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Overview: What every practitioner needs to know
Are you sure your patient has opioid withdrawal? What are the typical findings for this disease?
Opiate withdrawal may appear in the child of a mother dependent on heroin, opioid-based prescription medications, methadone, or buprenorphine or in an infant treated with opioids for pain in the neonatal period.
Most opioid-exposed neonates exhibit altered neurobehavioral features in the neonatal period; the most recognized condition described is the neonatal abstinence syndrome (NAS), a constellation of dysregulated neurobehaviors displayed after intrauterine opioid exposure ceases at delivery. NAS expression can vary between infants and in the same infant over time. Severity is not clearly related to any known maternal or infant factor but is likely to be a conglomerate of individual biologic vulnerabilities combined with environmental circumstances such as exposure to other substances (e.g., nicotine), the physical environment, and caregiver responses. New research has found that infants with variants in the OPRM1 and COMT genes have shorter lengths of hospital stays and require less medication for NAS, suggesting that genetic and epigenetic factors may play a significant role in NAS expression. Thus, each neonate can have an individual repertoire of dysregulated neurobehaviors that can alter ability to feed, sleep, gain weight, and interact.
Opioid exposure can be comprised of exposure to licit opioids (i.e., methadone or buprenorphine maintenance for a maternal opioid use disorder), misuse of licit opioids (i.e., opioid containing pain relievers) or illicit opioids (i.e., heroin) or any combination thereof. The timing of the onset of NAS signs is likely to vary with the type of opioid exposure. Heroin exposed infants often have an early NAS presentation, with a later presentation more common among methadone or buprenorphine exposed infants.
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Many opioid-exposed infants are exposed to other substances. Substances that can produce an independent "discontinuation" syndrome include alcohol, nicotine, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and benzodiazepines. Other substances, such as cocaine and marijuana, maternal psychiatric conditions, and/or medications during pregnancy can also produce altered neonatal neurobehavior. Any of the above can augment an infant's display of NAS. Features of each can overlap those of opioid abstinence, making a thorough maternal history and assessment important.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Assessment for maternal substance use should occur often in the prenatal period via an interview using a standardized tool such as the 4Ps Plus. Urine toxicology testing for the mother and/or infant at the time of delivery reflects only very recent use of most substances (except for chronic marijuana use and benzodiazepines). Meconium analysis can present difficulties to collection if meconium is lost in utero or its passage is delayed. Further, the utility of assessing maternal drug use in the second and third trimesters of pregnancy may be limited as it neither quantifies use nor reflect periods of drug abstinence closer to delivery. Testing of umbilical cord tissue or blood is easier to collect, but as for meconium, it neither quantifies use nor reflects drug abstinence. The utility of meconium and umbilical cord testing may be reserved for the infant who develops signs of NAS and whose mother denies substance use.
After confirmation of opioid exposure via maternal history, biologic matrices, or both, a thorough understanding of the infant's functioning is necessary for proper management as the need for pharmacotherapy is based on frequent and periodic assessment for the development of NAS. Maternal history should include drug use history and treatment, psychiatric co-morbidities, and licit (including opioid medications, nicotine, and alcohol) and illicit substances taken during pregnancy. The provider must approach the drug-dependent mother in a non-judgmental manner to facilitate communication. Punitive attitudes have no place in care.
Neonatal abstinence syndrome assessment
Best practices for assessment and treatment are currently undefined. The assessment and treatment strategy outlined below represents one method which uses a 19 item, weighted NAS scoring based on the Finnegan Scale and ia a symptom-based approach to treatment. Most practitioners use some variant of the Finnegan scale.
Assessment should begin at birth and continue for the duration of hospitalization, which should be a minimum of 4 days. Almost all opioid exposed infants will display some signs and symptoms of NAS, generally by 48-72 hours after delivery, but perhaps as late as several weeks. The infant should be evaluated every 3-4 hours and given a composite score reflecting behavior since the last assessment.
Signs and (and assigned score based on severity) include: excessive cry (2-3), time spent sleeping after feeding (1-3), hyperactive moro reflex (1-2), tremors: disturbed (1-2) and undisturbed (1-2), hypertonicity (1-2), excoriations (1-2), seizure (8), fever (>37.2; 1), frequent yawning (1), sweating (1), nasal stuffiness (1), sneezing (1), tachypnea (respiratory rate >60/min) (2), poor feeding (2), vomiting (2), loose stools (2), failure to thrive (weight >10% below birth weight) (2), excessive irritability (1-3).
Items are scored individually, but there can be some overlap, i.e., the infant with hypertonicity and tremors frequently presents with excoriations, but these are scored separately. Disturbed and undisturbed tremors are scored separately. Irritability may or may not occur with crying and are scored individually. Items are scored based on their severity.
At the end of every 3-4 hour assessment period, items are added to provide an overall score. If the score is less than a cut-off value, the infant continues to be scored in this fashion, receiving non-pharmacologic care, until discharge. An infant who reaches a cut-off score that defines the need for pharmacotherapeutic intervention is rescored in one hour after nursing care is provided, to ensure that the infant is not reacting to environmental stressors (i.e., being hungry, wet, tired, overstimulated etc.,). If the second score if above that cut-off value, medication therapy is to be instituted. The goal of providing pharmacotherapy is to permit the infant to sleep, feed and interact, not to sedate or "take the edge off." Oversedation may interfere with the infant's growth, development, and interactive capacities, and should be avoided.
Infant states are the stages of wakefulness between sleep and crying: State 1 is deep sleep, State 2 is light sleep, State 3 is drowsy, State 4 is quiet and alert, State 5 is fussy, and State 6 is irritable crying. It is important to consider an infant's state when scoring the infant for NAS. For example, infant tone should not be scored in a state 6 because it is likely to be elevated and not reflecting the true tone of that infant in an appropriate lower state.
It is important to consider an infant's state when scoring the infant for NAS. It is also important to consider both infant gestational and chronologic age in assessing NAS, as preterm infants express NAS differently than term infants, and older infants with NAS can have alterations in its presentation due to normal developmental processes, such as the ability to achieve a longer quiet alert state, sleeping for shorter periods of time, etc.
Infants older than 2 weeks of age may require adjustments to NAS scoring to reflect their developing capacities. An example of this is the omission of the sleeping scores, so that they do not "count against" an infant who is able to achieve and stay in a quiet alert state in between feedings.
The differential diagnosis for tremors or seizures includes metabolic disorders, such as acidosis, hypoglycemia, hyponatremia or hypocalcemia. Other causes for seizures, such as sepsis/meningitis, asphyxia, structural anomalies or intracranial hemorrhage should be considered. Irritability, fever, tachypnea, or color changes can indicate an infant with sepsis or infection. Fluctuations in tone are not uncommon, and infants can have tonal asymmetries as part of NAS that do not, in general, warrant imaging studies.
Myoclonic jerking, or rhythmic movements during sleep, occur not uncommonly in opioid-exposed infants, and should not be confused with seizure activity. Myoclonic jerking is the quick contraction(s) of muscle groups, generally of the extremities, occurring during infant sleep. The movements can be single or multiple, can be present in arms, legs and/or chin, and may be restricted to one side of the body. They do not stop when the extremity is held, and do not occur during awake states. Electroencephalograms in these infants are in general within normal limits and are not warranted.
The differential diagnosis for an infant with NAS should also consider the environment and handling that the infant is receiving. If there are environmental stressors, for example, medical procedures or insensitive handling that lead to the development of signs of NAS or augment an NAS display in any given infant, they should be removed and the infant re-evaluated.
NAS expression is variable, both between infants and in the same infant over time, in presentation, signs present and types of signs present, and in severity. The variability of the syndrome should be considered in any assessment of a substance-exposed infant.
It is important to note that occasionally infants present with a biphasic course of NAS, and require reassessment and infrequently rehospitalization after hospital discharge with or without the need for pharmacotherapy during the early neonatal period. Late onset NAS, or signs of NAS beginning at 2-4 weeks after birth, has been described, and may reflect poly drug exposures (particularly with benzodiazepines) in some infants. Mothers should be informed of this possibility, and infants should not leave the hospital without a pediatric care appointment to occur in the days after discharge. Contact with a knowledgeable primary care physician prior to discharge in case the infant experiences a rebound NAS prior to the institution of outpatient pediatric care is important due to the potentially serious consequences of untreated NAS.
Item definitions and assigned scores are as follows:
Excessive cry: Persistent infant crying is scored 1-3: Score = 1: With consoling (i.e., holding the infant's hands, talking, changing positions, pacifier use) the infant calms in 3-5 minutes; Score = 2: With consoling (holding, rocking, swaddling, pacifier use), the infant calms in 6-15 minutes. Score = 3: Reflects an infant who continues to cry after more than 15 minutes or one in whom no amount of consoling produces calm, (i.e., an inconsolable infant).
Sleeping:If the infant sleeps for 2-3 hours continuously, score 1. If the infant sleeps 1-2 hours continuously, score 2. If the infant sleeps less than 1 hour continuously, score 3. This item needs to be adjusted or omitted when scoring older infants who are able to maintain awake states for longer periods of time than infants in the immediate postnatal period. If the infant is able to maintain a quiet alert state in between feedings without displaying signs of discomfort, these periods should not be counted as lack of sleep. This item may also need to be adjusted for infants who are breastfed and may sleep for shorter periods of time due to decreased intervals between feedings. The individual development of the infant should be considered when making adjustments.
