Committee, another YBM subsidiary, in 2006.

TOEIC is one of the most well-known and popular English tests in Korea, and many universities and companies require TOEIC scores for graduation or job applications. According to the Committee, more than 2 million people took the exam in 2013 alone in the country.

Toward the end of 2005, there was a shift in South Korea, regarded as the second biggest consumer of the TOEIC per capita. However, a person's TOEIC score is still a major factor in hiring people for most professional jobs in South Korea. Starting in 2011, Korean universities will no longer be allowed to use TOEIC and TOEFL scores as part of the admission process. However, many universities in Korea still require a minimum score of 900. Thus, many universities in Korea require TOEIC scores for graduation or selection of overseas trainees. This is apparently to discourage private English education (there are many private institutions that teach TOEIC-based classes). TEPS, another English proficiency test (developed by Seoul National University, Chosun Ilbo), has been created as an alternative to TOEIC tests. However, it is considered unlikely to replace the status of TOEIC.

Taiwan
Chun Shin Limited administers the TOEIC test in Taiwan. In 2003, the Ministry of Education introduced English Graduation Benchmark Policy (EGB), enforcing universities in Taiwan to set English requirements for undergraduates. TOEIC benefited from this policy and its lower registration fees, and became a popular test for English proficiency in Taiwan. TOEIC has also became a widespread measurement of Taiwanese People's English ability. For example, Rosalia Wu, a member of the Legislative Yuan, used the TOEIC score to advocate English as an official language.

The policy sparked controversies for various reasons. For the TOEIC, educators were concerned about undergraduates' economic burden from the TOEIC registration fee and the conflict of interest between universities and the company operating TOEIC.

In 2016, a National Chengchi University (NCCU) student sued NCCU to challenge the EGB policy. In September 2018, the Supreme Administrative Court ordered the policy to be discarded, while the NCCU abolished the policy in January.

Thailand
The Center for Professional Assessment offers regular institutional testing every Monday through Saturday at 9:00AM and 1:00PM (local time).

United Kingdom
The TOEIC was a Home Office-accredited test for students applying for a UK visa.

In 2014, an undercover investigation by the BBC program Panorama exposed systematic cheating and fraud by a number of organizations and individuals involved in running the test. Cheating was found to take place at Eden College International in London, where freelance invigilators used to conduct the exam. The college claimed no prior knowledge of the cheating, and had previously sacked three invigilators. ETS stated it does not hire the invigilators and that it does everything it can to prevent cheating.

On 17 April 2014, ETS decided not to renew its license as a provider of a Secure English Language Test (SELT). This means that these English language tests are no longer honored for the purpose of being issued a UK visa.

In June 2014, the Home Office undertook its own investigation and claimed to have found 46,000 "invalid and questionable" tests. It suspended the TOEIC exam as being valid for entry to the UK. It also canceled the visas of around 45,000 students, seventy percent of whom were Indian. Some left voluntarily, but the majority were deported.

In March 2016, a tribunal ruled that the evidence the Home Office used to deport the students was not strong enough. , over 300 legal appeals against the government were pending, and the National Audit Office had opened an investigation into the government's handling of the issue, which some Members of Parliament had likened to the Windrush scandal.

United States
Both the TOEIC Listening & Reading and the TOEIC Speaking & Writing tests are now available in the United States. While the TOEIC Listening & Reading test has been available for decades, the TOEIC Speaking & Writing test was introduced in the United States only in 2009. Registration for the TOEIC Speaking & Writing test is handled by the English4Success division of the nonprofit organization Amideast.

title: TOEIC


text:
Talk:Nomic

Wikipedia Nomic?
I'm surprised that this page hasn't been more rigidly edited and improved. Perhaps we need to start giving D6 points for successful edits to either the article or talk page... --McGeddon 21:29, 26 October 2005 (UTC)
 * Can we have some examples of what sort of rules a player might propose? I'm coming to this page having never heard of the game, and having read it I don't have a clear idea of how it would play. Foolish Mortal 22:14, 1 November 2005 (UTC)
 * You can propose any rule whatsoever. The limits are on whether the rule takes effect, originally determined by majority vote.

