title: Remdesivir

text: In July 2020, the European Union granted a conditional marketing authorization for remdesivir with an indication for the treatment of coronavirus disease 2019 (COVID‑19) in adults and adolescents (aged twelve years and older with body weight at least ) with pneumonia requiring supplemental oxygen.


title: Remdesivir

text: Remdesivir has been also produced in Iran by Barakat; Iran is planning to increase the productions of Remdesivir ampoules from 20,000 to 150,000 ampoules per month. It has also the permission of the "Food and Drug Administration" of MOHME


title: Remdesivir

text: In May 2020, Japan's Ministry of Health, Labour and Welfare approved the drug for use in Japan, in a fast-tracked process, based on the US emergency authorization.


title: Remdesivir

text: In October 2020, Deputy Secretary of Prevention and Health Promotion Hugo López-Gatell Ramírez stated at a news conference that Mexico would not necessarily follow the United States in approving the drug for use in Mexico. López-Gatell explained that the Federal Commission for the Protection against Sanitary Risk (Cofepris) had already twice denied the approval of remdesivir because, in that agency's view, the evidence does not suggest "sufficient efficacy". In March 2020, Cofepris authorized the drug for emergency cases, advising to give continuous surveillance of the integral health of the patient.


title: Remdesivir

text: In June 2020, Singapore's Health Sciences Authority conditionally approved the usage of remdesivir in Singapore.


title: Remdesivir

text: In March 2020, United States President Donald Trump announced that remdesivir was available for "compassionate use" for people with COVID‑19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference. It was later revealed that Gilead had been providing remdesivir in response to compassionate use requests since 25 January. On 23 March 2020, Gilead voluntarily suspended access for compassionate use (excepting cases of critically ill children and pregnant women), for reasons related to supply, citing the need to continue to provide the agent for testing in clinical trials.


title: Remdesivir

text: In May 2020, the US Food and Drug Administration granted Gilead emergency use authorization (EUA) for remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID‑19. Severe COVID‑19 is defined as patients with an oxygen saturation (SpO2) <= 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO), a heart–lung bypass machine. Distribution of remdesivir under the EUA was controlled by the US government for use consistent with the terms and conditions of the EUA. Gilead supplied remdesivir to authorized distributors, or directly to a US government agency, who distributed it to hospitals and other healthcare facilities as directed by the US government, in collaboration with state and local government authorities, as needed. Gilead stated they were donating 1.5million vials for emergency use and estimated, as of April 2020, they had enough remdesivir for 140,000 treatment courses and expect to have 500,000 courses by October 2020, and one million courses by the end of 2020.


title: Remdesivir

text: The initial distribution of the drug in the US was tripped up by seemingly capricious decision-making and finger-pointing, resulting in over a week of confusion and frustration among health care providers and patients alike. On 9 May 2020, the United States Department of Health and Human Services (HHS) explained in a statement that it would be distributing remdesivir vials to state health departments, then would allow each department to redistribute vials to hospitals in their respective states based upon each department's insight into "community-level needs." HHS also clarified that only 607,000 vials of Gilead's promised donation of 1.5million vials would be going to American patients. However, HHS did not explain why several states with some of the highest caseloads had been omitted from the first two distribution rounds, including California, Florida, and Pennsylvania. In May 2020, Gilead indicated they would increase the number of doses donated to the US from 607,000 to around 940,000. Some of the initial distribution was sent to the wrong hospitals, to hospitals with no intensive care units, and to facilities without the needed refrigeration to store it.


title: Remdesivir

text: In June 2020, HHS announced an unusual agreement with Gilead in which HHS agreed to Gilead's wholesale acquisition price, HHS would continue to work together with state governments and drug wholesaler AmerisourceBergen to allocate shipments of remdesivir vials to American hospitals through the end of September 2020, and in exchange, during that three-month timeframe (July, August, and September), American patients would be allocated over 90% of Gilead's projected remdesivir output of more than 500,000 treatment courses. Absent from these announcements was any discussion of allocation of remdesivir production to the approximately 70 countries omitted from Gilead's generic drug licensing agreements—including much of Europe and countries as populous as Brazil, China, and Mexico—or the 127 countries listed on those agreements (during the time it will take for Gilead's generic licensees to ramp up their own production). As the implications of this began to sink in, several countries publicly confirmed the next day that they already had adequate supplies of remdesivir to cover current needs, including Australia, Germany, and the United Kingdom.


title: Remdesivir

text: In August 2020, the FDA broadened the Emergency Use Authorization (EUA) for remdesivir to include all hospitalized patients with suspected or laboratory-confirmed COVID‑19, irrespective of the severity of their disease. The Fact Sheet was updated to reflect the new guidance.


title: Remdesivir

text: In October 2020, Gilead and HHS announced that HHS was relinquishing control over remdesivir allocation because production of the drug had finally caught up with US domestic demand. AmerisourceBergen will remain the sole distributor of Veklury in the US through the end of 2020.


title: Remdesivir

text: On 22 October 2020, the FDA approved remdesivir and also revised the EUA to permit the use of remdesivir for treatment of suspected or laboratory confirmed COVID‑19 in hospitalized children weighing to less than or hospitalized children less than twelve years of age weighing at least . This decision was criticized for an alleged lack of previous consultation on part of the FDA given the complications of antiviral drug issues.


title: Remdesivir

text: In November 2020, the FDA issued an EUA for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory-confirmed COVID‑19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID). The EUA was issued to Eli Lilly and Company.


title: Remdesivir

text: Remdesivir received approval from the US Food and Drug Administration (FDA) in October 2020, for use in adults and children twelve years and older requiring hospitalization for treatment of severe COVID‑19 infections. In January 2022, the FDA gave regulatory approval to remdesivir for use in adults and children (twelve years of age and older who weigh at least and are positive for COVID‑19, not hospitalized, and are ill with COVID‑19 having high risk for developing severe COVID‑19, including hospitalization or death.


title: Remdesivir

text: The FDA also provided Emergency Use Authorization in 2022, for remdesivir treatment of children under age twelve who are COVID-positive and not hospitalized, but have mild-to-moderate COVID‑19 with high risk of developing severe infection, including hospitalization or death.


title: Remdesivir

text: In June 2020, Gilead announced that it had set the price of remdesivir at per vial for the governments of developed countries, including the United States, and for US private health insurance companies. The expected course of treatment is six vials over five days for a total cost of . Being a repurposed drug, the minimum production cost for remdesivir is estimated at per day of treatment.


title: Remdesivir

text: In July 2020, the European Union secured a () contract with Gilead, to make the drug available there in early August 2020. In October 2020, Gilead Sciences and the European Commission announced they had signed a joint procurement framework contract in which Gilead agreed to provide up to 500,000 remdesivir treatment courses over the next six months to 37 European countries. Among the contracting countries were all 27 EU member states plus the United Kingdom, "Albania, Bosnia & Herzegovina, Iceland, Kosovo, Montenegro, North Macedonia, Norway, and Serbia". At the time, the price per treatment course was not disclosed; Reuters reported the price was 2,070 euros, thereby implying the total value of the contract (if all 500,000 courses are ordered) is approximately €1.035 billion. Under the contract, each participating country will directly place orders with Gilead and pay Gilead directly for its own orders.


title: Remdesivir

text: Remdesivir is the international nonproprietary name (INN) while the development code name was GS-5734.


title: Remdesivir

text: Remdesivir was originally created and developed by Gilead Sciences in 2009, to treat hepatitis C and respiratory syncytial virus (RSV). It did not work against hepatitis C or RSV, but was then repurposed and studied as a potential treatment for Ebola virus disease and Marburg virus infections. According to the Czech News Agency, this new line of research was carried out under the direction of scientist Tomáš Cihlář. A collaboration of researchers from the Centers for Disease Control and Prevention (CDC) and Gilead Sciences subsequently discovered that remdesivir had antiviral activity "in vitro" against multiple filoviruses, pneumoviruses, paramyxoviruses, and coronaviruses.


title: Remdesivir

text: Preclinical and clinical research and development was done in collaboration between Gilead Sciences and various US government agencies and academic institutions.


title: Remdesivir

text: During the mid-2010s, the Mintz Levin law firm prosecuted various patent applications for remdesivir on behalf of Gilead Sciences before the United States Patent and Trademark Office (USPTO). The USPTO granted two patents on remdesivir to Gilead Sciences on 9 April 2019: one for filoviruses, and one which covered both arenaviruses and coronaviruses.


title: Remdesivir

text: In October 2015, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) announced preclinical results that remdesivir had blocked the Ebola virus in Rhesus monkeys. Travis Warren, who has been a USAMRIID principal investigator since 2007, said that the "work is a result of the continuing collaboration between USAMRIID and Gilead Sciences". The "initial screening" of the "Gilead Sciences compound library to find molecules with promising antiviral activity" was performed by scientists at the Centers for Disease Control and Prevention (CDC). As a result of this work, it was recommended that remdesivir "should be further developed as a potential treatment."


title: Remdesivir

text: Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in people with the disease. Preliminary results were promising; it was used in the emergency setting during the Kivu Ebola epidemic that started in 2018, along with further clinical trials, until August 2019, when Congolese health officials announced that it was significantly less effective than monoclonal antibody treatments such as ansuvimab and atoltivimab/maftivimab/odesivimab. The trials, however, established its safety profile.


title: Remdesivir

text: Remdesivir was approved for medical use in the United States in October 2020. The U.S. Food and Drug Administration (FDA) approved remdesivir based on the agency's analysis of data from three randomized, controlled clinical trials that included participants hospitalized with mild-to-severe COVID‑19. The FDA granted approval and reissued the revised EUA to Gilead Sciences Inc. The FDA approved remdesivir based primarily on evidence from three clinical trials (NCT04280705, NCT04292899, and NCT04292730) of 2043 hospitalized participants with COVID‑19. The trials were conducted at 226 sites in 17 countries including the United States.


