December 2014 Teacher's Guide for So Tired in the Morning: The Science of Sleep Table of Contents
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Background Information(teacher information) On average, humans spend about one third of their lives sleeping. From early times, scientists have asked:
More on scientific theories on the need for sleep The first reported evidence of brain activity during sleep was based on animal observations and studies. With current technology, neural scientists are able to use human brain scans to accurately determine the areas of the brain where activity occurs. Further, these studies identify the periods during human sleep when brain wave activity is the most robust (see later sections on REM and NREM sleep). Several theories have been proposed to explain our need for so much sleep. Harvard Medical School groups them as:
http://www.quantamagazine.org/20141022-mental-leaps-cued-by-memorys-ripples/. (from http://healthysleep.med.harvard.edu/healthy/matters/benefits-of-sleep/why-do-we-sleep) More on teen sleep research Research done by the University of California, Los Angeles (UCLA) Sleep Disorders Center (http://sleepcenter.ucla.edu/body.cfm?id=63) shows that “Most teenagers do not get the sleep that they need on a daily basis.” When lifestyles, early class start times, and obligations conflict with their ability to obtain the recommended nine hours of sleep, teens show signs of sleep deprivation. It is often difficult for them to learn to manage their out-of-class time. There may be excessive homework, exhausting and time-consuming sports and other activity obligations coupled with social demands from friends and families. In addition, some teens have to cope with work schedules and caring for younger siblings after school. Daily schedules need to be finely tuned to accommodate all these demands and leave at least nine hours for sleep. To alleviate some of the student stress, school districts and teachers are discussing limits on homework and, as demonstrated in this article, later times for the beginning of classes. More on sleep requirements for adolescents The National Sleep Association 2014 “Sleep in American Poll” shows that only 42% of 12–14 year olds and even less—35%—of teens 15–17 years old, are sleeping for nine hours or more according to their parents. Their research states that this is the amount of sleep that teens require to remain “healthy, focused and productive”. 
(http://sleepfoundation.org/sites/default/files/2014-NSF-Sleep-in-America-poll-summary-of-findings---FINAL-Updated-3-26-14-.pdf) More on the 2014 “Sleep in America Poll” The full 2014 “Sleep in America Poll” results contain information in the following sections:
(http://sleepfoundation.org/sites/default/files/2014-NSF-Sleep-in-America-poll-summary-of-findings---FINAL-Updated-3-26-14-.pdf) More on consequences of teen sleep deprivation—behavior problems Teens who are not receiving sufficient sleep each night will begin to show signs of sleep deprivation. In the classroom, they fall asleep, become irritable by afternoon, and their grades may drop due to lack of ability to concentrate on lessons. Lack of sleep may also impair teen athletic ability and cause drowsiness when driving. At home, teens who need more sleep may find it difficult to wake up in the morning and sleep for long periods on the weekend. The UCLA Sleep Center has found that signs of lack of sleep in teens may be confused with those of ADHD (attention-deficit/hyperactivity disorder). ADHD may be characterized by trouble concentrating, mood swings, hyperactivity, nervousness, and aggressive behavior. To promote good sleep habits, UCLA stresses the importance of a regular, relaxing routine that includes exercise and a healthy diet. An atmosphere conducive to a good night’s sleep for teens should be quiet. Caffeine and video games before bedtime should be avoided. Their studies also suggest that short naps (less than one hour) are beneficial, longer ones simply leave the teen groggy and may make it harder to fall asleep at night. (http://sleepcenter.ucla.edu/body.cfm?id=63) More on the politics of later start times for schools On August 25, 2014, the American Academy of Pediatrics issued a new policy statement, “School Start Times for Adolescents”, that “urges high schools and middle schools to aim for start times that allow students the opportunity to achieve optimal levels of sleep (8.5–9.5 hours).” See the full policy statement at: (http://pediatrics.aappublications.org/content/early/2014/08/19/peds.2014-1697) Political advocacy for delaying the time of the first period bell was spear-headed by New Jersey State Senator Richard Codey. He supports the recommendation of the American Academy of Pediatrics that school start times be delayed. Codey introduced a bill asking the state Department of Education to study how following this recommendation will benefit students. Codey said, “This is more than a matter of teenagers dozing at their desks. This is about their health and ability to learn, retain information and