Moro reflex:A Moro reflex that is hyperactive, i.e., the arms stay elevated for 3-4 seconds and there is jitteriness of the hands, is scored 1. A markedly hyperactive Moro reflex, in which the arms stay elevated for more than 4 seconds, is scored 2.
Tremors:Jitteriness or rhythmical quivering occurring around a fixed point (i.e., joint). Myoclonic jerking as described above is not tremors. Mild tremors (lasting less than 3 seconds) are scored 1, while more moderate to severe tremors (lasting 3 or more seconds) are scored a 2. Disturbed tremors occur with stimuli such as movement, touch or sound. Undisturbed tremors occur without an apparent stimulus.
Tone: Infant tone, or muscle resistance to movement, can be assessed via extremity recoil or head lag. The infant scores 1 for some resistance to extension or flexion of extremities, and the extremity returns quickly to its original position; 2 for difficult but possible straightening or bending the arms with head lag on pull to sit; 3 for not possible straightening/bending of arms with no head lag on pull to sit. This item should be scored in states 3, 4, or 5, and not during sleep or irritable crying.
Excoriation: The result of rubbing a skin surface against fabric or diaper due to increased tone, increased rooting or tremors. Excoriations generally occur on extremities at elbows and dorsi of hands, knees, chin or buttocks. Buttock excoriations must be distinguished from diaper dermatitis, particularly in older infants, and are the wearing of the top layer of skin in parallel patches at the point where the buttocks touch the diaper (and not, in general, in the perianal area). Using preventative diaper rash formulations may allay the development of excoriated buttocks in hypertonic or tremulous infants. Paper bibs or napkins used during feeding or cleaning the baby's face may contribute to chin excoriation and should be avoided.
Seizures: Seizures related to opioid withdrawal occur in infants with other significant signs and symptoms of NAS. When they occur they are scored 8 and treated with phenobarbital; though infants with NAS-related seizures do not generally warrant ongoing outpatient phenobarbital therapy. The true incidence, pathophysiology, and significance of NAS-related seizure activity are not known. They may represent a manifestation of poly-drug (likely barbiturate) or alcohol-related drug effects. They must be distinguished from tremors, exaggerated myoclonus, myoclonic jerking, and intracranial pathology. An EEG and brain imaging studies are usually warranted in the event of neonatal seizures.
Mottling: A feature of autonomic dysregulation, skin discoloration with a marbled or lace-like appearance of pink and pale or white areas, typically seen on chest, trunk and extremities. Mottling should not be assessed in a chilled infant. Scored 1.
Fever:A feature of autonomic dysregulation, fever is defined as an infant axillary temp of 37.3 degrees C or more, and scored 1. Infants presenting with fever may present a challenge to the practitioner if they are also hypertonic or have difficulties with arousal and need to be consistently swaddled. Fever must be distinguished from overheating due to excessive blankets or tight swaddling. May require further medical evaluation.
Yawning: If the infant yawns 4 or more times in 3-4 hours in the absence of stimuli, score 1.
Sweating: If the infant's forehead or upper lip is damp score 1. Must not be scored in an overheated or over swaddled infant, who is likely to be sweating on the back of the neck.
Nasal stuffiness: Any persistent nasal noises occurring with respirations, with or without a runny nose, are scored 1. Must be scored in infants whose nares have been cleared of any birth debris. Must not be scored in infants who have been overzealously suctioned at birth resulting in swollen, excoriated, or bloody nasal tissue. The practitioner should first try to clear the nose with saline drops and gentle suction prior to applying a score for this item.
Sneezing: If the infant sneezes 4 or more times in 3-4 hours, score 1. May occur serially or individually.
Tachypnea: If the infant at rest has respirations greater than 60 per minute, score 2. Respirations should be counted for a full minute. The presence of retractions or use of intercostals muscles with breathing, or nasal flaring or grunting should warrant further medical evaluation. This item should be scored in a quiet state (1-4) and not when the infant is fussy or crying (5 ,6).
Poor feeding: May be due to uncoordinated suck/swallow mechanism and frequently occurs in very hypertonic infants. It is recognized by the presence of gulping with frequent pauses for breathing, burping or spitting up, placement of tongue above or to the side of the nipple, inability to form a tight seal around the nipple and/or formula loss at the sides of the mouth. Often infants with poor feeding make clicking noises when sucking. Feeds in these infants often take 20 minutes or more. Poor feeding is scored 2. Every effort should be made to avoid gavage feeding in infants with NAS when possible, as the presence of the NG tube often potentiates other symptoms of NAS. Intervention for feeding problems by occupational therapy or lactation consultation may be necessary.
Vomiting: Defined as the effortless return of gastric contents from the infant's mouth or nose, is scored 2 when the infant frequently vomits the whole feeding or two or more times during a single feeding not associated with burping, or regurgitates large amounts with burping. Do not score occasional small regurgitations with burping. Gentle handling with feeding/burping should be provided particularly to sensitive infants who gag easily, as insensitive handling may contribute to vomiting which can then be scored unnecessarily. This item should be distinguished from the infant with retained secretions after birth.
Loose stools: Are scored 2 if the infant has a stool that is half liquid and half solid, or a liquid stool. Using preventative diaper rash formulations may allay the development of excoriated buttocks.
Failure to Thrive: Defined as the infant weight on any given day that is greater than or equal to 10% below birth weight, this item is scored 2 for as many days as this definition holds true. Infants who fail to thrive often have associated feeding and/or tonal symptoms of NAS in conjunction. If a feeding problem exists, appropriate interventions (i.e., consultation with occupational therapy, lactation consultant) should be instituted.
Excessive irritability: This item is distinct from, but may occur in tandem with crying, and is defined as fussy or irritable posturing or grimacing with any stimuli. These infants are often very sensitive to sound and light and become fussy with light touch or handling despite attempts to console them. This item may represent the infant's difficulty with modulation of arousal or tendency to easy overstimulation.
These infants generally require much observation to determine the source of the noxious stimuli, which may not be readily apparent (i.e., arm or leg bands, textures of blankets or clothing, pulse oximeter wires or noises, and/or other stimuli that do not affect other infants with or without significant NAS) and time spent in modifying their environments to assist them with regulation. This item is scored 1 to 3 depending on degree of irritable or hyper-aroused behavior(s) evident (3 generally representing infants who are not consolable with maximal intervention).
Beginning at hour three, each of the above items are scored and totalled. If the score is >8, the infant has nursing cares (feeding, diaper changing, soothing, modification of environment, and/or interactive patterns) and is rescored again in one hour. If the second score is >8, the infant requires pharmacotherapy which is instituted based on the higher of the two scores.
If you are able to confirm that the patient has neonatal opioid withdrawal, what treatment should be initiated?
Non-pharmacologic interventions
All opioid-exposed infants should receive non-pharmacologic interventions beginning at birth for as long as needed, regardless of the need for medication and/or prolonged hospitalization. Although not a substitute for pharmacotherapy, properly applied non-pharmacologic care can reduce or mitigate the need for medication. These interventions should be performed together with the mother or other caregivers to allow for appreciation of the infant's strengths, weaknesses, capabilities, and cueing abilities.
The mother may have feelings of guilt and anxiety or a co-morbid psychiatric problem that can impair her ability to interact with or understand her infant. This may produce unrealistic or distorted perceptions of the infant's behaviors and create maladaptive developmental trajectories in the infant. Awareness of her feelings and ability to deal with them in a positive way should be explored with the mother. This supportive care should continue in outpatient settings, such as the pediatric clinic, at every opportunity that the dyad presents for care, and the mother should be encouraged to perform the techniques that address her infant's specific needs at home.
Principles of non-pharmacologic interventions
Non-pharmacologic interventions should incorporate the following principles:
1. Individualized therapy and care for the infant, based on behavioral observations, with the goal of promoting organization, physiologic stability and competence in the infant's self-calming and interactive capabilities. Each infant should be observed carefully and over time to recognize:
a) the infant-specific signs of physiologic and behavioral regulation and dysregulation,
b) the particular sensory input that provides the source of morbidity for the infant (visual, auditory, tactile, or movement) and interventions that alleviate the discomfort,
c) support for the infant's efforts to become stable and organized.
2. Modification of the environment to support state control, autonomic, sensory, motor and interactive development.
3. Encourage parental involvement, working to develop an ongoing individualized care plan to support the infant's specific patterns of neurobehavior and simultaneously addressing parental perceptions of the infant and his/her development.
Pharmacologic interventions
Early identification and treatment of NAS will decrease infant morbidity; it is never acceptable to delay therapy for NAS to further observe the infant, nor is it acceptable to treat an infant with medication to prevent his display of NAS, as only a subset of opioid-exposed infants requires pharmacotherapy.
Infants receiving medication should be monitored and frequently evaluated for alterations in therapy and to avoid oversedation. Many medications have been used for first and second line NAS treatment. No best medication has been identified; however, many feel that opioid preparations such as morphine should be used as treatment for opioid withdrawal. Methadone is also employed. Phenobarbital is generally not used as a primary medication for opioid withdrawal, but it may play a role in the treatment of polydrug exposure. Buprenorphine and clonidine are experimental agents for first line NAS pharmacotherapy. When the infant's NAS display is uncontrolled on maximal doses of first line medication, a second drug is added. Second line medications include clonidine or phenobarbital.