 * I agree w/this editor that that would clarify the article. In general, seems to me the only way to help a reader understand this game is an attempt at the most common moves in an attempted history of the game.  This is a very strange game.  Wikipedia should have a list of games considered strange, / unusually, that list should include how strange the game is considered to b (or rather a best guess @ such).  I LOVE the concept/existence of strange games!Slarty1 (talk) 05:08, 24 May 2019 (UTC)

Disambiguation
I'm requesting that a disambiguation page be created for "Nomic". I actually came here looking for something entirely different -- an Amateur Radio accessory made by West Mountain Radio called the Rigblaster Nomic (or NoMic, depending on who you ask). It's a device used to attach a radio to a computer which has become rather genericized. If you do a Google or other web search for "nomic," aside from results relating to the game which is the subject of this article, most of the other links will be radio related. If not a full disambiguation page, perhaps at least we could put a "This is about the game "Nomic," if you're looking for information about the radio, see x," where x is a link to something amateur-radio related. -- Kadin2048 17:21, 3 February 2006 (UTC)

 * You can do this yourself, if you start an article on the radio nomic. All the available templates are described at Disambiguation.  Otheruses4 looks like what you're looking for.  — Laura Scudder ☎ 17:26, 3 February 2006 (UTC)

Anecdotes
I played the game with a small group. We got bogged down. Not in rules or rule making. In waiting for the other players to take their turn. In getting a required number of votes. Still it went on long enough to become quite complex (another drawback, actually). And few of us ever pretended to know what the current status of the rules were. Regardless how "long" games have lasted in the past, these things seem to make the game self-limiting.

I came up with a variation called ETHICS. The idea is that anyone may write a rule at any time, no turns, no votes. All rules are open to discussion and will be understood as amended owing to the fact that any rule is necessarily in conflict with all other rules, such that only through discussion can there be group consensus, and whereby even rules assumed to be popular might nonetheless bring about discussions to the contrary.

I see this as an open ended game and one that builds community. Those who are confused by the rules are no worse off than those who understand their inherent contradictions; and after all, it is the enforcement of them -- in this case through group awareness -- which makes such "no rule" rules binding.

 * Is ur game different somehow from the actual history of ethics as a subject of philosophy? Have u mentioned this game to make peeps wonder just exactly that?  I suspect u r a meddling philosopher.  I LOVE meddling philosophersSlarty1 (talk) 05:22, 24 May 2019 (UTC)

Online Nomic
I played an online game of Nomic in 1982 at Carnegie Mellon University, played using the university e-mail and bboard network. This must be one of the earliest such games ever played. --Dtobias 18:08, 2 Jan 2005 (UTC)

Fluxx
I found this article through mention in the Mornington Crescent article. I had not previously heard of nomics. However, there is one popular and comparatively well-known self-modifying game, the card game Fluxx. Is a mention of it in the article relevant? --Liam Proven 03:56, 18 Feb 2005 (UTC)

 * I don't think so - although the players are able to change the rules by their actions, they're only able to do so within the confines of the pre-printed cards, and there's no formal way for players to modify this mechanism. Fluxx isn't really that different to any other card game where the cards you play affect what happens in the game. --McGeddon 21:20, 26 October 2005 (UTC)

 * I came to this page with exactly the same question. That means there are more of us with this question then are coming forth to speak. This answer was most helpful. Perhaps explain on the article page why Fluxx doesn't qualify? Just my $0.02. -- TheInfamousJ --70.144.139.84 08:19, 19 December 2005 (UTC)

 * I agree w/70.144.139.84 on the point they have made, that why Fluxx is not considered to b in the same catagory of games should b mentioned in the articleSlarty1 (talk) 05:27, 24 May 2019 (UTC)

 * I think here we touch on a deep problem of nomic games; McGeddon's reason for not believing Fluxx to be a nomic game is because while Fluxx's rules can indeed be modified, there is no mechanism in the game to modify the meta-rules, and becuase he thinks more properly nomic games have meta-meta-rules, for modifying the meta-rules. But the problem here is where do we draw line? Isn't the prior definition of a nomic game not as nomic as a game with meta-meta-meta-rules? And come to think of it, doesn't the 3meta-game still put a large number of restrictions on the game's possibilities? And so shouldn't we add on some meta-meta-meta-meta-rules to make a 4meta-game?
 * But this could lead to an induction that the only true nomic game is the one with an infinite tower of meta-rules, and such a "game" would be unplayable by humans- I think humans can only handle so many levels.
 * This leads me to believe that there is a sharp dividing line between games which allow any modification of the rules at all (including all games in that infinite tower of meta-rules and associated games) and games which don't allow any modification of the rules. So while Fluxx may not be very nomic, I would still say it was nomic; the difference would be of degree, not kind. --Maru  (talk) Contribs 16:59, 19 December 2005 (UTC)

 * Maru makes a very good pointSlarty1 (talk) 05:31, 24 May 2019 (UTC)

 * Fluxx comes with several blank cards, and you can buy more blank cards, just an FYI that you can infact change the meta-rules to an arbitrary level given enough time and money. (Of which I've spent too much of both doing just that[for example cards which alter the order of turns{alphabetically, age, shoesize!} or change the order of steps]) many of the Loony Labs Games come with blanks. -Kode 02:41, 23 February 2006 (UTC)
 * Lots of games come with spare blank cards. They only become Nomics if "changing the rules is a move", if the change is a regulated part of the gameplay, rather than something that players do outside of the game. --McGeddon 05:10, 23 February 2006 (UTC)
 * What makes nomic nomic is that there aren't a hierarchy of rules: rules can be changed according to themselves. This makes it infinitely malleable, but also makes it very confusing.  Fluxx should not be here because ther are inviolate rules.