title: Remdesivir

text: In November 2020, the World Health Organization (WHO) updated its guideline on therapeutics for COVID‑19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial. Meanwhile, the Public Health Agency of Canada's COVID-19 Clinical Pharmacology Task Group recommended that remdesivir only be administered to hospitalized patients as part of a randomized controlled trial due to limited information on risks and benefits.


title: Remdesivir

text: In January 2022, the Canadian component of the WHO Solidarity Trial reported that in-hospital people with COVID‑19 treated with remdesivir had lower death rates (by about 4%) and reduced need for oxygen and mechanical ventilation compared to people receiving standard-of-care treatments.


title: Remdesivir

text: In September 2022, the WHO updated their guidelines to recommend use of remdesivir for both non-hospitalized and hospitalized patients. This was based on final results from the SOLIDARITY trial that showed a reduction in mortality or progression to mechanical ventilation for non-ventilated patients.


title: Remdesivir

text: In January 2022, a study indicated that nonhospitalized people who were at high risk for COVID-19 progression had an 87% lower risk of hospitalization or death after a 3-day course of intravenous remdesivir.


title: Remdesivir

text: In May 2020, the National Institute of Allergy and Infectious Diseases (NIAID) started the Adaptive COVID‑19 Treatment Trial 2 (ACTT-2) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus baricitinib for treating hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation.


title: Remdesivir

text: In November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the drug baricitinib, in combination with remdesivir, for the treatment of suspected or laboratory-confirmed COVID‑19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID). The EUA was issued to Eli Lilly and Company.


title: Remdesivir

text: In August 2020, the NIAID started the Adaptive COVID‑19 Treatment Trial 3 (ACTT 3) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus interferon beta-1a for hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation.


title: Remdesivir

text: In 2019, GS-441524 was shown to have promise for treating feline infectious peritonitis caused by a coronavirus. It has not been evaluated or approved by the US Food and Drug Administration (FDA) for the treatment of feline coronavirus or feline infectious peritonitis but has been available since 2019, through websites and social media as an unregulated black market substance. Because GS-441524 is the main circulating metabolite of remdesivir and because GS-441524 has similar potency against SARS-Cov-2 "in vitro", some researchers have argued for the direct administration of GS-441524 as a COVID‑19 treatment.


title: Erectile dysfunction

text: Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men. Through its connection to self-image and to problems in sexual relationships, erectile dysfunction can cause psychological harm.


title: Erectile dysfunction

text: In about 80% of cases, physical causes can be identified. These include cardiovascular disease; diabetes mellitus; neurological problems, such as those following prostatectomy; hypogonadism; and drug side effects. About 10% of cases are psychological impotence, caused by thoughts or feelings; here, there is a strong response to placebo treatment.


title: Erectile dysfunction

text: Treatment involves addressing the underlying causes, lifestyle modifications, and addressing psychosocial problems. In many cases, treatment is attempted by drugs, specifically PDE5 inhibitors (such as sildenafil), which dilate blood vessels, allowing more blood to flow through the spongy tissue of the penis (akin to opening a valve further in order to allow more water to enter a fire hose). Other treatments, less commonly used, include prostaglandin pellets, inserted in the urethra; smooth-muscle relaxants and vasodilators, injected into the penis; penile implants; penis pumps; and vascular reconstructive surgery.


title: Erectile dysfunction

text: ED is characterized by the regular or repeated inability to achieve or maintain an erection of sufficient rigidity to accomplish sexual activity. It is defined as the "persistent or recurrent inability to achieve and maintain a penile erection of sufficient rigidity to permit satisfactory sexual activity for at least 3 months."


title: Erectile dysfunction

text: ED often has an impact on the emotional well-being of both men and their partners. Many men do not seek treatment due to feelings of embarrassment. About 75% of diagnosed cases of ED go untreated.


title: Erectile dysfunction

text: Surgical intervention for a number of conditions may remove anatomical structures necessary to erection, damage nerves, or impair blood supply. ED is a common complication of treatments for prostate cancer, including prostatectomy and destruction of the prostate by external beam radiation, although the prostate gland itself is not necessary to achieve an erection. As far as inguinal hernia surgery is concerned, in most cases, and in the absence of postoperative complications, the operative repair can lead to a recovery of the sexual life of people with preoperative sexual dysfunction, while, in most cases, it does not affect people with a preoperative normal sexual life.


title: Erectile dysfunction

text: ED can also be associated with bicycling due to both neurological and vascular problems due to compression. The increased risk appears to be about 1.7-fold.


title: Erectile dysfunction

text: Concerns that use of pornography can cause ED have little support in epidemiological studies, according to a 2015 literature review. According to Gunter de Win, a Belgian professor and sex researcher, "Put simply, respondents who watch 60 minutes a week and think they're addicted were more likely to report sexual dysfunction than those who watch a care-free 160 minutes weekly."


title: Erectile dysfunction

text: Penile erection is managed by two mechanisms: the reflex erection, which is achieved by directly touching the penile shaft, and the psychogenic erection, which is achieved by erotic or emotional stimuli. The former involves the peripheral nerves and the lower parts of the spinal cord, whereas the latter involves the limbic system of the brain. In both cases, an intact neural system is required for a successful and complete erection. Stimulation of the penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of the smooth muscles of the corpora cavernosa (the main erectile tissue of the penis), and subsequently penile erection. Additionally, adequate levels of testosterone (produced by the testes) and an intact pituitary gland are required for the development of a healthy erectile system. As can be understood from the mechanisms of a normal erection, impotence may develop due to hormonal deficiency, disorders of the neural system, lack of adequate penile blood supply or psychological problems. Spinal cord injury causes sexual dysfunction, including ED. Restriction of blood flow can arise from impaired endothelial function due to the usual causes associated with coronary artery disease, but can also be caused by prolonged exposure to bright light.


title: Erectile dysfunction

text: In many cases, the diagnosis can be made based on the person's history of symptoms. In other cases, a physical examination and laboratory investigations are done to rule out more serious causes such as hypogonadism or prolactinoma.


title: Erectile dysfunction

text: One of the first steps is to distinguish between physiological and psychological ED. Determining whether involuntary erections are present is important in eliminating the possibility of psychogenic causes for ED. Obtaining full erections occasionally, such as nocturnal penile tumescence when asleep (that is, when the mind and psychological issues, if any, are less present), tends to suggest that the physical structures are functionally working. Similarly, performance with manual stimulation, as well as any performance anxiety or acute situational ED, may indicate a psychogenic component to ED.


title: Erectile dysfunction

text: Another factor leading to ED is diabetes mellitus, a well known cause of neuropathy). ED is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease, such as coronary artery disease and peripheral vascular disease. Screening for cardiovascular risk factors, such as smoking, dyslipidemia, hypertension, and alcoholism, is helpful.


title: Erectile dysfunction

text: In some cases, the simple search for a previously undetected groin hernia can prove useful since it can affect sexual functions in men and is relatively easily curable.


title: Erectile dysfunction

text: Penile ultrasonography with doppler can be used to examine the erect penis. Most cases of ED of organic causes are related to changes in blood flow in the corpora cavernosa, represented by occlusive artery disease (in which less blood is allowed to enter the penis), most often of atherosclerotic origin, or due to failure of the veno-occlusive mechanism (in which too much blood circulates back out of the penis). Before the Doppler sonogram, the penis should be examined in B mode, in order to identify possible tumors, fibrotic plaques, calcifications, or hematomas, and to evaluate the appearance of the cavernous arteries, which can be tortuous or atheromatous.


title: Erectile dysfunction

text: Erection can be induced by injecting 10–20 µg of prostaglandin E1, with evaluations of the arterial flow every five minutes for 25–30 min (see image). The use of prostaglandin E1 is contraindicated in patients with predisposition to priapism (e.g., those with sickle cell anemia), anatomical deformity of the penis, or penile implants. Phentolamine (2 mg) is often added. Visual and tactile stimulation produces better results. Some authors recommend the use of sildenafil by mouth to replace the injectable drugs in cases of contraindications, although the efficacy of such medication is controversial.


title: Erectile dysfunction

text: Before the injection of the chosen drug, the flow pattern is monophasic, with low systolic velocities and an absence of diastolic flow. After injection, systolic and diastolic peak velocities should increase, decreasing progressively with vein occlusion and becoming negative when the penis becomes rigid (see image below). The reference values vary across studies, ranging from > 25 cm/s to > 35 cm/s. Values above 35 cm/s indicate the absence of arterial disease, values below 25 cm/s indicate arterial insufficiency, and values of 25–35 cm/s are indeterminate because they are less specific (see image below). The data obtained should be correlated with the degree of erection observed. If the peak systolic velocities are normal, the final diastolic velocities should be evaluated, those above 5 cm/s being associated with venogenic ED.


title: Erectile dysfunction

text: Treatment depends on the underlying cause. In general, exercise, particularly of the aerobic type, is effective for preventing ED during midlife. Counseling can be used if the underlying cause is psychological, including how to lower stress or anxiety related to sex. Medications by mouth and vacuum erection devices are first-line treatments, followed by injections of drugs into the penis, as well as penile implants. Vascular reconstructive surgeries are beneficial in certain groups. Treatments, other than surgery, do not fix the underlying physiological problem, but are used as needed before sex.


title: Erectile dysfunction

text: The PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) are prescription drugs which are taken by mouth. As of 2018, sildenafil is available in the UK without a prescription. Additionally, a cream combining alprostadil with the permeation enhancer DDAIP has been approved in Canada as a first line treatment for ED. Penile injections, on the other hand, can involve one of the following medications: papaverine, phentolamine, and prostaglandin E1, also known as alprostadil. In addition to injections, there is an alprostadil suppository that can be inserted into the urethra. Once inserted, an erection can begin within 10 minutes and last up to an hour. Medications to treat ED may cause a side effect called priapism.