Some medication protocols call for a mg/kg dose of medication (weight-based protocols), others for a dose based on the severity of the infant's NAS display (symptom-based protocols). In either event, medication should be delivered to the infant at intervals no longer than every 4 hours (if a short-acting medication, i.e., morphine, is used) to avoid a rebound withdrawal and increase in NAS scores even if it means waking the infant to administer medication.
Medication is given to the infant until the infant achieves a plateau of NAS scores below the defined cut-off value. The infant is kept at this dose for 48 hours, and then the medication is gradually withdrawn. It is important to note that some infants can have a biphasic NAS course or require increases in medication dose once weaning has begun. Infants are weaned until the medication is withdrawn and then observed for 24 hours prior to hospital discharge.
Pediatric follow-up should occur in the days after discharge and frequently thereafter to assess maternal competence and comfort in her ability to care for the infant and to establish and maintain contact with an outpatient provider in the event of rebound NAS symptoms after discharge and to assist with the presence of residual dysregulated behaviors that are often present after hospital discharge. It is important to note that subacute NAS symptoms, such as tonal alterations, may persist for weeks or months after hospital discharge.
Inpatient treatment for NAS is generally advised, though many centers do wean medication on an outpatient basis. This calls for caregiver interpretation of infant signs and symptoms which may be altered by other agendas or inaccurate parental perceptions. Additionally, the presence of even small amounts of opioids in the home may place the caregiver at risk for relapse or harm by others.
It is important to mention that care of the mother should occur in tandem with care of the infant with NAS, and pediatric care staff may be most poised to observe and assist the mother, particularly for infants that require prolonged hospitalization. Maternal care may include referral to drug treatment that optimally is gender-specific and accepts the infant; referrals for psychiatric care when warranted; and parenting assistance and assurance of confidential and non-judgemental care. Avoidance of the use of terms such as "addicted newborn", "methadone baby", or "NAS baby", which are pejorative terms, should occur at all times. Rooming in care and inclusion of the mother in NAS scoring are optimal, but may not apply to all mothers.
It is important to note that optimal practice for this group has not been defined due to the lack of definitive research.
In summary, the opioid exposed infant more often than not presents a major challenge for the provider. A thorough understanding of the parent and the infant combined with early assessment and treatment as well as the assurance of ongoing care of the dyad is critical to avoid or allay possible maladaptive developmental trajectories.
Pharmacotherapy for neonatal abstinence syndrome
This algorithm uses oral morphine solution as a first line and clonidine as a second line medication, and is a symptom-based (doses of medication delivered based on the severity of the infant's NAS display as defined by NAS score) as opposed to weight-based (medication delivered on a mg/kg basis without regard for NAS scores) strategy. Oral morphine solution is administered at a maximum of every 4 hours to avoid rebound increases of NAS scores. It is important to note that optimal medication strategies for infants affected by NAS have not been determined. Medication administration for the pharmacological treatment of NAS may need to be individualized. For example, some infants require medication for NAS to be able to achieve a quiet state to feed, while others may become drowsy and unable to feed. Infants who achieve high states of arousal may require medication prior to interactions with caregivers.
Oral morphine solution (OMS; 0.04 mg/0.1 ml) is initially dosed as follows:
Infant NAS Score Dose OMS (0.04 mg/0.1 ml) every 3-4 hours with feeds
0-8 0 mg
9-12 0.04 mg
13-16 0.08 mg
17-20 0.12 mg
21-24 0.16 mg
> 25 0.20 mg
The infant is reassessed every 3-4 hours and the morphine dose increased as necessary based on the infant's NAS scores if they are >8. If the infant scores 0-8 after medication is initiated, maintain the current dose. If the infant's NAS score is:
9-12 then Increase dose by 0.02 mg q 3-4 hours
13-16 Increase dose by 0.04 mg
17-20 Increase dose by 0.06 mg
21-24 Increase dose by 0.08 mg
Once the initial objective of a plateau of NAS scores <9 has been achieved, the infant is maintained on the same dose of OMS for 48 hours prior to beginning the weaning process.
Weaning of OMS: OMS is weaned by 0.02 mg every day for scores of 0-8. Occasionally, infants will have elevated NAS scores during the weaning process and require a re-escalation of medication dosing. Defer the wean for a single score of 9-12.
Re-escalation of OMS dosing: If the infant scores 9-12 at the next scoring time, repeat the scoring after nursing cares and within one hour. If the score remains > 8, increase OMS as follows:
If the infant's score is:
9-12 then Increase dose by 0.01 mg
13-16 Increase dose by 0.02 mg
17-20 Increase dose by 0.03 mg
21-24 Increase dose by 0.04 mg
>24 Increase dose by 0.05 mg
Restart the weaning process when NAS scores are <9 for 48 hours, and de-escalate treatment as above.
Second medication (clonidine) use: If the infant at any point is receiving 0.20 mg OMS every 3 hours and continues to have NAS scores >8, a second medication is warranted. One medication used frequently as a second line medication is clonidine, 0.75 mcg/kg by mouth every 3 hours. If the infant continues to have NAS scores >8, increase to 1.0 mcg/kg every 3 hours. If the infant continues to have NAS scores >8, increase OMS as above. Infants on clonidine should be in a monitored bed. Vital signs and blood pressure should be monitored every 2 hours for a period of 12 hours at the beginning of clonidine treatment and again once clonidine is discontinued.
Weaning of infants on OMS and clonidine: Wean off morphine first. For infants on morphine doses greater than 0.20 mg of morphine per dose, wean 0.04 mg morphine every 24 hours for NAS scores <9 until the 0.20 mg per dose threshold is reached, then wean 0.02 mg morphine every 24 hours for NAS scores < 9, as above.
After morphine is discontinued, decrease clonidine by 0.5 mcg/kg/dose every 24 hours, keeping the infant's NAS scores <9. When clonidine has been discontinued, careful observation for rebound hypertension for 48 hours before hospital discharge is warranted.
If the infant has 2 consecutive NAS scores one hour apart >8 while weaning from clonidine, defer wean for scores 9-12 and resume de-escalation protocol after 24 hours if infant scores are <9. If infant has 2 consecutive scores of 13-16 while weaning clonidine, increase dose to previous dose (i.e., by 0.5 mcg/dose greater than current dose). Maintain this dose for 24 hours before restarting the de-escalation protocol. If the infant has 2 consecutive NAS scores >8 once off clonidine, begin morphine per protocol for new onset NAS. If the infant has failed a clonidine wean, i.e., has required re-escalation dosing during a clonidine wean, decrease the clonidine dose by 0.25 mcg/kg/dose after 24 hours. Continue to decrease clonidine by 0.25 mcg/kg/dose until the infant is off of clonidine.
Once off all medication, observe the infant for 24 hours prior to hospital discharge. If the infant has failed weaning at least once or receives clonidine for NAS treatment, observe for 48 hours prior to discharge.
What are the possible outcomes of neonatal opioid withdrawal?
Many factors can affect the opioid-exposed infant, either the effects of the opioid exposure itself or other factors associated with opioid exposure.
Fetal brain development and the development of neurotransmitter and neuromodulator systems can be directly and variably affected by substance exposure, depending on types and amount of substances of exposure, timing during gestation and a host of maternal and fetal risk and protective factors that modulate the effects on the infant.
Indirect mechanisms of harm include effects on fetal and infant development related to the effects of the drugs on the maternal-fetal-placental physiology (i.e., placental vasoconstriction, hypoxia, reduced transplacental transport of nutrients), risk factors associated with maternal addiction (such as use of several psychoactive substances, psychiatric co-morbidities, violence exposure, lack of medical care, poverty, poor nutrition and stress) and the caregiver's capabilities in providing a competent postnatal environment for the infant. Further, there are likely roles of genetic and epigenetic alterations that affect the neurobehaviors of the infant and the development of the child that have yet to be defined conclusively.
Despite the largely indefinable possibilities of harm mechanisms for the opioid-exposed child, the importance of early recognition and treatment for the dyad is clear. Appropriate and timely care of both the infant and the caregiver in the neonatal period may provide an avenue to prevent maladaptive developmental trajectories of development in the infant and improve both the short and long term consequences of maternal drug use on the child.
What is the evidence?
References/suggested reading
Jansson, LM, Velez, M, Harrow, C. "The opioid exposed newborn: assessment and pharmacologic management". Journal of Opioid Management. vol. 5. 2009. pp. 47-58.
Osborn, DA, Cole, MJ, Jeffrey, HE. "Opiate Treatment for Opiate Withdrawal in Newborn Infants (Review)". 2005.
Velez, M, Jansson, LM. "Non-pharmacologic care of the opioid dependent mother and her newborn". Journal of Addiction Medicine. vol. 2. 2008. pp. 113-120.
Wachman, EM, Hayes, MJ, Brown, MS. "Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome". JAMA. vol. 309. 2013. pp. 1821-1827.
Kocherlakota, P. "Neonatal Abstinence Syndrome". Pediatrics. vol. 134. 2014. pp. e547-561.