succeed.” (http://www.app.com/story/news/education/education-trends/2014/10/15/state-senator-richard-codey-calls-later-school-start-times/17337981/) To date, only seventy school districts throughout the United States have developed plans to delay the beginning of high schools until 8:30 a.m. or later. Both the logistics and politics of this type of change prove to be severe stumbling blocks. There are school budgets, bus schedules, and athletic programs. In addition, the needs of parents on fixed work schedules to transport children to classes each morning must be considered. Successful school start delays have usually occurred within small districts where task forces composed of the various stakeholders discuss both the data supporting the need for additional/later sleep for teens and the logistics of accomplishing this change. There are two large districts, Seattle and Fairfax County (Virginia), in the planning stages. (http://blogs.seattletimes.com/educationlab/2014/09/30/be-heard-on-school-start-times-for-teens-seattle-forms-task-force/) More on the biochemistry of sleep Sleeping is an active, endothermic process. While sleeping, the body uses energy to maintain metabolic processes such as breathing, digestion, and pumping blood. In addition, energy is being used to keep the brain active. Scientists use electroencephalograms (EEGs) to measure electrical changes in the brain; electrooculograms (EOG) to measure eye movements; and electromyograms (EMG) to measure muscle tension. These activities during sleep lead to the identification of two basic patterns of brain waves, characterized by different sleep patterns:
Figure 2. Placement of electrodes to determine EEG, EOG, and EMG. (https://science.education.nih.gov/supplements/nih3/sleep/guide/info-sleep.htm) During sleep, the body cycles between NREM (non-rapid eye movement) and REM (rapid eye movement) sleep. As you fall asleep, NREM begins the cycle. For approximately 75% of the night the body is in the NREM mode. The body switches into the REM portion of the cycle about 90 minutes after you fall asleep. The table below summarizes the difference in the processes that occur during the sleep cycle.
(https://science.education.nih.gov/supplements/nih3/sleep/guide/info-sleep.htm) Additional information on details of the function of the endocrine and renal systems and alimentary activity can be found at the National Institutes of Health Teacher’s Guide (see the URL above). Studies on rats show that their normal life spans of two to three years have been shortened to five months when they are deprived of REM (see section below on sleep). When deprived of all sleep, they may die in as little as three weeks. Some scientists consider lack of sleep as injurious to health as lack of food. (https://science.education.nih.gov/supplements/nih3/sleep/guide/info-sleep.htm) More on the quality of sleep and the NREM/REM cycles It is not only the nine hours of sleep before the alarm that are important for teens, but it is also the adequate quality of this sleep time that is required to produce a refreshed and alert morning wake up. There are four main stages of sleep: The Stages of Sleep
(http://www.helpguide.org/articles/sleep/how-much-sleep-do-you-need.htm) During deep sleep (NREM), the body restores the physical energy burned during the day, repairs muscles and tissues, and strengthens the immune system. A disruption during this time can be very damaging. The REM period is the time when the brain’s neural connections are renewed. In quality sleep, the NREM/REM sleep patterns cycle throughout the night. A quiet, stress free environment is necessary to maintain this pattern. Sleep disorders may occur when sleep is repeatedly interrupted. For example, when noise inside or outside the home, lights turned on and off, or other disturbances, repeatedly wake a person, the body cannot cycle normally through the NREM and REM patterns seen in the graph below: 
When you chart the sleep stages over the course of the night, the result looks like a city skyline— which is why it is called "sleep architecture". (http://www.helpguide.org/articles/sleep/how-much-sleep-do-you-need.htm) Both disruption in the sleep cycles shown above and/or the lack of sufficient hours of sleep may lead to problems related to sleep deprivation. The National Sleep Foundation published an article written directly for teenagers. Sleep is described as “food for the brain”. Below are lists of the “Facts” about sleep and the “Consequences” of inadequate sleep: FACTS:
CONSEQUENCES: Not getting enough sleep or having sleep difficulties can:
(http://sleepfoundation.org/sleep-topics/teens-and-sleep) More on the biological clock of teens During adolescence, the circadian rhythm of the body changes. A teen’s clock signals a later time for sleep. Actually this is only about one hour later but, in addition, many teens postpone bedtime for an additional two hours to keep up with the demands of academics, extracurricular activities, work schedules, social pressures and the tempting technology of video games and social media. Teens find it difficult to balance the needs of their bodies for sleep with outside time commitments. Life styles and biology combine to create a three hour sleep deficit for many teens, leaving them feeling groggy and tired when the morning alarm sounds. (http://sleepcenter.ucla.edu/body.cfm?id=63) The National Sleep Foundation refers to the changes in the circadian rhythms that occur during adolescence as “sleep phase delay”. The Cleveland Clinic defines “sleep phase delay” as a condition where a person’s sleep is delayed two or more hours beyond their usual bedtime. (http://my.clevelandclinic.org/services/neurological_institute/sleep-disorders-center/disorders-conditions/hic-delayed-sleep-phase-syndrome) Research done at the National Sleep Foundation shows: This shift (sleep phase delay) in teens' circadian rhythm causes them to naturally feel alert later at night, making it difficult for them to fall asleep before 11:00 pm. Since most teens have early school start times along with other commitments, this sleep phase delay can make it difficult to get the sleep teens need—an average of 9-1/4 hours, but at least 8-1/2 hours. This sleep deprivation can influence the circadian rhythm; for teens the strongest circadian “dips” tend to occur between 3:00–7:00 am and 2:00–5:00 pm, but the morning dip (3:00–7:00 am) can be even longer if teens haven’t had enough sleep, and can even last until 9:00 or 10:00 am. (http://sleepfoundation.org/sleep-topics/sleep-drive-and-your-body-clock) More on the enzymatic production of melatonin from serotonin and the use of melatonin supplements The production of melatonin is catalyzed by the hormone, serotonin N-acetyltransferase. 
Crystallographic structure of serotonin N-acetyltransferase (http://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/SNAT_PDB-code_1KUX.png/220px-SNAT_PDB-code_1KUX.png As described in the Harper sleep article, light detection by the eye’s retina signals the pineal gland in the brain to produce melatonin. According to the abstract for “Melatonin Biosynthesis” published in the journal Molecular Cell the structure of serotonin-N-acetyltransferase (SNAT) shown above and in the third structure of Figure 3 of the Harper sleep article suggests a catalytic mechanism for this biosynthesis as follows: Conversion of serotonin to N-acetylserotonin, the precursor of the circadian neurohormone melatonin, is catalyzed by serotonin N-acetyltransferase (AANAT) in a reaction requiring acetyl coenzyme A (AcCoA). AANAT is a globular protein consisting of an eight-stranded beta sheet flanked by five alpha helices; a conserved motif in the center of the beta sheet forms the cofactor binding site. Three polypeptide loops converge above the AcCoA binding site, creating a hydrophobic funnel leading toward the cofactor and serotonin binding sites in the protein interior. Two conserved histidines not found in other NATs are located at the bottom of the funnel in the active site, suggesting a catalytic mechanism for acetylation involving imidazole groups acting as general acid/base catalysts. (http://www.ncbi.nlm.nih.gov/pubmed/10024876) Scientific research shows that melatonin is the hormone that helps control our sleep-wake cycle. Some studies suggest that melatonin supplements may be useful in treating severe sleep disorders and jet lag by helping people fall asleep. Common side effects associated with the use of melatonin supplements include dizziness, headaches, and sleepiness in the daytime; and, less commonly, short-term feelings of depression, stomach cramps, and irritability. Additional information about the use and warnings associated with the use of melatonin supplements can be found on the Mayo Clinic website below. (http://www.mayoclinic.org/healthy-living/adult-health/expert-answers/melatonin-side-effects/faq-20057874) The circadian rhythm of people who are totally blind is permanently disrupted because the retina cannot detect light. Melatonin supplements may help regulate the biological clocks of the blind, thus improving their ability to follow normal sleep patterns. The National Institutes of Health warns: “Since the high doses of melatonin found in most supplements can build up in the body, long-term use of this substance may create new problems. Because the potential side effects of melatonin supplements are still largely unknown, most experts discourage melatonin use by the general public.” (http://www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm) Melatonin is sold as an over-the-counter supplement and considered safe for most adults when taken by mouth for a short period of time. Labels warn about the use for children. Due to its effects on other hormones, melatonin supplements may interfere with development during adolescence. (http://www.rxlist.com/melatonin/supplements.htm) More on jet lag, body clocks, and coping with jet lag Sports competitions, visits to grandparents, vacations, and school field trips that cross time zones often deliver tired and fatigued teens to their final destinations. In addition to the expected changes in eating habits and the effect of being squashed into small, dry airplane spaces, circadian rhythms are disrupted. Traveling from west to east creates more sleep problems because the body clock has to advance rather than delay the time to sleep. The medical journal The Lancet published a list comparing normal travel fatigue and jet lag: Differences between travel fatigue and jet lag