title: Erectile dysfunction

text: In a study published in 2016, based on US health insurance claims data, out of 19,833,939 US males aged ≥18 years, only 1,108,842 (5.6%), were medically diagnosed with erectile dysfunction or on a PDE5I prescription ("μ" age 55.2 years, "σ" 11.2 years). Prevalence of diagnosis or prescription was the highest for age group 60–69 at 11.5%, lowest for age group 18–29 at 0.4%, and 2.1% for 30–39, 5.7% for 40–49, 10% for 50–59, 11% for 70–79, 4.6% for 80–89, 0.9% for ≥90, respectively.


title: Erectile dysfunction

text: Focused shockwave therapy involves passing short, high frequency acoustic pulses through the skin and into the penis. These waves break down any plaques within the blood vessels, encourage the formation of new vessels, and stimulate repair and tissue regeneration.


title: Erectile dysfunction

text: Focused shockwave therapy appears to work best for men with vasculogenic ED, which is a blood vessel disorder that affects blood flow to tissue in the penis. The treatment is painless and has no known side effects. Treatment with shockwave therapy can lead to a significant improvement of the IIEF (International Index of Erectile Function).


title: Erectile dysfunction

text: Men with low levels of testosterone can experience ED. Taking testosterone may help maintain an erection. Men with type 2 diabetes are twice as likely to have lower levels of testosterone, and are three times more likely to experience ED than non-diabetic men.


title: Erectile dysfunction

text: A vacuum erection device helps draw blood into the penis by applying negative pressure. This type of device is sometimes referred to as penis pump and may be used just prior to sexual intercourse. Several types of FDA approved vacuum therapy devices are available under prescription. When pharmacological methods fail, a purpose-designed external vacuum pump can be used to attain erection, with a separate compression ring fitted to the base of the penis to maintain it. These pumps should be distinguished from other penis pumps (supplied without compression rings) which, rather than being used for temporary treatment of impotence, are claimed to increase penis length if used frequently, or vibrate as an aid to masturbation. More drastically, inflatable or rigid penile implants may be fitted surgically.


title: Erectile dysfunction

text: Often, as a last resort, if other treatments have failed, the most common procedure is prosthetic implants which involves the insertion of artificial rods into the penis. Some sources show that vascular reconstructive surgeries are viable options for some people.


title: Erectile dysfunction

text: The Food and Drug Administration (FDA) does not recommend alternative therapies to treat sexual dysfunction. Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of ED, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products. The FDA has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant. A 2021 review indicated that ginseng had "only trivial effects on erectile function or satisfaction with intercourse compared to placebo".


title: Erectile dysfunction

text: Attempts to treat ED date back well over 1,000 years. In the 8th century, men of Ancient Rome and Greece wore talismans of rooster and goat genitalia, believing these talismans would serve as an aphrodisiac and promote sexual function. In the 13th century Albertus Magnus recommended ingesting roasted wolf penis as a remedy for impotence.


title: Erectile dysfunction

text: During the late 16th and 17th centuries in France, male impotence was considered a crime, as well as legal grounds for a divorce. The practice, which involved inspection of the complainants by court experts, was declared obscene in 1677.


title: Erectile dysfunction

text: The first successful vacuum erection device, or penis pump, was developed by Vincent Marie Mondat in the early 1800s. A more advanced device, based on a bicycle pump, was developed by Geddings Osbon, a Pentecostal preacher, in the 1970s. In 1982, he received FDA approval to market the product as the ErecAid®.


title: Erectile dysfunction

text: John R. Brinkley initiated a boom in male impotence cures in the U.S. in the 1920s and 1930s. His radio programs recommended expensive goat gland implants and "mercurochrome" injections as the path to restored male virility, including operations by surgeon Serge Voronoff.


title: Erectile dysfunction

text: Modern drug therapy for ED made a significant advance in 1983, when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience his papaverine-induced erection. The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered established the fundamentals for the later development of specific, safe, and orally effective drug therapies.


title: Erectile dysfunction

text: Anthropological research presents ED not as a disorder but, as a normal, and sometimes even welcome sign of healthy aging. Wentzell's study of 250 Mexican men in their 50's and 60's found that “most simply did not see decreasing erectile function as a biological pathology”. The men interviewed described the decrease in erectile function “as an aid for aging in socially appropriate ways”. A common theme amongst the interviewees showed that respectable older men shifted their focus toward the domestic sphere into a “second stage of life”. The Mexican men of this generation often pursued sex outside of marriage; decreasing erectile function acted as an aid to overcoming infidelity thus helping to attain the ideal “second stage” of life. A 56-year-old about to retire from the public health service said he would now "dedicate myself to my wife, the house, gardening, caring for the grandchildren—the Mexican classic". Wentzell found that treating ED as a pathology was antithetical to the social view these men held of themselves, and their purpose at this stage of their lives.


title: Erectile dysfunction

text: In the 20th and 21st centuries, anthropologists investigated how common treatments for ED are built upon assumptions of institutionalized social norms. In offering a range of clinical treatments to ‘correct’ a person's ability to produce an erection, biomedical institutions encourage the public to strive for prolonged sexual function. Anthropologists argue that a biomedical focus places emphasis on the biological processes of fixing the body thereby disregarding holistic ideals of health and aging. By relying on a wholly medical approach, Western biomedicine can become blindsided by bodily dysfunctions which can be understood as appropriate functions of age, and not as a medical problem. Anthropologists understand that a biosocial approach to ED considers a person's decision to undergo clinical treatment more likely a result of "society, political economy, history, and culture" than a matter of personal choice. In rejecting biomedical treatment for ED, men can challenge common forms of medicalized social control by deviating from what is considered the normal approach to dysfunction.


title: Erectile dysfunction

text: The Latin term "impotentia coeundi" describes simple inability to insert the penis into the vagina; it is now mostly replaced by more precise terms, such as "erectile dysfunction" (ED). The study of ED within medicine is covered by andrology, a sub-field within urology. Research indicates that ED is common, and it is suggested that approximately 40% of males experience symptoms compatible with ED, at least occasionally. The condition is also on occasion called "phallic impotence". Its antonym, or opposite condition, is priapism.


title: Lactose intolerance

text: Lactose intolerance is a common condition caused by a decreased ability to digest lactose, a sugar found in dairy products. Those affected vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pain, bloating, diarrhea, flatulence, and nausea. These symptoms typically start thirty minutes to two hours after eating or drinking milk-based food. Their severity typically depends on the amount a person eats or drinks. Lactose intolerance does not cause damage to the gastrointestinal tract.


title: Lactose intolerance

text: Lactose intolerance is due to the lack of the enzyme lactase in the small intestines to break lactose down into glucose and galactose. There are four types: primary, secondary, developmental, and congenital. Primary lactose intolerance occurs as the amount of lactase declines as people age. Secondary lactose intolerance is due to injury to the small intestine. Such injury could be the result of infection, celiac disease, inflammatory bowel disease, or other diseases. Developmental lactose intolerance may occur in premature babies and usually improves over a short period of time. Congenital lactose intolerance is an extremely rare genetic disorder in which little or no lactase is made from birth. The onset of primary lactose intolerance, the most common type, is typically in late childhood or early adulthood, but prevalence increases with age.


title: Lactose intolerance

text: Diagnosis may be confirmed if symptoms resolve following eliminating lactose from the diet. Other supporting tests include a hydrogen breath test and a stool acidity test. Other conditions that may produce similar symptoms include irritable bowel syndrome, celiac disease, and inflammatory bowel disease. Lactose intolerance is different from a milk allergy. Management is typically by decreasing the amount of lactose in the diet, taking lactase supplements, or treating the underlying disease. People are able to drink at least one cup of milk without developing symptoms, with greater amounts tolerated if drunk with a meal or throughout the day.


title: Lactose intolerance

text: Worldwide, around 65% of adults are affected by lactose malabsorption. Other mammals usually lose the ability to digest lactose after weaning and this was the ancestral state of all humans before the recent evolution of lactase persistence, which extends lactose tolerance into adulthood. Lactase persistence evolved in several populations independently, probably as an adaptation to the domestication of dairy animals around 10,000 years ago. Today the prevalence of lactose tolerance varies widely between regions and ethnic groups. The ability to digest lactose is most common in people of European descent, and to a lesser extent in some parts of the Middle East and Africa. Lactose intolerance is common among people of Jewish descent, as well as in many African countries, the majority of Arab countries, Greece and Italy. Traditional food cultures reflect local variations in tolerance and historically many societies have adapted to low levels of tolerance by making dairy products that contain less lactose than fresh milk. The medicalization of lactose intolerance as a disorder has been attributed to biases in research history, since most early studies were conducted amongst populations which are normally tolerant, as well as the cultural and economic importance of milk in countries such as the United States.


title: Lactose intolerance

text: "Lactose intolerance" primarily refers to a syndrome with one or more symptoms upon the consumption of food substances containing lactose sugar. Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms.


title: Lactose intolerance

text: "Hypolactasia" is the term specifically for the small intestine producing little or no lactase enzyme. If a person with hypolactasia consumes lactose sugar, it results in "lactose malabsorption". The digestive system is unable to process the lactose sugar, and the unprocessed sugars in the gut produce the symptoms of "lactose intolerance".


title: Lactose intolerance

text: Lactose intolerance is not an allergy, because it is not an immune response, but rather a sensitivity to dairy caused by a deficiency of lactase enzyme. Milk allergy, occurring in about 2% of the population, is a separate condition, with distinct symptoms that occur when the presence of milk proteins trigger an immune reaction.


title: Lactose intolerance

text: The principal manifestation of lactose intolerance is an adverse reaction to products containing lactose (primarily milk), including abdominal bloating and cramps, flatulence, diarrhea, nausea, borborygmi, and vomiting (particularly in adolescents). These appear one-half to two hours after consumption. The severity of these signs and symptoms typically increases with the amount of lactose consumed; most lactose-intolerant people can tolerate a certain level of lactose in their diets without ill effects.


title: Lactose intolerance

text: Because lactose intolerance is not an allergy, it does not produce allergy symptoms (such as itching, hives, or anaphylaxis).