Kraft, WK, Stover, MW, Davis, JM. "Neonatal abstinence syndrome: pharmacologic strategies for the mother and infant". Semin Perinatol. 2016;Jan 18.
Kaltenbach, K, Jones, HE. "Neonatal abstinence syndrome: Presentation and treatment considerations". J Addict Med. 2016.
Ongoing controversies regarding etiology, diagnosis, treatment
Optimal scoring and treatment algorithms have not been defined. Protocols and medication choices displayed here are suggested.
While most opioid or polysubstance exposed infants are hospitalized for a period of 4-7 days after birth, optimal evaluation periods for the development of NAS signs have not been determined.
Biological screening that is universal may be beneficial in some areas where treatment for pregnant and parenting women is accessible, but can lead to punitive reactions against mothers (never fathers) that are not warranted and will serve to drive women with substance use disorders away from needed treatments during pregnancy.
The identification of a dyad as opioid-exposed can lead to the attribution of every infant adaptation to extra-uterine life as a sign of NAS and medication that may not be warranted.
Many hospitals treat infants with NAS in NICUs, which can be difficult for sensitive infants who are sensitive to their environment, causing an unnecessary elevation in NAS signs. Rooming in has been found to be associated with reduced lengths of hospitalizations in infants with NAS, but may not be appropriate for every dyad.
While inpatient management of NAS is advocated here, many hospitals use outpatient NAS management strategies, which are not standardized and may lead to unnecessary exposures to medications over long periods of time for the infant.
Breastfeeding infants with NAS can be challenging, and often requires intervention from a knowledgeable lactation consultant.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- Overview: What every practitioner needs to know
- Are you sure your patient has opioid withdrawal? What are the typical findings for this disease?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- If you are able to confirm that the patient has neonatal opioid withdrawal, what treatment should be initiated?
- What are the possible outcomes of neonatal opioid withdrawal?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment


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Winnie the Pooh Wins Viewers' Hearts
- Christian Hamaker Contributing Film and Culture Writer
- 2011 14 Jul
DVD Release Date: October 25, 2011
Theatrical Release Date: July 15, 2011
Rating: G
Genre: Animation, Kids/Family
Run Time: 69 min.
Director: Stephen J. Anderson, Dan Hall
Actors: Voices of John Cleese, Jim Cummings, Craig Ferguson, Bud Luckey, Travis Oates, Tom Kenny, Jack Boulter, Kristen Anderson-Lopez, Wyatt Dean Hall
When film studios take on beloved stories and characters, they usually update them, reinvent them or otherwise spin them to make them more appealing to contemporary audiences. For example, Dreamworks has reworked fairy tales in its Shrek series, while Disney has spun Shakespeare into a story about gnomes (Gnomeo & Juliet). With Winnie the Pooh, Disney has chosen a different route, resisting the temptation to modernize either the characters or A.A. Milne's gentle storytelling style. The studio's new adaptation of Pooh captures many of the qualities of the Pooh books—quite literally in some ways.
Incorporating strong voice talent and jaunty musical numbers, Winnie the Pooh is a refreshing throwback to a time when big-screen animated features weren't feverishly paced or loaded with rapid-fire jokes. One of the most laid-back family entertainments of recent years—the film is content to be merely enjoyable. If there's a criticism to be made, it's that the slight plotline makes the film's 69-minute run time feel a bit long, although never painful.
The new Pooh begins with a live-action shot of Christopher Robin's (Jack Boulter) bedroom and a narrator (John Cleese) who points out several stuffed animals therein—some of the beloved characters that inhabit the Hundred Acre Wood. These include Pooh (Jim Cummings), Rabbit (Tom Kenny), Eeyore (Bud Luckey), Owl (Craig Ferguson), Piglet (Travis Oates), Kanga (Kristen Anderson-Lopez) and Roo (Wyatt Dean Hall).
Live action cedes to animation as we enter the world of Hundred Acre Wood, where nothing much is happening. Pooh is, as he often is, hungry. His stomach is growling. He wants some honey but there's none to be found, so he sings a song about his search for sustenance.
Even a song can't help his morose friend, Eeyore, who's always expecting the worse. Eeyore's world gets bleaker still when Pooh informs him that Eeyore's tail is missing. Where did it go? Did someone take it? They gather their friends around and declare a contest to see who can find a tail for Eeyore. The prize? A pot of honey.
Joining the hunt are Owl, who can barely be bothered with the adventure given an ongoing writing project about his favorite subject—himself; Tigger; Kanga; Roo; and Piglet. The group is soon offering Eeyore a variety of tails, such as a clock and a knitted scarf, but none of them suit the donkey.
The friends are sidetracked from their task by a misconstrued note left by Christopher Robin that leads the gang to a more urgent search. They do so fearfully, believing Christopher Robin has been taken captive by the dreaded "Backson"—a forest creature no one has ever heard of prior to hearing Owl's recitation of Christopher Robin's note.
This is all charming, helped immensely by a visual presentation that pulls back from the main action to frame the story and its settings within the pages of a picture book. The story, written by the two co-directors plus five other scribes, goes so far as to incorporate words on the page into a crucial story development late in the film, and by then the film's winning qualities have coalesced in a way that makes any objections to such boundary bursting seem churlish.
Another key to the success of Winnie the Pooh, in addition to the whimsical, relaxed quality of the story, is the film's soundtrack, with original music by Henry Jackman and breezy, up-tempo songs performed by Zooey Deschanel ((500) Days of Summer).
Less appealing is an opening cartoon, The Ballad of Nessie, which lacks the punch and invention of the shorts that precede Pixar's features. Given the quality of the feature-length Winnie, this soft opener is forgivable, even as it shows how far Disney still has to go to match Pixar's inventiveness.
All in all, this brief Winnie the Pooh feature is no full-course meal, but it's as sweet and flavorful as Pooh's elusive pot of honey. Hopefully, there will be future Poohs—a prospect that's all the more appealing given the long list of soulless sequels and much less family-friendly blockbusters that have already been green-lit by the big studios. The prospects of those projects make this gentle, wise film even more worthy of your support.
- Language/Profanity: None.
- Alcohol/Smoking/Drugs: None.
- Sex/Nudity: None.
- Violence/Crime: A few cartoonish moments, such as when the characters fall into a pit, or Rabbit pounds Pooh's head in frustration, or Pooh accidentally catapults Piglet into a beehive; Eeyore says, resignedly, "We're all gonna die." In the dark woods, a frightened Piglet mistakes an unrecognizable Tigger for the "Backson" and tries to run away.
Questions? Comments? Contact the writer at firstname.lastname@example.com.

subset: commoncrawl


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Boeing Weighs Heavily on the Blue Chips
FOX Business: Capitalism Lives Here
Tumbling shares of aerospace heavyweight Boeing put the Dow under pressure Wednesday, putting the blue-chip average's five-day winning streak in jeopardy.
Today's Markets
As of 12:15 p.m. ET, the Dow Jones Industrial Average fell 26.4 points, or 0.19%, to 13509, the S&P 500 dipped 0.74 point, or 0.05%, to 1472 and the Nasdaq Composite rose 6.1 points, or 0.2%, to 3117.
Corporate news is one again taking the spotlight as earnings season revs up.
J.P. Morgan Chase (NYSE:JPM) posted a fourth-quarter profit of $1.35 a share, excluding certain items, topping Wall Street's expectations of $1.16. Revenues of $24.4 billion came in line with forecasts. Despite the beat, shares of the Dow component actually fell as analysts parsed through the details of the earnings, particularly the reviews of the "London Whale" loss.
Fellow blue chip Boeing (NYSE:BA) will also be in focus as problems mounted for its 787 "Dreamliner" aircraft. In the most recent setback, a 787 was forced to make an emergency landing in Japan early Wednesday Tokyo time.
Meanwhile, Goldman Sachs (NYSE:GS) earned $5.60 a share in the fourth quarter, compared to $1.84 in the same quarter in 2011, and considerably more than the $3.78 analysts forecast. The investment bank's revenues of $9.24 billion easily topped expectations of $7.83 billion. Shares jumped on the report.
Traders will also get a handful of economic reports on the day.
Consumer prices remained unchanged in December from November, as analysts expected. Excluding the food and energy components, prices were up 0.1%, slightly less than the 0.2% expected. A separate report showed U.S. factory output climbed 0.3% in December from the month before, which matched forecasts.
The Federal Reserve also releases its Beige Book in the afternoon. The release provides an anecdotal look at the U.S. economy from each of the central bank's districts.
Oil prices rallied. The benchmark crude contract rose 85 cents, or 0.95%, to $94.17 a barrel. Wholesale New York Harbor gasoline climbed 0.69% to $2.725 a gallon. In metals, gold dropped $3.90, or 0.23%, to $1,680.
Foreign Markets
The Euro Stoxx 50 rose 0.04% to 2703, the English FTSE 100 dipped 0.22% to 6104 and the German DAX gained 0.2% to 7691.
In Asia, the Japanese Nikkei 225 sold off by 2.6% to 10600 and the Chinese Hang Seng edged lower by 0.1% to 23357.


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text:
"I make my living off the Evening News
Just give me something: something I can use
People love it when you lose
They love dirty laundry.