To reduce the effects of jet lag it is recommended that you:
(The Lancet. 369 (9567), pp 1117–1129, 31 March 2007 doi: 10.1016/S0140-6736(07)60529-7. Available online at: http://www.v2020la.org/pub/PUBLICATIONS_BY_TOPICS/VARIOUS/Jet%20lag.....pdf) More on the effects of daylight saving time on the circadian rhythm It has been shown that sleep deprivation and the change of circadian rhythm can trigger mental illness and cause higher accident rates. While daylight saving time affects millions of people annually, the impacts of dealing with only a one hour change are still widely unknown. While the transitions into and out of daylight saving time change the circadian rhythm, daylight saving time results in a very small loss of sleep. The major study on the effects of the one hour transitions for daylight saving time was based on data from the Finish Hospital Discharge Register. Nationwide, during a time period including two weeks after and two weeks before daylight saving time for the years 1987-2003, there was no significant increase in hospital cases involving accidents, manic episodes, or signs of major sleep deprivation. The following website contains the abstract and free access to the full report: (http://www.ncbi.nlm.nih.gov/pubmed/18302734). In 2007, Till Roenneberg published the results of a study of 55,000 people in central Europe in the journal, Cell Biology. Roenneberg’s data came from surveys completed by the subjects in his study. His group concluded: “For both morning larks and night owls, their timing for sleep and peak activity easily adjusted when daylight saving time ended in the fall. However, it never adjusted to the return to daylight saving time in spring. This was especially true for night owls -- those who stay up late and sleep late.” (http://consumer.healthday.com/mental-health-information-25/behavior-health-news-56/body-s-clock-never-adjusts-to-daylight-saving-time-609394.html) More on teen sleep deprivation behaviors Sleep disorders may occur when there is insufficient time for sleep and/or when sleep is repeatedly interrupted and the body cannot cycle normally through the NREM and REM patterns. The Cleveland Clinic lists the following three signs that may indicate teen sleep deprivation:
(https://my.clevelandclinic.org/ccf/media/files/Sleep_Disorders_Center/09_Adolescent_factsheet.pdf) The behaviors above are similar to those found in students diagnosed with ADHD. According to Dr. Thakkar, professor of psychiatry at the New York University Langone Medical Center, many of the symptoms of ADHD are indistinguishable from those seen in sleep deprivation. Unfortunately, this frequently leads to a misdiagnosis of ADHD. In the article “ADHD or Sleep Disorder: Are We Getting it Wrong?” (Psychology Today, May 1, 2013) the author cites “lack of focus, agitated, excitable, impulsive” as behaviors common to both sleep disorders and ADHS. This article continues to state: “These behaviors associated with A.D.H.D. interfere with a child’s social and intellectual development, causing problems with relationships with peers and adults, at school and at home. But what if A.D.H.D. isn’t always the underlying cause of these symptoms? Signs of poor quality and insufficient sleep in children can look remarkably like symptoms of A.D.H.D., as a number of recent studies show.” (http://www.psychologytoday.com/blog/sleep-newzzz/201305/adhd-or-sleep-disorder-are-we-getting-it-wrong) More on some severe sleep disorders and medical diagnosis The American Association of Pediatrics (AAP) has expressed concern regarding the lack of screening children for sleep problems by pediatricians. This is necessary to reduce the incidence of misdiagnosis of behaviors and subsequent unnecessary treatment for ADHD. A 2012 study of sleep screening practices, Screening for Sleep Disorders in Pediatric Primary Care Are We There Yet?, published in CLIN PEDIATR (December 2012 vol. 51 no. 12 1125-1129) showed inadequate patient screening for sleep problems that might account for behaviors similar to sleep deprivation. It was found that less than 20% of the pediatricians surveyed had received training in the diagnosis of sleep-disorders. The study demonstrates the need for better training for physicians and more effective screening for sleep disorders to be certain that a medical diagnosis is accurate. Results and conclusions of the study show: Although guidelines were published by the American Academy of Pediatrics (AAP) a decade ago recommending routine screening of sleep-disordered breathing (SDB) in primary care settings, it remains unclear to what extent such guidelines have been implemented and resulted in effective SDB screening. The aim of this study was to determine if AAP guidelines are adhered