title: Lactose intolerance

text: Lactose intolerance is a consequence of lactase deficiency, which may be genetic (primary hypolactasia and primary congenital alactasia) or environmentally induced (secondary or acquired hypolactasia). In either case, symptoms are caused by insufficient levels of lactase in the lining of the duodenum. Lactose, a disaccharide molecule found in milk and dairy products, cannot be directly absorbed through the wall of the small intestine into the bloodstream, so, in the absence of lactase, passes intact into the colon. Bacteria in the colon can metabolise lactose, and the resulting fermentation produces copious amounts of gas (a mixture of hydrogen, carbon dioxide, and methane) that causes the various abdominal symptoms. The unabsorbed sugars and fermentation products also raise the osmotic pressure of the colon, causing an increased flow of water into the bowels (diarrhea).


title: Lactose intolerance

text: Lactose intolerance in infants (congenital lactase deficiency) is caused by mutations in the LCT gene. The "LCT" gene provides the instructions for making lactase. Mutations are believed to interfere with the function of lactase, causing affected infants to have a severely impaired ability to digest lactose in breast milk or formula. Lactose intolerance in adulthood is a result of gradually decreasing activity (expression) of the LCT gene after infancy, which occurs in most humans. The specific DNA sequence in the "MCM6" gene helps control whether the "LCT" gene is turned on or off. At least several thousand years ago, some humans developed a mutation in the "MCM6" gene that keeps the "LCT" gene turned on even after breast feeding is stopped. Populations that are lactose intolerant lack this mutation. The "LCT" and "MCM6" genes are both located on the long arm (q) of chromosome 2 in region 21. The locus can be expressed as 2q21. The lactase deficiency also could be linked to certain heritages and varies widely. A 2016 study of over 60,000 participants from 89 countries found regional prevalence of lactose malabsorption was "64% (54–74) in Asia (except Middle East), 47% (33–61) in eastern Europe, Russia, and former Soviet Republics, 38% (CI 18–57) in Latin America, 70% (57–83) in the Middle East, 66% (45–88) in northern Africa, 42% (13–71) in northern America, 45% (19–71) in Oceania, 63% (54–72) in sub-Saharan Africa, and 28% (19–37) in northern, southern and western Europe." According to Johns Hopkins Medicine, lactose intolerance is more common in Asian Americans, African Americans, Mexican Americans, and Native Americans. Analysis of the DNA of 94 ancient skeletons in Europe and Russia concluded that the mutation for lactose tolerance appeared about 4,300 years ago and spread throughout the European population.


title: Lactose intolerance

text: Some human populations have developed lactase persistence, in which lactase production continues into adulthood probably as a response to the benefits of being able to digest milk from farm animals. Some have argued that this links intolerance to natural selection favoring lactase-persistent individuals, but it is also consistent with a physiological response to decrease lactase production when it is not needed in cultures in which dairy products are not an available food source. Although populations in Europe, India, Arabia, and Africa were first thought to have high rates of lactase persistence because of a single mutation, lactase persistence has been traced to a number of mutations that occurred independently. Different alleles for lactase persistence have developed at least three times in East African populations, with persistence extending from 26% in Tanzania to 88% in the Beja pastoralist population in Sudan.


title: Lactose intolerance

text: The accumulation of epigenetic factors, primarily DNA methylation, in the extended "LCT" region, including the gene enhancer located in the "MCM6" gene near C/T-13910 SNP, may also contribute to the onset of lactose intolerance in adults. Age-dependent expression of "LCT" in mice intestinal epithelium has been DNA methylation in the gene enhancer.


title: Lactose intolerance

text: Primary hypolactasia, or primary lactase deficiency, is genetic, only affects adults, and is caused by the absence of a lactase persistence allele. In individuals without the lactase persistence allele, less lactase is produced by the body over time, leading to hypolactasia in adulthood. The frequency of lactase persistence, which allows lactose tolerance, varies enormously worldwide, with the highest prevalence in Northwestern Europe, declines across southern Europe and the Middle East and is low in Asia and most of Africa, although it is common in pastoralist populations from Africa.


title: Lactose intolerance

text: Secondary hypolactasia or secondary lactase deficiency, also called acquired hypolactasia or acquired lactase deficiency, is caused by an injury to the small intestine. This form of lactose intolerance can occur in both infants and lactase persistent adults and is generally reversible. It may be caused by acute gastroenteritis, coeliac disease, Crohn's disease, ulcerative colitis, chemotherapy, intestinal parasites (such as giardia), or other environmental causes.


title: Lactose intolerance

text: Primary congenital alactasia, also called congenital lactase deficiency, is an extremely rare, autosomal recessive enzyme defect that prevents lactase expression from birth. People with congenital lactase deficiency cannot digest lactose from birth, so cannot digest breast milk. This genetic defect is characterized by a complete lack of lactase (alactasia). About 40 cases have been reported worldwide, mainly limited to Finland. Before the 20th century, babies born with congenital lactase deficiency often did not survive, but death rates decreased with soybean-derived infant formulas and manufactured lactose-free dairy products.


title: Lactose intolerance

text: In order to assess lactose intolerance, intestinal function is challenged by ingesting more dairy products than can be readily digested. Clinical symptoms typically appear within 30 minutes, but may take up to two hours, depending on other foods and activities. Substantial variability in response (symptoms of nausea, cramping, bloating, diarrhea, and flatulence) is to be expected, as the extent and severity of lactose intolerance varies among individuals.


title: Lactose intolerance

text: The next step is to determine whether it is due to primary lactase deficiency or an underlying disease that causes secondary lactase deficiency. Physicians should investigate the presence of undiagnosed coeliac disease, Crohn disease, or other enteropathies when secondary lactase deficiency is suspected and infectious gastroenteritis has been ruled out.


title: Lactose intolerance

text: Lactose intolerance is distinct from milk allergy, an immune response to cow's milk proteins. They may be distinguished in diagnosis by giving lactose-free milk, producing no symptoms in the case of lactose intolerance, but the same reaction as to normal milk in the presence of a milk allergy. A person can have both conditions. If positive confirmation is necessary, four tests are available.


title: Lactose intolerance

text: In a hydrogen breath test, the most accurate lactose intolerance test, after an overnight fast, 25 grams of lactose (in a solution with water) are swallowed. If the lactose cannot be digested, enteric bacteria metabolize it and produce hydrogen, which, along with methane, if produced, can be detected on the patient's breath by a clinical gas chromatograph or compact solid-state detector. The test takes about 2.5 hours to complete. If the hydrogen levels in the patient's breath are high, they may have lactose intolerance. This test is not usually done on babies and very young children, because it can cause severe diarrhea.


title: Lactose intolerance

text: In conjunction, measuring blood glucose level every 10 to 15 minutes after ingestion will show a "flat curve" in individuals with lactose malabsorption, while the lactase persistent will have a significant "top", with a typical elevation of 50% to 100%, within one to two hours. However, due to the need for frequent blood sampling, this approach has been largely replaced by breath testing.


title: Lactose intolerance

text: After an overnight fast, blood is drawn and then 50 grams of lactose (in aqueous solution) are swallowed. Blood is then drawn again at the 30-minute, 1-hour, 2-hour, and 3-hour marks. If the lactose cannot be digested, blood glucose levels will rise by less than 20 mg/dl.


title: Lactose intolerance

text: This test can be used to diagnose lactose intolerance in infants, for whom other forms of testing are risky or impractical. The infant is given lactose to drink. If the individual is tolerant, the lactose is digested and absorbed in the small intestine; otherwise, it is not digested and absorbed, and it reaches the colon. The bacteria in the colon, mixed with the lactose, cause acidity in stools. Stools passed after the ingestion of the lactose are tested for level of acidity. If the stools are acidic, the infant is intolerant to lactose.


title: Lactose intolerance

text: An intestinal biopsy must confirm lactase deficiency following discovery of elevated hydrogen in the hydrogen breath test. Modern techniques have enabled a bedside test, identifying presence of lactase enzyme on upper gastrointestinal endoscopy instruments. However, for research applications such as mRNA measurements, a specialist laboratory is required.


title: Lactose intolerance

text: Chromatography can be used to separate and identify undigested sugars present in faeces. Although lactose may be detected in the faeces of people with lactose intolerance, this test is not considered reliable enough to conclusively diagnose or exclude lactose intolerance.


title: Lactose intolerance

text: Genetic tests may be useful in assessing whether a person has primary lactose intolerance. Lactase activity persistence in adults is associated with two polymorphisms: C/T 13910 and G/A 22018 located in the "MCM6" gene. These polymorphisms may be detected by molecular biology techniques at the DNA extracted from blood or saliva samples; genetic kits specific for this diagnosis are available. The procedure consists of extracting and amplifying DNA from the sample, following with a hybridation protocol in a strip. Colored bands are obtained as result, and depending on the different combinations, it would be possible to determine whether the patient is lactose intolerant. This test allows a noninvasive definitive diagnostic.


title: Lactose intolerance

text: Lactose intolerance is most common in people of East Asian descent, with 70 to 100 percent of people affected in these communities. Lactose intolerance is also more common in people of West African, Arab, and Jewish descent, while only about 5 percent of people of European descent are lactose intolerant.


title: Lactose intolerance

text: When lactose intolerance is due to secondary lactase deficiency, treatment of the underlying disease may allow lactase activity to return to normal levels. In people with celiac disease, lactose intolerance normally reverts or improves several months after starting a gluten-free diet, but temporary dietary restriction of lactose may be needed.


title: Lactose intolerance

text: People with primary lactase deficiency cannot modify their body's ability to produce lactase. In societies where lactose intolerance is the norm, it is not considered a condition that requires treatment. However, where dairy is a larger component of the normal diet, a number of efforts may be useful. There are four general principles in dealing with lactose intolerance: avoidance of dietary lactose, substitution to maintain nutrient intake, regulation of calcium intake, and use of enzyme substitute. Regular consumption of dairy food by lactase deficient individuals may also reduce symptoms of intolerance by promoting colonic bacteria adaptation.