— Don Henley, "Dirty Laundry"
Look up "Wikipedia loses" (with the quotes) and you get 20,800 results. Look up "Wikipedia has lost" and you get 56,900. (Or at least that's what I got this morning.) Most of those results tell a story, which is what news reports do. "What's the story?" may be the most common question asked of reporters by their managing editors. As humans, we are interested in stories — even if they're contrived, which is what we have with all "reality" television shows.
Lately Wikipedia itself is the subject of a story about losing editors. The coverage snowball apparently started rolling with Volunteers Log Off as Wikipedia Ages, by Julia Angwin and Geoffrey A. Fowler in The Wall Street Journal. It begins,
Wikipedia.org is the fifth-most-popular Web site in the world, with roughly 325 million monthly visitors. But unprecedented numbers of the millions of online volunteers who write, edit and police it are quitting.
That could have significant implications for the brand of democratization that Wikipedia helped to unleash over the Internet — the empowerment of the amateur.
Volunteers have been departing the project that bills itself as "the free encyclopedia that anyone can edit" faster than new ones have been joining, and the net losses have accelerated over the past year. In the first three months of 2009, the English-language Wikipedia …
That's all you get without paying. Still, it's enough.
Three elements make stories interesting: 1) a protagonist we know, or is at least interesting; 2) a struggle of some kind; and 3) movement (or possible movement) toward a resolution. Struggle is at the heart of a story. There has to be a problem (what to do with Afghanistan), a conflict (a game between good teams, going to the final seconds), a mystery (wtf was Tiger Woods' accident all about?), a wealth of complications (Brad and Angelina), a crazy success (the iPhone), failings of the mighty (Nixon and Watergate). The Journal's Wikipedia story is of the Mighty Falling variety.
The Journal's source is Wikipedia: A Quantitative Analysis, a doctoral thesis by José Phillipe Ortega of Universidad Rey San Carlos in Madrid. (The graphic at the top of this post is one among many from the study.) In Wikipedia's Volunteer Story, Erik Moeller and Erik Zachte of the Wikimedia Foundation write,
First, it's important to note that Dr. Ortega's study of editing patterns defines as an editor anyone who has made a single edit, however experimental. This results in a total count of three million editors across all languages. In our own analytics, we choose to define editors as people who have made at least 5 edits. By our narrower definition, just under a million people can be counted as editors across all languages combined. Both numbers include both active and inactive editors. It's not yet clear how the patterns observed in Dr. Ortega's analysis could change if focused only on editors who have moved past initial experimentation.
Even more importantly, the findings reported by the Wall Street Journal are not a measure of the number of people participating in a given month. Rather, they come from the part of Dr. Ortega's research that attempts to measure when individual Wikipedia volunteers start editing, and when they stop. Because it's impossible to make a determination that a person has left and will never edit again, there are methodological challenges with determining the long term trend of joining and leaving: Dr. Ortega qualifies as the editor's "log-off date" the last time they contributed. This is a snapshot in time and doesn't predict whether the same person will make an edit in the future, nor does it reflect the actual number of active editors in that month.
Dr. Ortega supplements this research with data about the actual participation (number of changes, number of editors) in the different language editions of our projects. His findings regarding actual participation are generally consistent with our own, as well as those of other researchers such as Xerox PARC's Augmented Social Cognition research group.
What do those numbers show? Studying the number of actual participants in a given month shows that Wikipedia participation as a whole has declined slightly from its peak 2.5 years ago, and has remained stable since then. (See WikiStats data for all Wikipedia languages combined.) On the English Wikipedia, the peak number of active editors (5 edits per month) was 54,510 in March 2007. After a more significant decline by about 25%, it has been stable over the last year at a level of approximately 40,000. (See WikiStats data for the English Wikipedia.) Many other Wikipedia language editions saw a rise in the number of editors in the same time period. As a result the overall number of editors on all projects combined has been stable at a high level over recent years. We're continuing to work with Dr. Ortega to specifically better understand the long-term trend in editor retention, and whether this trend may result in a decrease of the number of editors in the future.
They add details that amount to not much of a story, if you consider all the factors involved, including the maturity of Wikipedia itself.
As it happens I'm an editor of Wikipedia, at least by the organization's own definitions. I've made fourteen contributions, starting with one in April 2006, and ending, for the moment, with one I made this morning. Most involve a subject I know something about: radio. In particular, radio stations, and rules around broadcast engineering. The one this morning involved edits to the WQXR-FM entry. The edits took a lot longer than I intended — about an hour, total — and were less extensive than I would have made, had I given the job more time and had I been more adept at editing references and citations. (It's pretty freaking complicated.) The preview method of copy editing is also time consuming as well as endlessly iterative. It was sobering to see how many times I needed to go back and forth between edits and previews before I felt comfortable that I had contributed accurate and well-written copy.
In fact, as I look back over my fourteen editing efforts, I can see that most of them were to some degree experimental. I wanted to see if I had what it took to be a dedicated Wikipedia editor, because I regard that as a High Calling. The answer so far is a qualified no. I'll continue to help where I can. But on the whole my time is better spent doing other things, some of which also have leverage with Wikipedia, but not of the sort that Dr. Ortega measured in his study.
For example, photography.
As of today you can find 113 photos on Wikimedia Commons that I shot. Most of these have also found use in Wikipedia. (Click "Check Usage" at the top of any shot to see how it's been used, and where.) I didn't put any of these shots in Wikimedia Commons, nor have I put any of them in Wikipedia. Other people did all of that. To the limited degree I can bother to tell, I don't know anybody who has done any of that work. All I do is upload shots to my Flickr site, caption and tag them as completely as time allows, and let nature take its course. I have confidence that at least some of the shots I take will be useful. And the labor involved on my part is low.
I also spent about half an hour looking through Dr. Ortega's study. My take-away is that Wikipedia has reached a kind of maturity, and that the fall-off in participation is no big deal. This is not to say that Wikipedia doesn't have problems. It has plenty. But I see most of those as features rather than as bugs, even if they sometimes manifest, at least superficially, as the latter. That's not much of a story, but it's a hell of an accomplishment.


text:
M.Ed., Stanford University
Winner of multiple teaching awards
Patrick has been teaching AP Biology for 14 years and is the winner of multiple teaching awards.
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M.Ed., Stanford University
Winner of multiple teaching awards
Patrick has been teaching AP Biology for 14 years and is the winner of multiple teaching awards.
Do you ever watch any of those reality cooking shows like Hells Kitchen or Top Chef? There are some really good chefs out there who are complete morons. Kind of like my friend Galen here.
Now if I hand in recipe, like this. He can follow the instructions. However, Galen is easily destructed. And if he wondered away to go find some nuts or flowers or other ingredients, he gets destructed and starts chasing puppies or reflections on the wall. So instead, to keep him from running away from the instructions, what I've done is I have a bunch of helpers who bring him the ingredients as he needs them. See, Galen look cook. "Nuts." This way everything comes to him and he doesn't get destructed.
Same thing happen in your cells when they are building proteins during the process of translation. Translation for those of you who don't know, is the taking of a sequence of RNA, called messenger RNA, and using that to instruct a ribosome on how to build the amino acid sequence that we call polypeptides or proteins.
Now I'm going to go through and discuss with you, how is that sequence or RNA translated into the actual amino acids. Then I'll get deeper into the process and I'll show you how does this whole thing begin with initiation. Then once we begin building our amino acid chain, how do we elongate that chain. Then finally, how doers this whole process come to an end.
So you know that the mRNA comes out of the nucleus as a long series of As, Us, Gs and Cs. So how does the sequence or basis gets translated into a sequence of amino acids. Well it turns out that it does it in groups of three, kind of like in Morse Code. In Morse Code you have these series of three dits or dots. So like the sequence dit-dit-dit means S or the sequence dot-dot-dot means O.
So you may be wondering why three bases at a time? Well remember with A-U-G and C, that's only four possibilities. And we need to represent 20 different possible amino acids, and so four is not just enough. If we use two bases at a time, that will be four times four, 16, which is close, but still not enough. So instead by using three, that gives us four times four times four. That's a total of 64, which is more than enough and that's actually is a good thing. This makes the generic code redundant.
And that redundancy means if there is a mutation of changing your DNA. There is a decent chance that it'll actually not have any effect on which amino acid is called for in any particular part of the protein.
So how do we translate these groups of three bases which are called Codons into amino acids? Let's take a look at the common Codon chart. You'll see all these things all over the place. In textbooks and if they ask you to do any translation on the AP Biology exam, they are going to give you this Codon chart. Nobody except for a few Biochemist freaks actually memorise it.
So, how does this work. Let's say for example you've got the Codon AGC. When you take a look, what's the first letter? The first letter when we take a look at this, is A. So I go here to where it says the first base, and I find the letter A. And I see all these have the first letter A. So let me highlight that in.
The second letter is G, so let's see. Across the top is the second letter, so G. Where's G? G is here. So I go and I'll use a different colour now. And now I know it's somewhere in here. So A, G and now for my last letter now I find the C, the third base. So AGC is Serine, Ser for short. They commonly use three letter abbreviations for the names of the amino acids because the full names are usually too long to memorise.