to in pediatric primary care. Of the children screened for sleep-related issues, 34.1% (n = 86) snored, but the majority of them (61.6%, n = 53) received no further evaluation. In the present sample, 0.5% (n = 5) had a diagnosis of OSA. The low prevalence of obsessive sleep apnea (OSA) may be explained by the relatively low frequency of sleep-related problem screening by pediatricians and thus the inordinately low adherence to the AAP guidelines. Modification and transition to electronic medical records as well as expanded efforts to educate health care providers and caregivers may improve detection and timely treatment of children at risk for SDB. (http://cpj.sagepub.com/content/51/12/1125.abstract) The Mayo Clinic, the National Institutes of Health, and the UCLA Sleep Disorders Center provide similar lists of severe health effects attributed to sleep deprivation caused by both the number of sleep time hours (sleep quantity) and the disruptions during sleep (sleep quality). Excessive daytime sleepiness may be a sign of serious medical problems such as:
REM sleep in people with narcolepsy frequently occurs at sleep onset instead of after a period of NREM sleep. Consequently, researchers believe that the symptoms of narcolepsy result from a malfunction in some aspect of REM sleep initiation. Some scientists believe that the immune system causes narcolepsy by attacking the nervous system (that is, an autoimmune response). In this view, exposure to an unknown environmental factor results in an immune response against nerve cells in the brain circuits that control arousal and muscle tone. (https://science.education.nih.gov/supplements/nih3/sleep/guide/info-sleep.htm) More on sleep apnea (OSA) and obesity’s role in OSA The illustration below compares normal breathing with partial obstruction and complete blockage during OSA. 
(http://stanford.edu/~pdjones/sleepapnea/sleep-apnea/causes.html) OSA occurs when the soft tissue in narrow back of the throat collapses and physically blocks the airway preventing the air from reaching the lungs. Excessive body weight may exacerbate this condition due to the additional soft tissue present in the nasal area. These obstructions can occur frequently and may last from 10 to 30 seconds, severely disrupting the sleep cycles and the oxygen levels throughout the night. When breathing resumes, it is often accompanied by gasps or body jerks. These pauses in breathing severely disturb the quality of sleep resulting in fatigue and sleepiness in the morning. The reduction and irregularity of oxygen flow may cause heart arrhythmias. Swollen tonsils or adenoids or enlargement of soft tissue from excessive weight can further obstruct the air pathway. (http://www.aasmnet.org/resources/factsheets/sleepapnea.pdf) The Mayo Clinic produced a short video for YouTube to show the mechanics of OSA. (http://www.mayoclinic.org/diseases-conditions/sleep-apnea/multimedia/obstructive-sleep-apnea/vid-20084717) Various treatment methods include changing sleeping positions and diet; using mechanical devices that force air through the nasal passages and dental appliances designed to lower the jaw and tongue; and undergoing surgery to remove tonsils or to widen the pathway. (http://www.sleepapnea.org/treat/childrens-sleep-apnea.html) Sleep deprivation is often accompanied by weight gain. When sleep deprived, people frequently crave calorie-rich, sugary food to provide a quick boost of energy. In addition, those who stay awake late into the night are more prone to snacking in the long hours following dinner. The helpguide.org discussion, “How sleep deprivation can add to your waistline”, discusses the hormonal regulation of hunger: There are two hormones in your body that regulate normal feelings of hunger and fullness. Ghrelin stimulates appetite, while leptin sends signals to the brain when you are full. However, when don’t get the sleep you need, your ghrelin levels go up, stimulating your appetite so you want more food than normal, and your leptin levels go down, meaning you don’t feel satisfied and want to keep eating. So, the more sleep you lose, the more food your body will crave. (http://www.helpguide.org/articles/sleep/how-much-sleep-do-you-need.htm) More on dreams and nightmares Dreaming usually takes place during REM sleep, but it may also occur during NREM, usually soon after sleep begins. Most people spend about two hours dreaming during the night. Dreams may vary from fairly ordinary experiences to the very bizarre, but they rarely portray realistic experiences. (http://www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm#dreaming)  Scanning studies of the brain show the areas that are active during REM dreaming. The active areas are shown shaded in the image to the right. The areas responsible for higher level thinking skills such as planning, organizing, and problem solving reside in the frontal lobe of the brain (see diagram below). The frontal lobe is not active during dreaming. Many people speculate, but scientists have not determined, the meaning of dreams or the reasons for dreaming.