title: Lactose intolerance

text: The primary way of managing the symptoms of lactose intolerance is to limit the intake of lactose to a level that can be tolerated. Lactase deficient individuals vary in the amount of lactose they can tolerate, and some report that their tolerance varies over time, depending on health status and pregnancy. However, as a rule of thumb, people with primary lactase deficiency and no small intestine injury are usually able to consume at least 12 grams of lactose per sitting without symptoms, or with only mild symptoms, with greater amounts tolerated if consumed with a meal or throughout the day.


title: Lactose intolerance

text: There is no standardized method for measuring the lactose content of food. The stated dairy content of a product also varies according to manufacturing processes and labelling practices, and commercial terminology varies between languages and regions. As a result, absolute figures for the amount of lactose consumed (by weight) may not be very reliable. Kosher products labeled "pareve" or "fleishig" are free of milk. However, if a "D" (for "dairy") is present next to the circled "K", "U", or other "hechsher", the food product likely contains milk solids, although it may also simply indicate the product was produced on equipment shared with other products containing milk derivatives.


title: Lactose intolerance

text: Lactose is also a commercial food additive used for its texture, flavor, and adhesive qualities. It is found in additives labelled as casein, caseinate, whey, lactoserum, milk solids, modified milk ingredients, etc. As such lactose is found in foods such as processed meats (sausages/hot dogs, sliced meats, pâtés), gravy stock powder, margarines, sliced breads, breakfast cereals, potato chips, processed foods, medications, prepared meals, meal replacements (powders and bars), protein supplements (powders and bars), and even beers in the milk stout style. Some barbecue sauces and liquid cheeses used in fast-food restaurants may also contain lactose. Lactose is often used as the primary filler (main ingredient) in most prescription and non-prescription solid pill form medications, though product labeling seldom mentions the presence of 'lactose' or 'milk', and neither do product monograms provided to pharmacists, and most pharmacists are unaware of the very wide scale yet common use of lactose in such medications until they contact the supplier or manufacturer for verification.


title: Lactose intolerance

text: Plant-based milks and derivatives such as soy milk, rice milk, almond milk, coconut milk, hazelnut milk, oat milk, hemp milk, macadamia nut milk, and peanut milk are inherently lactose-free. Low-lactose and lactose-free versions of foods are often available to replace dairy-based foods for those with lactose intolerance.


title: Lactose intolerance

text: When lactose avoidance is not possible, or on occasions when a person chooses to consume such items, then enzymatic lactase supplements may be used.


title: Lactose intolerance

text: Lactase enzymes similar to those produced in the small intestines of humans are produced industrially by fungi of the genus "Aspergillus". The enzyme, β-galactosidase, is available in tablet form in a variety of doses, in many countries without a prescription. It functions well only in high-acid environments, such as that found in the human gut due to the addition of gastric juices from the stomach. Unfortunately, too much acid can denature it, so it should not be taken on an empty stomach. Also, the enzyme is ineffective if it does not reach the small intestine by the time the problematic food does. Lactose-sensitive individuals can experiment with both timing and dosage to fit their particular needs.


title: Lactose intolerance

text: While essentially the same process as normal intestinal lactose digestion, direct treatment of milk employs a different variety of industrially produced lactase. This enzyme, produced by yeast from the genus "Kluyveromyces", takes much longer to act, must be thoroughly mixed throughout the product, and is destroyed by even mildly acidic environments. Its main use is in producing the lactose-free or lactose-reduced dairy products sold in supermarkets.


title: Lactose intolerance

text: Regular consumption of dairy foods containing lactose can promote a colonic bacteria adaptation, enhancing a favorable microbiome, which allows people with primary lactase deficiency to diminish their intolerance and to consume more dairy foods. The way to induce tolerance is based on progressive exposure, consuming smaller amounts frequently, distributed throughout the day. Lactose intolerance can also be managed by ingesting live yogurt cultures containing lactobacilli that are able to digest the lactose in other dairy products.


title: Lactose intolerance

text: Worldwide, about 65% of people experience some form of lactose intolerance as they age past infancy, but there are significant differences between populations and regions. As few as 5% of northern Europeans are lactose intolerant, while as many as 90% of adults in parts of Asia are lactose intolerant.


title: Lactose intolerance

text: Some populations, from an evolutionary perspective, have a better genetic makeup for tolerating lactose than others. In northern European countries, early adoption of dairy farming conferred a selective evolutionary advantage to individuals that could better tolerate lactose. This led to higher frequencies of lactose tolerance in these countries. For example, almost 100% of Irish people are predicted to be lactose tolerant. Conversely, regions of the south, such as Africa, did not adopt dairy farming as early and tolerance from milk consumption did not develop the same way as in northern Europe. Lactose intolerance is common among people of Jewish descent, as well as from West Africa, the Arab countries, Greece, and Italy. Different populations will present certain gene constructs depending on the evolutionary and cultural pre-settings of the geographical region.


title: Lactose intolerance

text: Greater lactose tolerance has come about in two ways. Some populations have developed genetic changes to allow the digestion of lactose: lactase persistence. Other populations developed cooking methods like milk fermentation.


title: Lactose intolerance

text: Lactase persistence in humans evolved relatively recently (in the last 10,000 years) among some populations. Around 8,000 years ago in modern-day Turkey, humans became reliant on newly-domesticated animals that could be milked; such as cows, sheep, and goats. This resulted in higher frequency of lactase persistence. Lactase persistence became high in regions such as Europe, Scandinavia, the Middle East and Northwestern India. However, most people worldwide remain lactase "non"-persistent. Populations that raised animals not used for milk tend to have 90–100 percent of a lactose intolerant rate. For this reason, lactase persistence is of some interest to the fields of anthropology, human genetics, and archaeology, which typically use the genetically derived persistence/non-persistence terminology.


title: Lactose intolerance

text: The rise of dairy and producing dairy related products from cow milk alone, varies across different regions of the world, aside from genetic predisposition. The process of turning milk into cheese dates back earlier than 5200 BC.


title: Lactose intolerance

text: DNA analysis in February 2012 revealed that Ötzi was lactose intolerant, supporting the theory that lactose intolerance was still common at that time, despite the increasing spread of agriculture and dairying.


title: Lactose intolerance

text: Genetic analysis shows lactase persistence has developed several times in different places independently in an example of convergent evolution.


title: Lactose intolerance

text: It is not until relatively recently that medicine recognised the worldwide prevalence of lactose intolerance and its genetic causes. Its symptoms were described as early as Hippocrates (460–370 BC), but until the 1960s, the prevailing assumption was that tolerance was the norm. Intolerance was explained as the result of a milk allergy, intestinal pathogens, or as being psychosomatic – it being recognised that some cultures did not practice dairying, and people from those cultures often reacted badly to consuming milk. Two reasons have been given for this misconception. One was that early research was conducted solely on European-descended populations, which have an unusually low incidence of lactose intolerance and an extensive cultural history of dairying. As a result, researchers wrongly concluded that tolerance was the global norm. Another reason is that lactose intolerance tends to be under-reported: lactose intolerant individuals can tolerate at least some lactose before they show symptoms, and their symptoms differ in severity. The large majority of people are able to digest some quantity of milk, for example in tea or coffee, without developing any adverse effects. Fermented dairy products, such as cheese, also contain significantly less lactose than plain milk. Therefore, in societies where tolerance is the norm, many lactose intolerant people who consume only small amounts of dairy, or have only mild symptoms, may be unaware that they cannot digest lactose.


title: Lactose intolerance

text: Eventually, in the 1960s, it was recognised that lactose intolerance was correlated with race in the United States. Subsequent research revealed that lactose intolerance was more common globally than tolerance, and that the variation was due to genetic differences, not an adaptation to cultural practices.


title: Lactose intolerance

text: Most mammals normally cease to produce lactase and become lactose intolerant after weaning. The downregulation of lactase expression in mice could be attributed to the accumulation of DNA methylation in the "Lct" gene and the adjacent "Mcm6" gene.


title: William Friedkin

text: William "Billy" Friedkin (born August 29, 1935) is an American film and television director, producer and screenwriter closely identified with the "New Hollywood" movement of the 1970s. Beginning his career in documentaries in the early 1960s, he directed the crime thriller film "The French Connection" (1971), which won five Academy Awards, including Best Picture, Best Adapted Screenplay and Best Director, and the supernatural horror film "The Exorcist" (1973), which earned him a nomination for the Academy Award for Best Director.


title: William Friedkin

text: His other films include the drama "The Boys in the Band" (1970), the thriller "Sorcerer" (1977), the crime comedy drama "The Brink's Job" (1978), the crime thriller "Cruising" (1980), the neo-noir thriller "To Live and Die in L.A." (1985), the psychological horror film "Bug" (2006) and the black comedy "Killer Joe" (2011).


title: William Friedkin

text: Friedkin was born in Chicago, Illinois, the son of Rachael (née Green) and Louis Friedkin. His father was a semi-professional softball player, merchant seaman, and men's clothing salesman. His mother, whom Friedkin called "a saint", was an operating room registered nurse. His parents were Jewish emigrants from Ukraine. His grandparents, parents, and other relatives fled Ukraine during a particularly violent anti-Jewish pogrom in 1903. Friedkin's father was somewhat uninterested in making money, and the family was generally lower middle class while he was growing up. According to film historian Peter Biskind, "Friedkin viewed his father with a mixture of affection and contempt for not making more of himself." According to his memoir, "The Friedkin Connection", Friedkin had the utmost affection for his father.


title: William Friedkin

text: Friedkin attended public schools in Chicago. He enrolled at Senn High School, where he played basketball well enough to consider turning professional. However he was not a serious student and barely received grades good enough to graduate, which he did at the age of 16. According to Friedkin, this was because of social promotion and not because he was bright.