Let's take a look and see if you get this. What if I was doing say GCA? Go ahead, take a moment and see if you can figure it out, then I'll catch up to you. Let's see, G is the first letter, so that tells me it's G here. Then the second letter is C. C is down here and then A is last one. And I see it's Ala or Alanine for the long version. And you can see this is a good example of that redundancy.
Now there is a few particular Codons, these groups of three bases at a time, that you need to be very familiar with. First of those is AUG. That's how a ribosome, the organelle that actually does translation, knows where to begin. And so that is commonly called the START Codon. If we take a look here, let me go ahead and erase my high letter so you can see that. So here we see AUG, that code is for Methionine or Met for short.
So in every protein AUG is the START Codon. So every protein, the very first amino acid that's put in is Methionine. Now, that maybe later on clipped out after the protein is made if it's being put in the rough endoplasmic reticulum or the golgi apparatus for export. But again, AUG is the START codon and you got to burn that into your brain. Here is a simple way to remember it. In modern patterns, i.e. slang. How would you greet somebody that you've just met. You would say, "Hey you G, glad we met." So that's how you start a conversation.
How does the ribosome know when to end? That's what these guys are. UAA, UAG and UGA are known as the STOP Codons. All these others translate into particular amino acids. These translate into nothing. And when the ribosome hits this nothing it just stops waiting for something. And because there is nothing, it stops. So those are the STOP Codons.
Now you maybe saying, okay you know how this is done. You know how the Codons work but how is it actually translated. That requires the use of a special kind of RNA called tRNA or transfer RNA for the long name. So let's take a look at what a tRNA looks like. And that's this bizarre thing here and you can see it's a long sequence of RNA. Now you know that RNA is usually single stranded, but it can be double stranded for short sequences. That extra oxygen group that it has on it or OH group that it has on it, tends to make it unable to form double strands for long periods of time, but short sequences it can do.
Now the two key parts here, is this end here. This black end here carries what's called an anti Codon. You remember Chargaff's rules where A always joins to a U, if you're talking about RNA. G always joins to C. Well, if we've got the Codon AUG, then the anti-Codon will be UAC. So that's how this is able to match up to a Codon.
This end over here is the other key end. What this orange part here is, is it's an end that an enzyme else where in the cell recognises as the place to put in amino acid. So the tRNAs are properly called the transfer RNAs, because they transfer the amino acids from where they're being synthesized or where they're getting their food, to the ribosome where they can be used during translation or the building of the protein.
This would be really complicated for you to look at. So I'm going to simplify that a little bit when we're looking at our diagrams. So let's take a look at that.
So here we have our anti-Codon and here, this little hair thing, is the orange part. And my little pentagon or hexagon there, labelled Met, is our good friend Methionine. So this would be the tRNA that will be snatching up to AUG. It's got the correct anti-Codon and that's how we would start translation.
So now you know the messenger RNA codes for various amino acids, using these groups of three called Codons. Let's take a look at how this whole process begins. A scientist called the beginning of a process typically initiation. It's kind of like the 'initiation' process that you go through when you join a fraternity or a sorority. So how does initiation begin? Let's take a look.
Remember that messenger RNA has just come out of the nucleus, near its 5 prime end, you're going to have this structure here. This little orange blob here, come and find that 5 prime end, the beginning end of messenger RNA. Now what is this little thing here? That's the one half of a ribosome.
You should know that ribosomes have two parts. There is one part that's weak and then there is another part that's not so weak. Now scientists don't like using Scottish adjectives. So what they'll do is they'll call the small subunit. And then the other one that we'll take a look at in a little bit, the large subunit. Now near the 5 prime end is our buddy that START Codon AUG. So the small subunit will come along. And the small subunit has a groove in it that matches the shape of the sugar phosphate backbone of the messenger RNA. It will land on the mRNA and slide along it putting that mRNA into its groove until it stops with the AUG right there.
Now you'll also see the tRNA that matches up with its antiCodon, see A to U, U to A, G to C. Its anti-Codon match up to AUG, and it will bring with it that Met or Methionine as the first amino acid that we're going to put into our protein. Now what's this little red thing down there? That's a 'factor'. Specifically at this step since we're doing initiation. They call those initiation factors. And this is little trick about writing essays of any kind of molecular process, whether you're talking about protein synthesis or photosynthesis.
Scientists a lot of times when they first start studying these things they discover the main players. But then when they try to isolate it down to just those main players, they discover those other things that are involved that they haven't identified yet. They just clump those together as 'factors.'
So what they do is they just say, "We're doing initiation so there must be 'initiation' factors." So if you're writing an essay about protein synthesis, and you can't remember, toss in the name of the step that your in. Say initiation, say and this is helped by initiation factors. Later on, we're going to do elongation, that's helped by elongation factors. At the end we're going to do termination, termination factors. Remember on essays, you get points for being right, you don't loose points for being wrong. So if you happen to be right, you'll get a point. And if you're wrong, you don't loose anything. And remember, the readers are Biology teachers. Some are great at Botany some are great at Molecular Biology. You may trick a reader who's not all that great on say protein synthesis and they think, "Holy crap this kid knows more than I, I'll give him a point," because it sounds right.
What happens after the small subunits lands and we've got our tRNA there? The last step of initiation is when the large subunit comes along. So let's take a look at that. Here we see the large subunit coming in, now that we've got our small subunit, and our tRNA all lined up on this START Codon. The large subunit is this big blob here made up of RNA and proteins. The kind of RNA it's made of that's called rRNA. Not because it's a pirate but r for ribosomes, ribosome RNA.
Here we see it has three packets or sites in it. The E site, E there is in short for exit, because that's when we're done with tRNA they exit out that pocket. The P site is where we're going to be building our new protein and the A site is where new tRNAs arrive. When we're finally done with initiation, the whole initiation complex is going to look like this, with the large subunit landed on the START Codon. You can see that the large sub unit lands with that first tRNA sitting already in the P site. We've now finished initiation.
We've got the small subunit with and mRNA in its groove. We've got tRNA with it's appropriate anti-Codon matched up to the START Codon. And we've got its amino acid sitting right here on the P site, ready to be joined to whatever amino acid is brought by the next tRNA, which will come to its A site. So let's take a look in just a moment at how that happens during elongation.
So now that we have initiation completed, we're ready to go in, like I said, to elongation. So let's take a look at how that happens.
So during elongation we just make our amino acid chain or protein longer. So what happens is that, a tRNA comes along and matches up to the next Codon, that is sitting here in the A site. We have our start Codon, AUG here, the next Codon is CGA.
Now I'm too lazy to look up what CGA is. You can take a look at that in your Codon chart. So, because I'm too lazy, I just wrote amino acid number two. AA2 for short. So this tRNA carrying with it the correct amino acid that matches up to this Codon, it comes along. Now again, we've got one of our ready blobbed friends, that's the elongation factors. Since we're in elongation, we've got our helper molecules, elongation factor coming along. Now we've got our old tRNA sitting in the P site, our new one has arrived here in the A site. So now we're ready for the next step of elongation. And that's where we have to join these two amino acids together. This process is helped by an enzyme called Peptidyl transferase.
So we'll take a look at this now. And we'll see the Methionine is now joining to that second amino acid, that's what this black line here is. And just as a review for those of you who've been studying your proteins, what do we call the joint between one amino acid and the next? That's right, it's called a peptide bond. An old name for amino acids is peptides. We're building a multiple amino acid chain, or a polypeptide, with many of these peptide bonds.
But wait something is gone, "What is it?" See the little hair that used to be there? "You don't." This amino acid is still attached to it's tRNA, this one is not. Whenever you make bonds, you typically have to break bonds. So what happens is that the ribosome uses in it's special enzyme called Peptidyl Transferase, and breaks the bond between this tRNA and the amino acid or peptide, and transfers that bond to this amino acid. So now the ribosome is done with that first tRNA. It has no purpose for it. What's going to happen is that, the ribosome is going to shift and it's going to move down through three more bases, one more Codon.
So we're going to see the small subunit slide this way, and the large subunit slide along with it. And this movement is called translocation. For some reason, scientists think they are too cool to say they just move, so you'll see the term translocation appear a lot. Both in protein synthesis and it's a kind of chromosomal mutation just as a side note.
So we see first that tRNA which we have no more use for says, "Go away little boy." And it floats away. In comes the next tRNA. This of course is helped along by elongation factors. And it comes along and lands in this open Codon here in the A site. Why is the A site unoccupied? Remember that large subunits slid down bringing this tRNA, which used to be in A site, it stays still as the ribosome moves. And so now, our second tRNA it is in the P site. The first tRNA is going out the E site, and the new one is arriving in the A site. So E site, exit, P site growing protein, and A site is for new arrivals. And we just keep doing this over and over as the ribosomes down the mRNA adding in new amino acids as the tRNAs bring it in.
Now what happens to this guy? He goes off, finds the enzyme which recognises this anti-Codon and connects it with the correct amino acid. So we could see this same tRNA a little bit later bringing in another Methionine, if needed.
But how does this whole process end? That's called termination, which we'll address right now.