"Nomic is a game in which changing the rules is a move." By this statment which we have in the article quoted from the creator Fluxx is a nomic type game. As such, I'm adding a link back. -Kode 01:06, 22 March 2006 (UTC)
 * This is just a casual opening sentence from Suber, not a definition; the rest of the paragraph clearly doesn't describe Fluxx at all. Fluxx is no more a Nomic than Magic: The Gathering, Knightmare Chess, Give Me the Brain or any other game where some of the cards you play supercede the default ruleset - if Fluxx was calling its "Rule" cards "Enchantments", this conversation would never come up. --McGeddon 03:29, 22 March 2006 (UTC)
 * However, in Fluxx the cards are actually called new rules. Fluxx is a "Nomic Style" Game. Nomic is a unique game in that the rules change that's the unique part. We have references in there to Mornington Crescent and Calvinball, neither of which is a real game. It's possible to play any of the games you mention above without changing the rules in the slightest bit. It's impossible to play Fluxx without changing the rules, which should earn it at least a mention. -Kode 02:35, 24 March 2006 (UTC)
 * As the changed rules are limited by what is on the cards, Fluxx is not a nomic. It could be called a nomic-style or nomic-inspired game, but it is definitely not a nomic, as not all the rules can be modified. (As for the problem of infinite regression, I don't think it's impossible for humans to understand, as it seems likely that infinite regression is the explanation for the problem of universals in philosophy). Finally, having played a game of Mornington Cresecent on the Nationstates forum, I take issue with the contention that it's not a real game. Supersheep 13:34, 25 July 2006 (UTC)

Initial Ruleset
Any objections to removing the initial (Suber) ruleset and adding an external link to it instead? 29 rules seems a bit much for an encyclopedia article, especially when many Nomics use a variant ruleset anyway. Elysion 03:03, 27 Mar 2005 (UTC)

 * I don't have a problem with that. --Vik Reykja ♬ 03:12, 27 Mar 2005 (UTC)

Tofu
Nomic is the tofu of all games.... --164.106.164.197 03:02, 31 Mar 2005 (UTC)

 * It's a ricepaper recipe book. --McGeddon 21:23, 26 October 2005 (UTC)

 * Nomic is definitely more interesting, and I think it has more flavor.

Cambridge Standard 5 Card Mao
Nomic sounds very similar to a game called Cambridge Standard 5 Card Mao, which seems to be popular in the geek / Linux / Debian community based in and around Cambridge in the UK. Has anyone come across this? Does the name in fact refer to Cambridge, England, or to Cambridge, Ma.?

 * 'Mao' @ Everything2

Mao also has a Wikipedia page. --McGeddon 21:22, 26 October 2005 (UTC)

 * My initial look @ Mao makes me strongly suspect Mao is a contractual trick of @ least temporarily excepting the idea of corrupt leaders / patsies, w/rules as mere formal disguises for a particular form of cruelty.  Nomic may be as well, but if so, it's much better disguised.  Bloody Well Right.  I've gotten to the point where I seem to never know what's going on, politically, but know more / more what's going on spirituallySlarty1 (talk) 06:26, 24 May 2019 (UTC)

Discordianism
Wasn't there a nomic Discordian card game? I can't remember the date, but it might predate the one Hofstadter delineated in his column. --Maru (talk) Contribs 06:38, 29 October 2005 (UTC)
 * It's existance is rumored, but no confirmed reports have been found. It your duty to find a url proving it's existance, or create such a url.  Good luck.  Mathiastck 21:36, 7 July 2007 (UTC)

Calvinball, Drinking
I've played Calvinball and some drinking games that are clearly related to Nomic. I have no referrences though. Scix 07:13, 16 December 2005 (UTC)

 * One such game is: Asshole Drinking Game

 * The article for Calvin and Hobbes mentions Calvinball as being nomic in nature, and links back to this article. B7T 03:44, 30 March 2007 (UTC)