title: William Friedkin

text: Friedkin began going to movies as a teenager, and has cited "Citizen Kane "as one of his key influences. Several sources claim that Friedkin saw this motion picture as a teenager, but Friedkin himself says that he did not see the film until 1960, when he was 25 years old. Only then, Friedkin says, did he become a true cineaste. Among the movies which he saw as a teenager and young adult were "Les Diaboliques", "The Wages of Fear" (which many consider he remade as "Sorcerer (film)"), and "Psycho" (which he viewed repeatedly, like "Citizen Kane"). Televised documentaries such as 1960's "Harvest of Shame" were also important in his developing sense of cinema.


title: William Friedkin

text: He began working in the mail room at WGN-TV immediately after high school. Within two years (at the age of 18), he started his directorial career doing live television shows and documentaries. His efforts included "The People vs. Paul Crump" (1962), which won an award at the San Francisco International Film Festival and contributed to the commutation of Crump's death sentence. Its success helped Friedkin get a job with producer David L. Wolper. He also made the football-themed documentary "Mayhem on a Sunday Afternoon".


title: William Friedkin

text: As mentioned in his voice-over commentary on the DVD re-release of Alfred Hitchcock's "Vertigo", Friedkin directed one of the last episodes of "The Alfred Hitchcock Hour" in 1965, called "Off Season". Hitchcock admonished Friedkin for not wearing a tie while directing.


title: William Friedkin

text: In 1965, Friedkin moved to Hollywood and two years later released his first feature film, "Good Times" starring Sonny and Cher. He has referred to the film as "unwatchable". Several other "art" films followed: "The Birthday Party", based on an unpublished screenplay by Harold Pinter, which he adapted from his own play; the musical comedy "The Night They Raided Minsky's"; and the adaptation of Mart Crowley's play "The Boys in the Band".


title: William Friedkin

text: His next film, "The French Connection", was released to wide critical acclaim in 1971. Shot in a gritty style more suited for documentaries than Hollywood features, the film won five Academy Awards, including Best Picture and Best Director.


title: William Friedkin

text: Friedkin's next film was 1973's "The Exorcist", based on William Peter Blatty's best-selling novel, which revolutionized the horror genre and is considered by some critics to be one of the greatest horror movies of all time. "The Exorcist" was nominated for 10 Academy Awards, including Best Picture and Best Director. It won for Best Screenplay and Best Sound.


title: William Friedkin

text: Following these two pictures, Friedkin, along with Francis Ford Coppola and Peter Bogdanovich, was deemed one of the premier directors of New Hollywood. In 1973, the trio announced the formation of an independent production company at Paramount, The Directors Company. Whereas Coppola directed "The Conversation" and Bogdanovich, the Henry James adaptation, "Daisy Miller", Friedkin abruptly left the company, which was soon closed by Paramount. But Friedkin's later movies did not achieve the same success. "Sorcerer" (1977), a $22 million American remake of the French classic "The Wages of Fear", co-produced by both Universal and Paramount, starring Roy Scheider, was overshadowed by the blockbuster box-office success of "Star Wars", which had been released exactly one week prior. Friedkin considers it his finest film, and was personally devastated by its financial and critical failure (as mentioned by Friedkin himself in the documentary series "The Directors" (1999)).


title: William Friedkin

text: "Sorcerer" was shortly followed by the crime-comedy "The Brink's Job" (1978), based on the real-life Great Brink's Robbery in Boston, Massachusetts, which was also unsuccessful at the box-office. In 1980, he directed an adaptation of the Gerald Walker crime thriller "Cruising", starring Al Pacino, which was protested against even during its making and remains the subject of heated debate. The film was critically assailed, and was a financial disappointment.


title: William Friedkin

text: Friedkin suffered a major heart attack on March 6, 1981, due to a genetically caused defect in his circumflex left coronary artery, and nearly died. He spent months in rehabilitation.


title: William Friedkin

text: Throughout the 1980s and 1990s, Friedkin's films received mostly lackluster reviews and moderate ticket sales. "Deal of the Century" (1983), starring Chevy Chase, Gregory Hines and Sigourney Weaver, was sometimes regarded as a latter-day "Dr. Strangelove", though it was generally savaged by critics. However, his action/crime movie "To Live and Die in L.A." (1985), starring William Petersen and Willem Dafoe, was a critical favorite and drew comparisons to Friedkin's own "The French Connection" (particularly for its car-chase sequence), while his courtroom-drama/thriller "Rampage" (1987) received a fairly positive review from Roger Ebert despite major distribution problems. He next directed the horror film "The Guardian" (1990) and then the thriller "Jade" (1995), starring Linda Fiorentino. Though the latter film received an unfavorable response from critics and audiences, Friedkin said that "Jade" was the favorite of all the films he had made, as is "Sorcerer".


title: William Friedkin

text: In 2000, "The Exorcist" was re-released in theaters with extra footage and grossed $40 million in the U.S. alone. Friedkin directed the 2007 film "Bug" due to a positive experience watching the stage version in 2004. He was surprised to find that he was, metaphorically, on the same page as the playwright and felt that he could relate well to the story. The film won the FIPRESCI prize at the Cannes Film Festival.


title: William Friedkin

text: Later, Friedkin directed an episode of the TV series "" titled "Cockroaches", which re-teamed him with "To Live and Die in L.A." star William Petersen. He directed again for "CSI"s 200th episode, "Mascara".


title: William Friedkin

text: In 2011, Friedkin directed "Killer Joe", a black comedy written by Tracy Letts based on Letts' play, and starring Matthew McConaughey, Emile Hirsch, Juno Temple, Gina Gershon, and Thomas Haden Church. "Killer Joe" premiered at the 68th Venice International Film Festival, prior to its North American debut at the 2011 Toronto International Film Festival. It opened in U.S. theaters in July 2012, to some favorable reviews from critics but did poorly at the box office, possibly because of its restrictive NC-17 rating.


title: William Friedkin

text: In April 2013, Friedkin published a memoir, "The Friedkin Connection". He was presented with a lifetime achievement award at the 70th Venice International Film Festival in September.


title: William Friedkin

text: In 2017, Friedkin directed "The Devil and Father Amorth", a documentary showing the ninth exorcism of an Italian woman in the village of Venafro.


title: William Friedkin

text: In August 2022, it was announced that Friedkin would be returning to directing to helm an adaptation of the two-act play "The Caine Mutiny Court-Martial" starring Kiefer Sutherland as Lt. Commander Queeg.


title: William Friedkin

text: The moving image collection of William Friedkin is held at the Academy Film Archive. The material at the Academy Film Archive is complemented by material in the William Friedkin papers at the academy's Margaret Herrick Library.


title: William Friedkin

text: While he was filming "The Boys in the Band" in 1970, Friedkin began a relationship with Kitty Hawks, daughter of director Howard Hawks. It lasted two years, during which the couple announced their engagement, but the relationship ended about 1972. Friedkin began a four-year relationship with Australian dancer and choreographer Jennifer Nairn-Smith in 1972. Although they announced an engagement twice, they never married. They did, however, have a son, Cedric, born on November 27, 1976. Friedkin and his second wife, Lesley-Anne Down, also had a son, Jack, born in 1982. Friedkin was raised Jewish, but called himself an agnostic later in life. However, during an appearance and Q&A at a 40th anniversary screening of "The Exorcist" at the 2013 Dallas International Film Festival, Friedkin said he "believes strongly in God" and "the teachings of Jesus" and other religious figures, and that mankind is "in God's hands."


title: Blade Runner: Black Lotus

text: Blade Runner: Black Lotus is a CGI anime television series based on the "Blade Runner" franchise that aired from November 2021 to February 2022. The series was co-produced by Alcon Television Group and Williams Street in partnership with Crunchyroll and Adult Swim, which both aired simultaneously. The series was animated by Japanese anime studio Sola Digital Arts.


title: Blade Runner: Black Lotus

text: "Black Lotus" takes place in Los Angeles in 2032, 10 years into the aftermath of the "Black Out 2022", but before "", and centers on a female replicant protagonist. It also includes "familiar" characters from the "Blade Runner" universe.


title: Blade Runner: Black Lotus

text: The anime was announced in November 2018. The series was animated by Sola Digital Arts with Shinji Aramaki and Kenji Kamiyama serving as chief directors. Shinichirō Watanabe, director of "Blade Runner Black Out 2022", served as a creative producer. It aired on Adult Swim's Toonami programming block in the United States from November 14, 2021 to February 6, 2022. Crunchyroll also streamed the series in Japanese with English subtitles.


title: Blade Runner: Black Lotus

text: Canada's Corus Entertainment announced at their June 2021 upfronts that the series would air in the fall on Adult Swim Canada. It would later be confirmed that the series would air in simulcast with the U.S.


title: Blade Runner: Black Lotus

text: In July 2021, both Japanese and English casts were revealed along with the announcement of a planned panel for the virtual 2021 San Diego Comic-Con. The opening theme is "Feel You Now" performed by Alessia Cara.


title: Blade Runner: Black Lotus

text: In September 2022, Jason DeMarco confirmed that the series had been removed from Adult Swim's website.


title: Blade Runner: Black Lotus

text: Sony Pictures Television, the parent company of Crunchyroll which also handled international release for "Blade Runner 2049", distributes the series outside of the United States.


title: Blade Runner: Black Lotus

text: On Metacritic it has a score of 61 based on reviews from 4 critics, indicating "generally favorable reviews".


title: San Junipero

text: "San Junipero" is the fourth episode in the third series of the British science fiction anthology television series "Black Mirror". Written by series creator and showrunner Charlie Brooker and directed by Owen Harris, it premiered on Netflix on 21 October 2016, with the rest of series three.


title: San Junipero

text: The episode is set in a beach resort town named San Junipero, where the introverted Yorkie (Mackenzie Davis) meets the more outgoing Kelly (Gugu Mbatha-Raw). The town is part of a simulated reality the elderly can inhabit, even after death. "San Junipero" was the first episode written for series three of "Black Mirror"; initial drafts were based on nostalgia therapy and designed as a 1980s period piece. The first script was about a heterosexual couple and had an unhappy ending; the final version was about a same-sex couple and had a happy ending. Filming took place in London and Cape Town across a few weeks. The soundtrack interweaves 1980s songs with an original score by Clint Mansell.