So how does termination happen? Well as the ribosome goes along it's adding in its amino acids. Eventually it reaches one of those STOP Codons. Remember, I talked about how there's no tRNA that matches up to that, here we see UAA in the A site. So the ribosomes are going on saying, "Oh! I need AUG again." And along comes the Methionine. And then it says, "I need a UAA." And there is no tRNA that matches up. So the ribosome sits are going, "I need a UAA." And it just stops waiting for non-existent tRNA to come along and bring this non-existent amino acid. Eventually, another helper molecule, a 'releasing factor' comes along and it says, "Stop, release." And that's what the ribosome does.
And what happens is that this last bond here gets broken up, and then everything just falls apart. And that's what we'll see here after the realising factor has caused the large subunit to release. It floats away, the small subunit also floats away. This last tRNA, its job done, floats away. And now our assemble protein chain, our amino acid sequence grouped together into this long sequence here, it floats away to be folded up and made up into a functional protein.
Alternately, it could be put in the rough endoplasmic reticulum, where perhaps it could be combined in other polypeptide chains or modified in some particular way. And maybe even sent off to the golgi apparatus for a preparation for a secretion from the cell. But that's it. We've gone through this whole thing, that's termination.
So that's translation, but I want to run through that one last time and I'm going to recreate it this time using myself as a ribosome. These cards here as the messengerRNA Codons.
I'll be having some assistance coming in bringing in some amino acids that I'm going to be using little coloured pieces of paper to represent the different amino acids. Now, I'm not dedicated enough to your education to saw myself in half to represent the two halves of the ribosomes. So you're just going to have to live with that.
Right here is my P site, here is my A site. Now you remember in initiation, what happens is the small subunit approaches and finds the START Codon. In this case represented by letters R-E-D which represents the colour of piece of paper red. Just like AUG, the START Codon represents the amino acid Methionine. So my small subunit comes along right here.
Now what else do I need? I need that first tRNA. How does it know to come here? Because it recognises the Codon RED using its anti-Codon. So, "RED." Moans the ribosome and along comes. Look it's the first tRNA, bringing with it its red amino acid. And it holds it right above the RED Codon. So I now look, notice she is in my P site. My A side is open, I'm ready to elongate. So my A side is where the new ones is going to arrive, so I go, "GREEN." And along comes green.
Now I'm going to use my enzyme Peptidyl transferase, so I have to break this bond here holding this red piece of paper on to the tRNA. And I make a peptide bond and she floats out my E site as I translocate or putting the blue Codon into my A site. He's now in my P site. Notice, he doesn't move. I do.
Okay, "Blue." And the tRNA that recognises with his anti-Codon, the BLUE Codon,e brings over the blue amino acid again, "Give me that." I break the bond, I make the bond. He goes out of my E site as I translocate down. Now I read the next Codon, "STOP." Now, there is no stop tRNA.
But the ribosome doesn't know that. It just poses because there is no tRNA that matches up to any of those STOP Codons, UAG, UGA or UAA. So I just sit there until finally a releasing factor, "STOP." Comes along and whacks me upside the back of my head. That breaks off our protein which may assemble into a protein channel or into an enzyme, or whatever. He floats away, I drift off and translation is done. That's it.
Now I really recommend that if you want to do really well on the AP Biology essay questions, that you spend some time either with your textbook or watch my episode on transcription. The process of actually making this messenger RNA. But if you get that down, you're going to do really well on one of the essays that they love to ask questions about. This topic reappears maybe every four years. So, get ready for it.


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Many of us think that as we grow older our eyesight is destined to deteriorate. We talk about "tired" or "old" eyes as if we are fated to have the gift of vision taken from us simply because we have aged. For example, in what might be the earliest reference to cataracts in the Bible (Genesis, Chapter 27, Verse 1) we learn that, "And it came to pass, that Isaac was old, and his eyes were dim..." The truth is that, with today's treatment options, there is no intrinsic reason for our vision to worsen with time. In theory, we should be able to retain undiminished our capability to accept, process and experience visual sensory input.
But, as with most conventional wisdom, there is an element of truth to the notion that age-related processes can affect our eyesight. The good news is that identifying and treating these processes can often result in the preservation or restoration of excellent vision for an entire lifetime.
A good understanding of vision loss requires a brief foray into the basic structure of the eye. Although it might be considered a clich, it is still useful to compare the eye to a video camera. Thus, as light enters the eye--or the camera--it travels through four main structures. By understanding this basic eye anatomy we can begin to understand the ways in which the light signal can be degraded or distorted, resulting in poor vision.
The entry point for light is the cornea, the transparent tissue in the very front of the eye that functions as the window through which all light has to pass on its way to forming a visual perception. Next, the light signal encounters the lens, which focuses it finely on the third structure of the eye: the retina. The retina is analogous to the film in the back of the camera. It is on the retina that the light is converted into a neural signal that is ultimately interpreted by the brain as an image. Finally, the optic nerve, which carries these signals to the brain, functions like a cable that connects the video camera to the television screen. The deterioration of our vision with age is invariably the result of a problem with one of these four structures.
The integrity of the corneal surface is very important for the reception of a clear image. If its surface is not smooth and intact the image will suffer, much like the image from a scratched camera. A very thin layer of tears coats the surface of the cornea. This tear surface, produced by various cells, some of which line the inner surface of the eyelid, is vital to maintaining the corneas smooth surface and precise optical characteristics. Any condition that disrupts this tear film can lead to a breakdown of the corneas surface and, thus, degradation of the image.
With age, this smooth surface can be damaged by conditions such as blepharitis, an inflammation of the eyelids. If the inflammation is severe enough, then the cells that produce the tears can be damaged, with an attendant impact on the tears coating the cornea. In this situation an individual may experience symptoms such as the sensation of a "film" over the eye, which is usually transient and relieved with blinking. More serious symptoms can also occur, such as blurry vision, which is due to evaporation of the tears and drying out of the corneal surface. This condition can become chronic and is known as dry eyes. Treatment options for blepharitis and dry eyes depend on the cause of the inflammation of the lid surface but can include warm compresses, artificial tears, oral antibiotics and even topical immunosuppressive agents to decrease the inflammatory response leading to the degraded tears.
The lens is also subject to the aging process, and the resulting conditions--cataracts and presbyopia--will eventually affect just about everyone. When we are born our lenses are crystal clear, meaning that the image entering the eye is not degraded by any opacity. They are also very pliable, meaning that the lens can change its shape to help focus images that are very far away as well as very close. Unfortunately, as we grow older two things happen to the lens: it clouds up and it becomes less pliable. The clouding of the lens--or cataract--forces an image to travel through a distorted medium, resulting in diminished vision. Similarly, when the lens loses its pliability it also loses its ability to focus over a wide range of distances. A hardened lens becomes more fixed on distant objects and cannot focus as well on nearby objects or vice versa. This hardening often occurs in middle age, when people notice the need to hold the newspaper farther away in order to read the print, and is known as presbyopia from the Greek words presbus, meaning old man, and opia, meaning eye.
Fortunately, there are treatments for both these conditions. A lens that has developed a cataract can be removed surgically and replaced by an artificial one. The implanted lens is clear and allows the image to pass through the eye nondegraded. As for presbyopia, the solution is even simpler--reading glasses or bifocals.
Finally, the retina and the optic nerve work in tandem and deterioration in either can lead to serious, even blinding, conditions. The retina is an extremely complex tissue that converts the light image entering the eye into a neural signal. This signal is then transmitted to the brain by extensions of the ganglion cells. It is the extensions of these cells that form the optic nerve so, in a sense, the optic nerve is an extension of the retina. Numerous studies have shown that, in the absence of disease, there is no significant age-related deterioration in visual capacity of the retina or optic nerve. Unfortunately, age-related diseases of the retina and optic nerve are not entirely rare. Macular degeneration (loss of central retinal function) and glaucoma (damage to the optic nerve due to increased intraocular pressure) lead the list. Early detection of these diseases can often prevent or minimize the extent of vision loss, particularly as new and improved therapies become available.
In summary, as our population ages, society is not fated to having millions of people with "dim" eyes. Rather, with proper proactive ophthalmic care and an emphasis on the development of new therapies for blinding diseases we can continue to make "great vision" a reality for those past the first blush of youth.


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Send system notifications to a remote syslog server
The syslog export option enables you to send alerts from an ExtraHop system to any remote system that receives syslog input for long-term archiving and correlation with other sources.
Only one remote syslog server can be configured for each ExtraHop system.
- Log in to the Administration settings on the ExtraHop system through https://<extrahop-hostname-or-IP-address>/admin.
- In the Network Settings section, click Notifications.
- In the Destination field, type the IP address of the remote syslog server.
- From the Protocol drop-down menu, select TCP or UDP. This option specifies the protocol over which the information will be sent to your remote syslog server.
- In the Port field, type the port number for your remote syslog server. By default, this value is set to 514.
Click Test Settings to verify that
your syslog settings are correct. If the settings are correct, you should see an
entry in the syslog log file on the syslog server similar to the
Jul 27 21:54:56 extrahop name="ExtraHop Test" event_id=1
- Click Save.
Next stepsAfter you confirm that your new settings are working as expected, preserve your configuration changes through system restart and shutdown events by saving the Running Config file.