Agora
"Agora has been running since 1993" -  This is the only reference to Agora in the article... what is it, and why has it been running since 1993? —Preceding unsigned comment added by 70.103.142.226 (talk • contribs) 16:23, 29 January 2007
 * It's a game of Nomic. The full sentence is "Games of Nomic sometimes last for a very long time - Agora has been running since 1993." --McGeddon 17:38, 29 January 2007 (UTC)

Bonkers?
Would the board game Bonkers qualify as nomic? I was thinking of linking it back to this article. B7T 03:48, 30 March 2007 (UTC)

 * It doesn't look like it's quite a pure Nomic; not all rules are changeable. Certain aspects of the game board can change based on cards played on it, so it's got a degree of mutability not found in typical board games, but it's still not freely alterable the way Nomic is. *Dan T.* 03:57, 30 March 2007 (UTC)

Origin
The article holds that the game's ruleset was first published by Douglas Hofstadter in his Metamagical Themas column in Scientific American in the early 80s. I clearly remember the game discussed years earlier by Hofstadter's predecessor Martin Gardner in Gardner's Mathematic Games column in the sam publication. Unfortunately I don't have my collection of SAs fro the 60s and 70s any longer. Can anyone verify that somehow? It may have been a game under a differently name, but the rules were the same. --69.193.103.250 (talk) 00:30, 2 December 2010 (UTC)
 * You might try looking at old issues at library in your area. SlowJog (talk) 15:22, 7 August 2022 (UTC)

Minimum Nomic
In one academic paper, Masaomi Hatakeyama and Takashi Hashimoto pare down the rules of nomic to a minimal subset to study rule dynamics. I believe this would be a notable addition to the variants section, especially since it simplifies the initial ruleset while explaining its rationale for every rule it kept. --Havvy (168.156.154.52 (talk) 20:29, 10 August 2011 (UTC))

cleanup tag removed
there was no stated reason for the tag, no relevant discussion here on the talk page. typically, i find that when i want others to do my own work, the bare minimum required is telling them what to do. Cheers. Jay Dubya (talk) 20:23, 29 March 2014 (UTC)

Adding different nomic sites
There are two sites I would like to add this page as external links.

First is nomic.net, a website that has been online a long time that contains documentation of lots of nomic games from about 1996-2001.

Second is nomic.club, a wiki, launched last year, that is primarily focused on documenting newer dead nomic games and currently active games. I'm a frequent contributor to nomic.club. I write lots of essays about nomic games I've participated in under the name Trigon.

Seeing as only a few nomic games are actually linked in this page, I feel like having a good database of nomic games, both new and old, would be helpful to prospective players. — Preceding unsigned comment added by CodeTriangle (talk • contribs) 18:25, 12 April 2019 (UTC)
 * , thanks for the suggestions. I would take a look at Wikipedia's criteria for inlcusion of external links, particularly WP:ELNO, and weigh both your suggestions heavily against all the criteria in them. It's my inexpert opinion that ELNO: 10 11 and 12 would likely disclude these as by your description, they are both fan sites and/or external wikis. But it's great that you're asking here on the talk page to gather consensus first. Elfabet (talk) 12:10, 15 April 2019 (UTC)

title: Talk:Nomic


text:
GKS

GKS may refer to:

 * GK Software, a German enterprise software developer
 * Gifted kid syndrome, a syndrome for gifted kids and former gifted kids
 * Goskomstat, in the Soviet Union; now the Russian Federal State Statistics Service
 * Gottfried Keller-Stiftung, a foundation and Cultural Heritage in Switzerland
 * Graphical Kernel System, a computer graphics standard
 * Stadion GKS, a multi-purpose stadium in Bełchatów, Poland
 * Den gamle kongelige samling (The Old Royal Collection) in the Royal Library, Denmark

title: GKS


text:
Water jacket

A water jacket is a water-filled casing surrounding a device, typically a metal sheath having intake and outlet vents to allow water to be pumped through and circulated. The flow of water to an external heating or cooling device allows precise temperature control of the device.

Applications
Water jackets are often used for water cooling or heating. They are also used in laboratory glassware: Liebig, Graham, and Allihn condensers. Water jackets were used to cool the barrels of machine guns until several years after the First World War, but modern machine guns are air-cooled to conserve weight and hence increase portability.

In a reciprocating piston internal combustion engine, the water jacket is a series of holes either cast or bored through the main engine block and connected by inlet and outlet valves to a radiator.

Equipment such as tissue culture incubators may be enclosed in a water jacket kept at a constant temperature.

A water jacket is used in an Orsat analyzer to prevent any change in temperature from affecting the density of the gas being analyzed.

title: Water jacket