title: San Junipero

text: The episode received critical acclaim, with particular praise for Mbatha-Raw and Davis' performances, its plot twist, its visual style, and its uplifting tone (atypical for the show). It had higher critical ratings than the show's other episodes, while some critics considered it one of the best television episodes of 2016. In addition to several other accolades, "San Junipero" won two Primetime Emmy Awards for Outstanding Television Movie and Outstanding Writing for a Limited Series, Movie, or Dramatic Special.


title: San Junipero

text: In 1987, a shy young woman, Yorkie (Mackenzie Davis), visits the nightclub Tucker's in San Junipero. Kelly (Gugu Mbatha-Raw), a vivacious party girl, rebuffs the advances of Wes (Gavin Stenhouse) to talk to Yorkie. Kelly and Yorkie dance, but Yorkie becomes uncomfortable and leaves the club. Kelly follows and sexually propositions Yorkie, who declines, saying she is engaged. The following week, Yorkie returns to the bar and observes Kelly flirting with another man. Yorkie and Kelly reunite in the bathroom, kiss there and end up having sex at Kelly's beach house. Yorkie confesses that it was her first time having sex, and Kelly reveals that she was once married.


title: San Junipero

text: The next week, Yorkie visits another nightclub, the BDSM-themed Quagmire, looking for Kelly. Wes advises her to "try a different time". Yorkie visits Tucker's in a few different decades until she finds Kelly in 2002, but Kelly rejects her. After Yorkie leaves, Kelly follows and confesses she is dying; Kelly had avoided Yorkie because she feared developing feelings for her. The two have sex again, and Yorkie reluctantly tells Kelly she lives in Santa Rosa, California, so they can meet.


title: San Junipero

text: San Junipero is revealed to be a simulated reality where the deceased can live and the elderly can visit, all inhabiting their younger selves' bodies in a time of their choice. In the physical world, the elderly Kelly (Denise Burse) visits Yorkie (Annabel Davis). She learns from Yorkie's nurse, Greg (Raymond McAnally), that Yorkie was paralysed at age 21 after crashing her car when her parents reacted negatively to her coming out. Yorkie wishes to be euthanised to live in San Junipero permanently, but her family objects; she intends to marry Greg so that he can consent for her. Kelly offers to marry Yorkie instead, and after she enthusiastically accepts, Kelly authorises Yorkie's euthanasia.


title: San Junipero

text: During Kelly's next visit to San Junipero, Yorkie asks her to stay full-time. Kelly says she plans to die without being uploaded to the simulation; her husband chose the same fate because their daughter died before San Junipero existed. Yorkie and Kelly argue, and Kelly leaves in her car, which she intentionally crashes. Yorkie catches up to her just as Kelly disappears, her visiting time over for the week.


title: San Junipero

text: Time passes, and Kelly decides she is ready to enter San Junipero permanently. She is euthanised and buried alongside her family, and she happily reunites with Yorkie in San Junipero.


title: San Junipero

text: "San Junipero" is the fourth episode of series three of "Black Mirror"; all six episodes in this series were simultaneously released on Netflix on 21 October 2016. Whilst series one and two of "Black Mirror" were shown on Channel 4 in the UK, Netflix commissioned the series for 12 episodes (split into two series of six episodes) in September 2015 with a bid of $40 million, and in March 2016, Netflix outbid Channel 4 for the right to distribute series three in the UK. Due to its move to Netflix, the show had a larger budget than in previous series, and a larger episode order which allowed the show to vary its genre and tone more than previous series. Alongside series three episode "Nosedive", "San Junipero" was first shown in 2016 ahead of its Netflix release at the Toronto International Film Festival.


title: San Junipero

text: "San Junipero" was the first script produced for series three, written by Charlie Brooker as a "conscious decision to change the series". The show previously focused on technology's negative effects; this episode served as proof that uplifting "Black Mirror" episodes are possible.


title: San Junipero

text: Brooker initially envisioned an episode in which technology is used to investigate whether an afterlife exists, thinking of the genres of horror and supernatural fiction. He later became inspired by nostalgia therapy for older people. Brooker and executive producer Annabel Jones felt that their concept of virtual consciousness, established in the episode "White Christmas", had more potential. One of Brooker's original concepts was based on the episode "Be Right Back", in which deceased persons' personalities are uploaded into artificial entities in a theme park that relatives can visit. This idea was scrapped with the 2016 broadcast of "Westworld", in which humans visit a theme park inhabited by androids. He then recalled the 2010 BBC series "The Young Ones", in which older celebrities live in a home decorated in the fashion of the 1970s and find themselves rejuvenated by the setting. Having repeatedly thought of writing an episode set in the past, Brooker wrote "San Junipero" as a period episode.


title: San Junipero

text: Brooker has said that he wrote the script for the episode in four days. In the initial draft, the love story was about a heterosexual couple, but Brooker changed it to give the episode an extra resonance, as same-sex marriage was not legal in 1987. He has said that having a twist makes the writing process easier, as "when you know that 85 percent of what's happening you can't reveal till later on, it actually sort of narrows your options in a useful way". One draft of the episode contained a scene where Kelly visits a kindergarten in San Junipero, full of children who had died, but it was removed because "it was too sad and too poignant of a note to hit in that story". Brooker chose the setting of California, a location in America rather than Britain, as a way to "upend" people's preconceptions of "Black Mirror". One reviewer noted that all of the characters in "San Junipero" are American.


title: San Junipero

text: The episode was originally to have an unhappy ending. Brooker told "The Daily Beast" that in the rough treatment, the episode ended with the scene where Kelly and Yorkie meet in the hospital, but "when I sat down to actually write it, I was enjoying it so much that I thought, "No, I'm going to keep going"!" He conceived of Yorkie's euthanasia and expanded on Kelly's backstory, writing her emotional speech to Yorkie in one sitting. The ending came about when Brooker heard "Heaven is a Place on Earth" off a streaming playlist while writing the script, and wanted to license the song for the episode. After listening to the song and lyrics several times, he came to the final shot, which shows a bank of computer servers with flashing lights, giving literal weight to the song's title. An unused idea for the ending had the audience see Kelly and Yorkie in many different eras, such as the 1920s.


title: San Junipero

text: Following the episode's release, Brooker was asked about a Reddit post speculating that Kelly is simulated for Yorkie's benefit, rather than really there; he replied "Wrong! They are together", and commented that "[t]hey have the happiest ending imaginable. [...] it's not a big rainbow sandwich, but what appears to be happening there, is happening there."


title: San Junipero

text: The nightclub settings featured arcade games, which Brooker took an interest in choosing as he was a teenager during the 1980s and has worked as a video game journalist. Director Owen Harris described the 1980s as a "period in life that was really optimistic". He chose the year 1987 "fairly arbitrarily" and mentioned "very specific movie posters" in the script. Brooker put together a playlist of music from 1987 on Spotify. Some songs, such as Belinda Carlisle's "Heaven Is a Place on Earth" and the Smiths' "Girlfriend in a Coma", hint at the episode's plot twist, as do arcade games "Time Crisis" and "The House of the Dead". Each song had to be cleared for roughly 15 years for Netflix. Every song was successfully cleared except one by Prince.


title: San Junipero

text: "Heaven Is a Place on Earth" plays at the episode's beginning and over the end credits. Brooker first heard it while running, and believed it would be perfect for the final scene, admitting in an interview he would have been "absolutely distraught" if they had been unable to use it. "Girlfriend in a Coma" features in the episode "for about five seconds", yet cost "an outrageous amount of money", Brooker said. Jones said the song's inclusion "was indulgent but at the same time, it was so important that we set up that era so it felt different". Robbie Nevil's song "C'est La Vie" was chosen by Harris, as it was one of the first singles he ever purchased.


title: San Junipero

text: The episode also featured an original score by Clint Mansell. Mansell was approached by Harris, and based the score around the previously chosen songs, including "Heaven Is a Place on Earth". He has said that the "calm electronic" score was influenced by John Hughes movies and the death of his girlfriend a year before. In December 2016, Lakeshore Records released the score for downloading and streaming.


title: San Junipero

text: Gugu Mbatha-Raw, who plays Kelly, had heard of the show but not seen it when she received the script, though she did watch the series two episode "Be Right Back" before the shoot. Mbatha-Raw read the entire script as soon as she received it, on a bus journey from Oxford Circus to Brixton. Mackenzie Davis, who plays Yorkie, first saw the show with a friend who had pirated it; they watched "The National Anthem". Denise Burse plays the elder Kelly in the real world, as using prosthetics on Mbatha-Raw was quickly discounted. Annabel Davis was cast as elder Yorkie.


title: San Junipero

text: The episode's director was Owen Harris, who previously directed "Be Right Back" – an episode he described as "strangely similar" to this one as both are "relationship-led". Joel Collins served as production designer. The 1986 teen films "Pretty in Pink" and "Ferris Bueller's Day Off" were considered as inspiration to anchor the audience in "a place they know". The episode was filmed in 15 days across a three-week period, with shooting split equally between London for most of the interior shots, and Cape Town, South Africa for most external scenes. They did not film in the United States as a cost-cutting measure. Mbatha-Raw said there was little time to rehearse, and she had little opportunity to meet Davis before shooting. Kelly's outfit was inspired by celebrities of the 1980s such as Janet Jackson and Whitney Houston, while Yorkie's outfit "looks like her mum laid it out on her bed", according to Davis. Her clothing is constant throughout the episode to subvert a "transforming geek" trope in fiction, also allowing her change to be internal rather than external.