text: Guest guest Report post Posted January 9, 2008 By People frequently ask me what I think of Autism Speaks and are surprised by my answer. I believe the creative team, the administrative staff, the incredibly hard working special event and Walk staffers are amazing. They all could be pursuing more lucrative careers elsewhere but truly want to help autistic kids and their families. My parents, Bob and Suzanne , are also tireless in their efforts to bring attention to the needs of our families. At a time when it seems as if the whole world, especially in the Middle East, is angry with the United States, my Mom has successfully engaged in a wonderful collaboration with the Sheika of Qatar in order to have the United Nations declare a World Autism Day. This is only the third time the U.N. has recognized a disease in such a way. Autism Speaks has, undoubtedly, lifted the shame and isolation so many families felt by forcing autism into many public forums in the media and government. Their work on insurance re-imburs ement is also extremely important to all our cash strapped families. It is Autism Speaks' scientific advisors that I find myself at great pains to understand. It appears as if they are wedded to the past and are non-responsive to what parents want and the immediate needs of our children. By any measure, autism is worse than ever and traditional research has yielded few breakthroughs for children living today. So many ASD children are living with horrible GI disease, seizures, serious immune deficiencies, pain induced self-abusive behavior… Meanwhile AS has funded eye gazing research on fruit flies, a study on the olfactory senses in worms, endless gene research, yet nothing relevant to the pain my child lives with on a daily basis. Parents have waited for three years in hopes of seeing real biomedical research. Of course there is a place for gene and brain research in autism, but not at the expense of toxicology, immunology, regression, gastrointestinal and vaccine safety research. Preservatives in children's vaccines such as: aluminum, ammonia, formaldehyde, mercury and human embryos have never been adequate ly researched or proven to be safe, nor has the CDC's extremely aggressive vaccination schedule. Everyday infants are injected with these preservatives, combination vaccines and live viruses. There is no more time to waste. We are in the midst of a catastrophe and must be unafraid in pursuit of answers. It appears as if AS grants are selected less as a result of the significance of a research proposal but more as a consequence of the financial resources of academic institutions to put forth in producing most professional and conservative grant applications. Instead of funding impactful, breakthrough science, millions of dollars are spent on researching the same safe subjects over and over again. Numerous exciting, innovative and progressive biomedical grants on GI disease, methylation pathways and toxicity, vaccinated and unvaccinated siblings have been repeatedly rejected due to ignorance and fear. It is past time for the scientific advisory boards to think outside the box and pursue the bold research parents want and our children desperately need. Trump's recent comments are wonderfully illustrative of how out of touch with reality the AS' SAC is. Mr. Trump is the parent of a young boy and is horrified by the recent explosion of autism. Mr. Trump stated that he believes the " massive " increase in vaccines for infants could account for autism's rising numbers. Mrs. Melania Trump has spoken openly about how she spaces out Barron's vaccinations. So while some SAC scientists still debate whether or not autism is actually increasing, why it one in 90 American boys in the spectrum does not equal an epidemic and pursue their lonely quest to find the " autism genes, " parents have moved on. Regarding the most recent grants for young investigators, I question the wisdom in investing such great financial resources in researchers new to the field while the grants of experienced DAN! physicians who work to recover kids every day are continually ignored. AS needs to invest in doctors who have been treating and recovering so many autistic children, not just in academics with the best team of professional grant writers. Hopefully, Autism Speaks' summertime clinical grants will reflect a broader, more biomedical and relevant approach to helping our children. In the meantime, I encourage parents to educate themselves about biomedical interventions via other websites, such as: NAA, SafeMinds, ARI, TACA, Generation Rescue, FAIR Media and Thoughtful House. I know that Autism Speaks is trying to change. There are some truly courageous voices on the SAC, but they are too few. I am, however, optimistic that Dr. Baskin's new environmental committee will green light some exciting research. I am also hopeful that Dr. Geraldine Dawson, AS' new Chief Scientific Officer, will be more proactive than her predecessor and champion the innovative environmental research families want to see funded. On another subject I want to thank Deirdre Imus for her wonderful essay in the Huffington Post about the New Jersey vaccine mandate. I feel heartbroken for the New Jersey parents who must choose between day care, school and more vaccines for their toddlers and school age children. Why mercury has not been removed from every flu vaccine simply defies comprehension. One would think that New Jersey, possibly the autism capital in the country, would approach vaccine mandates with great caution. One in 60 New Jersey boys is on the autist ic spectrum and the vast majority of parents believe that vaccines played a role in triggering the disorder in their children. It is astounding that the American Academy of Pediatrics yet again, ignores parents' concerns and testifies, again, in favor of the adding even more vaccines to the overcrowded schedule. Exemptions will be almost impossible to procure. Parents with one ASD child are now placed in the horrible position of having to over-vaccinate younger siblings, despite their well-founded concerns about the impact of so many live viruses, dangerous preservatives and combination vaccines on a developing brain. It is time for the researchers, politicians and the AAP to stop listening only to each other and start listening to the families of autistic kids. has two young boys. Her oldest son, Christian, is severely affected by autism. He developed normally; smiling, talking, walking; only to lose every skill and every word by the age of 2 and a half. Upon the advice of medical professionals and her husband were advised to pursue only high quality behavioral therapy, speech and OT for Christian. It had no meaningful impact on Christian until his parents sought help from DAN! doctors who treated the underlying causes of Christian's descent into autism. Christian has improved but still has far to go. He has Inflammatory Bowel Disease, the measles virus in his gut and an immune system akin to a late stage AIDS patient. Christian does not have a psychiatric disorder. Before autism, was the Clinical Director of Sexual Assault Crisis Center in Stamfo rd Connecticut. is proud to serve on the Boards of NAA and SafeMinds. ________________________________________________________________________________\ ____ Looking for last minute shopping deals? Find them fast with Yahoo! Search. http://tools.search.yahoo.com/newsearch/category.php?category=shopping Quote Share this post Link to post Share on other sites


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The polymer tip of the V-Max bullet is the key to its dramatic accuracy and devastating expansion, even in long range, low-velocity situations. The tip raises the ballistic coefficient for improved velocity and flight stability, and on impact initiates bullet expansion. The copper jacket is designed to work with the tip to deliver incredible accuracy at long range, and it assists the V-Max's dramatic expansion. The copper jacket provides the necessary bearing surface for maximum in-flight stability. The jacket is built to withstand the faster twist rates of many of today's advanced varmint rifles. It all means the bullet will hold together until impact.
- Diameter: .224"
- Weight: 60gr
- Ballistic Coeffeciant: .265 G1
- Type: V-Max
- Quantity: 100


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A2B Assessments - Disabled Students Allowance (DSA)
1 in 5 students have a disability or support need. We help students who have: Dyslexia, dyspraxia, attention deficit-hyperactivity disorder (ADHD) and other specific learning difficulties Anxiety, depression and other mental health conditions Autism and Asperger's Syndrome Long-term illnesses Physical impairments Sensory impairments These students may…
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text: The Smith & Wesson J-Frame has become the most popular small frame personal defense revolver on the market. With decades of reliable performance to its credit, the J-frame line offers models capable of firing .22 LR, .22 Magnum®, .38 S&W Special and the more powerful .357 Magnum® loads. Smith & Wesson offers these revolvers from our production, M&P, Pro Series, and Classics lines in three diverse hammer designs; internal, exposed and shrouded.


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Maths Primary Resources
Our primary resources for Maths are great for helping your pupils explore a variety of mathematical problems and concepts, such as measuring different weights, lengths and volumes using different units of measurement; creating 2D shapes; and working with numbers to count, add and subtract.
National Geographic Kids offers free resources that cover a range of KS1 and KS2 Maths and Numeracy objectives from the National Curriculum and the Scottish Curriculum for Excellence, including geometry, measuring and counting — delivered in such a way that your pupils will learn core maths skills without even realising it.
We've divided our resources into clear sections, which are aligned to the curriculum and easy to navigate, helping to speed up lesson planning.
Ada Lovelace primary resource
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Employers and co-workers team up for Bike Commute Challenge success
September in Oregon means many things: great weather, kids returning to school, the Vaux Swifts' dramatic nightly nesting at Chapman Elementary, and the Bike Commute Challenge.
The Bike Commute Challenge is the nation's most popular bike commute event, pitting employers throughout the state against each other to attain the highest bike commute rate. Over 11,000 people from nearly 1400 employers participated in this free and fun event. The Portland Bureau of Transportation is a long-time sponsor of the BCC.
Employers and co-workers have both been especially successful in encouraging and assisting new riders to begin biking to work. Here are a few examples:
- CH2M Hill saw its participation in the BCC skyrocket after incorporating peer-to-peer encouragement. Employees placed small bags of M&M's around the handlebars of co-workers that biked to work. Near the end of the Challenge, CH2M employees gave bike commuters the red carpet treatment, providing bike valet parking and the type of pageantry one associates with the Oscars. The result: CH2M Hill jumped to third place among private sector firms with more than 500 employees.
- Sockeye Creative fostered a fun atmosphere during the BCC by holding special prize drawings throughout the month for those who bike to work.
- PECI employees provide any new rider the opportunity to have an experienced bike commuter join them for their first trip to work by bicycle.
If you have yet to register, it's not too late. And anyone who logs at least one bike trip in a week is entered in a BTA drawing for prizes. If you need help signing up, check the BTA's Help/FAQ page