(https://science.education.nih.gov/supplements/nih3/sleep/guide/info-sleep.htm) 
(http://www.cancerresearchuk.org/prod_consump/groups/cr_common/@cah/@gen/documents/image/cr_116646.jpg) Nightmares are often considered within a collection of sleep disorders designated as parasomnias. This group also includes walking and/or talking during sleep and bed-wetting. Nightmares usually occur during the REM stage, but extreme nightmares may occur during NREM sleep. Nightmares may be vivid and disturbing; often involve an instant wake-up and recall of the content; and result in feelings of stress, anxiety, and fear. Quality sleep is often disrupted during nightmares, thus leading to sleep deprivation. Nightmares usually relate to a traumatic event that involved emotions similar to those experienced at the time of wakeup. More on risky teen behaviors when coping with lack of sleep Teen sleep disorders, both mild and severe, may lead to behavioral problems, poor athletic and academic performance, and emotional problems. The United States Center for Disease Control and Prevention (CDC) study found that the probability of risky behaviors increased, when teens were sleep deprived. These behaviors include substance abuse, lack of physical exercise, excess computer use, consumption of excess caffeine, and suicide attempts. (http://www.cdc.gov/media/releases/2011/a0926_insufficient_sleep.html) In a study published in the American Journal of Health Behavior, the weekday and weekend sleep patterns of 242 teens (average age, 16.4 years) were compared to their risky behaviors. It was found that adequate weekday sleep was directly related to fewer incidents of substance abuse, depression, and school truancy. In contrast, those teens that lacked sufficient quality sleep during the week and/or whose weekly sleep schedule was erratic, displayed a larger percentage of risky behaviors. The study summary, published in the American Journal of Health Behavior, shows: In conclusion, adequate sleep during the school week appears to be associated with lower risk behaviors and lower levels of depression in youth. However, this research suggests that parents need to pay attention not only to sleep patterns and amount of sleep that their teens get during the school week, but they also need to be alert that late bedtimes and rising times on weekends may be signaling risk-taking behaviors. Setting weekend curfews may help reduce a variety of risk behaviors. Given the demands of adolescence and the importance of this developmental period, it is critical that we better understand how lack of sleep, in addition to changing sleep patterns, may influence risk behaviors and the health of adolescents. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086400/) To cope with lack of sleep, teens frequently turn to coffee or other caffeine-laden energy drinks or products. The Mayo Clinic suggests that teens should limit themselves to 100 mg of caffeine per day, which is equivalent to one 5-oz cup of coffee. (http://www.mayoclinic.org/healthy-living/nutrition-and-healthy-eating/in-depth/caffeine/art-20045678) The cover story of the February 4, 2013 issue of Chemical and Engineering News (C&E N) is “Caffeine Jitters”. (http://cen.acs.org/articles/91/i5/Caffeine-Jitters.html) As the title infers, there are serious side effects associated with the consumption of too much caffeine. The symptoms are similar to those produced by amphetamines: nervousness, headache, rapid heartbeat, and possible death. The graph below shows the rapid increase in emergency room (ER) visits associated with the overconsumption of caffeine from foods and energy drinks from the year 2007 to 2011. 
(http://cen.acs.org/articles/91/i5/Caffeine-Jitters.html) The article “Caffeine” in ChemMatters, October 2013 introduces the multitude of caffeine laden products on supermarket shelves; discusses how caffeine is metabolized in the body; and describes the dangers involved in the consumption of excess caffeine. This article is cited in the “References” section of this Teacher’s Guide. | |||||||||||||||||||||||||||||||||||||