title: San Junipero

text: The first day of filming was in London for the Quagmire nightclub, shot on location in the Electrowerkz nightclub venue in Islington. For the club Tucker's, a 3D model was made, which Brooker and Harris viewed with a virtual reality headset. Mbatha-Raw and Davis worked with a dance choreographer and danced to Janet Jackson's "What Have You Done for Me Lately", though Alexander O'Neal's "Fake" was used in the final edit. The alleyway scene features rain, which Harris insisted on including despite Brooker's protestations that the simulated world would not have rain. Harris said that Cape Town "has these really rich, beautiful settings" that allowed him to craft a "slightly heightened" version of California. He noted that whilst shooting Kelly and Yorkie's argument on the beach, an "incredible mist rolled in from the ocean", which caused difficulties but led to "some really lovely texture". Mbatha-Raw said that almost every scene was shot at night or dusk, particularly the exterior scenes.


title: San Junipero

text: The episode contains hints leading up to the reveal of the twist. For example, the choice of the song "Girlfriend in a Coma", and the use of the arcade games "Time Crisis" and "The House of the Dead" allude to the true reality of the episode. More overtly, Yorkie reacts viscerally to seeing a car accident in an arcade game, an element that Brooker was surprised was not picked up by viewers earlier. A factor considered during the editing process was how overt the hints should be. Annabel Jones said that "there may be visual signifiers that you think were going to work and then didn't, so you need more exposition in the edit". Adjustments were also made using sound design techniques such as sound effects.


title: San Junipero

text: The titles of the six episodes that make up series 3 were announced in July 2016, along with the release date. A trailer for series three, featuring an amalgamation of clips and sound bites from the six episodes, was released by Netflix on 7 October 2016. A short clip "Orange Is the New Black Mirror", released by Netflix in 2017, is a crossover between this episode and "Orange is the New Black", featuring characters Poussey and Taystee from the latter reunited in San Junipero.


title: San Junipero

text: Reviewers have described "San Junipero" as a highly optimistic, emotionally rooted love story and a work of science fiction. It features the first same-sex couple in "Black Mirror". Rebecca Nicholson of "The Guardian" wrote that it "leaves you believing in the power of love to fight pain and loneliness". Some reviewers noted that the love story "transcends consciousness". The episode also has unhappy elements and has been called "bittersweet". It evokes nostalgia for the 1980s with its soundtrack and its style, and can be considered a period piece. It also raises questions about death and the afterlife. "Esquire" reviewer Emma Dibdin called it a "modern fairy tale".


title: San Junipero

text: At the time of its release, "San Junipero" was said to be the most different from other "Black Mirror" episodes due to its more hopeful tone. Mat Elfring of "GameSpot" described it as the only episode with "warmth to it", and "Digital Spy" reviewer Morgan Jeffery called it the "most upbeat and positive". Zack Handlen of "The A.V. Club" believed that the previous episodes' sad tone heightens the effectiveness of "San Junipero", and Jacob Stolworthy of "The Independent" thought that it was consequently the show's most ambitious episode. "Variety" critic Sonia Saraiya pointed out that technology is portrayed as good in "San Junipero", a rarity in the show. "The Atlantic" reviewer David Sims noted that the episode follows the season's darkest episode, "Shut Up and Dance".


title: San Junipero

text: The episode subverts a common trope in television of killing off lesbian characters: though Kelly and Yorkie die, they have a happy ending. Its Emmy Award wins were considered by some to mark a cultural shift in relation to portrayal of lesbianism, or as proof of concept that works dealing with LGBT characters do not have to be tragic. "San Junipero" has also been cited as an example of bisexual lighting, in which neon pink and deep blue – the colours on the bisexual pride flag – represent bisexual characters. Amelia Perrin of "Cosmopolitan" criticised that this and the episode's nightclub setting reinforce a stereotype of bisexuality as "a 'phase' or something experimental".


title: San Junipero

text: The episode's plot raises many philosophical questions, including the nature of consciousness and experience and the consequences of digitally simulated existence, though these issues are not the focus of the episode. Reviewers have questioned what San Junipero would mean to believers in an afterlife, and what would happen to its inhabitants in case of technical malfunctions.


title: San Junipero

text: At the time of its release, "San Junipero" was "Black Mirror"s most popular episode among fans, which has been attributed to its emotive presentation of a love story with a happy ending. It has been favourably received by critics, garnering an approval from 92% of 25 critics on Rotten Tomatoes, and an average rating of 8/10. Critics' consensus on the website reads, ""Black Mirror" delivers an uncharacteristically uplifting and enjoyable ending in "San Junipero", an especially bright and sweetly surprising episode that benefits greatly from its vibrant lead performances." The episode was rated five stars out of five in the "Irish Independent" and an A in "The A.V. Club". Along with "Nosedive", Benjamin Lee of "The Guardian" gave the episode four stars, while "The Telegraph" gave "San Junipero" three stars. It has been described by critics as one of the "best hours" and one of the "most beautiful, cinematic episodes" of television in 2016.


title: San Junipero

text: Mbatha-Raw's and Davis's performances were universally praised. Sims lauded the couple's chemistry and said the pair concisely communicate "a whole lifetime of angst and desires". Mullane commented that the strong acting keeps the audience interested prior to the plot twist. Caitlin Welsh of "Junkee" complimented the "understated, pitch-perfect" performances for making the characters' relationship feel genuine. Mbatha-Raw and Davis were praised for their emotional range, for giving "fierce and vulnerable performances", and for anchoring the episode.


title: San Junipero

text: Mbatha-Raw and Davis also received praise in negative reviews. Robbie Collin of "The Daily Telegraph" criticised the characters' dialogue but praised that the ending is emotional due to Mbatha-Raw's "vivacity and conviction". Aubrey Page of "Collider" reviewed that the episode is unoriginal, but this is compensated by the perfect casting and emotion of the acting. However, Andrew Wallenstein of "Variety" criticised Mbatha-Raw and Davis for an inability to "pack the emotional punch" needed for the episode to stand out.


title: San Junipero

text: The episode's plot twist, revealing that San Junipero is a simulated reality, was commended by critics. Pat Stacey of "Irish Independent" called the twist "ingenious" while Louisa Mellor of "Den of Geek" described it as "captivating". Adam Chitwood of "Collider" noted that there is more to the episode than its twist and praised Harris for how the story unfolds. Similarly, Alex Mullane of "Digital Spy" said the developments in the story are "refreshing" as they are not presented as twists. Handlen liked how the episode finds a balance between revealing information and making the audience care about the characters.


title: San Junipero

text: The episode's visual style and music, which evoke the 1980s, were well-received. IndieWire praised both the production design and soundtrack. Mullane called Mansell's score "wonderfully tender". "The Wrap" reviewers said that the episode was "visually stunning" and its nostalgia for the 80s was "joyous".


title: San Junipero

text: Many critics admired the emotion the episode evokes, and how it ventured into a new genre for the show. Corey Atad of "Esquire" and Tim Goodman of "The Hollywood Reporter" both opined that the story would leave viewers in tears, and Adam David of CNN Philippines cried whilst watching it. Stacey found the episode "extremely moving". Scott Meslow of "GQ" called it "breathtakingly and tear-jerkingly human". Lee was surprised by the episode's poignancy, while Mellor wrote that it is "genuinely moving". Mullane said the episode demonstrated that the show can tell stories without a dark tone, and Jacob Hall of "/Film" concurred. Wallenstein called the episode "satisfyingly daring", although he ranked it poorly in comparison to other episodes.


title: San Junipero

text: The episode has also received negative criticism from a minority of critics. Collin noted that the episode's central conceit has been widely used within the science fiction genre. Stolworthy criticised the third act as "overloaded" and commented that "San Junipero", rather than "Hated in the Nation", should have been 90 minutes long.


title: San Junipero

text: "San Junipero" appeared on many critics' rankings of the 23 instalments in the "Black Mirror" series, from best to worst.


title: San Junipero

text: Following the fifth series, Brian Tallerico of "Vulture" rated Mbatha-Raw's performance the fourth best of "Black Mirror". Additionally, Proma Khosla of "Mashable" ranked the 22 "Black Mirror" instalments excluding "" by tone, concluding that "San Junipero" is the second-least pessimistic episode of the show after "Hang the DJ".


title: San Junipero

text: "San Junipero" has been widely described as the best episode of series three of "Black Mirror". It has also appeared at various ranks on critics' lists of series three episodes by quality.


title: San Junipero

text: Other critics listed their favourite episodes of television in 2016, without giving an order. "San Junipero" appears on these lists:


title: San Junipero

text: In 2017, "San Junipero" won two Primetime Emmy Awards, as well as two BAFTA Television Craft Awards. It has also won or been nominated for several other accolades:


title: San Junipero

text: In August 2017, Brooker said there were no plans for a sequel episode to "San Junipero". He told the "Los Angeles Times" that "we want to keep [Kelly and Yorkie] happy there". In an interview with "NME", Brooker mentioned that some ideas for the episode were later removed, such as a scene with a kindergarten in San Junipero that "felt like a whole world in and of itself". He raised the idea of doing a sequel in "a completely different form", such as a graphic novel or "an experience". "San Junipero" has been alluded to through Easter eggs in subsequent episodes: for example, "Black Museum" shows Kelly's and Yorkie's dresses on display in a museum, and features a hospital named Saint Juniper's.


title: Humanities

text: Humanities are academic disciplines that study aspects of human society and culture. In the Renaissance, the term contrasted with divinity and referred to what is now called classics, the main area of secular study in universities at the time. Today, the humanities are more frequently defined as any fields of study outside of professional training, mathematics, and the natural and social sciences. They use methods that are primarily critical, or speculative, and have a significant historical element—as distinguished from the mainly empirical approaches of the natural sciences; yet, unlike the sciences, the humanities have no general history.


title: Humanities

text: The humanities include the studies of foreign languages, history, philosophy, language arts (literature, writing, oratory, rhetoric, poetry, etc.), performing arts (theater, music, dance, etc.), and visual arts (painting, sculpture, photography, filmmaking, etc.); culinary art or cookery is interdisciplinary and may be considered both a humanity and a science. Some definitions of the humanities include law and religion, but these are not universally accepted. Although anthropology, archaeology, geography, linguistics, logic, and sociology share some similarities with the humanities, these are widely considered sciences; similarly economics, finance, and political science are not typically considered humanities.